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Sample records for disc degeneration model

  1. Modeling and optimization of an elastic arthroplastic disc for a degenerated disc

    NASA Astrophysics Data System (ADS)

    Ghouchani, Azadeh; Ravari, Mohammad; Mahmoudi, Farid

    2011-10-01

    A three-dimensional finite element model (FEM) of the L3-L4 motion segment using ABAQUS v 6.9 has been developed. The model took into account the material nonlinearities and is imposed different loading conditions. In this study, we validated the model by comparison of its predictions with several sets of experimental data. Disc deformation under compression and segmental rotational motions under moment loads for the normal disc model agreed well with the corresponding in vivo studies. By linking ABAQUS with MATLAB 2010.a, we determined the optimal Young s modulus as well as the Poisson's ratio for the artificial disc under different physiologic loading conditions. The results of the present study confirmed that a well-designed elastic arthroplastic disc preferably has an annulus modulus of 19.1 MPa and 1.24 MPa for nucleus section and Poisson ratio of 0.41 and 0.47 respectively. Elastic artificial disc with such properties can then achieve the goal of restoring the disc height and mechanical function of intact disc under different loading conditions and so can reduce low back pain which is mostly caused due to disc degeneration.

  2. A Review of Animal Models of Intervertebral Disc Degeneration: Pathophysiology, Regeneration, and Translation to the Clinic

    PubMed Central

    Ghosh, Peter

    2016-01-01

    Lower back pain is the leading cause of disability worldwide. Discogenic pain secondary to intervertebral disc degeneration is a significant cause of low back pain. Disc degeneration is a complex multifactorial process. Animal models are essential to furthering understanding of the degenerative process and testing potential therapies. The adult human lumbar intervertebral disc is characterized by the loss of notochordal cells, relatively large size, essentially avascular nature, and exposure to biomechanical stresses influenced by bipedalism. Animal models are compared with regard to the above characteristics. Numerous methods of inducing disc degeneration are reported. Broadly these can be considered under the categories of spontaneous degeneration, mechanical and structural models. The purpose of such animal models is to further our understanding and, ultimately, improve treatment of disc degeneration. The role of animal models of disc degeneration in translational research leading to clinical trials of novel cellular therapies is explored. PMID:27314030

  3. Experimental model of intervertebral disc degeneration by needle puncture in Wistar rats

    PubMed Central

    Issy, A.C.; Castania, V.; Castania, M.; Salmon, C.E.G.; Nogueira-Barbosa, M.H.; Bel, E. Del; Defino, H.L.A.

    2013-01-01

    Animal models of intervertebral disc degeneration play an important role in clarifying the physiopathological mechanisms and testing novel therapeutic strategies. The objective of the present study is to describe a simple animal model of disc degeneration involving Wistar rats to be used for research studies. Disc degeneration was confirmed and classified by radiography, magnetic resonance and histological evaluation. Adult male Wistar rats were anesthetized and submitted to percutaneous disc puncture with a 20-gauge needle on levels 6-7 and 8-9 of the coccygeal vertebrae. The needle was inserted into the discs guided by fluoroscopy and its tip was positioned crossing the nucleus pulposus up to the contralateral annulus fibrosus, rotated 360° twice, and held for 30 s. To grade the severity of intervertebral disc degeneration, we measured the intervertebral disc height from radiographic images 7 and 30 days after the injury, and the signal intensity T2-weighted magnetic resonance imaging. Histological analysis was performed with hematoxylin-eosin and collagen fiber orientation using picrosirius red staining and polarized light microscopy. Imaging and histological score analyses revealed significant disc degeneration both 7 and 30 days after the lesion, without deaths or systemic complications. Interobserver histological evaluation showed significant agreement. There was a significant positive correlation between histological score and intervertebral disc height 7 and 30 days after the lesion. We conclude that the tail disc puncture method using Wistar rats is a simple, cost-effective and reproducible model for inducing disc degeneration. PMID:23532265

  4. Biomechanics of Disc Degeneration

    PubMed Central

    Palepu, V.; Kodigudla, M.; Goel, V. K.

    2012-01-01

    Disc degeneration and associated disorders are among the most debated topics in the orthopedic literature over the past few decades. These may be attributed to interrelated mechanical, biochemical, and environmental factors. The treatment options vary from conservative approaches to surgery, depending on the severity of degeneration and response to conservative therapies. Spinal fusion is considered to be the “gold standard” in surgical methods till date. However, the association of adjacent level degeneration has led to the evolution of motion preservation technologies like spinal arthroplasty and posterior dynamic stabilization systems. These new technologies are aimed to address pain and preserve motion while maintaining a proper load sharing among various spinal elements. This paper provides an elaborative biomechanical review of the technologies aimed to address the disc degeneration and reiterates the point that biomechanical efficacy followed by long-term clinical success will allow these nonfusion technologies as alternatives to fusion, at least in certain patient population. PMID:22745914

  5. In Vivo Mouse Intervertebral Disc Degeneration Model Based on a New Histological Classification

    PubMed Central

    Ohnishi, Takashi; Sudo, Hideki; Iwasaki, Koji; Tsujimoto, Takeru; Ito, Yoichi M.; Iwasaki, Norimasa

    2016-01-01

    Although human intervertebral disc degeneration can lead to several spinal diseases, its pathogenesis remains unclear. This study aimed to create a new histological classification applicable to an in vivo mouse intervertebral disc degeneration model induced by needle puncture. One hundred six mice were operated and the L4/5 intervertebral disc was punctured with a 35- or 33-gauge needle. Micro-computed tomography scanning was performed, and the punctured region was confirmed. Evaluation was performed by using magnetic resonance imaging and histology by employing our classification scoring system. Our histological classification scores correlated well with the findings of magnetic resonance imaging and could detect degenerative progression, irrespective of the punctured region. However, the magnetic resonance imaging analysis revealed that there was no significant degenerative intervertebral disc change between the ventrally punctured and non-punctured control groups. To induce significant degeneration in the lumbar intervertebral discs, the central or dorsal region should be punctured instead of the ventral region. PMID:27482708

  6. Glucosamine Supplementation Demonstrates a Negative Effect On Intervertebral Disc Matrix in an Animal Model of Disc Degeneration

    PubMed Central

    Jacobs, Lloydine; Vo, Nam; Coehlo, J. Paulo; Dong, Qing; Bechara, Bernard; Woods, Barrett; Hempen, Eric; Hartman, Robert; Preuss, Harry; Balk, Judith; Kang, James; Sowa, Gwendolyn

    2013-01-01

    Study Design Laboratory based controlled in vivo study Objective To determine the in vivo effects of oral glucosamine sulfate on intervertebral disc degeneration Summary of Background Data Although glucosamine has demonstrated beneficial effect in articular cartilage, clinical benefit is uncertain. A CDC report from 2009 reported that many patients are using glucosamine supplementation for low back pain (LBP), without significant evidence to support its use. Because disc degeneration is a major contributor of LBP, we explored the effects of glucosamine on disc matrix homeostasis in an animal model of disc degeneration. Methods Eighteen skeletally mature New Zealand White rabbits were divided into four groups: control, annular puncture, glucosamine, and annular puncture+glucosamine. Glucosamine treated rabbits received daily oral supplementation with 107mg/day (weight based equivalent to human 1500mg/day). Annular puncture surgery involved puncturing the annulus fibrosus (AF) of 3 lumbar discs with a 16G needle to induce degeneration. Serial MRIs were obtained at 0, 4, 8, 12, and 20 weeks. Discs were harvested at 20 weeks for determination of glycosaminoglycan(GAG) content, relative gene expression measured by RT-PCR, and histological analyses. Results The MRI index and NP area of injured discs of glucosamine treated animals with annular puncture was found to be lower than that of degenerated discs from rabbits not supplemented with glucosamine. Consistent with this, decreased glycosaminoglycan was demonstrated in glucosamine fed animals, as determined by both histological and GAG content. Gene expression was consistent with a detrimental effect on matrix. Conclusions These data demonstrate that the net effect on matrix in an animal model in vivo, as measured by gene expression, MRI, histology, and total proteoglycan is anti-anabolic. This raises concern over this commonly used supplement, and future research is needed to establish the clinical relevance of these

  7. A novel approach for the annulus needle puncture model of intervertebral disc degeneration in rabbits

    PubMed Central

    Lei, Tao; Zhang, Yuan; Zhou, Qiang; Luo, Xiaoji; Tang, Ke; Chen, Rongsheng; Yu, Chang; Quan, Zhengxue

    2017-01-01

    Objective: To create the rabbit animal model of intervertebral disc (IVD) degeneration by the annulus needle puncture technique through a novel transabdominal approach. Methods: Thirteen New Zealand White rabbits underwent annular puncture at the L3/4, L4/5, and L5/6 discs through a transabdominal approach. For a longitudinal study to assess changes in disc height over time, serial X-rays, T2-weighted magnetic resonance imaging (MRI) (T2WI), and T2 mapping MRI were performed pre-operation and at 2, 4, and 6 weeks after puncture. Three rabbits were randomly selected for histological evaluation at 4 weeks post-operation. In addition, the remaining rabbits underwent a second surgery at 6 weeks after puncture. Results: All rabbits underwent the initial and second surgeries successfully without nerve-related complications. The operations had no significant effects on the rabbit body weight, and partial mild intra-abdominal adhesions were found in only 1 rabbit. The punctured discs were confirmed to be those of interest post-surgery and displayed progressive degeneration in disc height index (%), T2WI, and T2 relaxation time over time. At 4 weeks after puncture, a histological analysis revealed notochordal cell loss from the nucleus pulposus, fibrocartilage filling the nucleus pulposus space, and annulus fibrosus disorganization. Conclusion: The annular needle puncture model established through a transabdominal approach, which demonstrates better visualization, exact identification, consistent degeneration degrees and minimal complications, is radiologically and histologically consistent with human IVD degeneration. T2 mapping MRI can quantitatively discriminate between grades of mild degeneration. PMID:28386320

  8. A rat tail temporary static compression model reproduces different stages of intervertebral disc degeneration with decreased notochordal cell phenotype.

    PubMed

    Hirata, Hiroaki; Yurube, Takashi; Kakutani, Kenichiro; Maeno, Koichiro; Takada, Toru; Yamamoto, Junya; Kurakawa, Takuto; Akisue, Toshihiro; Kuroda, Ryosuke; Kurosaka, Masahiro; Nishida, Kotaro

    2014-03-01

    The intervertebral disc nucleus pulposus (NP) has two phenotypically distinct cell types-notochordal cells (NCs) and non-notochordal chondrocyte-like cells. In human discs, NCs are lost during adolescence, which is also when discs begin to show degenerative signs. However, little evidence exists regarding the link between NC disappearance and the pathogenesis of disc degeneration. To clarify this, a rat tail disc degeneration model induced by static compression at 1.3 MPa for 0, 1, or 7 days was designed and assessed for up to 56 postoperative days. Radiography, MRI, and histomorphology showed degenerative disc findings in response to the compression period. Immunofluorescence displayed that the number of DAPI-positive NP cells decreased with compression; particularly, the decrease was notable in larger, vacuolated, cytokeratin-8- and galectin-3-co-positive cells, identified as NCs. The proportion of TUNEL-positive cells, which predominantly comprised non-NCs, increased with compression. Quantitative PCR demonstrated isolated mRNA up-regulation of ADAMTS-5 in the 1-day loaded group and MMP-3 in the 7-day loaded group. Aggrecan-1 and collagen type 2α-1 mRNA levels were down-regulated in both groups. This rat tail temporary static compression model, which exhibits decreased NC phenotype, increased apoptotic cell death, and imbalanced catabolic and anabolic gene expression, reproduces different stages of intervertebral disc degeneration.

  9. Notochordal cell disappearance and modes of apoptotic cell death in a rat tail static compression-induced disc degeneration model

    PubMed Central

    2014-01-01

    Introduction The intervertebral disc has a complex structure originating developmentally from both the mesenchyme and notochord. Notochordal cells disappear during adolescence, which is also when human discs begin to show degenerative signs. During degeneration later in life, disc cells decline because of apoptosis. Although many animal models have been developed to simulate human disc degeneration, few studies have explored the long-term changes in cell population and phenotype. Our objective was to elucidate the time-dependent notochordal cell disappearance and apoptotic cell death in a rat tail static compression-induced disc degeneration model. Methods Twenty-four 12-week-old male Sprague–Dawley rat tails were instrumented with an Ilizarov-type device and loaded statically at 1.3 MPa for up to 56 days. Loaded and distal-unloaded discs were harvested. Changes in cell number and phenotype were assessed with histomorphology and immunofluorescence. Apoptosis involvement was determined with terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and immunohistochemistry. Results The number of disc nucleus pulposus and annulus fibrosus cells decreased with the loading period; particularly, the decrease was notable at day 7 in larger, vacuolated, cytokeratin-8- and galectin-3-co-positive cells, indicating notochordal origin. Subsequently, the proportion of cells positive for TUNEL and cleaved caspase-3, markers of apoptosis induction, increased from day 7 through day 56. Although the percentage of cells immunopositive for cleaved caspase-8, a marker of apoptosis initiation through the death-receptor pathway, increased only at day 7, the percentage of cells immunopositive for cleaved caspase-9 and p53-regulated apoptosis-inducing protein 1 (p53AIP1), markers of apoptosis initiation through the p53-mediated mitochondrial pathway, increased from day 7 through day 56. The percentage of cells immunopositive for B-cell lymphoma 2 (Bcl-2) and silent

  10. Inflammation in intervertebral disc degeneration and regeneration

    PubMed Central

    Molinos, Maria; Almeida, Catarina R.; Caldeira, Joana; Cunha, Carla; Gonçalves, Raquel M.; Barbosa, Mário A.

    2015-01-01

    Intervertebral disc (IVD) degeneration is one of the major causes of low back pain, a problem with a heavy economic burden, which has been increasing in prevalence as populations age. Deeper knowledge of the complex spatial and temporal orchestration of cellular interactions and extracellular matrix remodelling is critical to improve current IVD therapies, which have so far proved unsatisfactory. Inflammation has been correlated with degenerative disc disease but its role in discogenic pain and hernia regression remains controversial. The inflammatory response may be involved in the onset of disease, but it is also crucial in maintaining tissue homeostasis. Furthermore, if properly balanced it may contribute to tissue repair/regeneration as has already been demonstrated in other tissues. In this review, we focus on how inflammation has been associated with IVD degeneration by describing observational and in vitro studies as well as in vivo animal models. Finally, we provide an overview of IVD regenerative therapies that target key inflammatory players. PMID:25673296

  11. Cell therapy for the degenerating intervertebral disc.

    PubMed

    Tong, Wei; Lu, Zhouyu; Qin, Ling; Mauck, Robert L; Smith, Harvey E; Smith, Lachlan J; Malhotra, Neil R; Heyworth, Martin F; Caldera, Franklin; Enomoto-Iwamoto, Motomi; Zhang, Yejia

    2017-03-01

    Spinal conditions related to intervertebral disc (IVD) degeneration cost billions of dollars in the US annually. Despite the prevalence and soaring cost, there is no specific treatment that restores the physiological function of the diseased IVD. Thus, it is vital to develop new treatment strategies to repair the degenerating IVD. Persons with IVD degeneration without back pain or radicular leg pain often do not require any intervention. Only patients with severe back pain related to the IVD degeneration or biomechanical instability are likely candidates for cell therapy. The IVD progressively degenerates with age in humans, and strategies to repair the IVD depend on the stage of degeneration. Cell therapy and cell-based gene therapy aim to address moderate disc degeneration; advanced stage disease may require surgery. Studies involving autologous, allogeneic, and xenogeneic cells have all shown good survival of these cells in the IVD, confirming that the disc niche is an immunologically privileged site, permitting long-term survival of transplanted cells. All of the animal studies reviewed here reported some improvement in disc structure, and 2 studies showed attenuation of local inflammation. Among the 50 studies reviewed, 25 used some type of scaffold, and cell leakage is a consistently noted problem, though some studies showed reduced cell leakage. Hydrogel scaffolds may prevent cell leakage and provide biomechanical support until cells can become established matrix producers. However, these gels need to be optimized to prevent this leakage. Many animal models have been leveraged in this research space. Rabbit is the most frequently used model (28 of 50), followed by rat, pig, and dog. Sheep and goat IVDs resemble those of humans in size and in the absence of notochordal cells. Despite this advantage, there were only 2 sheep and 1 goat studies of 50 studies in this cohort. It is also unclear if a study in large animals is needed before clinical trials since

  12. Cell transplantation in lumbar spine disc degeneration disease.

    PubMed

    Hohaus, C; Ganey, T M; Minkus, Y; Meisel, H J

    2008-12-01

    Low back pain is an extremely common symptom, affecting nearly three-quarters of the population sometime in their life. Given that disc herniation is thought to be an extension of progressive disc degeneration that attends the normal aging process, seeking an effective therapy that staves off disc degeneration has been considered a logical attempt to reduce back pain. The most apparent cellular and biochemical changes attributable to degeneration include a decrease in cell density in the disc that is accompanied by a reduction in synthesis of cartilage-specific extracellular matrix components. With this in mind, one therapeutic strategy would be to replace, regenerate, or augment the intervertebral disc cell population, with a goal of correcting matrix insufficiencies and restoring normal segment biomechanics. Biological restoration through the use of autologous disc chondrocyte transplantation offers a potential to achieve functional integration of disc metabolism and mechanics. We designed an animal study using the dog as our model to investigate this hypothesis by transplantation of autologous disc-derived chondrocytes into degenerated intervertebral discs. As a result we demonstrated that disc cells remained viable after transplantation; transplanted disc cells produced an extracellular matrix that contained components similar to normal intervertebral disc tissue; a statistically significant correlation between transplanting cells and retention of disc height could displayed. Following these results the Euro Disc Randomized Trial was initiated to embrace a representative patient group with persistent symptoms that had not responded to conservative treatment where an indication for surgical treatment was given. In the interim analyses we evaluated that patients who received autologous disc cell transplantation had greater pain reduction at 2 years compared with patients who did not receive cells following their discectomy surgery and discs in patients that

  13. Notochord Cells in Intervertebral Disc Development and Degeneration

    PubMed Central

    McCann, Matthew R.; Séguin, Cheryle A.

    2016-01-01

    The intervertebral disc is a complex structure responsible for flexibility, multi-axial motion, and load transmission throughout the spine. Importantly, degeneration of the intervertebral disc is thought to be an initiating factor for back pain. Due to a lack of understanding of the pathways that govern disc degeneration, there are currently no disease-modifying treatments to delay or prevent degenerative disc disease. This review presents an overview of our current understanding of the developmental processes that regulate intervertebral disc formation, with particular emphasis on the role of the notochord and notochord-derived cells in disc homeostasis and how their loss can result in degeneration. We then describe the role of small animal models in understanding the development of the disc and their use to interrogate disc degeneration and associated pathologies. Finally, we highlight essential development pathways that are associated with disc degeneration and/or implicated in the reparative response of the tissue that might serve as targets for future therapeutic approaches. PMID:27252900

  14. RADIOLOGICAL ANALYSIS OF EXPERIMENTAL DISC DEGENERATION IN RABBITS

    PubMed Central

    Vialle, Emiliano; Vialle, Luiz Roberto; Arruda, André de Oliveira; Riet, Ricardo Nascimento; Krieger, Antônio Bernardo de Queiroz

    2015-01-01

    Objective: To validate radiographic evaluation of a rabbit model for disc degeneration. Methods: Lumbar intervertebral discs of New Zealand rabbits were stabbed three times with a 18G needle at a limited depth of 5mm, through lateral approach. Serial radiographic images were taken on the early pre-and postoperative periods, and after four, eight and 12 weeks of the procedure, with subsequent analysis of disc height, osteophyte formation, endplate sclerosis, and presence of disc degeneration. The statistical analysis of data was validated by the Kappa coefficient, with a confidence interval (CI) of 95%. Results: A significant reduction of disc space was found on AP X-ray images after 12 postoperative weeks, with Kappa = 0.489 for CI 95% (0.25-0.72) with p < 0.001. X-ray signs of disc degeneration also presented Kappa = 0.63 for CI 95% (0.39-0.86) with p < 0.001. The remaining assessed criteria showed positive results, but with a lower Kappa value. Conclusion: The disc degeneration model using rabbits as proposed in this study was shown to be feasible, with positive X-ray correlation between pre- and postoperative images, validating the potential to induce disc degeneration in this animal model for future studies. PMID:27022512

  15. Development and Kinematic Verification of a Finite Element Model for the Lumbar Spine: Application to Disc Degeneration

    PubMed Central

    Ibarz, Elena; Herrera, Antonio

    2013-01-01

    The knowledge of the lumbar spine biomechanics is essential for clinical applications. Due to the difficulties to experiment on living people and the irregular results published, simulation based on finite elements (FE) has been developed, making it possible to adequately reproduce the biomechanics of the lumbar spine. A 3D FE model of the complete lumbar spine (vertebrae, discs, and ligaments) has been developed. To verify the model, radiological images (X-rays) were taken over a group of 25 healthy, male individuals with average age of 27.4 and average weight of 78.6 kg with the corresponding informed consent. A maximum angle of 34.40° is achieved in flexion and of 35.58° in extension with a flexion-extension angle of 69.98°. The radiological measurements were 33.94 ± 4.91°, 38.73 ± 4.29°, and 72.67°, respectively. In lateral bending, the maximum angles were 19.33° and 23.40 ± 2.39, respectively. In rotation a maximum angle of 9.96° was obtained. The model incorporates a precise geometrical characterization of several elements (vertebrae, discs, and ligaments), respecting anatomical features and being capable of reproducing a wide range of physiological movements. Application to disc degeneration (L5-S1) allows predicting the affection in the mobility of the different lumbar segments, by means of parametric studies for different ranges of degeneration. PMID:23509766

  16. MRI evaluation of spontaneous intervertebral disc degeneration in the alpaca cervical spine.

    PubMed

    Stolworthy, Dean K; Bowden, Anton E; Roeder, Beverly L; Robinson, Todd F; Holland, Jacob G; Christensen, S Loyd; Beatty, Amanda M; Bridgewater, Laura C; Eggett, Dennis L; Wendel, John D; Stieger-Vanegas, Susanne M; Taylor, Meredith D

    2015-12-01

    Animal models have historically provided an appropriate benchmark for understanding human pathology, treatment, and healing, but few animals are known to naturally develop intervertebral disc degeneration. The study of degenerative disc disease and its treatment would greatly benefit from a more comprehensive, and comparable animal model. Alpacas have recently been presented as a potential large animal model of intervertebral disc degeneration due to similarities in spinal posture, disc size, biomechanical flexibility, and natural disc pathology. This research further investigated alpacas by determining the prevalence of intervertebral disc degeneration among an aging alpaca population. Twenty healthy female alpacas comprised two age subgroups (5 young: 2-6 years; and 15 older: 10+ years) and were rated according to the Pfirrmann-grade for degeneration of the cervical intervertebral discs. Incidence rates of degeneration showed strong correlations with age and spinal level: younger alpacas were nearly immune to developing disc degeneration, and in older animals, disc degeneration had an increased incidence rate and severity at lower cervical levels. Advanced disc degeneration was present in at least one of the cervical intervertebral discs of 47% of the older alpacas, and it was most common at the two lowest cervical intervertebral discs. The prevalence of intervertebral disc degeneration encourages further investigation and application of the lower cervical spine of alpacas and similar camelids as a large animal model of intervertebral disc degeneration.

  17. Effect of Survivin gene therapy via lentivirus vector on the course of intervertebral disc degeneration in an in vivo rabbit model

    PubMed Central

    Yue, Bin; Lin, Yazhou; Ma, Xuexiao; Zhang, Guoqing; Chen, Bohua

    2016-01-01

    The aim of the current study was to use gene therapy to attenuate or reverse the degenerative process within the intervertabral disc. The effect of survivin gene therapy via lentiviral vector transfection on the course of intervertebral disc degeneration was investigated in the current study in an in vivo rabbit model. A total of 15 skeletally mature female New Zealand White rabbits were randomly divided into three groups: Punctured blank control group (group A, n=5), punctured empty vector control group (group B, n=5) and the treatment group (group C, n=5). Computed tomography-guided puncture was performed at the L3-L4 and L4-L5 discs, in accordance with a previously validated rabbit annulotomy model for intervertebral disc degeneration. After 3 weeks, a lentiviral vector (LV) carrying survivin was injected into the nucleus pulposus. The results demonstrated that through magnetic resonance imaging, histology, gene expression, protein content and apoptosis analyses, group A and B were observed to exhibit disc degeneration, which increased over time, and no significant difference was observed between the two groups (P>0.05). However, there was reduced disc degeneration in group C compared with the punctured control groups, and the difference was statistically significant (P<0.05). Overall, the results of the present study demonstrated that injection of the LV carrying survivin into punctured rabbit intervertebral discs acted to delay changes associated with the degeneration of the discs. Although data from animal models should be extrapolated to the human condition with caution, the present study suggests potential for the use of gene therapy to decelerate disc degeneration. PMID:27748828

  18. Decellularized allogeneic intervertebral disc: natural biomaterials for regenerating disc degeneration

    PubMed Central

    Hu, Zhijun; Chen, Kai; Shan, Zhi; Chen, Shuai; Wang, Jiying; Mo, Jian; Ma, Jianjun; Xu, Wenbing; Qin, An; Fan, Shunwu

    2016-01-01

    Intervertebral disc degeneration is associated with back pain and disc herniation. This study established a modified protocol for intervertebral disc (IVD) decellularization and prepared its extracellular matrix (ECM). By culturing mesenchymal stem cells (MSCs)(3, 7, 14 and 21 days) and human degenerative IVD cells (7 days) in the ECM, implanting it subcutaneously in rabbit and injecting ECM microparticles into degenerative disc, the biological safety and efficacy of decellularized IVD was evaluated both in vitro and in vivo. Here, we demonstrated that cellular components can be removed completely after decellularization and maximally retain the structure and biomechanics of native IVD. We revealed that allogeneic ECM did not evoke any apparent inflammatory reaction in vivo and no cytotoxicity was found in vitro. Moreover, IVD ECM can induce differentiation of MSCs into IVD-like cells in vitro. Furthermore, allogeneic ECM microparticles are effective on the treatment of rabbit disc degeneration in vivo. In conclusion, our study developed an optimized method for IVD decellularization and we proved decellularized IVD is safe and effective for the treatment of degenerated disc diseases. PMID:26933821

  19. 1990 Volvo Award in experimental studies. Anulus tears and intervertebral disc degeneration. An experimental study using an animal model.

    PubMed

    Osti, O L; Vernon-Roberts, B; Fraser, R D

    1990-08-01

    An animal model was developed to test the hypothesis that discrete peripheral tears within the anulus lead to secondary degenerative changes in other disc components. In 21 adult sheep, a cut was made in the left anterolateral anulus of three randomly selected lumbar discs. The cut was parallel and adjacent to the inferior end-plate, and had a controlled depth of 5 mm. This left the inner third of the anulus and the nucleus pulposus intact and closely reproduced the rim Lear lesion described by Schmorl. Animals were randomly allocated to different groups in relation to the length of time interval between operation and death, varying from 1 to 18 months. At death, the lumbar spine was cut into individual joint units and each disc sectioned into six parasagittal slabs. After observation of the slabs under the dissecting microscope, two of the six slabs, the one containing the anulus lesion and a contralateral, were processed for histology. The results of this study suggest that, despite the great care taken at operation to ensure that the inner anulus was left intact, progressive failure of the inner anulus was seen in all sheep and occurred in the majority of discs between 4 and 12 months after the operation. Although the outermost anulus showed the ability to heal, the defect induced by the cut led initially to deformation and bulging of the collagen bundles, and eventually to inner extension of the tear and complete failure. These findings suggest that discrete tears of the outer anulus may have a role in the formation of concentric clefts and in accelerating the development of radiating clefts. Peripheral tears of the anulus fibrosus therefore may play an important role in the degeneration of the intervertebral joint complex.

  20. A papain-induced disc degeneration model for the assessment of thermo-reversible hydrogel-cells therapeutic approach.

    PubMed

    Malonzo, C; Chan, S C W; Kabiri, A; Eglin, D; Grad, S; Bonél, H M; Benneker, L M; Gantenbein-Ritter, B

    2015-12-01

    Nucleus pulposus (NP) regeneration by the application of injectable cell-embedded hydrogels is an appealing approach for tissue engineering. We investigated a thermo-reversible hydrogel (TR-HG), based on a modified polysaccharide with a thermo-reversible polyamide [poly(N-isopropylacrylamide), pNIPAM], which is made to behave as a liquid at room temperature and hardens at > 32 °C. In order to test the hydrogel, a papain-induced bovine caudal disc degeneration model (PDDM), creating a cavity in the NP, was employed. Human mesenchymal stem cells (hMSCs) or autologous bovine NP cells (bNPCs) were seeded in TR-HG; hMSCs were additionally preconditioned with rhGDF-5 for 7 days. Then, TR-HG was reversed to a fluid and the cell suspension injected into the PDDM and kept under static loading for 7 days. Experimental design was: (D1) fresh disc control + PBS injection; (D2) PDDM + PBS injection; (D3) PDDM + TR-HG (material control); (D4) PDDM + TR-HG + bNPCs; (D5) PDDM + TR-HG + hMSCs. Magnetic resonance imaging performed before and after loading, on days 9 and 16, allowed imaging of the hydrogel-filled PDDM and assessment of disc height and volume changes. In gel-injected discs the NP region showed a major drop in volume and disc height during culture under static load. The RT-PCR results of injected hMSCs showed significant upregulation of ACAN, COL2A1, VCAN and SOX9 during culture in the disc cavity, whereas the gene expression profile of NP cells remained unchanged. The cell viability of injected cells (NPCs or hMSCs) was maintained at over 86% in 3D culture and dropped to ~72% after organ culture. Our results underline the need for load-bearing hydrogels that are also cyto-compatible.

  1. Protective effect of ligustrazine on lumbar intervertebral disc degeneration of rats induced by prolonged upright posture.

    PubMed

    Liang, Qian-Qian; Ding, Dao-Fang; Xi, Zhi-Jie; Chen, Yan; Li, Chen-Guang; Liu, Shu-Fen; Lu, Sheng; Zhao, Yong-Jian; Shi, Qi; Wang, Yong-Jun

    2014-01-01

    Most chronic low back pain is the result of degeneration of the lumbar intervertebral disc. Ligustrazine, an alkaloid from Chuanxiong, reportedly is able to relieve pain, suppress inflammation, and treat osteoarthritis and it has the protective effect on cartilage and chondrocytes. Therefore, we asked whether ligustrazine could reduce intervertebral disc degeneration. To determine the effect of ligustrazine on disc degeneration, we applied a rat model. The intervertebral disc degeneration of the rats was induced by prolonged upright posture. We found that pretreatment with ligustrazine for 1 month recovered the structural distortion of the degenerative disc; inhibited the expression of type X collagen, matrix metalloproteinase (MMP)-13, and MMP3; upregulated type II collagen; and decreased IL-1 β , cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expression. In conclusion, ligustrazine is a promising agent for treating lumbar intervertebral disc degeneration disease.

  2. Intervertebral disc degeneration: evidence for two distinct phenotypes

    PubMed Central

    Adams, Michael A; Dolan, Patricia

    2012-01-01

    We review the evidence that there are two types of disc degeneration. ‘Endplate-driven’ disc degeneration involves endplate defects and inwards collapse of the annulus, has a high heritability, mostly affects discs in the upper lumbar and thoracic spine, often starts to develop before age 30 years, usually leads to moderate back pain, and is associated with compressive injuries such as a fall on the buttocks. ‘Annulus-driven’ disc degeneration involves a radial fissure and/or a disc prolapse, has a low heritability, mostly affects discs in the lower lumbar spine, develops progressively after age 30 years, usually leads to severe back pain and sciatica, and is associated with repetitive bending and lifting. The structural defects which initiate the two processes both act to decompress the disc nucleus, making it less likely that the other defect could occur subsequently, and in this sense the two disc degeneration phenotypes can be viewed as distinct. PMID:22881295

  3. Genetic Factors in Intervertebral Disc Degeneration

    PubMed Central

    Feng, Yi; Egan, Brian; Wang, Jinxi

    2016-01-01

    Low back pain (LBP) is a major cause of disability and imposes huge economic burdens on human society worldwide. Among many factors responsible for LBP, intervertebral disc degeneration (IDD) is the most common disorder and is a target for intervention. The etiology of IDD is complex and its mechanism is still not completely understood. Many factors such as aging, spine deformities and diseases, spine injuries, and genetic factors are involved in the pathogenesis of IDD. In this review, we will focus on the recent advances in studies on the most promising and extensively examined genetic factors associated with IDD in humans. A number of genetic defects have been correlated with structural and functional changes within the intervertebral disc (IVD), which may compromise the disc’s mechanical properties and metabolic activities. These genetic and proteomic studies have begun to shed light on the molecular basis of IDD, suggesting that genetic factors are important contributors to the onset and progression of IDD. By continuing to improve our understanding of the molecular mechanisms of IDD, specific early diagnosis and more effective treatments for this disabling disease will be possible in the future. PMID:27617275

  4. Simulation of the Progression of Intervertebral Disc Degeneration due to Decreased Nutrition Supply

    PubMed Central

    Gu, Weiyong; Zhu, Qiaoqiao; Gao, Xin; Brown, Mark D.

    2014-01-01

    Study Design Simulate the progression of human disc degeneration. Objective The objective of this study was to quantitatively analyze and simulate the changes in cell density, nutrition level, proteoglycan content, water content, and volume change during human disc degeneration using a numerical method. Summary of Background Data Understanding the etiology and progression of intervertebral disc (IVD) degeneration is crucial for developing effective treatment strategies for IVD-degeneration related diseases. During tissue degeneration, the disc undergoes losses of cell viability and activities, changes in extracellular matrix composition and structure, and compromise of the tissue-level integrity and function, which is significantly influenced by the inter-coupled biological, chemical, electrical, and mechanical signals in the disc. Characterizing these signals in human discs in vivo is difficult. Methods A realistic 3D finite element model of the human IVD was developed based on biomechano-electrochemical continuum mixture theory. The theoretical framework and the constitutive relationships were all biophysics based. All the material properties were obtained from experimental results. The cell-mediated disc degeneration process caused by lowered nutrition levels at disc boundaries was simulated and validated by comparing with experimental results. Results Cell density reached equilibrium state in 30 days after reduced nutrition supply at the disc boundary, while the proteoglycan (PG) and water contents reached a new equilibrium state in 55 years. The simulated results for the distributions of PG and water contents within the disc were consistent with the results measured in the literature, except for the distribution of PG content in the sagittal direction. Conclusions Poor nutrition supply has a long-term effect on disc degeneration. PMID:25188596

  5. Lumbar intervertebral disc degeneration and related factors in Korean firefighters

    PubMed Central

    Jang, Tae-Won; Ahn, Yeon-Soon; Byun, Junsu; Lee, Jong-In; Kim, Kun-Hyung; Kim, Youngki; Song, Han-Soo; Lee, Chul-Gab; Kwon, Young-Jun; Yoon, Jin-Ha; Jeong, Kyoungsook

    2016-01-01

    Objectives The job of firefighting can cause lumbar burden and low back pain. This study aimed to identify the association between age and lumbar intervertebral disc degeneration and whether the association differs between field and administrative (non-field) firefighters. Methods Subjects were selected using a stratified random sampling method. Firefighters were stratified by geographic area, gender, age and type of job. First, 25 fire stations were randomly sampled considering regional distribution. Then firefighters were stratified by gender, age and their job and randomly selected among the strata. A questionnaire survey and MRI scans were performed, and then four radiologists used Pfirrmann classification methods to determine the grade of lumbar intervertebral disc degeneration. Results Pfirrmann grade increased with lumbar intervertebral disc level. Analysis of covariance showed that age was significantly associated with lumbar intervertebral disc degeneration (p<0.05). The value of β (parameter estimate) was positive at all lumbar intervertebral disc levels and was higher in the field group than in the administrative group at each level. In logistic regression analysis, type of job was statistically significant only with regard to the L4–5 intervertebral disc (OR 3.498, 95% CI 1.241 to 9.860). Conclusions Lumbar intervertebral disc degeneration is associated with age, and field work such as firefighting, emergency and rescue may accelerate degeneration in the L4–5 intervertebral disc. The effects of field work on lumbar intervertebral disc degeneration were not clear in discs other than at the level L4–5. PMID:27354080

  6. Effect of disc degeneration on the muscle recruitment pattern in upright posture: a computational analysis.

    PubMed

    Kim, Young Eun; Choi, Hae Won

    2015-01-01

    Based on the sensor driving control mechanism model, the effect of disc degeneration on the trunk muscle recruitment (TMR) pattern was analysed in erect standing posture. A previously developed computational model was used for this analysis, with modifications incorporating the T12-L1 motion segment and additional muscle fascicles. To generate disc degeneration at three different levels (L3-L4, L4-L5, or L5-S1), the material properties of the ground matrix of the annulus and bulk modulus of the nucleus were reduced. The finite element method combined with an optimization technique was applied to calculate the muscle forces. Minimization of deviations in the averaged tensile stress in the annulus fibres at the outermost layer in the five discs was selected for muscle force calculations. The results indicated that the disc degeneration noticeably increased the activation of the superficial muscle (IT and R) even though there was no clear change in the longissimus thoracis. Unlike some of the superficial muscles, activation in the deep muscles (multifidus (ML, MS, MT), LL and Q) was decreased. The change in TMR pattern generated an intervertebral disc angle difference and nucleus pressure increased in the upper level. These differences are expected to be functional in that they reduce the stress at the degenerated disc by changing the muscle activation, which slows down the progress of disc degeneration.

  7. Progranulin Knockout Accelerates Intervertebral Disc Degeneration in Aging Mice

    PubMed Central

    Zhao, Yun-peng; Tian, Qing-yun; Liu, Ben; Cuellar, Jason; Richbourgh, Brendon; Jia, Tang-hong; Liu, Chuan-ju

    2015-01-01

    Intervertebral disc (IVD) degeneration is a common degenerative disease, yet much is unknown about the mechanisms during its pathogenesis. Herein we investigated whether progranulin (PGRN), a chondroprotective growth factor, is associated with IVD degeneration. PGRN was detectable in both human and murine IVD. The levels of PGRN were upregulated in murine IVD tissue during aging process. Loss of PGRN resulted in an early onset of degenerative changes in the IVD tissue and altered expressions of the degeneration-associated molecules in the mouse IVD tissue. Moreover, PGRN knockout mice exhibited accelerated IVD matrix degeneration, abnormal bone formation and exaggerated bone resorption in vertebra with aging. The acceleration of IVD degeneration observed in PGRN null mice was probably due to the enhanced activation of NF-κB signaling and β-catenin signaling. Taken together, PGRN may play a critical role in homeostasis of IVD, and may serve as a potential molecular target for prevention and treatment of disc degenerative diseases. PMID:25777988

  8. Protective Effects of Cannabidiol on Lesion-Induced Intervertebral Disc Degeneration

    PubMed Central

    Silveira, João W.; Issy, Ana Carolina; Castania, Vitor A.; Salmon, Carlos E. G.; Nogueira-Barbosa, Marcello H.; Guimarães, Francisco S.; Defino, Helton L. A.; Bel, Elaine Del

    2014-01-01

    Disc degeneration is a multifactorial process that involves hypoxia, inflammation, neoinnervation, accelerated catabolism, and reduction in water and glycosaminoglycan content. Cannabidiol is the main non-psychotropic component of the Cannabis sativa with protective and anti-inflammatory properties. However, possible therapeutic effects of cannabidiol on intervertebral disc degeneration have not been investigated yet. The present study investigated the effects of cannabidiol intradiscal injection in the coccygeal intervertebral disc degeneration induced by the needle puncture model using magnetic resonance imaging (MRI) and histological analyses. Disc injury was induced in the tail of male Wistar rats via a single needle puncture. The discs selected for injury were punctured percutaneously using a 21-gauge needle. MRI and histological evaluation were employed to assess the results. The effects of intradiscal injection of cannabidiol (30, 60 or 120 nmol) injected immediately after lesion were analyzed acutely (2 days) by MRI. The experimental group that received cannabidiol 120 nmol was resubmitted to MRI examination and then to histological analyses 15 days after lesion/cannabidiol injection. The needle puncture produced a significant disc injury detected both by MRI and histological analyses. Cannabidiol significantly attenuated the effects of disc injury induced by the needle puncture. Considering that cannabidiol presents an extremely safe profile and is currently being used clinically, these results suggest that this compound could be useful in the treatment of intervertebral disc degeneration. PMID:25517414

  9. Protective effects of cannabidiol on lesion-induced intervertebral disc degeneration.

    PubMed

    Silveira, João W; Issy, Ana Carolina; Castania, Vitor A; Salmon, Carlos E G; Nogueira-Barbosa, Marcello H; Guimarães, Francisco S; Defino, Helton L A; Del Bel, Elaine

    2014-01-01

    Disc degeneration is a multifactorial process that involves hypoxia, inflammation, neoinnervation, accelerated catabolism, and reduction in water and glycosaminoglycan content. Cannabidiol is the main non-psychotropic component of the Cannabis sativa with protective and anti-inflammatory properties. However, possible therapeutic effects of cannabidiol on intervertebral disc degeneration have not been investigated yet. The present study investigated the effects of cannabidiol intradiscal injection in the coccygeal intervertebral disc degeneration induced by the needle puncture model using magnetic resonance imaging (MRI) and histological analyses. Disc injury was induced in the tail of male Wistar rats via a single needle puncture. The discs selected for injury were punctured percutaneously using a 21-gauge needle. MRI and histological evaluation were employed to assess the results. The effects of intradiscal injection of cannabidiol (30, 60 or 120 nmol) injected immediately after lesion were analyzed acutely (2 days) by MRI. The experimental group that received cannabidiol 120 nmol was resubmitted to MRI examination and then to histological analyses 15 days after lesion/cannabidiol injection. The needle puncture produced a significant disc injury detected both by MRI and histological analyses. Cannabidiol significantly attenuated the effects of disc injury induced by the needle puncture. Considering that cannabidiol presents an extremely safe profile and is currently being used clinically, these results suggest that this compound could be useful in the treatment of intervertebral disc degeneration.

  10. Intervertebral Disc Degeneration and Ectopic Bone Formation in Apolipoprotein E Knockout Mice

    PubMed Central

    Zhang, Dawei; Jin, Li; Reames, Davis L.; Shen, Francis H.; Shimer, Adam L.; Li, Xudong

    2012-01-01

    Cardiovascular risk factors are known to be associated with intervertebral disc degeneration, but the underlying mechanism is still unclear. ApoE knockout (KO) mouse is a well-established model for arthrosclerosis. We hypothesize that ApoE may involve in maintaining disc health and ApoE KO mouse develops early disc degeneration. Discs of ApoE KO and wild-type (WT) mice were characterized with histological/immunological, biochemical, and real time RT-PCR assays. A comparison of the extracellular matrix production was also performed in disc cells. We demonstrated that ApoE was highly expressed in the endplates of WT discs and ectopic bone formed in the endplates of ApoE KO discs. Glycosaminoglycan content was decreased in both ApoE KO annulus fibrosus (AF) and nucleus pulpsous (NP) cells. Collagen levels were increased in AF and decreased in NP cells. Matrix metalloproteinases-3, 9, and 13 expression was increased which may partially explain the impaired matrix production. We also found increased collagen I, II, aggrecan and biglycan mRNA expressions in AF cells but decreased in NP cells. Apoptosis was increased in the ApoE KO NP tissue. These results suggest early disc degeneration changes in ApoE KO mice. ApoE, plus its importance to cardiovascular disease, may play a critical role in disc integrity and function. PMID:22915292

  11. Disc in Flames: Roles of TNF-α and IL-1β in Intervertebral Disc Degeneration

    PubMed Central

    Johnson, Zariel I.; Schoepflin, Zachary R.; Choi, Hyowon; Shapiro, Irving M.; Risbud, Makarand V.

    2016-01-01

    The intervertebral disc is an important mechanical structure that allows range of motion of the spinal column. Degeneration of the intervertebral disc, incited by aging, traumatic insult, genetic predisposition, or other factors, is often defined by functional and structural changes in the tissue, including excessive breakdown of the extracellular matrix, increased disc cell senescence and death, and compromised biomechanical function of the tissue. Intervertebral disc degeneration is strongly correlated with low back pain, which is a highly prevalent and costly condition, significantly contributing to loss in productivity and health care costs. Disc degeneration is a chronic, progressive condition, and current therapies are limited and often focused on symptomatic pain relief rather than curtailing the progression of the disease. Inflammatory processes, exacerbated by cytokines TNF-α and IL-1β are believed to be key mediators of disc degeneration and low back pain. In this review, we describe the contributions of TNF-α and IL-1β to changes seen during disc degeneration at the cellular and tissue level, new evidence suggesting a link between infection of the spine and low back pain, and the emerging therapeutic modalities aimed at combating these processes. PMID:26388614

  12. Lumbar Disc Degenerative Disease: Disc Degeneration Symptoms and Magnetic Resonance Image Findings

    PubMed Central

    Saleem, Shafaq; Rehmani, Muhammad Asim Khan; Raees, Aisha; Alvi, Arsalan Ahmad; Ashraf, Junaid

    2013-01-01

    Study Design Cross sectional and observational. Purpose To evaluate the different aspects of lumbar disc degenerative disc disease and relate them with magnetic resonance image (MRI) findings and symptoms. Overview of Literature Lumbar disc degenerative disease has now been proven as the most common cause of low back pain throughout the world. It may present as disc herniation, lumbar spinal stenosis, facet joint arthropathy or any combination. Presenting symptoms of lumbar disc degeneration are lower back pain and sciatica which may be aggravated by standing, walking, bending, straining and coughing. Methods This study was conducted from January 2012 to June 2012. Study was conducted on the diagnosed patients of lumbar disc degeneration. Diagnostic criteria were based upon abnormal findings in MRI. Patients with prior back surgery, spine fractures, sacroiliac arthritis, metabolic bone disease, spinal infection, rheumatoid arthritis, active malignancy, and pregnancy were excluded. Results During the targeted months, 163 patients of lumbar disc degeneration with mean age of 43.92±11.76 years, came into Neurosurgery department. Disc degeneration was most commonly present at the level of L4/L5 105 (64.4%).Commonest types of disc degeneration were disc herniation 109 (66.9%) and lumbar spinal stenosis 37 (22.7%). Spondylolisthesis was commonly present at L5/S1 10 (6.1%) and associated mostly with lumbar spinal stenosis 7 (18.9%). Conclusions Results reported the frequent occurrence of lumbar disc degenerative disease in advance age. Research efforts should endeavor to reduce risk factors and improve the quality of life. PMID:24353850

  13. 1980 Volvo award in basic science. Proteoglycans in experimental intervertebral disc degeneration.

    PubMed

    Lipson, S J; Muir, H

    1981-01-01

    An animal model of intervertebral disc degeneration induced surgically by ventral nuclear herniation in the rabbit produces morphologic changes of disc degeneration. Histologic characteristics and proteoglycan changes have been studied at various times after herniation. After injury, there was metaplasia into fibrocartilage originating from the cells along the margins of the annular wound, with proliferation of cells changing almost the entire disc space into fibrocartilage. A vertebral osteophyte occurred through an endochondral ossification sequence. Aggregating proteoglycans had two periods of repletion in the early course of degeneration. The water content of the disc was rapidly but only transiently restored in the first two days after herniation, whilst the changes in the total proteoglycan content of the disc paralleled these changes. Hyaluronic acid content decreased rapidly after herniation, but the size of the proteoglycan monomers did not change with degeneration. It is suggested that loss of confined fluid mechanics signals an abortive repair attempt rather than that of biochemical changes in proteoglycans initiate disc degeneration.

  14. Biological treatment strategies for disc degeneration: potentials and shortcomings

    PubMed Central

    Nerlich, Andreas G.; Boos, Norbert

    2006-01-01

    Recent advances in molecular biology, cell biology and material sciences have opened a new emerging field of techniques for the treatment of musculoskeletal disorders. These new treatment modalities aim for biological repair of the affected tissues by introducing cell-based tissue replacements, genetic modifications of resident cells or a combination thereof. So far, these techniques have been successfully applied to various tissues such as bone and cartilage. However, application of these treatment modalities to cure intervertebral disc degeneration is in its very early stages and mostly limited to experimental studies in vitro or in animal studies. We will discuss the potential and possible shortcomings of current approaches to biologically cure disc degeneration by gene therapy or tissue engineering. Despite the increasing number of studies examining the therapeutic potential of biological treatment strategies, a practicable solution to routinely cure disc degeneration might not be available in the near future. However, knowledge gained from these attempts might be applied in a foreseeable future to cure the low back pain that often accompanies disc degeneration and therefore be beneficial for the patient. PMID:16983559

  15. 3D finite element analysis of nutrient distributions and cell viability in the intervertebral disc: effects of deformation and degeneration.

    PubMed

    Jackson, Alicia R; Huang, Chun-Yuh C; Brown, Mark D; Gu, Wei Yong

    2011-09-01

    The intervertebral disc (IVD) receives important nutrients, such as glucose, from surrounding blood vessels. Poor nutritional supply is believed to play a key role in disc degeneration. Several investigators have presented finite element models of the IVD to investigate disc nutrition; however, none has predicted nutrient levels and cell viability in the disc with a realistic 3D geometry and tissue properties coupled to mechanical deformation. Understanding how degeneration and loading affect nutrition and cell viability is necessary for elucidating the mechanisms of disc degeneration and low back pain. The objective of this study was to analyze the effects of disc degeneration and static deformation on glucose distributions and cell viability in the IVD using finite element analysis. A realistic 3D finite element model of the IVD was developed based on mechano-electrochemical mixture theory. In the model, the cellular metabolic activities and viability were related to nutrient concentrations, and transport properties of nutrients were dependent on tissue deformation. The effects of disc degeneration and mechanical compression on glucose concentrations and cell density distributions in the IVD were investigated. To examine effects of disc degeneration, tissue properties were altered to reflect those of degenerated tissue, including reduced water content, fixed charge density, height, and endplate permeability. Two mechanical loading conditions were also investigated: a reference (undeformed) case and a 10% static deformation case. In general, nutrient levels decreased moving away from the nutritional supply at the disc periphery. Minimum glucose levels were at the interface between the nucleus and annulus regions of the disc. Deformation caused a 6.2% decrease in the minimum glucose concentration in the normal IVD, while degeneration resulted in an 80% decrease. Although cell density was not affected in the undeformed normal disc, there was a decrease in cell

  16. Inhibitory Effects of Platelet-Rich Plasma on Intervertebral Disc Degeneration: A Preclinical Study in a Rabbit Model

    PubMed Central

    Gui, Keke; Ren, Weimin; Yu, Yonglin; Li, Xin; Dong, Jiachun; Yin, Wangping

    2015-01-01

    Background Platelet-rich plasma (PRP) contains multiple growth hormones that may stimulate tissue repair. This study aimed to assess the effects of PRP in a rabbit model of IDD (annulus fibrosus puncture). Material/Methods Thirty-six adult New Zealand white rabbits were randomly divided into 3 groups: 0.1 mL PRP (group A), 0.1 mL phosphate-buffered saline (group B), and control (group C) (n=12/group). Annulus fibrosus puncture was performed to establish L4/5 and L5/6 IDD models. Two and 4 weeks later, 6 rabbits from each group were given an IVD injection at L4/5 and L5/6. Two or 4 weeks after injection, rabbits were scanned with X-ray and MRI before being sacrificed. IVDs were collected for hematoxylin and eosin, Masson’s trichrome, and Safranin O staining, and type II collagen immunohistochemistry. Results Over time, IVD height and disc imaging signal intensity decreased gradually in groups B and C, but only slightly in group A (baseline: 100% for all groups; A: 95.9±4.2% at 4 weeks, 90.1±8.4 at 6 weeks; B: 75.3±5.7% at 4 weeks, 70.8±6.4% at 6 weeks; C: 74.7±5.5% at 4 weeks, 69.9±6.2% at 6 weeks; all P<0.001, P<0.01 between A vs. B and C). Degenerative histological changes in IVDs in groups B and C were more severe compared with group A. Conclusions Platelet-rich plasma interventions can effectively attenuate the IDD process in rabbits. PMID:25965093

  17. Histological Identification of Propionibacterium acnes in Nonpyogenic Degenerated Intervertebral Discs

    PubMed Central

    Yuan, Ye; Zhou, Zezhu; Jiao, Yucheng; Zheng, Yuehuan; Lin, Yazhou; Xiao, Jiaqi

    2017-01-01

    Purpose. Low-virulence anaerobic bacteria, especially the Propionibacterium acnes (P. acnes), have been thought to be a new pathogeny for a series of disc diseases. However, until now, there has been no histological evidence to confirm this link. The purpose of this study was to confirm the presence of P. acnes in nonpyogenic intervertebral discs via histological observation. Method. Degenerated intervertebral discs were harvested from 76 patients with low back pain and/or sciatica but without any symptoms of discitis or spondylodiscitis. The samples were cultured under anaerobic conditions and then examined using 16S rDNA PCR to screen for P. acnes. Samples found to be positive for P. acnes were stained with hematoxylin-eosin (HE) and modified Brown-Brenn staining and observed under a microscope. Results. Here, 16 intervertebral discs were found to be positive for P. acnes via 16S rDNA PCR and the prevalence was 21.05% (16/76). Among them, 7 samples had visible microbes stained with HE and modified Brown-Brenn staining. Morphological examination showed the bacteria to be Gram-positive and rod-shaped, so they were considered P. acnes. Conclusion. P. acnes is capable of colonizing some degenerated intervertebral discs without causing discitis, and its presence could be further confirmed by histological evidence. Targeting these bacteria may be a promising therapy method for some disc diseases.

  18. Angiogenesis in the degeneration of the lumbar intervertebral disc

    PubMed Central

    David, Gh; Iencean, SM; Mohan, A

    2010-01-01

    The goal of the study is to show the histological and biochemical changes that indicate the angiogenesis of the intervertebral disc in lumbar intervertebral disc hernia and the existence of epidemiological correlations between these changes and the risk factors of lumbar intervertebral disc hernia, as well as the patient's quality of life (QOL). We have studied 50 patients aged between 18 and 73 years old, who have undergone lumbar intervertebral disc hernia surgery, making fibroblast growth factor and vascular endothelial growth factor level measurements, as elements in the process of appreciating the disc angiogenesis. Also, pre–surgery and post–surgery QOL has been measured, as well as the intensity of the pain syndrome. We have identified factors capable of stimulating vascular endothelial growth (VEGF, FGF–2) for the examined disc material, but histological examination did not show angiogenesis. The process of angiogenesis at the degenerated intervertebral disc level affects the patient's quality of life both pre and postoperatively, and may be a predictive factor for the post–operative results. Patients can prevent the appearance of angiogenesis type degenerative processes of the intervertebral disc by avoiding angiogenesis correlated factors (weight control, physical effort, and smoking). PMID:20968201

  19. ROS: Crucial Intermediators in the Pathogenesis of Intervertebral Disc Degeneration

    PubMed Central

    Yang, Minghui; Lan, Minghong; Liu, Chang; Zhang, Yang; Huang, Bo

    2017-01-01

    Excessive reactive oxygen species (ROS) generation in degenerative intervertebral disc (IVD) indicates the contribution of oxidative stress to IVD degeneration (IDD), giving a novel insight into the pathogenesis of IDD. ROS are crucial intermediators in the signaling network of disc cells. They regulate the matrix metabolism, proinflammatory phenotype, apoptosis, autophagy, and senescence of disc cells. Oxidative stress not only reinforces matrix degradation and inflammation, but also promotes the decrease in the number of viable and functional cells in the microenvironment of IVDs. Moreover, ROS modify matrix proteins in IVDs to cause oxidative damage of disc extracellular matrix, impairing the mechanical function of IVDs. Consequently, the progression of IDD is accelerated. Therefore, a therapeutic strategy targeting oxidative stress would provide a novel perspective for IDD treatment. Various antioxidants have been proposed as effective drugs for IDD treatment. Antioxidant supplementation suppresses ROS production in disc cells to promote the matrix synthesis of disc cells and to prevent disc cells from death and senescence in vitro. However, there is not enough in vivo evidence to support the efficiency of antioxidant supplementation to retard the process of IDD. Further investigations based on in vivo and clinical studies will be required to develop effective antioxidative therapies for IDD. PMID:28392887

  20. Role of Cytokines in Intervertebral Disc Degeneration: Pain and Disc-content

    PubMed Central

    Risbud, Makarand V.; Shapiro, Irving. M

    2014-01-01

    Degeneration of the intervertebral disc is the major contributor to back/neck and radicular pain. It is characterized by an elevation in levels of the inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1 α/β, IL-6 and IL-17 secreted by the disc cells themselves; these cytokines promote matrix degradation, chemokine production and changes in cell phenotype. The resulting imbalance between catabolic and anabolic responses leads to degeneration, as well as herniation and radicular pain. Release of chemokines from degenerating discs promote infiltration and activation of T and B cells, macrophages, neutrophils, and mast cells further amplifying the inflammatory cascade. Immunocyte migration into the disc is accompanied by the appearance of microvasculature and nerve fibers arising from the dorsal root ganglion (DRG). In this inflammatory milieu, neurogenic factors in particular nerve growth factor (NGF) and brain-derive neurotrophic factor (BDNF) generated by disc and immune cells induce expression of pain associated cation channels in DRGs. Depolarization of these channels is likely to promote discogenic and radicular pain and reinforce the cytokine-mediated degenerative cascade. Taken together, the enhanced understanding of the contribution of cytokines and immune cells to catabolic and nociceptive processes provide new targets for treating symptomatic disc disease. PMID:24166242

  1. Effects of Tobacco Smoking on the Degeneration of the Intervertebral Disc: A Finite Element Study

    PubMed Central

    Elmasry, Shady; Asfour, Shihab; de Rivero Vaccari, Juan Pablo; Travascio, Francesco

    2015-01-01

    Tobacco smoking is associated with numerous pathological conditions. Compelling experimental evidence associates smoking to the degeneration of the intervertebral disc (IVD). In particular, it has been shown that nicotine down-regulates both the proliferation rate and glycosaminoglycan (GAG) biosynthesis of disc cells. Moreover, tobacco smoking causes the constriction of the vascular network surrounding the IVD, thus reducing the exchange of nutrients and anabolic agents from the blood vessels to the disc. It has been hypothesized that both nicotine presence in the IVD and the reduced solute exchange are responsible for the degeneration of the disc due to tobacco smoking, but their effects on tissue homeostasis have never been quantified. In this study, a previously presented computational model describing the homeostasis of the IVD was deployed to investigate the effects of impaired solute supply and nicotine-mediated down-regulation of cell proliferation and biosynthetic activity on the health of the disc. We found that the nicotine-mediated down-regulation of cell anabolism mostly affected the GAG concentration at the cartilage endplate, reducing it up to 65% of the value attained in normal physiological conditions. In contrast, the reduction of solutes exchange between blood vessels and disc tissue mostly affected the nucleus pulposus, whose cell density and GAG levels were reduced up to 50% of their normal physiological levels. The effectiveness of quitting smoking on the regeneration of a degenerated IVD was also investigated, and showed to have limited benefit on the health of the disc. A cell-based therapy in conjunction with smoke cessation provided significant improvements in disc health, suggesting that, besides quitting smoking, additional treatments should be implemented in the attempt to recover the health of an IVD degenerated by tobacco smoking. PMID:26301590

  2. Menopause causes vertebral endplate degeneration and decrease in nutrient diffusion to the intervertebral discs.

    PubMed

    Wang, Yi-Xiang J; Griffith, James F

    2011-07-01

    The vasculature in the outer annulus supplies only the periphery of the disc so that nutrition to the bulk of the disc, including all the inner annulus and nucleus pulposus, is derived from the vertebral epiphyseal end arteries where nutrients diffuse across the cartilaginous endplate to reach the disc. In this regard the vertebral endplate plays an important role in disc nutrition. Compromise of diffusion of nutrients to the disc cells may play a large part in the progression or even initiation of disc degeneration. Increasing evidence suggests that estrogen deficiency also influence the severity of disc degeneration in post-menopausal females. Structural disorganization of the vertebral endplate occurs with disc degeneration, with the most common endplate changes observed clinically being Schmorl's node. Schmorl's node is more commonly seen in post-menopausal women than younger women. Osteosclerosis, osteonecrosis and fibrosis associated with Schmorl's nodes can impede nutrient diffusion into the disc as well as removal of metabolites from the disc. We hypothesize that menopause negatively affects vertebral endplate quality and induces endplate degeneration. This endplate degeneration decreases nutrients diffusion from vertebral body into discs, and also impedes removal of metabolites, leads to further disc degeneration. To confirm our hypothesis, a cross-sectional post-contrast MRI study can be performed in pre-menopausal and post-menopausal women. If the hypothesis is confirmed, then low dose hormone replacement treatment may retard disc degeneration in post menopausal women and thereby limit the consequences associated with disc degeneration such as low back pain.

  3. Mitochondrial-derived reactive oxygen species (ROS) play a causal role in aging-related intervertebral disc degeneration.

    PubMed

    Nasto, Luigi A; Robinson, Andria R; Ngo, Kevin; Clauson, Cheryl L; Dong, Qing; St Croix, Claudette; Sowa, Gwendolyn; Pola, Enrico; Robbins, Paul D; Kang, James; Niedernhofer, Laura J; Wipf, Peter; Vo, Nam V

    2013-07-01

    Oxidative damage is a well-established driver of aging. Evidence of oxidative stress exists in aged and degenerated discs, but it is unclear how it affects disc metabolism. In this study, we first determined whether oxidative stress negatively impacts disc matrix metabolism using disc organotypic and cell cultures. Mouse disc organotypic culture grown at atmospheric oxygen (20% O(2)) exhibited perturbed disc matrix homeostasis, including reduced proteoglycan synthesis and enhanced expression of matrix metalloproteinases, compared to discs grown at low oxygen levels (5% O(2)). Human disc cells grown at 20% O(2) showed increased levels of mitochondrial-derived superoxide anions and perturbed matrix homeostasis. Treatment of disc cells with the mitochondria-targeted reactive oxygen species (ROS) scavenger XJB-5-131 blunted the adverse effects caused by 20% O(2). Importantly, we demonstrated that treatment of accelerated aging Ercc1(-/Δ) mice, previously established to be a useful in vivo model to study age-related intervertebral disc degeneration (IDD), also resulted in improved disc total glycosaminoglycan content and proteoglycan synthesis. This demonstrates that mitochondrial-derived ROS contributes to age-associated IDD in Ercc1(-/Δ) mice. Collectively, these data provide strong experimental evidence that mitochondrial-derived ROS play a causal role in driving changes linked to aging-related IDD and a potentially important role for radical scavengers in preventing IDD.

  4. Reconstitution of degenerated ovine lumbar discs by STRO-3-positive allogeneic mesenchymal precursor cells combined with pentosan polysulfate.

    PubMed

    Oehme, David; Ghosh, Peter; Goldschlager, Tony; Itescu, Silviu; Shimon, Susan; Wu, Jiehua; McDonald, Courtney; Troupis, John M; Rosenfeld, Jeffrey V; Jenkin, Graham

    2016-05-01

    OBJECTIVE Disc degeneration and associated low-back pain are major causes of suffering and disability. The authors examined the potential of mesenchymal precursor cells (MPCs), when formulated with pentosan polysulfate (PPS), to ameliorate disc degeneration in an ovine model. METHODS Twenty-four sheep had annular incisions made at L2-3, L3-4, and L4-5 to induce degeneration. Twelve weeks after injury, the nucleus pulposus of a degenerated disc in each animal was injected with ProFreeze and PPS formulated with either a low dose (0.1 million MPCs) or a high dose (0.5 million MPCs) of cells. The 2 adjacent injured discs in each spine were either injected with PPS and ProFreeze (PPS control) or not injected (nil-injected control). The adjacent noninjured L1-2 and L5-6 discs served as noninjured control discs. Disc height indices (DHIs) were obtained at baseline, before injection, and at planned death. After necropsy, 24 weeks after injection, the spines were subjected to MRI and morphological, histological, and biochemical analyses. RESULTS Twelve weeks after the annular injury, all the injured discs exhibited a significant reduction in mean DHI (low-dose group 17.19%; high-dose group 18.01% [p < 0.01]). Twenty-four weeks after injections, the discs injected with the low-dose MPC+PPS formulation recovered disc height, and their mean DHI was significantly greater than the DHI of PPS- and nil-injected discs (p < 0.001). Although the mean Pfirrmann MRI disc degeneration score for the low-dose MPC+PPS-injected discs was lower than that for the nil- and PPS-injected discs, the differences were not significant. The disc morphology scores for the nil- and PPS-injected discs were significantly higher than the normal control disc scores (p < 0.005), whereas the low-dose MPC+PPS-injected disc scores were not significantly different from those of the normal controls. The mean glycosaminoglycan content of the nuclei pulposus of the low-dose MPC+PPS-injected discs was significantly

  5. Clinical Impact of Sagittal Spinopelvic Parameters on Disc Degeneration in Young Adults.

    PubMed

    Oh, Young-Min; Eun, Jong-Pil

    2015-10-01

    The sagittal balance plays an important role in the determination of shear and compressive forces applied on the anterior (vertebral bodies and intervertebral discs) and posterior (facet joints) elements of the lumbar vertebral column. Many studies have also examined the effect of structural changes in the disc on the biomechanical characteristics of the spinal segment. Nevertheless, the relationship between sagittal balance and the degree of disc degeneration has not been extensively explored. Thus, here we investigated the relationships between various sagittal spinopelvic parameters and the degree of disc degeneration in young adults.A total of 278 young adult male patients were included in this study (age range: 18-24 years old). Multiple sagittal spinopelvic parameters, including pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), lumbar lordosis (LL), sacral inclination (SI), lumbosacral angle (LSA), and sacral table angle (STA), were measured from standing lateral lumbosacral radiographs. The degree of intervertebral disc degeneration was classified using a modified Pfirrmann scale. To assess the pain intensity of each patient, the visual analogue scale (VAS) score for low back pain (LBP) was obtained from all the patients. Finally, the relationships between these spinopelvic parameters and the degree of disc degeneration in young adults were analyzed. Also, we performed multiple logistic regression study.Out of all the spinopelvic parameters measured in this study, a low STA and a low SI were the only significant risk factors that were associated with disc degeneration in young adults. It means that patients with disc degeneration tend to have more severe sacral kyphosis and vertical sacrum.We found that patients with disc degeneration showed a lower SI and lower STA compared with patients without disc degeneration in young adults. Therefore, we suggest that the patients with disc degeneration tend to have more vertical sacrum, more sacral kyphosis

  6. Landscape of RNAs in human lumbar disc degeneration

    PubMed Central

    Pei, Yan-Jun; Wu, Zhi-Gang; Yu, Yang; Yang, Yong-Feng; Liu, Xu; Che, Lu; Ma, Chi-Jiao; Xie, Yan-Ke; Hu, Qing-Jie; Wan, Zhong-Yuan; Wang, Hai-Qiang

    2016-01-01

    Accumulating evidence indicates noncoding RNAs (ncRNAs) fine-tune gene expression with mysterious machinery. We conducted a combination of mRNA, miRNA, circRNA, LncRNA microarray analyses on 10 adults' lumbar discs. Moreover, we performed additional global exploration on RNA interacting machinery in terms of in silico computational pipeline. Here we show the landscape of RNAs in human lumbar discs. In general, the RNA-abundant landscape comprises 14,635 mRNAs (37.93%), 2,059 miRNAs (5.34%), 18,995 LncRNAs (49.23%) and 2,894 (7.5%) circRNAs. Chromosome 1 contributes for RNA transcription at most (10%). Bi-directional transcription contributes evenly for RNA biogenesis, in terms of 5′ to 3′ and 3′ to 5′. Despite the majority of circRNAs are exonic, antisense (1.49%), intergenic (0.035%), intragenic (1.69%), and intronic (6.29%) circRNAs should not be ignored. A single miRNA could interact with a multitude of circRNAs. Notably, CDR1as or ciRS-7 harbors 66 consecutive binding sites for miR-7-5p (previous miR-7), evidencing our pipeline. The majority of binding sites are perfect-matched (78.95%). Collectively, global landscape of RNAs sheds novel insights on RNA interacting mechanisms in human intervertebral disc degeneration. PMID:27542248

  7. Comparative Role of Disc Degeneration and Ligament Failure on Functional Mechanics of the Lumbar Spine

    PubMed Central

    Ellingson, Arin M.; Shaw, Miranda N.; Giambini, Hugo; An, Kai-Nan

    2015-01-01

    Understanding spinal kinematics is essential for distinguishing between pathological conditions of spine disorders, which ultimately lead to low back pain. It’s of high importance to understand how changes in mechanical properties affect the response of the lumbar spine, specifically in an effort to differentiate those associated with disc degeneration from ligamentous changes, allowing for more precise treatment strategies. To do this the goals of this study were twofold: 1) develop and validate a finite element (FE) model of the lumbar spine and 2) systematically alter the properties of the intervertebral disc and ligaments to define respective roles in functional mechanics. A three-dimensional non-linear FE model of the lumbar spine (L3-Sacrum) was developed and validated for pure moment bending. Disc degeneration and sequential ligament failure was modeled. Intersegmental range of motion (ROM) and bending stiffness was measured. The prediction of the FE model to moment loading in all three planes of bending showed very good agreement, where global and intersegmental ROM and bending stiffness of the model fell within one standard deviation of the in vitro results. Degeneration decreased ROM for all directions. Stiffness increased for all directions except axial rotation, where it initially increased then decreased for moderate and severe degeneration, respectively. Incremental ligament failure produced increased ROM and decreased stiffness. This effect was much more pronounced for all directions except lateral bending, which is minimally impacted by ligaments. These results indicate that lateral bending may be more apt to detect the subtle changes associated with degeneration, without being masked by associated changes of surrounding stabilizing structures. PMID:26404463

  8. Association between apparent diffusion coefficient and intervertebral disc degeneration in patients with ankylosing spondylitis

    PubMed Central

    Resorlu, Mustafa; Gokmen, Ferhat; Resorlu, Hatice; Adam, Gurhan; Akbal, Ayla; Cevizci, Sibel; Sariyildirim, Abdullah; Savas, Yilmaz; Guven, Mustafa; Aras, Adem Bozkurt

    2015-01-01

    Purpose: To assess the relation between ankylosing spondylitis (AS) and degenerative disc disease emerging in association with various intrinsic and extrinsic factors and to evaluate the correlation between degree of degeneration in intervertebral discs and apparent diffusion coefficient (ADC) values. Methods: Thirty-five patients with AS and a control group of 35 patients were included in the study. Three hundred fifty intervertebral discs were assessed in terms of degeneration by analyzing signal intensities and morphologies on T2 weighted series of a 1.5 Tesla magnetic resonance scanner. ADC values were determined in diffusion weighted images (DWI) using a “b value of 500 s/mm2”. Patients in the AS and control groups were compared in terms of intervertebral disc degeneration, and association between degree of degeneration and ADC values was analyzed. Results: The mean of total degeneration degrees for five lumbar intervertebral discs was significantly higher in the patients with AS compared to the control group (16.77±4.67 vs 13.00±4.08, respectively; P=0.001). When intervertebral discs were analyzed separately, disc degeneration was again significantly higher in patients with AS compared to the control group, with the exception of L5-S1. Age, cholesterol level, triglyceride level, duration of disease and BASFI index were significantly associated with degree of degeneration in patients with AS. A negative correlation was determined between disc degeneration and ADC value. Conclusion: AS is a risk factor for degenerative disc disease due to its systemic effects, the fact it leads to posture impairment and its inflammatory effects on the vertebrae. A decrease in ADC values is observed as degeneration worsens in degenerative disc disease. PMID:25785119

  9. The role of interleukin-1 in the pathogenesis of human Intervertebral disc degeneration

    PubMed Central

    Le Maitre, Christine Lyn; Freemont, Anthony J; Hoyland, Judith Alison

    2005-01-01

    In this study, we investigated the hypotheses that in human intervertebral disc (IVD) degeneration there is local production of the cytokine IL-1, and that this locally produced cytokine can induce the cellular and matrix changes of IVD degeneration. Immunohistochemistry was used to localize five members of the IL-1 family (IL-1α, IL-1β, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1β-converting enzyme)) in non-degenerate and degenerate human IVDs. In addition, cells derived from non-degenerate and degenerate human IVDs were challenged with IL-1 agonists and the response was investigated using real-time PCR for a number of matrix-degrading enzymes, matrix proteins, and members of the IL-1 family. This study has shown that native disc cells from non-degenerate and degenerate discs produced the IL-1 agonists, antagonist, the active receptor, and IL-1β-converting enzyme. In addition, immunopositivity for these proteins, with the exception of IL-1Ra, increased with severity of degeneration. We have also shown that IL-1 treatment of human IVD cells resulted in increased gene expression for the matrix-degrading enzymes (MMP 3 (matrix metalloproteinase 3), MMP 13 (matrix metalloproteinase 13), and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs)) and a decrease in the gene expression for matrix genes (aggrecan, collagen II, collagen I, and SOX6). In conclusion we have shown that IL-1 is produced in the degenerate IVD. It is synthesized by native disc cells, and treatment of human disc cells with IL-1 induces an imbalance between catabolic and anabolic events, responses that represent the changes seen during disc degeneration. Therefore, inhibiting IL-1 could be an important therapeutic target for preventing and reversing disc degeneration. PMID:15987475

  10. Paeoniflorin inhibits nucleus pulposus cell apoptosis by regulating the expression of Bcl-2 family proteins and caspase-9 in a rabbit model of intervertebral disc degeneration

    PubMed Central

    SHI, LIJUN; TENG, HONGLIN; ZHU, MINYU; LI, CHI; HUANG, KELUN; CHEN, BI; DAI, YUSEN; WANG, JING

    2015-01-01

    Apoptosis plays a key role in the pathogenesis of internal disc disruption (IDD); therefore, the inhibition of apoptosis may offer a novel approach for treating IDD diseases. The aim of the present study was to investigate the effects and the underlying mechanisms of paeoniflorin through the detection of relevant indicators in a rabbit model of IDD. In total, 144 rabbits were used in the study and divided into four groups (n=36 per group). Rabbits successfully modeled with IDD received an intragastric injection of 120 mg/kg·day paeoniflorin (high-dose group), 30 mg/kg·day paeoniflorin (low-dose group) or saline (model saline group), while rabbits without IDD were used as a normal control group. The apoptosis rate of disc nucleus pulposus cells was detected using flow cytometry. In addition, the expression levels of Bcl-2, Bax and caspase-9 in the disc tissues were detected using immunohistochemistry and western blot analysis prior to and following the treatment. The results indicated that the expression levels of Bax in the low- and high-dose paeoniflorin groups were significantly reduced, while the Bcl-2 expression levels were significantly increased when compared with the model saline group (P<0.01). In addition, the expression levels of cleaved caspase-3 and cleaved caspase-9 were reduced in the low- and high-dose paeoniflorin groups, as compared with the model saline group (P<0.05). Furthermore, the average apoptotic index of the high- and low-dose paeoniflorin groups was decreased when compared with the model saline group (P<0.05). In conclusion, paeoniflorin was demonstrated to inhibit the apoptosis of nucleus pulposus cells and the activation of caspase-3 and caspase-9 through the regulation of Bcl-2 family protein expression. These results provide an experimental basis for the future treatment of IDD with paeoniflorin. PMID:26170945

  11. Role of biomechanics on intervertebral disc degeneration and regenerative therapies: What needs repairing in the disc and what are promising biomaterials for its repair?

    PubMed Central

    Iatridis, James C.; Nicoll, Steven B.; Michalek, Arthur J.; Walter, Benjamin A.; Gupta, Michelle S.

    2013-01-01

    Background Context Degeneration and injuries of the intervertebral disc result in large alterations in biomechanical behaviors. Repair strategies using biomaterials can be optimized based on biomechanical and biological requirements. Purpose To review current literature on 1) effects of degeneration, simulated degeneration, and injury on biomechanics of the intervertebral disc with special attention paid to needle puncture injuries which are a pathway for diagnostics and regenerative therapies; and 2) promising biomaterials for disc repair with a focus on how those biomaterials may promote biomechanical repair. Study Design/Setting A narrative review to evaluate the role of biomechanics on disc degeneration and regenerative therapies with a focus on what biomechanical properties need to be repaired and how to evaluate and accomplish such repairs using biomaterials. Model systems for screening of such repair strategies are also briefly described. Methods Papers were selected from two main Pubmed searches using keywords: intervertebral AND biomechanics (1823 articles) and intervertebral AND biomaterials (361 articles). Additional keywords (injury, needle puncture, nucleus pressurization, biomaterials, hydrogel, sealant, tissue engineering) were used to narrow articles to the topics most relevant to this review. Results Degeneration and acute disc injuries have the capacity to influence nucleus pulposus pressurization and annulus fibrosus integrity, which are necessary for effective disc function, and therefore, require repair. Needle injection injuries are of particular clinical relevance with potential to influence disc biomechanics, cellularity, and metabolism, yet these effects are localized or small, and more research is required to evaluate and reduce potential clinical morbidity using such techniques. NP replacement strategies, such as hydrogels, are required to restore NP pressurization or lost volume. AF repair strategies, including crosslinked hydrogels

  12. Qualitative and quantitative assessment of degeneration of cervical intervertebral discs and facet joints.

    PubMed

    Walraevens, Joris; Liu, Baoge; Meersschaert, Joke; Demaerel, Philippe; Delye, Hans; Depreitere, Bart; Vander Sloten, Jos; Goffin, Jan

    2009-03-01

    Degeneration of intervertebral discs and facet joints is one of the most frequently encountered spinal disorders. In order to describe and quantify degeneration and evaluate a possible relationship between degeneration and biomechanical parameters, e.g., the intervertebral range of motion and intradiscal pressure, a scoring system for degeneration is mandatory. However, few scoring systems for the assessment of degeneration of the cervical spine exist. Therefore, two separate objective scoring systems to qualitatively and quantitatively assess the degree of cervical intervertebral disc and facet joint degeneration were developed and validated. The scoring system for cervical disc degeneration consists of three variables which are individually scored on neutral lateral radiographs: "height loss" (0-4 points), "anterior osteophytes" (0-3 points) and "endplate sclerosis" (0-2 points). The scoring system for facet joint degeneration consists of four variables which are individually scored on neutral computed tomography scans: "hypertrophy" (0-2 points), "osteophytes" (0-1 point), "irregularity" on the articular surface (0-1 point) and "joint space narrowing" (0-1 point). Each variable contributes with varying importance to the overall degeneration score (max 9 points for the scoring system of cervical disc degeneration and max 5 points for facet joint degeneration). Degeneration of 20 discs and facet joints of 20 patients was blindly assessed by four raters: two neurosurgeons (one senior and one junior) and two radiologists (one senior and one junior), firstly based on first subjective impression and secondly using the scoring systems. Measurement errors and inter- and intra-rater agreement were determined. The measurement error of the scoring system for cervical disc degeneration was 11.1 versus 17.9% of the subjective impression results. This scoring system showed excellent intra-rater agreement (ICC = 0.86, 0.75-0.93) and excellent inter-rater agreement (ICC = 0

  13. Evidence for an Important Role of Smad-7 in Intervertebral Disc Degeneration

    PubMed Central

    Li, Bo; Su, Yi-Jun; Zheng, Xin-Feng; Yang, Yue-Hua; Jiang, Sheng-Dan

    2015-01-01

    Smad-7 inhibited the transforming growth factor beta (TGF-β)-induced proteoglycan synthesis in chondrocytes and completely antagonized the effect of TGF-β on the proliferation of the cells. The aim of this study was to evaluate the contribution of Smad-7 to the pathophysiology of disc degeneration by determining the expression of Smad-7 in the degenerative intervertebral discs and its effect on the extracellular matrix metabolism of disc cells. Instability of the lumbar spine produced by imbalanced dynamic and static forces was used to induce intervertebral disc degeneration in rats. The expression of Smad-7 was assessed by the immunohistochemical method. Disc cell apoptosis was detected by in situ TUNEL staining. The effect of Smad-7 overexpression on the matrix metabolism of disc cells was analyzed in vitro by real-time polymerase chain reaction (PCR) and Western blotting. Finally, intradiscal injection of the Smad-7 overexpression lentivirus was performed to evaluate the in vivo effect of Smad-7 on disc degeneration. Radiographic and histomorphological examinations showed that lumbar disc degeneration became more and more severe in the rats with induced instability. Immunohistochemical observation demonstrated increasing protein expression of Smad-7 in the degenerative discs. A significantly positive correlation was found between Smad-7 expression and the degree of disc degeneration and between Smad-7 expression and disc cell apoptosis. Overexpression of Smad-7 in disc cells inhibited the expression of TGF-β1, collagen type-I, collagen type-II, and aggrecan and promoted the expression of MMP-13, but did not change the expression of ADAMTS-5. The in vivo findings illustrated that intradiscal injection of lentivirus vector with Smad-7 overexpression accelerated the progress of disc degeneration. In conclusion, Smad-7 was highly expressed in the degenerative discs. Overexpression of Smad-7 weakened the protective role of TGF-β and accelerated the progress of

  14. Solute transport in intervertebral disc: experiments and finite element modeling.

    PubMed

    Das, D B; Welling, A; Urban, J P G; Boubriak, O A

    2009-04-01

    Loss of nutrient supply to the human intervertebral disc (IVD) cells is thought to be a major cause of disc degeneration in humans. To address this issue, transport of molecules of different size have been analyzed by a combination of experimental and modeling studies. Solute transport has been compared for steady-state and transient diffusion of several different solutes with molecular masses in the range 3-70 kDa, injected into parts of the disc where degeneration is thought most likely to occur first and into the blood supply to the disc. Diffusion coefficients of fluorescently tagged dextran molecules of different molecular weights have been measured in vitro using the concentration gradient technique in thin specimens of disc outer annulus and nucleus pulposus. Diffusion coefficients were found to decrease with molecular weight following a nonlinear relationship. Diffusion coefficients changed more rapidly for solutes with molecular masses less than 10 kDa. Although unrealistic or painful, solutes injected directly into the disc achieve the largest disc coverage with concentrations that would be high enough to be of practical use. Although more practical, solutes injected into the blood supply do not penetrate to the central regions of the disc and their concentrations dissipate more rapidly. Injection into the disc would be the best method to get drugs or growth factors to regions of degeneration in IVDs quickly; else concentrations of solute must be kept at a high value for several hours in the blood supply to the discs.

  15. Effect of calcitonin pretreatment on naturally occurring intervertebral disc degeneration in guinea pig

    PubMed Central

    Jiang, Xiaohua; Tian, Faming; Wang, Wenya; Yan, Jinyin; Liu, Huanjiang; Liu, Binbin; Song, Huiping; Zhang, Yingze; Shen, Yong; Zhang, Liu

    2015-01-01

    Introduction: Our previous study suggested protective effects of calcitonin (CT) on experimental osteoarthritis. The aim of the present study was to provide evidence of whether CT pretreatment could prevent naturally occurring intervertebral disc degeneration in guinea pigs. Methods: Forty-two 3 months old female guinea pigs were randomly assigned into 2 groups as follows: Twenty-four were treated by normal saline as control group and sacrificed at 3, 6, 9 and 12 months of age (6 animals at each time point), the other 18 were received salmon CT (8 ug/kg/day, everyday) treatment at 3 months of age and sacrificed at the age of 6, 9 and 12 months respectively. Van Gieson stain and the histological score were used to identify the histological changes of the lumbar intervertebral discs. The disc height and vertebral body height were measured. Immunohistochemistry measurements for glycosaminoglycan, type II collagen, and matrix metalloprotease (MMP)-1 expressions were performed. Bone quality and microstructural changes in the L3-6 lumbar vertebral bodies were assessed by bone mineral density (BMD), micro-CT analysis and biomechanical testing. Results: Histological analysis indicated significantly higher disc degeneration scores in 9-month-old guinea pigs in comparison with younger animals, and grew higher with increasing age. CT treatment significantly reduced the histological score, and increased the disc height and the ratio to vertebral body height in 12 months old animals, as well as upregulated the glycosaminoglycan, type II collagen and inhibited the MMP-1 expression. Micro-CT analysis showed decreased percent bone volume (BV/TV) and increased trabecular separation (Tb.Sp), structural model index (SMI) in 12 months old animals in comparison with the younger animals. Markedly increased BV/TV and decreased Tb.Sp were observed in CT treated animals when compared with control animals. The biomechanical properties including maximum load, maximum stress, yield stress and

  16. Sitting versus standing: does the intradiscal pressure cause disc degeneration or low back pain?

    PubMed

    Claus, Andrew; Hides, Julie; Moseley, G Lorimer; Hodges, Paul

    2008-08-01

    Studies of lumbar intradiscal pressure (IDP) in standing and upright sitting have mostly reported higher pressures in sitting. It was assumed clinically that flexion of the lumbar spine in sitting relative to standing, caused higher IDP, disc degeneration or rupture, and low back pain. IDP indicates axial compressive load upon a non-degenerate disc, but provides little or no indication of shear, axial rotation or bending. This review is presented in two main parts. First, in vivo IDP data in standing and upright sitting for non-degenerate discs are comprehensively reviewed. As methodology, results and interpretations varied between IDP studies, in vivo studies measuring spinal shrinkage and spinal internal-fixator loads to infer axial compressive load to the discs are also reviewed. When data are considered together, it is clear that IDP is often similar in standing and sitting. Secondly, clinical assumptions related to IDP in sitting are considered in light of basic and epidemiologic studies. Current studies indicate that IDP in sitting is unlikely to pose a threat to non-degenerate discs, and sitting is no worse than standing for disc degeneration or low back pain incidence. If sitting is a greater threat for development of low back pain than standing, the mechanism is unlikely to be raised IDP.

  17. A Novel Catechol-O-Methyltransferase Variant Associated with Human Disc Degeneration

    PubMed Central

    Gruber, Helen E.; Sha, Wei; Brouwer, Cory R.; Steuerwald, Nury; Hoelscher, Gretchen L.; Hanley, Edward N. Jr.

    2014-01-01

    Background: Disc degeneration and its associated low back pain are a major health care concern causing disability with a prominent role in this country's medical, social and economic structure. Low back pain is devastating and influences the quality of life for millions. Low back pain lifetime prevalence approximates 80% with an estimated direct cost burden of $86 billion per year. Back pain patients incur higher costs, greater health care utilization, and greater work loss than patients without back pain. Methods: Research was performed following approval of our Institutional Review Board. DNA was isolated, processed and amplified using routine techniques. Amplified DNA was hybridized to Affymetrix Genome-Wide Human SNP Arrays. Quality control and genotyping analysis were performed using Affymetrix Genotyping Console. The Birdseed v2 algorithm was used for genotyping analysis. 2589 SNPs were selected a priori to enter statistical analysis using lotistic regression in SAS. Results: Our objective was to search for novel single nucleotide polymorphisms (SNPs) associated with disc degeneration. Four SNPs were found to have a significant relationship to disc degeneration; three are novel. Rs165656, a new SNP found to be associated with disc degeneration, was in catechol-O-methyltransferase (COMT), a gene with well-recognized pain involvement, especially in female subjects (p=0.01). Analysis confirmed the previously association between COMT SNP rs4633 and disc degeneration. We also report two novel disc degeneration-related SNPs (rs2095019 and rs470859) located in intergenic regions upstream to thrombospondin 2. Conclusions: Findings contribute to the challenging field of disc degeneration and pain, and are important in light of the high clinical relevance of low back pain and the need for improved understanding of its fundamental basis. PMID:24904231

  18. MRI quantification of human spine cartilage endplate geometry: Comparison with age, degeneration, level, and disc geometry.

    PubMed

    DeLucca, John F; Peloquin, John M; Smith, Lachlan J; Wright, Alexander C; Vresilovic, Edward J; Elliott, Dawn M

    2016-08-01

    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.

  19. Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo

    PubMed Central

    Chen, Deheng; Xia, Dongdong; Pan, Zongyou; Xu, Daoliang; Zhou, Yifei; Wu, Yaosen; Cai, Ningyu; Tang, Qian; Wang, Chenggui; Yan, Meijun; Zhang, Jing Jie; Zhou, Kailiang; Wang, Quan; Feng, Yongzeng; Wang, Xiangyang; Xu, Huazi; Zhang, Xiaolei; Tian, Naifeng

    2016-01-01

    Intervertebral disc degeneration (IDD) is a complicated process that involves both cellular apoptosis and senescence. Metformin has been reported to stimulate autophagy, whereas autophagy is shown to protect against apoptosis and senescence. Therefore, we hypothesize that metformin may have therapeutic effect on IDD through autophagy stimulation. The effect of metformin on IDD was investigated both in vitro and in vivo. Our study showed that metformin attenuated cellular apoptosis and senescence induced by tert-butyl hydroperoxide in nucleus pulposus cells. Autophagy, as well as its upstream regulator AMPK, was activated by metformin in nucleus pulposus cells in a dose- and time-dependent manner. Inhibition of autophagy by 3-MA partially abolished the protective effect of metformin against nucleus pulposus cells' apoptosis and senescence, indicating that autophagy was involved in the protective effect of metformin on IDD. In addition, metformin was shown to promote the expression of anabolic genes such as Col2a1 and Acan expression while inhibiting the expression of catabolic genes such as Mmp3 and Adamts5 in nucleus pulposus cells. In vivo study illustrated that metformin treatment could ameliorate IDD in a puncture-induced rat model. Thus, our study showed that metformin could protect nucleus pulposus cells against apoptosis and senescence via autophagy stimulation and ameliorate disc degeneration in vivo, revealing its potential to be a therapeutic agent for IDD. PMID:27787519

  20. Glucosamine and chondroitin sulfate supplementation to treat symptomatic disc degeneration: Biochemical rationale and case report

    PubMed Central

    van Blitterswijk, Wim J; van de Nes, Jos CM; Wuisman, Paul IJM

    2003-01-01

    Background Glucosamine and chondroitin sulfate preparations are widely used as food supplements against osteoarthritis, but critics are skeptical about their efficacy, because of the lack of convincing clinical trials and a reasonable scientific rationale for the use of these nutraceuticals. Most trials were on osteoarthritis of the knee, while virtually no documentation exists on spinal disc degeneration. The purpose of this article is to highlight the potential of these food additives against cartilage degeneration in general, and against symptomatic spinal disc degeneration in particular, as is illustrated by a case report. The water content of the intervertebral disc is a reliable measure of its degeneration/ regeneration status, and can be objectively determined by Magnetic Resonance Imaging (MRI) signals. Case presentation Oral intake of glucosamine and chondroitin sulfate for two years associated with disk recovery (brightening of MRI signal) in a case of symptomatic spinal disc degeneration. We provide a biochemical explanation for the possible efficacy of these nutraceuticals. They are bioavailable to cartilage chondrocytes, may stimulate the biosynthesis and inhibit the breakdown of their extracellular matrix proteoglycans. Conclusion The case suggests that long-term glucosamine and chondroitin sulfate intake may counteract symptomatic spinal disc degeneration, particularly at an early stage. However, definite proof requires well-conducted clinical trials with these food supplements, in which disc de-/regeneration can be objectively determined by MRI. A number of biochemical reasons (that mechanistically need to be further resolved) explain why these agents may have cartilage structure- and symptom-modifying effects, suggesting their therapeutic efficacy against osteoarthritis in general. PMID:12797867

  1. Organ culture bioreactors--platforms to study human intervertebral disc degeneration and regenerative therapy.

    PubMed

    Gantenbein, Benjamin; Illien-Jünger, Svenja; Chan, Samantha C W; Walser, Jochen; Haglund, Lisbet; Ferguson, Stephen J; Iatridis, James C; Grad, Sibylle

    2015-01-01

    In recent decades the application of bioreactors has revolutionized the concept of culturing tissues and organs that require mechanical loading. In intervertebral disc (IVD) research, collaborative efforts of biomedical engineering, biology and mechatronics have led to the innovation of new loading devices that can maintain viable IVD organ explants from large animals and human cadavers in precisely defined nutritional and mechanical environments over extended culture periods. Particularly in spine and IVD research, these organ culture models offer appealing alternatives, as large bipedal animal models with naturally occurring IVD degeneration and a genetic background similar to the human condition do not exist. Latest research has demonstrated important concepts including the potential of homing of mesenchymal stem cells to nutritionally or mechanically stressed IVDs, and the regenerative potential of "smart" biomaterials for nucleus pulposus or annulus fibrosus repair. In this review, we summarize the current knowledge about cell therapy, injection of cytokines and short peptides to rescue the degenerating IVD. We further stress that most bioreactor systems simplify the real in vivo conditions providing a useful proof of concept. Limitations are that certain aspects of the immune host response and pain assessments cannot be addressed with ex vivo systems. Coccygeal animal disc models are commonly used because of their availability and similarity to human IVDs. Although in vitro loading environments are not identical to the human in vivo situation, 3D ex vivo organ culture models of large animal coccygeal and human lumbar IVDs should be seen as valid alternatives for screening and feasibility testing to augment existing small animal, large animal, and human clinical trial experiments.

  2. Herb formula "Fufangqishe-Pill" prevents upright posture-induced intervertebral disc degeneration at the lumbar in rats.

    PubMed

    Liang, Qian-Qian; Xi, Zhi-Jie; Bian, Qin; Cui, Xue-Jun; Li, Chen-Guang; Hou, Wei; Shi, Qi; Wang, Yong-Jun

    2010-01-01

    Degeneration of the lumbar spine plays an important role in most chronic low back pain. Prevention of lumbar intervertebral disc (IVD) degeneration is therefore a high research priority. Both our previous multicenter clinical trials and pharmacological research showed that Fufangqishe-Pill (FFQSP), a newly patented traditional Chinese medicine, could effectively relieve the symptoms of neck pain and prevent cervical degeneration. To clarify the effect of FFQSP on lumbar IVD degeneration, we applied a lumbar IVD degeneration rat model induced by prolonged upright posture. Pretreatment of FFQSP for one month prevented the histological changes indicating IVD disorganization; increased type II-collagen level, decreased type X-collagen protein level, and increased Col2alpha1 mRNA expression at all time points; and decreased Col10alpha1, matrix metalloproteinase (MMP)-3, MMP13, and Interleukin (IL)-1beta mRNA expression induced by upright posture for 7 and 9 months. These results suggest that FFQSP prevents lumbar IVD degeneration induced by upright posture. FFQSP is a promising medicine for lumbar IVD degeneration disease.

  3. Correlation between T2∗ (T2 star) relaxation time and cervical intervertebral disc degeneration

    PubMed Central

    Huang, Minghua; Guo, Yong; Ye, Qiong; Chen, Lei; Zhou, Kai; Wang, Qingjun; Shao, Lixin; Shi, Qinglei; Chen, Chun

    2016-01-01

    Abstract Purpose: To demonstrate the potential benefits of T2∗ relaxation time of intervertebral discs (IVDs) regarding the detection and grading of degenerative disc disease using 3.0-T magnetic resonance imaging (MRI) in a clinical setting. Materials and Methods: Cervical sagittal T2-weighted, T2∗ relaxation MRI was performed at 3.0-T in 61 subjects, covering discs C2–3 to C6–7. All discs were morphologically assessed based on the Pfirrmann grade, and regions of interests (ROIs) were drawn over the T2∗ mapping. Receiver operating characteristic (ROC) analysis was performed among grades to determine the cut-off values. Results: Cervical intervertebral discs (IVDs) of patients were commonly determined to be at Pfirrmann grades III to V. The nucleus pulposus (NP) values did not differ significantly between sexes at the same anatomic level (P > 0.05). In the NP, the T2∗ values tended to decrease with increasing grade (P < 0.000), and a significant difference was found in the T2 values between grades I to V (P < 0.05). T2∗ values based on disc degeneration level classification were as follows: grade I (>30 milliseconds), grade II (24.55–29.99 milliseconds), grade III (21.65–24.54 milliseconds), grade IV (18.35–21.64 milliseconds), and grade V (<18.34 milliseconds). Conclusion: Our standardized method of region-specific quantitative T2∗ relaxation time evaluation seems capable of characterizing different degrees of disc degeneration quantitatively. The T2∗ values obtained in these cervical IVDs may serve as baseline values for future T2∗ measurements in both healthy and degenerated cervical discs. PMID:27893652

  4. Endplate degeneration may be the origination of the vacuum phenomenon in intervertebral discs.

    PubMed

    Li, Fang-Cai; Zhang, Ning; Chen, Wei-Shan; Chen, Qi-Xin

    2010-08-01

    The intravertebral vacuum phenomenon (VP) is usually associated with degenerative disc disease, which could be related to the low back pain. Various theories related to the pathogenesis of VP have been proposed, but these theories have not been critically examined and remain hypothetical. In this article, we review the possible role of endplate degeneration in the pathogenesis of VP, and discuss several pathways possibly linked to them. Due to the endplate calcification and activated cytokines, the transport pathway of the nutrition for the intervertebral disc was blocked, resulting in the metabolic unbalance and decrease of the synthesis of matrix structural proteins. It could promote the matrix decomposition, causing the decrease of the quantity of matrix and the changes of stress distribution in intervertebral disc. As a result, the structure of intervertebral discs became increasingly unstable. While compression happened, the intravertebral cleft could occur and be gradually filled with gas, which may cause low back pain and aggravate the intervertebral discs degeneration. As outlined above, we hypothesize that endplate degeneration might be the origination of the vacuum phenomenon.

  5. Hydrogen sulfide protects against endoplasmic reticulum stress and mitochondrial injury in nucleus pulposus cells and ameliorates intervertebral disc degeneration.

    PubMed

    Xu, Daoliang; Jin, Haiming; Wen, Jianxia; Chen, Jiaoxiang; Chen, Deheng; Cai, Ningyu; Wang, Yongli; Wang, Jianle; Chen, Yu; Zhang, Xiaolei; Wang, Xiangyang

    2017-03-01

    It has been suggested that excessive apoptosis in intervertebral disc cells induced by inflammatory cytokines, such as interleukin (IL)-1β, is related to the process of intervertebral disc degeneration (IVDD). Hydrogen sulfide (H2S), a gaseous signaling molecule, has drawn attention for its anti-apoptosis role in various pathophysiological processes in degenerative diseases. To date, there has been no investigation of the correlation of H2S production and IVDD or of the effects of H2S on IL-1β-induced apoptosis in nucleus pulposus (NP) cells. Here, we found that the expression levels of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), two key enzymes in the generation of H2S, were significantly decreased in human degenerate NP tissues as well as in IL-1β-treated NP cells. NaHS (H2S donor) administration showed a protective effect by inhibiting the endoplasmic reticulum (ER) stress response and mitochondrial dysfunction induced by IL-1β stimulation in vitro, the effect was related to activation of the PI3K/Akt and ERK1/2 signaling pathways. Suppression of these pathways by specific inhibitors, LY294002 and PD98059, partially reduced the protective effect of NaHS. Moreover, in the percutaneous needle puncture disc degeneration rat tail model, disc degeneration was partially reversed by NaHS administration. Taken together, our results suggest that H2S plays a protective role in IVDD and the underlying mechanism involves PI3K/Akt and ERK1/2 signaling pathways-mediated suppression of ER stress and mitochondrial dysfunction in IL-1β-induced NP cells.

  6. Longitudinal Comparison of Enzyme- and Laser-Treated Intervertebral Disc by MRI, X-Ray, and Histological Analyses Reveals Discrepancies in the Progression of Disc Degeneration: A Rabbit Study

    PubMed Central

    Colombier, Pauline; Lesoeur, Julie; Youl, Samy; Madec, Stéphane; Gauthier, Olivier; Hamel, Olivier; Guicheux, Jérôme; Clouet, Johann

    2016-01-01

    Regenerative medicine is considered an attractive prospect for the treatment of intervertebral disc (IVD) degeneration. To assess the efficacy of the regenerative approach, animal models of IVD degeneration are needed. Among these animal models, chemonucleolysis based on the enzymatic degradation of the Nucleus Pulposus (NP) is often used, but this technique remains far from the natural physiopathological process of IVD degeneration. Recently, we developed an innovative animal model of IVD degeneration based on the use of a laser beam. In the present study, this laser model was compared with the chemonucleolysis model in a longitudinal study in rabbits. The effects of the treatments were studied by MRI (T2-weighted signal intensity (T2wsi)), radiography (IVD height index), and histology (NP area and Boos' scoring). The results showed that both treatments induced a degeneration of the IVD with a decrease in IVD height and T2wsi as well as NP area and an increase in Boos' scoring. The enzyme treatment leads to a rapid and acute process of IVD degeneration. Conversely, laser radiation induced more progressive and less pronounced degeneration. It can be concluded that laser treatment provides an instrumental in vivo model of slowly evolving IVD degenerative disease that can be of preclinical relevance for assessing new prophylactic biological treatments of disc degeneration. PMID:27247937

  7. Lack of association between lumbar disc degeneration and osteophyte formation in elderly japanese women with back pain.

    PubMed

    Oishi, Y; Shimizu, K; Katoh, T; Nakao, H; Yamaura, M; Furuko, T; Narusawa, K; Nakamura, T

    2003-04-01

    Our study was designed to assess the contributions of the physical and constitutional factors to osteophyte formation, disc degeneration, and bone mineral density (BMD) in lumbar vertebrae of elderly postmenopausal women. A total of 126 Japanese women with back pain, aged over 60 years, were invited to participate in the study. Then 80 subjects with a full set of data for physical examinations, radiographs, MRI, and DXA were examined. TaqI polymorphism of vitamin D receptor (VDR) gene was examined in 60 subjects. Prevalence rates of osteophytes (on radiographs) and disc degeneration (on MRI) were 61 and 68%, respectively. Body weight and BMI correlated significantly with anteroposterior (AP) and lateral (LAT) BMD (r = 0.354 for weight, r = 0.347 for BMI) and mean osteophyte area (r = 0.557 for weight, r = 0.486 for BMI), and body weight also correlated with number of discs with osteophytes. However, these did not correlate with the disc area or the number of degenerated discs. Stepwise regression analysis revealed that body weight and LAT-BMD values independently related to the osteophyte area. Disc area (r = 0.386 for AP view) and osteophyte area (r = 0.384 for AP view) significantly correlated with BMD. However, disc area and osteophyte area did not correlate with each other (r = 0.056). The proportion of degenerated discs was higher in the lower lumbar discs, but not the proportion of discs with osteophytes. Frequencies of T and t alleles of VDR did not correlate with disc degeneration, osteophyte formation, or osteoporosis. Our data showed that increases in osteophyte formation and BMD in the lumbar vertebrae are influenced by body weight and BMI, but did not correlate with disc area, which correlated inversely with BMD. Disc degeneration and osteophyte formation seem to represent two different factors that affect lumbar spine in elderly women.

  8. Disc Degeneration Assessed by Quantitative T2* (T2 star) Correlated with Functional Lumbar Mechanics

    PubMed Central

    Ellingson, Arin M.; Mehta, Hitesh; Polly, David W.; Ellermann, Jutta; Nuckley, David J.

    2013-01-01

    Study Design Experimental correlation study design to quantify features of disc health, including signal intensity and distinction between the annulus fibrosus (AF) and nucleus pulposus (NP), with T2* magnetic resonance imaging (MRI) and correlate with the functional mechanics in corresponding motion segments. Objective Establish the relationship between disc health assessed by quantitative T2* MRI and functional lumbar mechanics. Summary of Background Data Degeneration leads to altered biochemistry in the disc, affecting the mechanical competence. Clinical routine MRI sequences are not adequate in detecting early changes in degeneration and fails to correlate with pain or improve patient stratification. Quantitative T2* relaxation time mapping probes biochemical features and may offer more sensitivity in assessing disc degeneration. Methods Cadaveric lumbar spines were imaged using quantitative T2* mapping, as well as conventional T2-weighted MRI sequences. Discs were graded by the Pfirrmann scale and features of disc health, including signal intensity (T2* Intensity Area) and distinction between the AF and NP (Transition Zone Slope), were quantified by T2*. Each motion segment was subjected to pure moment bending to determine range of motion (ROM), neutral zone (NZ), and bending stiffness. Results T2* Intensity Area and Transition Zone Slope were significantly correlated with flexion ROM (p=0.015; p=0.002), ratio of NZ/ROM (p=0.010; p=0.028), and stiffness (p=0.044; p=0.026), as well as lateral bending NZ/ROM (p=0.005; p=0.010) and stiffness (p=0.022; p=0.029). T2* Intensity Area was also correlated with LB ROM (p=0.023). Pfirrmann grade was only correlated with lateral bending NZ/ROM (p=0.001) and stiffness (p=0.007). Conclusions T2* mapping is a sensitive quantitative method capable of detecting changes associated with disc degeneration. Features of disc health quantified with T2* predicted altered functional mechanics of the lumbar spine better than

  9. The Effects of Platelet-Rich Plasma on Halting the Progression in Porcine Intervertebral Disc Degeneration.

    PubMed

    Cho, Hongsik; Holt, David C; Smith, Richard; Kim, Song-Ja; Gardocki, Raymond J; Hasty, Karen A

    2016-02-01

    Disc degeneration and the subsequent herniation and/or rupture of the intervertebral disc (IVD) are due to a failure of the extracellular matrix of the annulus to contain the contents of the nucleus. This results from inadequate maintenance of the matrix components as well as the proteolytic activity of matrix metalloproteinases (MMPs) that degrade matrix molecules. Arresting progression of disc degeneration in the annulus holds greater clinical potential at this point than prevention of its onset in the nucleus. Therefore, in this study, we have therapeutic aims that would decrease levels of the cytokines and growth factors that indirectly lead to disc degeneration via stimulating MMP and increase levels of several beneficial growth factors, such as transforming growth factor-β, with the addition of platelet-rich plasma (PRP) that would stimulate cell growth and matrix synthesis. For this study, we attempted to address these imbalances of metabolism by using tumor necrosis factor-α treated annulus fibrosus cells isolated from porcine IVD tissue and incubating the cells in a growth factor rich environment with PRP. These results indicate that the PRP in vitro increased the production of the major matrix components (type II collagen and aggrecan) and decreased the inhibitory collagenase MMP-1. This application will address a therapeutic approach for intervening early in the degenerative process.

  10. Reliable Magnetic Resonance Imaging Based Grading System for Cervical Intervertebral Disc Degeneration

    PubMed Central

    Chen, Antonia F.; Kang, James D.; Lee, Joon Y.

    2016-01-01

    Study Design Observational. Purpose To develop a simple and comprehensive grading system for cervical discs that precisely, consistently and meaningfully presents radiologic and morphologic data. Overview of Literature The Thompson grading system is commonly used to classify the severity of degenerative lumbar discs on magnetic resonance imaging (MRI). Inherent differences in the morphological and physiological characteristics of cervical discs have hindered development of precise classification systems. Other grading systems have been developed for degenerating cervical discs, but their versatility and feasibility in the clinical setting is suboptimal. Methods MRIs of 46 human cervical discs were de-identified and displayed in PowerPoint format. Each slide depicted a single disc with a normal (grade 0) disc displayed in the top right corner for reference. The presentation was given to 25 physicians comprising attending spine surgeons, spine fellows, orthopaedic residents, and two attending musculoskeletal radiologists. The grading system included Grade 0 (normal height compared to C2–3, mid cleft still visible), grade 1 (dark disc, normal height), grade 2 (collapsed disc, few osteophytes), and grade 3 (collapsed disc, many osteophytes). The ease of use of the system was gauged in the participants and the interobserver reliability was calculated. Results The intraclass correlation coefficient for interobserver reliability was 0.87, and 0.94 for intraobserver reliability, indicating excellent reliability. Ninety-five percent and 85 percent of the clinicians judged the grading system to be clinically feasible and useful in daily practice, respectively. Conclusions The grading system is easy to use, has excellent reliability, and can be used for precise and consistent clinician communication. PMID:26949461

  11. 1991 Volvo Award in clinical sciences. Smoking and lumbar intervertebral disc degeneration: an MRI study of identical twins.

    PubMed

    Battié, M C; Videman, T; Gill, K; Moneta, G B; Nyman, R; Kaprio, J; Koskenvuo, M

    1991-09-01

    The primary objective of this study was to determine whether disc degeneration, as assessed through magnetic resonance imaging, is greater in smokers than in nonsmokers. To control for the maximum number of potentially confounding variables, pairs of identical twins highly discordant for cigarette smoking were selected as study subjects. Data analyses revealed 18% greater mean disc degeneration scores in the lumbar spines of smokers as compared with nonsmokers. The effect was present across the entire lumbar spine, implicating a mechanism acting systemically. This investigation demonstrates the efficiency of using carefully selected controls in studying conditions of multifactorial etiology, such as disc degeneration.

  12. A role for TNFα in intervertebral disc degeneration: A non-recoverable catabolic shift

    SciTech Connect

    Purmessur, D.; Walter, B.A.; Roughley, P.J.; Laudier, D.M.; Hecht, A.C.; Iatridis, James

    2013-03-29

    Highlights: ► TNFα induced catabolic changes similar to human intervertebral disc degeneration. ► The metabolic shift induced by TNFα was sustained following removal. ► TNFα induced changes suggestive of cell senescence without affecting cell viability. ► Interventions are required to stimulate anabolism and increase cell proliferation. -- Abstract: This study examines the effect of TNFα on whole bovine intervertebral discs in organ culture and its association with changes characteristic of intervertebral disc degeneration (IDD) in order to inform future treatments to mitigate the chronic inflammatory state commonly found with painful IDD. Pro-inflammatory cytokines such as TNFα contribute to disc pathology and are implicated in the catabolic phenotype associated with painful IDD. Whole bovine discs were cultured to examine cellular (anabolic/catabolic gene expression, cell viability and senescence using β-galactosidase) and structural (histology and aggrecan degradation) changes in response to TNFα treatment. Control or TNFα cultures were assessed at 7 and 21 days; the 21 day group also included a recovery group with 7 days TNFα followed by 14 days in basal media. TNFα induced catabolic and anti-anabolic shifts in the nucleus pulposus (NP) and annulus fibrosus (AF) at 7 days and this persisted until 21 days however cell viability was not affected. Data indicates that TNFα increased aggrecan degradation products and suggests increased β-galactosidase staining at 21 days without any recovery. TNFα treatment of whole bovine discs for 7 days induced changes similar to the degeneration processes that occur in human IDD: aggrecan degradation, increased catabolism, pro-inflammatory cytokines and nerve growth factor expression. TNFα significantly reduced anabolism in cultured IVDs and a possible mechanism may be associated with cell senescence. Results therefore suggest that successful treatments must promote anabolism and cell proliferation in

  13. Ultrastructure of inclusion bodies in annulus cells in the degenerating human intervertebral disc.

    PubMed

    Gruber, H E; Hanley, E N

    2009-06-01

    The rough endoplasmic reticulum (rER) of the cell has an architectural editing function that checks whether protein structure and three-dimensional assembly have occurred properly prior to export of newly synthesized material out of the cell. If these have been faulty, the material is retained within the rER as an inclusion body. Inclusion bodies have been identified previously in chondrocytes and osteoblasts in chondrodysplasias and osteogenesis imperfecta. Inclusion bodies in intervertebral disc cells, however, have only recently been recognized. Our objectives were to use transmission electron microscopy to analyze more fully inclusion bodies in the annulus pulposus and to study the extracellular matrix (ECM) surrounding cells containing inclusion bodies. ECM frequently encapsulated cells with inclusion bodies, and commonly contained prominent banded aggregates of Type VI collagen. Inclusion body material had several morphologies, including relatively smooth, homogeneous material, or a rougher, less homogeneous feature. Such findings expand our knowledge of the fine structure of the human disc cell and ECM during disc degeneration, and indicate the potential utility of ultrastructural identification of discs with intracellular inclusion bodies as a screening method for molecular studies directed toward identification of defective gene products in degenerating discs.

  14. Degeneration of the intervertebral disc with new approaches for treating low back pain.

    PubMed

    Le Maitre, C L; Binch, A L; Thorpe, A A; Hughes, S P

    2015-03-01

    This review paper discusses the process of disc degeneration and the current understanding of cellular degradation in patients who present with low back pain. The role of surgical treatment for low back pain is analysed with emphasis on the proven value of spinal fusion. The interesting and novel developments of stem cell research in the treatment of low back pain are presented with special emphasis on the importance of the cartilaginous end plate and the role of IL-1 in future treatment modalities.

  15. MSC response to pH levels found in degenerating intervertebral discs

    SciTech Connect

    Wuertz, Karin Godburn, Karolyn; Iatridis, James C.

    2009-02-20

    Painful degenerative disc disease is a major health problem and for successful tissue regeneration, MSCs must endure and thrive in a harsh disc microenvironment that includes matrix acidity as a critical factor. MSCs were isolated from bone marrow of Sprague-Dawley rats from two different age groups (<1 month, n = 6 and 4-5 months, n = 6) and cultured under four different pH conditions representative of the healthy, mildly or severely degenerated intervertebral disc (pH 7.4, 7.1, 6.8, and 6.5) for 5 days. Acidity caused an inhibition of aggrecan, collagen-1, and TIMP-3 expression, as well as a decrease in proliferation and viability and was associated with a change in cell morphology. Ageing had generally minor effects but young MSCs maintained greater mRNA expression levels. As acidic pH levels are typical of increasingly degenerated discs, our findings demonstrate the importance of early interventions and predifferentiation when planning to use MSCs for reparative treatments.

  16. Effects of psoralen on chondrocyte degeneration in lumbar intervertebral disc of rats.

    PubMed

    Yang, Libin; Sun, Xiaohui; Geng, Xiaolin

    2015-03-01

    Discuss the internal mechanism of delaying degeneration of lumber intervertebral disc. The cartilage of lumbar intervertebral disc of SD rats was selected in vitro, then cultured by tissue explant method, and identified by HE staining, toluidine blue staining and immunofluorescence. The optimal concentration of psoralen was screened by cell proliferation assay and RT-PCR method. The cells in third generation with good growth situation is selected and placed in 6-well plate at concentration of 1×10(5)/well and its expression was tested. Compared to concentration of 0, the mRNA expression of Col2al (Collagen Ⅱ) secreted by was up regulated chondrocyte of lumbar intervertebral disc at the concentration of 12.5 and 25μM (P<0.0 or P<0.01). The aggrecan mRNA of psoralen group was higher than blank control group (P<0.01); compared with IL-1β induced group, the mRNA expression of Col2al was significantly increased but the mRNA expression of ADAMTS-5 was significantly decreased in psoralen group (P<0.01). These findings suggest that, psoralen can remit the degeneration of lumbar intervertebral disc induced by IL-1β to some extent, and affect the related factors of IL-1β signaling pathway.

  17. Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation.

    PubMed

    Vadalà, Gianluca; Sowa, Gwendolyn; Hubert, Mark; Gilbertson, Lars G; Denaro, Vincenzo; Kang, James D

    2012-05-01

    Recent studies have shown that mesenchymal stem cell (MSC)-based therapy might be an effective approach for the treatment of intervertebral disc degeneration (IDD). However, many unanswered questions remain before clinical translation, such as the most effective stem cell type, a reliable transplantation method, including the carrier choice, and the fate of stem cells after misdirected delivery, among others. The objective of the study was to evaluate the fate and effect of allogenic bone marrow MSCs after transplantation into an IDD model. The L2-3, L3-4 and L4-5 intervertebral discs (IVDs) of four rabbits were stabbed to create IDD. Rabbit MSCs were expanded in vitro and in part transduced with retrovirus/eGFP. After 3 weeks, 1 × 10(5) MSCs were injected into the IVDs. The rabbits were followed by X-ray and MRI 3 and 9 weeks after injection. Then the animals were sacrificed and the spines analysed histologically. MRI showed no signs of regeneration. X-ray and gross anatomy inspection demonstrated large anterolateral osteophytes. Histological analysis showed that the osteophytes were composed of mineralized tissue surrounded by chondrocytes, with the labelled MSCs among the osteophyte-forming cells. The labelled MSCs were not found in the nucleus. Inflammatory cells were not observed in any injected IVDs. These results raise concern that MSCs can migrate out of the nucleus and undesirable bone formation may occur. While cause cannot be inferred from this study, the presence of MSCs in the osteophytes suggests a potential side-effect with this approach. IVD regeneration strategies need to focus on cell carrier systems and annulus-sealing technologies to avoid pitfalls.

  18. The Involvement of Protease Nexin-1 (PN1) in the Pathogenesis of Intervertebral Disc (IVD) Degeneration

    PubMed Central

    Wu, Xinghuo; Liu, Wei; Duan, Zhenfeng; Gao, Yong; Li, Shuai; Wang, Kun; Song, Yu; Shao, Zengwu; Yang, Shuhua; Yang, Cao

    2016-01-01

    Protease nexin-1 (PN-1) is a serine protease inhibitor belonging to the serpin superfamily. This study was undertaken to investigate the regulatory role of PN-1 in the pathogenesis of intervertebral disk (IVD) degeneration. Expression of PN-1 was detected in human IVD tissue of varying grades. Expression of both PN-1 mRNA and protein was significantly decreased in degenerated IVD, and the expression levels of PN-1 were correlated with the grade of disc degeneration. Moreover, a decrease in PN-1 expression in primary NP cells was confirmed. On induction by IL-1β, the expression of PN-1 in NP cells was decreased at day 7, 14, and 21, as shown by western blot analysis and immunofluorescence staining. PN-1 administration decreased IL-1β-induced MMPs and ADAMTS production and the loss of Agg and Col II in NP cell cultures through the ERK1/2/NF-kB signaling pathway. The changes in PN-1 expression are involved in the pathogenesis of IVD degeneration. Our findings indicate that PN-1 administration could antagonize IL-1β-induced MMPs and ADAMTS, potentially preventing degeneration of IVD tissue. This study also revealed new insights into the regulation of PN-1 expression via the ERK1/2/NF-kB signaling pathway and the role of PN-1 in the pathogenesis of IVD degeneration. PMID:27460424

  19. Injection of human umbilical tissue–derived cells into the nucleus pulposus alters the course of intervertebral disc degeneration in vivo

    PubMed Central

    Leckie, Steven K.; Sowa, Gwendolyn A.; Bechara, Bernard P.; Hartman, Robert A.; Coelho, Joao Paulo; Witt, William T.; Dong, Qing D.; Bowman, Brent W.; Bell, Kevin M.; Vo, Nam V.; Kramer, Brian C.; Kang, James D.

    2016-01-01

    Background context Patients often present to spine clinic with evidence of intervertebral disc degeneration (IDD). If conservative management fails, a safe and effective injection directly into the disc might be preferable to the risks and morbidity of surgery. Purpose To determine whether injecting human umbilical tissue–derived cells (hUTC) into the nucleus pulposus (NP) might improve the course of IDD. Design Prospective, randomized, blinded placebo–controlled in vivo study. Patient sample Skeletally mature New Zealand white rabbits. Outcome measures Degree of IDD based on magnetic resonance imaging (MRI), biomechanics, and histology. Methods Thirty skeletally mature New Zealand white rabbits were used in a previously validated rabbit annulotomy model for IDD. Discs L2–L3, L3–L4, and L4–L5 were surgically exposed and punctured to induce degeneration and then 3 weeks later the same discs were injected with hUTC with or without a hydrogel carrier. Serial MRIs obtained at 0, 3, 6, and 12 weeks were analyzed for evidence of degeneration qualitatively and quantitatively via NP area and MRI Index. The rabbits were sacrificed at 12 weeks and discs L4–L5 were analyzed histologically. The L3–L4 discs were fixed to a robotic arm and subjected to uniaxial compression, and viscoelastic displacement curves were generated. Results Qualitatively, the MRIs demonstrated no evidence of degeneration in the control group over the course of 12 weeks. The punctured group yielded MRIs with the evidence of disc height loss and darkening, suggestive of degeneration. The three treatment groups (cells alone, carrier alone, or cells+carrier) generated MRIs with less qualitative evidence of degeneration than the punctured group. MRI Index and area for the cell and the cell+carrier groups were significantly distinct from the punctured group at 12 weeks. The carrier group generated MRI data that fell between control and punctured values but failed to reach a statistically

  20. Characterization of in vivo effects of platelet-rich plasma and biodegradable gelatin hydrogel microspheres on degenerated intervertebral discs.

    PubMed

    Sawamura, Kazuhide; Ikeda, Takumi; Nagae, Masateru; Okamoto, Shin-ichi; Mikami, Yasuo; Hase, Hitoshi; Ikoma, Kazuya; Yamada, Tetsuya; Sakamoto, Hirotaka; Matsuda, Ken-ichi; Tabata, Yasuhiko; Kawata, Mitsuhiro; Kubo, Toshikazu

    2009-12-01

    We have previously shown that administration of platelet-rich plasma-impregnated gelatin hydrogel microspheres (PRP-GHMs) into a degenerated intervertebral disc (IVD) markedly suppresses progression of IVD degeneration. In the current study, we characterized the in vivo effects of PRP-GHM treatment in a degenerated IVD model in rabbit. On magnetic resonance images, the IVD height was significantly greater after treatment with PRP-GHMs compared with phosphate-buffered saline-impregnated GHMs, PRP without GHMs, and needle puncture only. Water content was also preserved in PRP-GHM-treated IVDs. Consistent with this observation, the mRNA expression of proteoglycan core protein and type II collagen was significantly higher after PRP-GHM treatment compared with other treatment groups. No proliferating cells were found in the nucleus pulposus and inner annulus fibrosus in any groups, but the number of apoptotic cells in the nucleus pulposus after PRP-GHM treatment was significantly lower than that after other treatments. These results provide an improved understanding of the therapeutic effects of PRP-GHM treatment of degenerated IVDs.

  1. Injectable microcryogels reinforced alginate encapsulation of mesenchymal stromal cells for leak-proof delivery and alleviation of canine disc degeneration.

    PubMed

    Zeng, Yang; Chen, Chun; Liu, Wei; Fu, Qinyouen; Han, Zhihua; Li, Yaqian; Feng, Siyu; Li, Xiaokang; Qi, Chunxiao; Wu, Jianhong; Wang, Deli; Corbett, Christopher; Chan, Barbara P; Ruan, Dike; Du, Yanan

    2015-08-01

    In situ crosslinked thermo-responsive hydrogel applied for minimally invasive treatment of intervertebral disc degeneration (IVDD) may not prevent extrusion of cell suspension from injection site due to high internal pressure of intervertebral disc (IVD), causing treatment failure or osteophyte formation. In this study, mesenchymal stromal cells (MSCs) were encapsulated in alginate precursor and loaded into previously developed macroporous PGEDA-derived microcryogels (PMs) to form three-dimensional (3D) microscale cellular niches, enabling non-thermo-responsive alginate hydrogel to be injectable. The PMs reinforced alginate hydrogel showed superior elasticity compared to alginate hydrogel alone and could well protect encapsulated cells through injection. Chondrogenic committed MSCs in the injectable microniches expressed higher level of nucleus pulposus (NP) cell markers compared to 2D cultured cells. In an ex vivo organ culture model, injection of MSCs-laden PMs into NP tissue prevented cell leakage, improved cell retention and survival compared to free cell injection. In canine IVDD models, alleviated degeneration was observed in MSCs-laden PMs treated group after six months which was superior to other treated groups. Our results provide in-depth demonstration of injectable alginate hydrogel reinforced by PMs as a leak-proof cell delivery system for augmented regenerative therapy of IVDD in canine models.

  2. Cell and molecular biology of intervertebral disc degeneration: current understanding and implications for potential therapeutic strategies.

    PubMed

    Wang, S Z; Rui, Y F; Lu, J; Wang, C

    2014-10-01

    Intervertebral disc degeneration (IDD) is a chronic, complex process associated with low back pain; mechanisms of its occurrence have not yet been fully elucidated. Its process is not only accompanied by morphological changes, but also by systematic changes in its histological and biochemical properties. Many cellular and molecular mechanisms have been reported to be related with IDD and to reverse degenerative trends, abnormal conditions of the living cells and altered cell phenotypes would need to be restored. Promising biological therapeutic strategies still rely on injection of active substances, gene therapy and cell transplantation. With advanced study of tissue engineering protocols based on cell therapy, combined use of seeding cells, bio-active substances and bio-compatible materials, are promising for IDD regeneration. Recently reported progenitor cells within discs themselves also hold prospects for future IDD studies. This article describes the background of IDD, current understanding and implications of potential therapeutic strategies.

  3. High Prevalence of Disc Degeneration and Spondylolysis in the Lumbar Spine of Professional Beach Volleyball Players

    PubMed Central

    Külling, Fabrice A.; Florianz, Hannes; Reepschläger, Bastian; Gasser, Johann; Jost, Bernhard; Lajtai, Georg

    2014-01-01

    Background: Beach volleyball is an intensive sport with high impact on the lumbar spine. Low back pain (LBP) is frequent among elite players. Increased prevalence of pathological changes on magnetic resonance imaging (MRI) in the lumbar spine of elite athletes has been reported. Hypothesis: There is an increased prevalence of disc degeneration and spondylolysis in the MRI of the lumbar spine of professional beach volleyball players. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Twenty-nine fully competitive professional male volleyball players (mean age, 28 years) completed outcomes questionnaires and underwent a complete clinical examination and an MRI of their lumbar spine. Results: Whereas 86% of players suffered from LBP during their career, the incidence of LBP in the last 4 weeks was 35%. Pain rated using a visual analog scale (VAS) averaged 3 points (range, 0-8). Twenty-three of 29 players (79%) had at least 1 degenerated disc of Pfirrmann grade ≥3. The most affected spinal levels were L4-5 in 14 (48%) and L5-S1 in 15 players (52%); both levels were involved in 5 players (17%). Six of 29 (21%) players showed a spondylolysis grade 4 according to the Hollenburg classification; there was evidence of spondylolisthesis in 2 players. There was no significant correlation between LBP and MRI abnormalities. Conclusion: In the lumbar spine MRI of professional beach volleyball players, the prevalence of disc degeneration is 79%. Spondylolysis (21%) is up to 3 times higher compared with the normal population. Abnormal MRI findings did not correlate with LBP, thus MRIs have to be interpreted with caution. PMID:26535316

  4. 2D segmentation of intervertebral discs and its degree of degeneration from T2-weighted magnetic resonance images

    NASA Astrophysics Data System (ADS)

    Castro-Mateos, Isaac; Pozo, José Maria; Lazary, Aron; Frangi, Alejandro F.

    2014-03-01

    Low back pain (LBP) is a disorder suffered by a large population around the world. A key factor causing this illness is Intervertebral Disc (IVD) degeneration, whose early diagnosis could help in preventing this widespread condition. Clinicians base their diagnosis on visual inspection of 2D slices of Magnetic Resonance (MR) images, which is subject to large interobserver variability. In this work, an automatic classification method is presented, which provides the Pfirrmann degree of degeneration from a mid-sagittal MR slice. The proposed method utilizes Active Contour Models, with a new geometrical energy, to achieve an initial segmentation, which is further improved using fuzzy C-means. Then, IVDs are classified according to their degree of degeneration. This classification is attained by employing Adaboost on five specific features: the mean and the variance of the probability map of the nucleus using two different approaches and the eccentricity of the fitting ellipse to the contour of the IVD. The classification method was evaluated using a cohort of 150 intervertebral discs assessed by three experts, resulting in a mean specificity (93%) and sensitivity (83%) similar to the one provided by every expert with respect to the most voted value. The segmentation accuracy was evaluated using the Dice Similarity Index (DSI) and Root Mean Square Error (RMSE) of the point-to-contour distance. The mean DSI ± 2 standard deviation was 91:7% ±5:6%, the mean RMSE was 0:82mm and the 95 percentile was 1:36mm. These results were found accurate when compared to the state-of-the-art.

  5. [Correlation between shape and direction of small articular surface in lower lumbar vertebrae and degeneration of intervertebral disc].

    PubMed

    Tan, L; Bai, X; Li, D

    1997-01-01

    To assess the possible correlation between the shape and the direction of the small articular surface in the lower lumbar vertebrae and the degeneration of the intervertebral disc, we investigated with computed tomography (CT) and evaluated with statistics the small articular surface and the transverse interface-joint angle (TIFA) of the L4-5 and the L5-S1 in 152 cases who had normal or degenerative discs verified through CT, MRI or operation. The small articular surface was found arc in 69.1% of the L4-5 and in 23.0% of the L5-S1. The TIFA of the L4-5 was less than that of the L5-S1. There was no correlation between the ratio of degeneration of the intervertebral disc at the L4-5 and the TIFA of the L4-5 and the L5-S1, but the ratio of degeneration of the intervertebral disc at the L5-S1 had postive correlation with the TIFA of the L4-5, negative correlation with the TIFA of the L5-S1, and particular correlation with the TIFA of the L5-S1 and L4-5. These results suggest that the shape and direction of the lower lumbar facet joint are related to the lumbar degeneration of intervertebral disc and the causes of degeneration at the L4-5 disc differ from those at the L5-S1 disc in biomechanics.

  6. Lumbar disc degeneration was not related to spine and hip bone mineral densities in Chinese: facet joint osteoarthritis may confound the association.

    PubMed

    Pan, Jianjiang; Lu, Xuan; Yang, Ge; Han, Yongmei; Tong, Xiang; Wang, Yue

    2017-12-01

    A sample of 512 Chinese was studied and we observed that greater disc degeneration on MRI was associated with greater spine DXA BMD. Yet, this association may be confounded by facet joint osteoarthritis. BMD may not be a risk factor for lumbar disc degeneration in Chinese.

  7. lncRNAs: novel players in intervertebral disc degeneration and osteoarthritis.

    PubMed

    Chen, Wen-Kang; Yu, Xiao-Hua; Yang, Wei; Wang, Cheng; He, Wen-Si; Yan, Yi-Guo; Zhang, Jian; Wang, Wen-Jun

    2017-02-01

    The term long non-coding RNA (lncRNA) refers to a group of RNAs with length more than 200 nucleotides, limited protein-coding potential, and having widespread biological functions, including regulation of transcriptional patterns and protein activity, formation of endogenous small interfering RNAs (siRNAs) and natural microRNA (miRNA) sponges. Intervertebral disc degeneration (IDD) and osteoarthritis (OA) are the most common chronic, prevalent and age-related degenerative musculoskeletal disorders. Numbers of lncRNAs are differentially expressed in human degenerative nucleus pulposus tissue and OA cartilage. Moreover, some lncRNAs have been shown to be involved in multiple pathological processes during OA, including extracellular matrix (ECM) degradation, inflammatory responses, apoptosis and angiogenesis. In this review, we summarize current knowledge concerning lncRNAs, from their biogenesis, classification and biological functions to molecular mechanisms and therapeutic potential in IDD and OA.

  8. Oestrogen and parathyroid hormone alleviate lumbar intervertebral disc degeneration in ovariectomized rats and enhance Wnt/β-catenin pathway activity

    PubMed Central

    Jia, Haobo; Ma, Jianxiong; Lv, Jianwei; Ma, Xinlong; Xu, Weiguo; Yang, Yang; Tian, Aixian; Wang, Ying; Sun, Lei; Xu, Liyan; Fu, Lin; Zhao, Jie

    2016-01-01

    To investigate the mitigation effect and mechanism of oestrogen and PTH on disc degeneration in rats after ovariectomy, as well as on Wnt/β-catenin pathway activity, thirty 3-month-old rats were ovariectomized and divided into three groups. Ten additional rats were used as controls. Eight weeks later, the rats were administered oestrogen or PTH for 12 weeks, and then discs were collected for tests. Results showed that nucleus pulposus cells in the Sham group were mostly notochord cells, while in the OVX group, cells gradually developed into chondrocyte-like cells. Oestrogen or PTH could partly recover the notochord cell number. After ovariectomy, the endplate roughened and endplate porosity decreased. After oestrogen or PTH treatment, the smoothness and porosity of endplate recovered. Compared with the Sham group, Aggrecan, Col2a and Wnt/β-catenin pathway expression in OVX group decreased, and either oestrogen or PTH treatment improved their expression. The biomechanical properties of intervertebral disc significantly changed after ovariectomy, and oestrogen or PTH treatment partly recovered them. Disc degeneration occurred with low oestrogen, and the underlying mechanisms involve nutrition supply disorders, cell type changes and decreased Wnt/β-catenin pathway activity. Oestrogen and PTH can retard disc degeneration in OVX rats and enhance Wnt/β-catenin pathway activity in nucleus pulposus. PMID:27279629

  9. The Effect of Discectomy and the Dependence on Degeneration of Human Intervertebral Disc Strain in Axial Compression

    PubMed Central

    O’Connell, Grace D.; Malhotra, Neil R.; Vresilovic, Edward J; Elliott, Dawn M.

    2011-01-01

    Study Design Biomechanics of human intervertebral discs before and after nucleotomy. Objective To noninvasively quantify the effect of nucleotomy on internal strains under axial compression in flexion, neutral, and extension positions, and to determine whether the change in strains depended on degeneration. Summary of Background Data Herniation and discectomy may accelerate the progression of disc degeneration. Removal of NP tissue has resulted in altered disc mechanics in vitro, including in a decrease in internal pressure and an increase in the deformations at physiologically relevant strains. We recently presented a technique to quantify internal disc strains using magnetic resonance imaging. Methods Degeneration was quantitatively assessed by the T1ρ relaxation in the nucleus pulposus (NP). Samples were prepared from human levels L3-L4 and/or L4-L5. A 1000N compressive load was applied while in the MR scanner. Nucleotomy was performed by removing 2g of NP through the posterior-lateral AF. The discs were rehydrated, reimaged and retested. The analyzed parameters include axial deformation, AF radial bulge and strains. Results The axial deformation was more compressive following nucleotomy. In the neutral position, the axial deformation following nucleotomy correlated with degeneration (as quantified by T1ρ in the NP), with minimal alteration in nondegenerated discs. Nucleotomy altered the radial displacements and strains in the neutral position, such that the inner AF radial bulge decreased and the radial strains were more tensile in the lateral AF and less tensile in the posterior AF. In the bending loading positions the radial strains were not affected by nucleotomy. Conclusions Nucleotomy alters the internal radial and axial AF strains in the neutral position, which may leave the AF vulnerable to damage and microfractures. In bending, the effects of nucleotomy were minimal; likely due to more of the applied load being directed over the AF. Some of the

  10. Elevated interleukin-6 expression levels are associated with intervertebral disc degeneration

    PubMed Central

    DENG, XIAO; ZHAO, FENG; KANG, BAOLIN; ZHANG, XIN

    2016-01-01

    The present study aimed to investigate whether serum interleukin-6 (IL-6) expression levels were associated with the onset and progression of intervertebral disc degeneration (IDD). A comprehensive meta-analysis of the scientific literature from numerous electronic databases was performed, in order to obtain published studies associated with the topic of interest. Relevant case-control studies that had previously assessed a correlation between IL-6 expression levels and IDD were identified using predetermined inclusion and exclusion criteria. The STATA version 12.0 software was used for statistical analysis of the extracted data. A total of 112 studies were initially retrieved, with eight studies meeting the inclusion criteria. These contained a total of 392 subjects, of which 263 were patients with IDD and 129 were healthy controls. A meta-analysis of the eight studies demonstrated that serum IL-6 protein expression levels may be associated with IDD, and this was irrespective of IDD subtype (bulging, protrusion, or sequestration). Notably, serum expression levels of the IL-6 protein were upregulated in intervertebral disc (IVD) protrusion tissue, as compared with normal IVD tissue; thus suggesting that IL-6 may have an important role in the pathophysiological process of IDD. PMID:27073460

  11. Acidic pH promotes intervertebral disc degeneration: Acid-sensing ion channel -3 as a potential therapeutic target

    PubMed Central

    Gilbert, Hamish T. J.; Hodson, Nathan; Baird, Pauline; Richardson, Stephen M.; Hoyland, Judith A.

    2016-01-01

    The aetiology of intervertebral disc (IVD) degeneration remains poorly understood. Painful IVD degeneration is associated with an acidic intradiscal pH but the response of NP cells to this aberrant microenvironmental factor remains to be fully characterised. The aim here was to address the hypothesis that acidic pH, similar to that found in degenerate IVDs, leads to the altered cell/functional phenotype observed during IVD degeneration, and to investigate the involvement of acid-sensing ion channel (ASIC) -3 in the response. Human NP cells were treated with a range of pH, from that of a non-degenerate (pH 7.4 and 7.1) through to mildly degenerate (pH 6.8) and severely degenerate IVD (pH 6.5 and 6.2). Increasing acidity of pH caused a decrease in cell proliferation and viability, a shift towards matrix catabolism and increased expression of proinflammatory cytokines and pain-related factors. Acidic pH resulted in an increase in ASIC-3 expression. Importantly, inhibition of ASIC-3 prevented the acidic pH induced proinflammatory and pain-related phenotype in NP cells. Acidic pH causes a catabolic and degenerate phenotype in NP cells which is inhibited by blocking ASIC-3 activity, suggesting that this may be a useful therapeutic target for treatment of IVD degeneration. PMID:27853274

  12. MyD88-dependent Toll-like receptor 4 signal pathway in intervertebral disc degeneration

    PubMed Central

    Qin, Chuqiang; Zhang, Bo; Zhang, Liang; Zhang, Zhi; Wang, Le; Tang, Long; Li, Shuangqing; Yang, Yixi; Yang, Fuguo; Zhang, Ping; Yang, Bo

    2016-01-01

    Lower back pain (LBP) is a common and remitting problem. One of the primary causes of LBP is thought to be degeneration of the intervertebral disc (IVD). The aim of the present study was to investigate the role of the myeloid differentiation primary-response protein 88 (MyD88)-dependent Toll-like receptor 4 (TLR4) signal pathway in the mechanism of IVD degeneration. IVD nucleus pulposus cells isolated and cultured from the lumbar vertebrae of Wistar rats were stimulated by various doses of lipopolysaccharide (LPS; 0.1, 1, 10 and 100 µg/ml) to simulate IVD degeneration. Cells were rinsed and cultured in serum-free Dulbecco's modified Eagle's medium/F12. Reverse transcription-quantitative polymerase chain reaction was used to determine the levels of TLR4, MyD88, tumor necrosis factor α (TNFα), and interleukin-1β (IL-1β) mRNA expression after 1, 3, 6, 9 and 12 h of incubation. Additionally, western blot and enzyme-linked immunosorbent assay analyses were used to determine the levels of TLR4, MyD88, TNFα, and IL-1β protein expression after 24, 48 and 72 h of incubation. The levels of TLR4, MyD88, TNFα and IL-1β mRNA all increased in the cells stimulated by 10 µg/ml LPS at 3, 6 and 9 h (all P<0.001). Furthermore, the levels of TLR4, MyD88, TNFα and IL-1β protein all increased at 24, 48 and 72 h (all P<0.001). Additionally, the mRNA and protein levels of TLR4, MyD88, TNFα and IL-1β increased significantly in the cells stimulated by 1, 10 and 100 µg/ml LPS compared with the control group, and reached a peak in the 10 µg/ml LPS group (all P<0.001). These results suggest that the MyD88-dependent TLR4 signal pathway is a target pathway in IVD degeneration. This pathway is time phase- and dose-dependent, and when activated can lead to the release of inflammatory factors that participate in IVD degeneration. PMID:27446251

  13. An organ culture system to model early degenerative changes of the intervertebral disc II: profiling global gene expression changes

    PubMed Central

    2013-01-01

    Introduction Despite many advances in our understanding of the molecular basis of disc degeneration, there remains a paucity of preclinical models which can be used to study the biochemical and molecular events that drive disc degeneration, and the effects of potential therapeutic interventions. The goal of this study is to characterize global gene expression changes in a disc organ culture system that mimics early nontraumatic disc degeneration. Methods To mimic a degenerative insult, rat intervertebral discs were cultured in the presence of TNF-α, IL-1β and serum-limiting conditions. Gene expression analysis was performed using a microarray to identify differential gene expression between experimental and control groups. Differential pattern of gene expression was confirmed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) or Western blot. Results Treatment resulted in significant changes in expression of more than 1,000 genes affecting many aspects of cell function including cellular movement, the cell cycle, cellular development, and cell death and proliferation. Many of the most highly upregulated and downregulated genes have known functions in disc degeneration and extracellular matrix hemostasis. Construction of gene networks based on known cellular pathways and expression data from our analysis demonstrated that the network associated with cell death, cell cycle regulation and DNA replication and repair was most heavily affected in this model of disc degeneration. Conclusions This rat organ culture model uses cytokine exposure to induce wide gene expression changes with the most affected genes having known reported functions in disc degeneration. We propose that this model is a valuable tool to study the etiology of disc degeneration and evaluate potential therapeutic treatments. PMID:24171898

  14. Enhancement of Lumbar Fusion and Alleviation of Adjacent Segment Disc Degeneration by Intermittent PTH(1-34) in Ovariectomized Rats.

    PubMed

    Zhou, Zhuang; Tian, Fa-Ming; Gou, Yu; Wang, Peng; Zhang, Heng; Song, Hui-Ping; Shen, Yong; Zhang, Ying-Ze; Zhang, Liu

    2016-04-01

    Osteoporosis, which is prevalent in postmenopausal or aged populations, is thought to be a contributing factor to adjacent segment disc degeneration (ASDD), and the incidence and extent of ASDD may be augmented by osteopenia. Parathyroid hormone (PTH) (1-34) has already been shown to be beneficial in osteoporosis, lumbar fusion and matrix homeostasis of intervertebral discs. However, whether PTH(1-34) has a reversing or retarding effect on ASDD in osteopenia has not been confirmed. In the present study, we evaluated the effects of intermittent PTH(1-34) on ASDD in an ovariectomized (OVX) rat model. One hundred 3-month-old female Sprague-Dawley rats underwent L4 -L5 posterolateral lumbar fusion (PLF) with spinous-process wire fixation 4 weeks after OVX surgery. Control groups were established accordingly. PTH(1-34) was intermittently administered immediately after PLF surgery and lasted for 8 weeks using the following groups (n = 20) (V = vehicle): Sham+V, OVX+V, Sham+PLF+V, OVX+PLF+V, OVX+PLF+PTH. The fused segments showed clear evidence of eliminated motion on the fusion-segment based on manual palpation. Greater new bone formation in histology was observed in PTH-treated animals compared to the control group. The extent of ASDD was significantly increased by ovariotomy. Intermittent PTH(1-34) significantly alleviated ASDD by preserving disc height, microvessel density, relative area of vascular buds, endplate thickness and the relative area of endplate calcification. Moreover, protein expression results showed that PTH(1-34) not only inhibited matrix degradation by decreasing MMP-13, ADAMTS-4 and Col-I, but also promote matrix synthesis by increasing Col-II and Aggrecan. In conclusion, PTH(1-34), which effectively improves lumbar fusion and alleviates ASDD in ovariectomized rats, may be a potential candidate to ameliorate the prognosis of lumbar fusion in osteopenia.

  15. Growth factor expression in degenerated intervertebral disc tissue. An immunohistochemical analysis of transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor.

    PubMed

    Tolonen, Jukka; Grönblad, Mats; Vanharanta, Heikki; Virri, Johanna; Guyer, Richard D; Rytömaa, Tapio; Karaharju, Erkki O

    2006-05-01

    Degenerated intervertebral disc has lost its normal architecture, and there are changes both in the nuclear and annular parts of the disc. Changes in cell shape, especially in the annulus fibrosus, have been reported. During degeneration the cells become more rounded, chondrocyte-like, whereas in the normal condition annular cells are more spindle shaped. These chondrocyte-like cells, often forming clusters, affect extracellular matrix turnover. In previous studies transforming growth factor beta (TGFbeta) -1 and -2, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) have been highlighted in herniated intervertebral disc tissue. In the present study the same growth factors are analysed immunohistochemically in degenerated intervertebral disc tissue. Disc material was obtained from 16 discs operated for painful degenerative disc disease. Discs were classified according to the Dallas Discogram Description. Different disc regions were analysed in parallel. As normal control disc tissue material from eight organ donors was used. Polyclonal antibodies against different growth factors and TGFbeta receptor type II were used, and the immunoreaction was detected by the avidin biotin complex method. All studied degenerated discs showed immunoreactivity for TGFbeta receptor type II and bFGF. Fifteen of 16 discs were immunopositive for TGFbeta-1 and -2, respectively, and none showed immunoreaction for PDGF. Immunopositivity was located in blood vessels and in disc cells. In the nucleus pulposus the immunoreaction was located almost exclusively in chondrocyte-like disc cells, whereas in the annular region this reaction was either in chondrocyte-like disc cells, often forming clusters, or in fibroblast-like disc cells. Chondrocyte-like disc cells were especially prevalent in the posterior disrupted area. In the anterior area of the annulus fibrosus the distribution was more even between these two cell types. bFGF was expressed in the anterior annulus

  16. Early stage disc degeneration does not have an appreciable affect on stiffness and load transfer following vertebroplasty and kyphoplasty

    PubMed Central

    Keller, Tony S.; Schizas, Constantin

    2008-01-01

    Vertebroplasty and kyphoplasty have been reported to alter the mechanical behavior of the treated and adjacent-level segments, and have been suggested to increase the risk for adjacent-level fractures. The intervertebral disc (IVD) plays an important role in the mechanical behavior of vertebral motion segments. Comparisons between normal and degenerative IVD motion segments following cement augmentation have yet to be reported. A microstructural finite element model of a degenerative IVD motion segment was constructed from micro-CT images. Microdamage within the vertebral body trabecular structure was used to simulate a slightly (I = 83.5% of intact stiffness), moderately (II = 57.8% of intact stiffness), and severely (III = 16.0% of intact stiffness) damaged motion segment. Six variable geometry single-segment cement repair strategies (models A–F) were studied at each damage level (I–III). IVD and bone stresses, and motion segment stiffness, were compared with the intact and baseline damage models (untreated), as well as, previous findings using normal IVD models with the same repair strategies. Overall, small differences were observed in motion segment stiffness and average stresses between the degenerative and normal disc repair models. We did however observe a reduction in endplate bulge and a redistribution in the microstructural tissue level stresses across both endplates and in the treated segment following early stage IVD degeneration. The cement augmentation strategy placing bone cement along the periphery of the vertebra (model E) proved to be the most advantageous in treating the degenerative IVD models by showing larger reductions in the average bone stresses (vertebral and endplate) as compared to the normal IVD models. Furthermore, only this repair strategy, and the complete cement fill strategy (model F), were able to restore the slightly damaged (I) motion segment stiffness above pre-damaged (intact) levels. Early stage IVD degeneration

  17. An In Vivo Model of Reduced Nucleus Pulposus Glycosaminoglycan Content in the Rat Lumbar Intervertebral Disc

    PubMed Central

    Boxberger, John I.; Auerbach, Joshua D.; Sen, Sounok; Elliott, Dawn M.

    2009-01-01

    Study Design An in vivo model resembling early stage disc degeneration in the rat lumbar spine. Objective Simulate the reduced glycosaminoglycan content and altered mechanics observed in intervertebral disc degeneration using a controlled injection of chondroitinase ABC (ChABC). Summary of Background Data Nucleus glycosaminoglycan reduction occurs early during disc degeneration; however, mechanisms through which degeneration progresses from this state are unknown. Animal models simulating this condition are essential for understanding disease progression and for development of therapies aimed at early intervention. Methods ChABC was injected into the nucleus pulposus, and discs were evaluated via micro-CT, mechanical testing, biochemical assays, and histology 4 and 12 weeks after injection. Results At 4 weeks, reductions in nucleus glycosaminoglycan level by 43%, average height by 12%, neutral zone modulus by 40%, and increases in range of motion by 40%, and creep strain by 25% were found. Neutral zone modulus and range of motion were correlated with nucleus glycosaminoglycan. At 12 weeks, recovery of some mechanical function was detected as range of motion and creep returned to control levels; however, this was not attributed to glycosaminoglycan restoration, because mechanics were no longer correlated with glycosaminoglycan. Conclusion An in vivo model simulating physiologic levels of glycosaminoglycan loss was created to aid in understanding the relationships between altered biochemistry, altered mechanics, and altered cellular function in degeneration. PMID:18197098

  18. The Relation Between Sacral Angle and Vertical Angle of Sacral Curvature and Lumbar Disc Degeneration

    PubMed Central

    Ghasemi, Ahmad; Haddadi, Kaveh; Khoshakhlagh, Mohammad; Ganjeh, Hamid Reza

    2016-01-01

    Abstract The purpose of this study is to determine the reliability and validity of a goniometric measurement of the vertical angle of the sacrum and sacral angle (SA), and their relationships to lumbar degeneration. A herniated lumbar disc is one of the most frequent medical issues. Investigators in a number of studies have reported associated risk factors for prevalent disc degeneration. Atypical lumbosacral angles and curvature are thought to contribute to the degradation of the spine by many researchers. This study analyzed 360 patients referred to our clinic from 2013 to 2015 due to low back pain. A cross-sectional case–control study was designed in order to compare the sagittal alignment of the lumbosacral area in 3 groups of patients suffering from LBP. A total 120 patients were in a control group with a normal lumbar magnetic resonance imaging (MRI), 120 patients had lumbar disk herniation (LDH), and 120 patients had spinal stenosis. From the sagittal plan of lumbar MRI, SA and vertical angle of sacral curvature (VASC) were determined and then analyzed. The means of VASC in these groups were: 38.98 (SD: 6.36 ± 0.58), 40.89 (SD: 7.69 ± 0.69), and 40.54 (SD: 7.13 ± 0.92), respectively (P = 0.089). Moreover, studies of SA in 3 groups showed that the means of SA were: 39.30 (SD: 6.69 ± 0.63), 40.52 (SD: 7.47 ± 0.65), and 35.63 (SD: 6.07 ± 0.79), respectively. Relation between SA and spinal stenosis was just statistically significant (P ≤ 0.05). One significant limitation of our study is the lack of standing MRI for increased accuracy of measurement. However, we were reluctant to give patients needless exposure to radiation from conventional X-ray, and instead used MRI scans. We did not find any significant correlation between the VASC and LDH in lumbar MRI. Also, SA is not an independent risk factor for LDH in men and women. We suggested that there are several biomechanical factors involved in LDH. PMID:26871821

  19. Dynamical modelling of galactic disc outskirts

    NASA Astrophysics Data System (ADS)

    Athanassoula, E.

    2017-03-01

    I review briefly some dynamical models of structures in the outer parts of disc galaxies, including models of polar rings, tidal tails and bridges. I then discuss the density distribution in the outer parts of discs. For this, I compare observations to results of a model in which the disc galaxy is in fact the remnant of a major merger, and find good agreement. This comparison includes radial profiles of the projected surface density and of stellar age, as well as time evolution of the break radius and of the inner and outer disc scale lengths. I also compare the radial projected surface density profiles of dynamically motivated mono-age populations and find that, compared to older populations, younger ones have flatter density profiles in the inner region and steeper in the outer one. The break radius, however, does not vary with stellar age, again in good agreement with observations.

  20. The Effects of Age, Gender, Ethnicity, and Spinal Level on the Rate of Intervertebral Disc Degeneration. A review of 1712 Intervertebral Discs

    PubMed Central

    Siemionow, Krzysztof; An, Howard; Masuda, Koichi; Andersson, Gunnar; Cs-Szabo, Gabriella

    2010-01-01

    Study Design A gross anatomical and magnetic resonance imaging (MRI) study of intervertebral disc (IVD) degeneration in fresh cadaveric lumbar spines. Objective The purpose of this study was to find the rate of IVD degeneration. Summary of Background Data Age, sex, race, and lumbar level are among some of the factors that play a role in IVD degeneration. The rate at which IVDs degenerate is unknown. Methods Complete lumbar spine segments (T11/12 to S1) were received within 24 hours of death. The nucleus pulposus, annulus fibrosus, cartilaginous and bony end-plate, and the peripheral verterbral body were assessed with MRI and IVD degeneration was graded by two observers from grade 1(nondegenerated) to grade 5(severely degenerated) based on a scale developed by Tanaka et al. The specimens were then sectioned and gross anatomical evaluation was performed according to Thompson et al. Results 433 donors and 1712 IVDs were analyzed. There were 366 Caucasians, 47 Africans, 16 Hispanics, 4 Asian. There were 306 males and 127 females. The age range was 14–81 years, (average 60.5+/−11.3). For donors greater than age 40, the L5/S1 IVD degenerated at a significantly faster rate of 0.043/year compared to 0.031, 0.034, 0.033, 0.027 for L12, L23, L34, L45, respectively. For donors younger than 40, L5/S1 IVD degenerated at a significantly faster rate of 0.141/year compared to 0.033,0.021, 0.031, 0.050 for L12, L23, L34, L45, respectively. Multiple regression analysis revealed that gender had no significant effect on IVD degeneration whereas African ethnicity was associated with lower Thompson score at L12, L23, L34, L45 when compared to Caucasians. Conclusions The relatively early degeneration at L5-S1 in all races and lower Thompson grade in donors of African ethnicity needs further investigation. Factors such as sagittal alignment, facet joint arthritis, and genetics potentially play a role in IVD degeneration. PMID:21217432

  1. Interleukin 1 Polymorphisms Contribute to Intervertebral Disc Degeneration Risk: A Meta-Analysis

    PubMed Central

    Fu, Changfeng; Xu, Feng; Chen, Yong; Wang, Zhenyu; Liu, Yi

    2016-01-01

    Objective We performed a meta-analysis to assess association between interleukin 1 (IL-1) polymorphisms and the risk of Intervertebral Disc Degeneration (IDD). Background A series of studies have investigated the association between common single nucleotide polymorphisms in IL-1 and IDD risk; however, the overall results are inconclusive. Methods Two independent investigators conducted a systematic search for relevant available studies. Allele frequencies were extracted from each study. The association between the IL-1α (+889C/T) or IL-1β (+3954C/T) polymorphism and IDD risk was measured by odds ratios (OR) with 95% confidence intervals (95% CI). Results Five and six studies, respectively, were ultimately included in the meta-analysis for the IL-1α (+889C/T) and IL-1β (+3954C/T) polymorphism. The combined results showed that the IL-1α (+889C/T) polymorphism was significantly associated with increased susceptibility to IDD, particularly in Caucasians (TT versus CC: OR = 2.95, 95% CI: 1.45, 6.04; Pheterogeneity = 0.82; TT versus CC/CT: OR = 2.29, 95% CI: 1.18, 4.47; Pheterogeneity = 0.20). In contrast, the IL-1β (+3954C/T) polymorphism showed a trend towards increased risk in Caucasians but no association in Asians. Conclusion This meta-analysis suggested that the IL-1α (+889C/T) polymorphism is significantly associated with risk of IDD, especially in Caucasian populations. PMID:27253397

  2. Genome-Wide Identification of Long Noncoding RNAs in Human Intervertebral Disc Degeneration by RNA Sequencing

    PubMed Central

    Zhao, Bo; Lu, Minjuan; Wang, Dong; Li, Haopeng

    2016-01-01

    Long noncoding RNAs (lncRNAs) are emerging as crucial players in a myriad of biological processes. However, the precise mechanism and functions of most lncRNAs are poorly characterized. In this study, we presented genome-wide identification of lncRNAs in the patients with intervertebral disc degeneration (IDD) and spinal cord injury (control) using RNA sequencing (RNA-seq). A total of 124.6 million raw reads were yielded using Hiseq 2500 platform and approximately 88% clean reads could be aligned to human reference genome in both IDD and control groups. RNA-seq profiling indicated that 1,854 lncRNAs were differentially expressed (log2 fold change ≥ 1 or ≤−1, p < 0.05), in which 1,530 could potentially target 6,386 genes via cis-regulatory effects. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for these target genes suggested that lncRNAs were involved in diverse pathways, such as lysosome, focal adhesion, and MAPK signaling. In addition, a competing endogenous RNA (ceRNA) network was constructed for analyzing the function of lncRNAs. Further, quantitative real time PCR (qRT-PCR) was used to confirm the differentially expressed lncRNAs and ceRNA network. In conclusion, our results present the first global identification of lncRNAs in IDD and may provide candidate diagnostic biomarkers for IDD treatment. PMID:28097131

  3. Stem Cell Therapies for Intervertebral Disc Degeneration: Immune Privilege Reinforcement by Fas/FasL Regulating Machinery.

    PubMed

    Ma, Chi-Jiao; Liu, Xu; Che, Lu; Liu, Zhi-Heng; Samartzis, Dino; Wang, Hai-Qiang

    2015-01-01

    As a main contributing factor to low back pain, intervertebral disc degeneration (IDD) is the fundamental basis for various debilitating spinal diseases. The pros and cons of current treatment modalities necessitate biological treatment strategies targeting for reversing or altering the degeneration process in terms of molecules or genes. The advances in stem cell research facilitate the studies aiming for possible clinical application of stem cell therapies for IDD. Human NP cells are versatile with cell morphology full of variety, capable of synthesizing extracellular matrix components, engulfing substances by autophagy and phagocytosis, mitochondrial vacuolization indicating dysfunction, expressing Fas and FasL as significant omens of immune privileged sites. Human discs belong to immune privilege organs with functional FasL expression, which can interact with invasive immune cells by Fas-FasL regulatory machinery. IDD is characterized by decreased expression level of FasL with dysfunctional FasL, which in turn unbalances the interaction between NP cells and immune cells. Certain modulation factors might play a role in the process, such as miR-155. Accumulating evidence indicates that Fas-FasL network expresses in a variety of stem cells. Given the expression of functional FasL and insensitive Fas in stem cells (we term as FasL privilege), transplantation of stem cells into the disc may regenerate the degenerative disc by not only differentiating into NP-like cells, increasing extracellular matrix, but also reinforce immune privilege via interaction with immune cells by Fas-FasL network.

  4. TGFβ and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions

    PubMed Central

    Zieba, Jennifer; Forlenza, Kimberly Nicole; Khatra, Jagteshwar Singh; Sarukhanov, Anna; Duran, Ivan; Rigueur, Diana; Lyons, Karen M.; Cohn, Daniel H.; Merrill, Amy E.; Krakow, Deborah

    2016-01-01

    Spondylocarpotarsal synostosis (SCT) is an autosomal recessive disorder characterized by progressive vertebral fusions and caused by loss of function mutations in Filamin B (FLNB). FLNB acts as a signaling scaffold by linking the actin cytoskleteon to signal transduction systems, yet the disease mechanisms for SCT remain unclear. Employing a Flnb knockout mouse, we found morphologic and molecular evidence that the intervertebral discs (IVDs) of Flnb–/–mice undergo rapid and progressive degeneration during postnatal development as a result of abnormal cell fate changes in the IVD, particularly the annulus fibrosus (AF). In Flnb–/–mice, the AF cells lose their typical fibroblast-like characteristics and acquire the molecular and phenotypic signature of hypertrophic chondrocytes. This change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix, expression of Collagen X, increased apoptosis, and inappropriate ossification of the disc tissue. We show that conversion of the AF cells into chondrocytes is coincident with upregulated TGFβ signaling via Smad2/3 and BMP induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and Ctgf. These findings indicate that FLNB is involved in attenuation of TGFβ/BMP signaling and influences AF cell fate. Furthermore, we demonstrate that the IVD disruptions in Flnb–/–mice resemble aging degenerative discs and reveal new insights into the molecular causes of vertebral fusions and disc degeneration. PMID:27019229

  5. Vitamin D Receptor Gene, Matrix Metalloproteinase 3 Polymorphisms and the Risk of Intervertebral Disc Degeneration Susceptibility: Meta-Analysis

    PubMed Central

    Huang, Yongjing; Zhao, Shujie; Xu, Nanwei

    2016-01-01

    Several studies have evaluated the association between vitamin D receptor, matrix metalloproteinase 3 (MMP-3) polymorphisms and the risk of intervertebral disc degeneration susceptibility. The findings were inconsistent. This meta-analysis aimed to systematically assess the association between vitamin D receptor, MMP-3 polymorphisms and the risk of intervertebral disc degeneration susceptibility. A search of various databases was done covering all papers published until December 31th, 2014. Eight, 4, 3 studies were finally included that addressed the risk of intervertebral disc degeneration susceptibility and vitamin D receptor FokI (rs2228570), ApaI (rs7975232), and MMP-3 (rs731236) polymorphisms, respectively. FokI (f vs. F: summary odds ratio [OR], 1.13; 95% confidence interval [CI], 0.76–1.69; ff vs. FF: OR, 1.02; 95% CI, 0.59–1.77; ff vs. Ff/FF: OR, 1.05; 95% CI, 0.70–1.58), ApaI (a vs. A: OR, 0.73; 95% CI, 0.45–1.19; aa vs. AA: OR, 0.53; 95% CI, 0.22–1.25 p=0.14; aa vs. AA/Aa: OR, 0.69; 95% CI, 0.53–0.89) in the vitamin D receptor gene and MMP3 polymorphisms (5A vs. 6A: OR, 1.92; 95% CI, 0.77–4.80; 5A5A vs. 6A6A: OR, 2.17; 95% CI, 0.75–6.24; 5A5A vs. 5A6A/6A6A: OR, 1.58; 95% CI, 0.72–3.44) were not obviously associated with risk of intervertebral disc degeneration susceptibility. FokI, ApaI polymorphisms in the vitamin D receptor gene and MMP-3 polymorphism are not obvious risk factors for intervertebral disc degeneration susceptibility. PMID:27790329

  6. Metabolic Syndrome Components Are Associated with Intervertebral Disc Degeneration: The Wakayama Spine Study

    PubMed Central

    Teraguchi, Masatoshi; Yoshimura, Noriko; Hashizume, Hiroshi; Muraki, Shigeyuki; Yamada, Hiroshi; Oka, Hiroyuki; Minamide, Akihito; Ishimoto, Yuyu; Nagata, Keiji; Kagotani, Ryohei; Tanaka, Sakae; Kawaguchi, Hiroshi; Nakamura, Kozo; Akune, Toru; Yoshida, Munehito

    2016-01-01

    Objective The objective of the present study was to examine the associations between metabolic syndrome (MS) components, such as overweight (OW), hypertension (HT), dyslipidemia (DL), and impaired glucose tolerance (IGT), and intervertebral disc degeneration (DD). Design The present study included 928 participants (308 men, 620 women) of the 1,011 participants in the Wakayama Spine Study. DD on magnetic resonance imaging was classified according to the Pfirrmann system. OW, HT, DL, and IGT were assessed using the criteria of the Examination Committee of Criteria for MS in Japan. Results Multivariable logistic regression analysis revealed that OW was significantly associated with cervical, thoracic, and lumbar DD (cervical: odds ratio [OR], 1.28; 95% confidence interval [CI], 0.92–1.78; thoracic: OR, 1.75; 95% CI, 1.24–2.51; lumbar: OR, 1.87; 95% CI, 1.06–3.48). HT and IGT were significantly associated with thoracic DD (HT: OR, 1.54; 95% CI, 1.09–2.18; IGT: OR, 1.65; 95% CI, 1.12–2.48). Furthermore, subjects with 1 or more MS components had a higher OR for thoracic DD compared with those without MS components (vs. no component; 1 component: OR, 1.58; 95% CI, 1.03–2.42; 2 components: OR, 2.60; 95% CI, 1.62–4.20; ≥3 components: OR, 2.62; 95% CI, 1.42–5.00). Conclusion MS components were significantly associated with thoracic DD. Furthermore, accumulation of MS components significantly increased the OR for thoracic DD. These findings support the need for further studies of the effects of metabolic abnormality on DD. PMID:26840834

  7. T1ρ MRI and Discography Pressure as Novel Biomarkers for Disc Degeneration and Low Back Pain

    PubMed Central

    Borthakur, Arijitt; Maurer, Philip M.; Fenty, Matthew; Wang, Chenyang; Berger, Rachelle; Yoder, Jonathon; Balderston, Richard A.; Elliott, Dawn M.

    2012-01-01

    Study Design Prospective MRI study of LBP patients requiring discography as part of their routine clinical diagnoses and asymptomatic age-matched volunteers. Objective To determine whether T1ρ MRI and discography opening pressure are quantitative biomarkers of disc degeneration in LBP patients and in asymptomatic volunteers. Summary of Background Data Disc degenerative disease (DDD), a common cause of low back pain (LBP), is related to the patient’s prognosis and serves as a target for therapeutic interventions. However, there are few quantitative measures in the clinical setting. Discography opening pressure (OP) and T1ρ MRI are potential biomarkers of DDD related to biochemical composition the intervertebral disc (IVD). Methods The Institutional Review Board approved all experiments and informed consent was provided by each subject. Patients being treated for LBP (n=17, 68 levels, mean age 44±6 years, range 30–53) and control (CTL) subjects (n=11, 44 levels, mean age 43±17, range 22–76) underwent T1ρ and T2 MRI on a Siemens 3T Tim Trio clinical scanner. The LBP patients also received multi-level provocative discography before their MRI. Opening Pressure (OP) was recorded as the pressure when fluid first enters the nucleus of the IVD. Results T1ρ was significantly lower in the painful discs (55.3ms±3.0 ms, mean ± std. error) from control (92.0±4.9 ms, p<0.001) and non-painful discs (83.6±3.2 ms, p<0.001). Mean OP for the painful discs (11.8±1.0 psi, mean ± std. error) was significantly lower than non-painful discs (19.1±0.7 psi, p<0.001). Both T1ρ and OP correlated moderately with Pfirrmann degenerative grade. ROC area under the curve was 0.91 for T1ρ MRI and 0.84 for OP for predicting painful discs. Conclusions T1ρ and OP are quantitative measures of degeneration that are consistent across both control subjects and LBP patients. A significant and strong correlation exists between T1ρ values and in vivo OP measurements obtained by

  8. Photoreceptor Cells Influence Retinal Vascular Degeneration in Mouse Models of Retinal Degeneration and Diabetes

    PubMed Central

    Liu, Haitao; Tang, Jie; Du, Yunpeng; Saadane, Aicha; Tonade, Deoye; Samuels, Ivy; Veenstra, Alex; Palczewski, Krzysztof; Kern, Timothy S.

    2016-01-01

    Purpose Loss of photoreceptor cells is associated with retinal vascular degeneration in retinitis pigmentosa, whereas the presence of photoreceptor cells is implicated in vascular degeneration in diabetic retinopathy. To investigate how both the absence and presence of photoreceptors could damage the retinal vasculature, we compared two mouse models of photoreceptor degeneration (opsin−/− and RhoP23H/P23H ) and control C57Bl/5J mice, each with and without diabetes. Methods Retinal thickness, superoxide, expression of inflammatory proteins, ERG and optokinetic responses, leukocyte cytotoxicity, and capillary degeneration were evaluated at 1 to 10 months of age using published methods. Results Retinal photoreceptor cells degenerated completely in the opsin mutants by 2 to 4 months of age, and visual function subsided correspondingly. Retinal capillary degeneration was substantial while photoreceptors were still present, but slowed after the photoreceptors degenerated. Diabetes did not further exacerbate capillary degeneration in these models of photoreceptor degeneration, but did cause capillary degeneration in wild-type animals. Photoreceptor cells, however, did not degenerate in wild-type diabetic mice, presumably because the stress responses in these cells were less than in the opsin mutants. Retinal superoxide and leukocyte damage to retinal endothelium contributed to the degeneration of retinal capillaries in diabetes, and leukocyte-mediated damage was increased in both opsin mutants during photoreceptor cell degeneration. Conclusions Photoreceptor cells affect the integrity of the retinal microvasculature. Deterioration of retinal capillaries in opsin mutants was appreciable while photoreceptor cells were present and stressed, but was less after photoreceptors degenerated. This finding proves relevant to diabetes, where persistent stress in photoreceptors likewise contributes to capillary degeneration. PMID:27548901

  9. Spine degeneration in a murine model of chronic human tobacco smokers

    PubMed Central

    Wang, Dong; Nasto, Luigi A; Roughley, Peter; Leme, Adriana S.; Houghton, McGarry; Usas, Arvydas; Sowa, Gwendolyn; Lee, Joon; Niedernhofer, Laura; Shapiro, Steven; Kang, James; Vo, Nam

    2012-01-01

    Objective To investigate the mechanisms by which chronic tobacco smoking promotes intervertebral disc degeneration (IDD) and vertebral degeneration in mice. Methods Three months old C57BL/6 mice were exposed to tobacco smoke by direct inhalation (5 cigarettes/day, 5 days/week for 6 months) to model long-term smoking in humans. Total disc proteoglycan content (DMMB assay), aggrecan proteolysis (immunobloting analysis), and cellular senescence (p16INK4a immunohistochemistry) were analyzed. Proteoglycan and collagen syntheses (35S-sulfate and 3H-proline incorporation, respectively) were measured using disc organotypic culture. Vertebral osteoporosity was measured by micro-computed tomography. Results Disc proteoglycan content of smoke-exposed mice was 63% of unexposed control, while new proteoglycan and collagen syntheses were 59% and 41% of those of untreated mice, respectively. Exposure to tobacco smoke dramatically increased metalloproteinase-mediated proteolysis of disc aggrecan within its interglobular domain (IGD). Cellular senescence was elevated two folds in discs of smoke-exposed mice. Smoke exposure increased vertebral endplate porosity, which closely correlates with IDD in humans. Conclusions These findings further support tobacco smoke as a contributor to spinal degeneration. Furthermore, the data provide a novel mechanistic insight, indicating that smoking-induced IDD is a result of both reduced PG synthesis and increased degradation of a key disc extracellular matrix protein, aggrecan. Cleavage of aggrecan IGD is extremely detrimental as this result in the loss of the entire glycosaminoglycan-attachment region of aggrecan, which is vital for attracting water necessary to counteract compressive forces. Our results suggest identification and inhibition of specific metalloproteinases responsible for smoke-induced aggrecanolysis as a potential therapeutic strategy to treat IDD. PMID:22531458

  10. Oxidative damage induces apoptosis and promotes calcification in disc cartilage endplate cell through ROS/MAPK/NF-κB pathway: Implications for disc degeneration.

    PubMed

    Han, Yingchao; Li, Xinhua; Yan, Meijun; Yang, Mingjie; Wang, Shanjin; Pan, Jie; Jun, Lili; Tan, Jun

    2017-03-23

    Cartilage endplate (CEP) cell calcification and apoptosis play a vital role in the intervertebral disc degeneration (IVDD). Oxidative stress is a key factor in inducing programmed cell death and cartilage calcification. However, the cell death and calcification of cartilage endplate cells under oxidative stress have never been described. The present study investigated the apoptosis and calcification in the cartilage endplate cell under oxidative stress induced by H2O2 to understand the underlying mechanism of IVDD. The cartilage endplate cells isolated from human lumbar discs were subjected to different concentrations of H2O2 for various time periods. The cell viability was determined by CCK-8 assay, whereas Western blot, immunofluorescence, and Alcian blue, Alizarin red, and Von Kossa staining evaluated the apoptosis and calcification. The level of mitochondria-specific reactive oxygen species (ROS) was quantified with an oxygen radical-sensitive probe-MitoSOX. The potential signaling pathways were investigated by Western blot after the addition of N-acetyl-l-cysteine (NAC). We found that the oxidative stress induced by H2O2 increased the apoptosis and subsequently the calcification in the cartilage endplate cells through the ROS/p38/ERK/p65 pathway. The apoptosis and the calcification of the cartilage endplate cells induced by H2O2 can be abolished by NAC. These results suggested that regulating the apoptosis and the calcification in the cartilage endplate cells under oxidative stress should be advantageous for the survival of cells and might delay the process of disc degeneration.

  11. Minimum 10-Year Follow-up Study of Anterior Lumbar Interbody Fusion for Degenerative Spondylolisthesis: Progressive Pattern of the Adjacent Disc Degeneration

    PubMed Central

    Yasuda, Taketoshi; Hori, Takeshi; Suzuki, Kayo; Kawaguchi, Yoshiharu

    2012-01-01

    Study Design Retrospective study. Purpose The aims of the current study are to evaluate the minimum 10-year follow-up clinical results of anterior lumbar interbody fusion (ALIF) for degenerative spondylolisthesis. Overview of Literature ALIF has been widely used as a treatment regimen in the management of lumbar spondylolisthesis. Still much controversy exists regarding the factors that affect the postoperative clinical outcomes. Methods The author performed a retrospective review of 20 patients with degenerative spondylolisthesis treated with ALIF (follow-up, 16.4 years). The clinical results were assessed by the Japanese Orthopaedic Association (JOA) score for low back pain, vertebral slip and disc height index on the radiographs. Results The mean preoperative JOA score was 7.1 ± 1.8 points (15-point-method). At 1 year, 5 years, and 10 years or more after surgery, the JOA scores were assessed as 12.4 ± 2.2 points, 12.7 ± 2.6 points, 12.0 ± 2.5 points, respectively (excluding the data of reoperated cases). The adjacent disc degeneration developed in all cases during the long-term follow-up. The progressive pattern of disc degeneration was divided into three types. Initially, disc degeneration occurred due to disc space narrowing. After that, the intervertebral discs showed segmental instability with translation at the upper level. But the lower discs showed osteophyte formation, and occasionally lead to the collapse or spontaneous union. Conclusions The clinical results of the long-term follow-up data after ALIF became worse due to the adjacent disc degeneration. The progressive pattern of disc degeneration was different according to the adjacent levels. PMID:22708014

  12. A meta-model analysis of a finite element simulation for defining poroelastic properties of intervertebral discs.

    PubMed

    Nikkhoo, Mohammad; Hsu, Yu-Chun; Haghpanahi, Mohammad; Parnianpour, Mohamad; Wang, Jaw-Lin

    2013-06-01

    Finite element analysis is an effective tool to evaluate the material properties of living tissue. For an interactive optimization procedure, the finite element analysis usually needs many simulations to reach a reasonable solution. The meta-model analysis of finite element simulation can be used to reduce the computation of a structure with complex geometry or a material with composite constitutive equations. The intervertebral disc is a complex, heterogeneous, and hydrated porous structure. A poroelastic finite element model can be used to observe the fluid transferring, pressure deviation, and other properties within the disc. Defining reasonable poroelastic material properties of the anulus fibrosus and nucleus pulposus is critical for the quality of the simulation. We developed a material property updating protocol, which is basically a fitting algorithm consisted of finite element simulations and a quadratic response surface regression. This protocol was used to find the material properties, such as the hydraulic permeability, elastic modulus, and Poisson's ratio, of intact and degenerated porcine discs. The results showed that the in vitro disc experimental deformations were well fitted with limited finite element simulations and a quadratic response surface regression. The comparison of material properties of intact and degenerated discs showed that the hydraulic permeability significantly decreased but Poisson's ratio significantly increased for the degenerated discs. This study shows that the developed protocol is efficient and effective in defining material properties of a complex structure such as the intervertebral disc.

  13. Single Nucleotide Variants of Candidate Genes in Aggrecan Metabolic Pathway Are Associated with Lumbar Disc Degeneration and Modic Changes

    PubMed Central

    Dissanayake, Poruwalage Harsha; Senarath, Upul; Wijayaratne, Lalith Sirimevan; Karunanayake, Aranjan Lional; Dissanayake, Vajira Harshadeva Weerabaddana

    2017-01-01

    Introduction Lumbar disc degeneration (LDD) is genetically determined and severity of LDD is associated with Modic changes. Aggrecan is a major proteoglycan in the intervertebral disc and end plate. Progressive reduction of aggrecan is a main feature of LDD and Modic changes. Objectives The study investigated the associations of single nucleotide variants (SNVs) of candidate genes in the aggrecan metabolic pathway with the severity of LDD and Modic changes. In-silico functional analysis of significant SNVs was also assessed. Methods A descriptive cross sectional study was carried out on 106 patients with chronic mechanical low back pain. T1, T2 sagittal lumbar MRI scans were used to assess the severity of LDD and Modic changes. 62 SNVs in ten candidate genes (ACAN, IL1A, IL1B, IL6, MMP3, ADAMTS4, ADAMTS5, TIMP1, TIMP2 and TIMP3) were genotyped on Sequenom MassARRAY iPLEX platform. Multiple linear regression analysis was carried out using PLINK 1.9 in accordance with additive genetic model. In-silico functional analysis was carried out using Provean, SIFT, PolyPhen and Mutation Taster. Results Mean age was 52.42±9.42 years. 74 (69.8%) were females. The rs2856836, rs1304037, rs17561 and rs1800587 variants of the IL1A gene were associated with the severity of LDD and Modic changes. The rs41270041 variant of the ADAMTS4 gene and the rs226794 variant of the ADAMTS5 gene were associated with severity of LDD while the rs34884997 variant of the ADAMTS4 gene, the rs55933916 variant of the ADAMTS5 gene and the rs9862 variant of the TIMP3 gene were associated with severity of Modic changes. The rs17561 variant of the IL1A gene was predicted as pathogenic by the PolyPhen prediction tool. Conclusions SNVs of candidate genes in ACAN metabolic pathway are associated with severity of LDD and Modic changes in patients with chronic mechanical low back pain. Predictions of in-silico functional analysis of significant SNVs are inconsistent. PMID:28081267

  14. Analysis of the Relationship between Ligamentum Flavum Thickening and Lumbar Segmental Instability, Disc Degeneration, and Facet Joint Osteoarthritis in Lumbar Spinal Stenosis

    PubMed Central

    Yoshiiwa, Toyomi; Notani, Naoki; Ishihara, Toshinobu; Kawano, Masanori; Tsumura, Hiroshi

    2016-01-01

    Study Design Cross-sectional study. Purpose To investigate the relationship between ligamentum flavum (LF) thickening and lumbar segmental instability and disc degeneration and facet joint osteoarthritis. Overview of Literature Posterior spinal structures, including LF thickness, play a major role in lumbar spinal canal stenosis pathogenesis. The cause of LF thickening is multifactorial and includes activity level, age, and mechanical stress. LF thickening pathogenesis is unknown. Methods We examined 419 patients who underwent computed tomography (CT) myelography and magnetic resonance imaging after complaints of clinical symptoms. To investigate LF hypertrophy, 57 patients whose lumbar vertebra had normal disc heights at L4–5 were selected to exclude LF buckling as a hypertrophy component. LF thickness, disc space widening angulation in flexion, segmental angulation, presence of a vacuum phenomenon, and lumbar lordosis at T12–S1 were investigated. Disc and facet degeneration were also evaluated. Facet joint orientation was measured via an axial CT scan. Results The mean LF thickness in all patients was 4.4±1.0 mm at L4–5. There was a significant correlation between LF thickness and disc degeneration; LF thickness significantly increased with severe disc degeneration and facet joint osteoarthritis. There was a tendency toward increased LF thickness in more sagittalized facet joints than in coronalized facet joints. Logistic regression analysis showed that LF thickening was influenced by segmental angulation and facet joint osteoarthritis. Patient age was associated with LF thickening. Conclusions LF hypertrophy development was associated with segmental instability and severe disc degeneration, severe facet joint osteoarthritis, and a sagittalized facet joint orientation. PMID:27994791

  15. Calcification in the ovine intervertebral disc: a model of hydroxyapatite deposition disease

    PubMed Central

    Burkhardt, D.; Taylor, T. K. F.; Dillon, C. T.; Read, R.; Cake, M.; Little, C. B.

    2009-01-01

    The study design included a multidisciplinary examination of the mineral phase of ovine intervertebral disc calcifications. The objective of the study was to investigate the mineral phase and its mechanisms of formation/association with degeneration in a naturally occurring animal model of disc calcification. The aetiology of dystrophic disc calcification in adult humans is unknown, but occurs as a well-described clinical disorder with hydroxyapatite as the single mineral phase. Comparable but age-related pathology in the sheep could serve as a model for the human disorder. Lumbar intervertebral discs (n = 134) of adult sheep of age 6 years (n = 4), 8 years (n = 12) and 11 years (n = 2) were evaluated using radiography, morphology, scanning and transmission electron microscopy, energy dispersive X-ray spectroscopy, X-ray powder diffraction, histology, immunohistology and proteoglycan analysis. Half of the 6-year, 84% of the 8-year and 86% of the 11-year-old discs had calcific deposits. These were not well delineated by plain radiography. They were either: (a) punctate deposits in the outer annulus, (b) diffuse deposits in the transitional zone or inner annulus fibrosus with occasional deposits in the nucleus, or (c) large deposits in the transitional zone extending variably into the nucleus. Their maximal incidence was in the lower lumbar discs (L4/5–L6/7) with no calcification seen in the lumbosacral or lower thoracic discs. All deposits were hydroxyapatite with large crystallite sizes (800–1,300 Å) compared to cortical bone (300–600 Å). No type X-collagen, osteopontin or osteonectin were detected in calcific deposits, although positive staining for bone sialoprotein was evident. Calcified discs had less proteoglycan of smaller hydrodynamic size than non-calcified discs. Disc calcification in ageing sheep is due to hydroxyapatite deposition. The variable, but large, crystal size and lack of protein markers indicate that this does not occur by

  16. Grand Challenges in Protoplanetary Disc Modelling

    NASA Astrophysics Data System (ADS)

    Haworth, Thomas J.; Ilee, John D.; Forgan, Duncan H.; Facchini, Stefano; Price, Daniel J.; Boneberg, Dominika M.; Booth, Richard A.; Clarke, Cathie J.; Gonzalez, Jean-François; Hutchison, Mark A.; Kamp, Inga; Laibe, Guillaume; Lyra, Wladimir; Meru, Farzana; Mohanty, Subhanjoy; Panić, Olja; Rice, Ken; Suzuki, Takeru; Teague, Richard; Walsh, Catherine; Woitke, Peter; Community authors

    2016-10-01

    The Protoplanetary Discussions conference-held in Edinburgh, UK, from 2016 March 7th-11th-included several open sessions led by participants. This paper reports on the discussions collectively concerned with the multi-physics modelling of protoplanetary discs, including the self-consistent calculation of gas and dust dynamics, radiative transfer, and chemistry. After a short introduction to each of these disciplines in isolation, we identify a series of burning questions and grand challenges associated with their continuing development and integration. We then discuss potential pathways towards solving these challenges, grouped by strategical, technical, and collaborative developments. This paper is not intended to be a review, but rather to motivate and direct future research and collaboration across typically distinct fields based on community-driven input, to encourage further progress in our understanding of circumstellar and protoplanetary discs.

  17. Matrix stiffness promotes cartilage endplate chondrocyte calcification in disc degeneration via miR-20a targeting ANKH expression

    PubMed Central

    Liu, Ming-Han; Sun, Chao; Yao, Yuan; Fan, Xin; Liu, Huan; Cui, You-Hong; Bian, Xiu-Wu; Huang, Bo; Zhou, Yue

    2016-01-01

    The mechanical environment is crucial for intervertebral disc degeneration (IDD). However, the mechanisms underlying the regulation of cartilage endplate (CEP) calcification by altered matrix stiffness remain unclear. In this study, we found that matrix stiffness of CEP was positively correlated with the degree of IDD, and stiff matrix, which mimicked the severe degeneration of CEP, promoted inorganic phosphate-induced calcification in CEP chondrocytes. Co-expression analysis of the miRNA and mRNA profiles showed that increasing stiffness resulted in up-regulation of miR-20a and down-regulation of decreased ankylosis protein homolog (ANKH) during inorganic phosphate-induced calcification in CEP chondrocytes. Through a dual luciferase reporter assay, we confirmed that miR-20a directly targets 3′-untranslated regions of ANKH. The inhibition of miR-20a attenuated the calcium deposition and calcification-related gene expression, whereas the overexpression of miR-20a enhanced calcification in CEP chondrocytes on stiff matrix. The rescue of ANKH expression restored the decreased pyrophosphate efflux and inhibited calcification. In clinical samples, the levels of ANKH expression were inversely associated with the degeneration degree of CEP. Thus, our findings demonstrate that the miR-20a/ANKH axis mediates the stiff matrix- promoted CEP calcification, suggesting that miR-20a and ANKH are potential targets in restraining the progression of IDD. PMID:27142968

  18. Translation of an engineered nanofibrous disc-like angle-ply structure for intervertebral disc replacement in a small animal model.

    PubMed

    Martin, John T; Milby, Andrew H; Chiaro, Joseph A; Kim, Dong Hwa; Hebela, Nader M; Smith, Lachlan J; Elliott, Dawn M; Mauck, Robert L

    2014-06-01

    Intervertebral disc degeneration has been implicated in the etiology of low back pain; however, the current surgical strategies for treating symptomatic disc disease are limited. A variety of materials have been developed to replace disc components, including the nucleus pulposus (NP), the annulus fibrosus (AF) and their combination into disc-like engineered constructs. We have previously shown that layers of electrospun poly(ε-caprolactone) scaffold, mimicking the hierarchical organization of the native AF, can achieve functional parity with native tissue. Likewise, we have combined these structures with cell-seeded hydrogels (as an NP replacement) to form disc-like angle-ply structures (DAPS). The objective of this study was to develop a model for the evaluation of DAPS in vivo. Through a series of studies, we developed a surgical approach to replace the rat caudal disc with an acellular DAPS and then stabilized the motion segment via external fixation. We then optimized cell infiltration into DAPS by including sacrificial poly(ethylene oxide) layers interspersed throughout the angle-ply structure. Our findings illustrate that DAPS are stable in the caudal spine, are infiltrated by cells from the peri-implant space and that infiltration is expedited by providing additional routes for cell migration. These findings establish a new in vivo platform in which to evaluate and optimize the design of functional disc replacements.

  19. Lumbar intervertebral disc degeneration associated with axial and radiating low back pain in ageing SPARC-null mice.

    PubMed

    Millecamps, Magali; Tajerian, Maral; Naso, Lina; Sage, E Helene; Stone, Laura S

    2012-06-01

    Chronic low back pain (LBP) is a complex, multifactorial disorder with unclear underlying mechanisms. In humans and rodents, decreased expression of secreted protein acidic rich in cysteine (SPARC) is associated with intervertebral disc (IVD) degeneration and signs of LBP. The current study investigates the hypothesis that IVD degeneration is a risk factor for chronic LBP. SPARC-null and age-matched control mice ranging from 6 to 78 weeks of age were evaluated in this study. X-ray and histologic analysis revealed reduced IVD height, increased wedging, and signs of degeneration (bulging and herniation). Cutaneous sensitivity to cold, heat, and mechanical stimuli were used as measures of referred (low back and tail) and radiating pain (hind paw). Region specificity was assessed by measuring icilin- and capsaicin-evoked behaviour after subcutaneous injection into the hind paw or upper lip. Axial discomfort was measured by the tail suspension and grip force assays. Motor impairment was determined by the accelerating rotarod. Physical function was evaluated by voluntary activity after axial strain or during ambulation with forced lateral flexion. SPARC-null mice developed (1) region-specific, age-dependent hypersensitivity to cold, icilin, and capsaicin (hind paw only), (2) axial discomfort, (3) motor impairment, and (4) reduced physical function. Morphine (6 mg/kg, i.p.) reduced cutaneous sensitivity and alleviated axial discomfort in SPARC-null mice. Ageing SPARC-null mice mirror many aspects of the complex and challenging nature of LBP in humans and incorporate both anatomic and functional components of the disease. The current study supports the hypothesis that IVD degeneration is a risk factor for chronic LBP.

  20. Atomic Absorption Spectrometry Analysis of Trace Elements in Degenerated Intervertebral Disc Tissue

    PubMed Central

    Kubaszewski, Łukasz; Zioła-Frankowska, Anetta; Frankowski, Marcin; Nowakowski, Andrzej; Czabak-Garbacz, Róża; Kaczmarczyk, Jacek; Gasik, Robert

    2014-01-01

    Background Few studies have investigated trace elements (TE) in human intervertebral disc (IVD) tissue. Trace element presence can have diverse meanings: essential TE show the metabolic modalities of the tissue, while environmentally-related TE indicate pollution and tissue-specific absorption and accumulation. IVD is a highly specific compartment with impaired communication with adjacent bone. Analysis of TE in IVD provides new insights regarding tissue metabolism and IVD communication with other tissues. Material/Methods Thirty intervertebral discs were acquired from 22 patients during surgical treatment for degenerative disease. Atomic absorption spectrometry was used to evaluate the concentrations of Al, Cd, Pb, Cu, Ni, Mo, Mg, and Zn. Results Al, Pb, Cu, Mg, and Zn were detected in all samples. Pb was significantly positively correlated with age, and Ni concentration was weakly correlated with population count in the patient’s place of residence. Only Cu was observed in higher concentrations in IVD compared to in other tissues. Significant positive correlations were observed between the following pairs: Mg/Zn, Mg/Al, Mg/Pb, Zn/Al, Zn/Pb, and Al/Pb. Negative correlations were observed between Mg/Cd, Zn/Cd, Mg/Mo, and Mo/Pb. Conclusions This study is one of few to profile the elements in intervertebral discs in patients with degenerative changes. We report significant differences between trace element concentrations in intervertebral discs compared to in other tissues. Knowledge of the TE accumulation pattern is vital for better understanding intervertebral disc nutrition and metabolism. PMID:25366266

  1. Association of matrilin‐3 polymorphisms with spinal disc degeneration and osteoarthritis of the first carpometacarpal joint of the hand

    PubMed Central

    Min, J L; Meulenbelt, I; Riyazi, N; Kloppenburg, M; Houwing‐Duistermaat, J J; Seymour, A B; van Duijn, C M; Slagboom, P E

    2006-01-01

    Background Seven polymorphisms in the matrilin‐3(MATN3) gene were previously tested for genetic association with hand osteoarthritis in an Icelandic cohort. One of the variants, involving a conserved amino acid substitution (T303M; SNP5), was related to idiopathic hand osteoarthritis. Objectives To investigate SNP5 and two other promising polymorphisms (rs2242190; SNP3, rs8176070; SNP6) for association with radiographic and symptomatic hand osteoarthritis phenotypes, as well as other heritable phenotypes. Methods Polymorphisms were examined in two distinct cohorts of subjects: a population based sample from the Rotterdam study (n = 809), and affected siblings from the genetics, osteoarthrosis and progression (GARP) study (n = 382). Results The originally described association of T303M with the hand osteoarthritis phenotype was not observed in the populations studied. In the Rotterdam sample, however, carrying the T allele of T303M conferred an odds ratio of 2.9 (95% confidence interval (CI), 1.2 to 7.3; p = 0.02) for spinal disc degeneration. In the GARP study, carriers of the A allele of SNP6 had an odds ratio of 2.0 (95% CI, 1.3 to 3.1, p = 0.004) for osteoarthritis of the first carpometacarpal joint (CMC1) as compared with the Rotterdam sample as a control group. Subsequent haplotype analysis showed that a common haplotype, containing the risk allele of SNP6, conferred a significant risk in sibling pairs with CMC1 osteoarthritis (odds ratio = 1.7 (95% CI, 1.1 to 2.7, p = 0.02)). Conclusions These associations suggest that the MATN3 region also determines susceptibility to spinal disc degeneration and CMC1 osteoarthritis. PMID:16396979

  2. Heme oxygenase-1 attenuates IL-1β induced alteration of anabolic and catabolic activities in intervertebral disc degeneration

    PubMed Central

    Hu, Bo; Shi, Changgui; Xu, Chen; Cao, Peng; Tian, Ye; Zhang, Ying; Deng, Lianfu; Chen, Huajiang; Yuan, Wen

    2016-01-01

    Intervertebral disc degeneration (IDD) is characterized by disordered extracellular matrix (ECM) metabolism, implicating subdued anabolism and enhanced catabolic activities in the nucleus pulposus (NP) of discs. Pro-inflammatory cytokines such as interleukin-1β (IL-1β) are considered to be potent mediators of ECM breakdown. Hemeoxygenase-1 (HO-1) has been reported to participate in cellular anti-inflammatory processes. The purpose of this study was to investigate HO-1 modulation of ECM metabolism in human NP cells under IL-1β stimulation. Our results revealed that expression of HO-1 decreased considerably during IDD progression. Induction of HO-1 by cobalt protoporphyrin IX attenuated the inhibition of sulfate glycosaminoglycan and collagen type II (COL-II) synthesis and ameliorated the reduced expressions of aggrecan, COL-II, SOX-6 and SOX-9 mediated by IL-1β. Induction of HO-1 also reversed the effect of IL-1β on expression of the catabolic markers matrix metalloproteinases-1, 3, 9 and 13. This was combined with inhibition of the activation of mitogen-activated protein kinase signaling. These findings suggest that HO-1 might play a pivotal role in IDD, and that manipulating HO-1 expression might mitigate the impairment of ECM metabolism in NP, thus potentially offering a novel therapeutic approach to the treatment of IDD. PMID:26877238

  3. Animal models of age related macular degeneration.

    PubMed

    Pennesi, Mark E; Neuringer, Martha; Courtney, Robert J

    2012-08-01

    Age related macular degeneration (AMD) is the leading cause of vision loss of those over the age of 65 in the industrialized world. The prevalence and need to develop effective treatments for AMD has lead to the development of multiple animal models. AMD is a complex and heterogeneous disease that involves the interaction of both genetic and environmental factors with the unique anatomy of the human macula. Models in mice, rats, rabbits, pigs and non-human primates have recreated many of the histological features of AMD and provided much insight into the underlying pathological mechanisms of this disease. In spite of the large number of models developed, no one model yet recapitulates all of the features of human AMD. However, these models have helped reveal the roles of chronic oxidative damage, inflammation and immune dysregulation, and lipid metabolism in the development of AMD. Models for induced choroidal neovascularization have served as the backbone for testing new therapies. This article will review the diversity of animal models that exist for AMD as well as their strengths and limitations.

  4. Animal models of age related macular degeneration

    PubMed Central

    Pennesi, Mark E.; Neuringer, Martha; Courtney, Robert J.

    2013-01-01

    Age related macular degeneration (AMD) is the leading cause of vision loss of those over the age of 65 in the industrialized world. The prevalence and need to develop effective treatments for AMD has lead to the development of multiple animal models. AMD is a complex and heterogeneous disease that involves the interaction of both genetic and environmental factors with the unique anatomy of the human macula. Models in mice, rats, rabbits, pigs and non-human primates have recreated many of the histological features of AMD and provided much insight into the underlying pathological mechanisms of this disease. In spite of the large number of models developed, no one model yet recapitulates all of the features of human AMD. However, these models have helped reveal the roles of chronic oxidative damage, inflammation and immune dysregulation, and lipid metabolism in the development of AMD. Models for induced choroidal neovascularization have served as the backbone for testing new therapies. This article will review the diversity of animal models that exist for AMD as well as their strengths and limitations. PMID:22705444

  5. Physiological Loading Can Restore the Proteoglycan Content in a Model of Early IVD Degeneration

    PubMed Central

    Gawri, Rahul; Moir, Janet; Ouellet, Jean; Beckman, Lorne; Steffen, Thomas; Roughley, Peter; Haglund, Lisbet

    2014-01-01

    A hallmark of early IVD degeneration is a decrease in proteoglycan content. Progression will eventually lead to matrix degradation, a decrease in weight bearing capacity and loss of disc height. In the final stages of IVD degradation, fissures appear in the annular ring allowing extrusion of the NP. It is crucial to understand the interplay between mechanobiology, disc composition and metabolism to be able to provide exercise recommendations to patients with early signs of disc degeneration. This study evaluates the effect of physiological loading compared to no loading on matrix homeostasis in bovine discs with induced degeneration. Bovine discs with trypsin-induced degeneration were cultured for 14 days in a bioreactor under dynamic loading with maintained metabolic activity. Chondroadherin abundance and structure was used to confirm that a functional matrix was preserved in the chosen loading environment. No change was observed in chondroadherin integrity and a non-significant increase in abundance was detected in trypsin-treated loaded discs compared to unloaded discs. The proteoglycan concentration in loaded trypsin-treated discs was significantly higher than in unloaded disc and the newly synthesised proteoglycans were of the same size range as those found in control samples. The proteoglycan showed an even distribution throughout the NP region, similar to that of control discs. Significantly more newly synthesised type II collagen was detected in trypsin-treated loaded discs compared to unloaded discs, demonstrating that physiological load not only stimulates aggrecan production, but also that of type II collagen. Taken together, this study shows that dynamic physiological load has the ability to repair the extracellular matrix depletion typical of early disc degeneration. PMID:24992586

  6. Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: an in situ zymographic and gene therapy study

    PubMed Central

    Le Maitre, Christine L; Hoyland, Judith A; Freemont, Anthony J

    2007-01-01

    Data implicate IL-1 in the altered matrix biology that characterizes human intervertebral disc (IVD) degeneration. In the current study we investigated the enzymic mechanism by which IL-1 induces matrix degradation in degeneration of the human IVD, and whether the IL-1 inhibitor IL-1 receptor antagonist (IL-1Ra) will inhibit degradation. A combination of in situ zymography (ISZ) and immunohistochemistry was used to examine the effects of IL-1 and IL-1Ra on matrix degradation and metal-dependent protease (MDP) expression in explants of non-degenerate and degenerate human IVDs. ISZ employed three substrates (gelatin, collagen, casein) and different challenges (IL-1β, IL-1Ra and enzyme inhibitors). Immunohistochemistry was undertaken for MDPs. In addition, IL-1Ra was introduced into degenerate IVD explants using genetically engineered constructs. The novel findings from this study are: IL-1Ra delivered directly onto explants of degenerate IVDs eliminates matrix degradation as assessed by multi-substrate ISZ; there is a direct relationship between matrix degradation assessed by ISZ and MDP expression defined by immunohistochemistry; single injections of IVD cells engineered to over-express IL-1Ra significantly inhibit MDP expression for two weeks. Our findings show that IL-1 is a key cytokine driving matrix degradation in the degenerate IVD. Furthermore, IL-1Ra delivered directly or by gene therapy inhibits IVD matrix degradation. IL-1Ra could be used therapeutically to inhibit degeneration of the IVD. PMID:17760968

  7. Bone architecture and disc degeneration in the lumbar spine of mice lacking GDF-8 (myostatin).

    PubMed

    Hamrick, Mark W; Pennington, Catherine; Byron, Craig D

    2003-11-01

    GDF-8, also known as myostatin, is a member of the transforming growth factor-beta superfamily of secreted growth and differentiation factors that is expressed in vertebrate skeletal muscle. Myostatin functions as a negative regulator of skeletal muscle growth and myostatin null mice show a doubling of muscle mass compared to normal mice. We describe here morphology of the lumbar spine in myostatin knockout (Mstn(-/-)) mice using histological and densitometric techniques. The Mstn(-/-) mice examined in this study weigh approximately 10% more than controls (p<0.001) but the iliopsoas muscle is over 50% larger in the knockout mice than in wild-type mice (p<0.001). Peripheral quantitative computed tomography (pQCT) data from the fifth lumbar vertebra show that mice lacking myostatin have approximately 50% greater trabecular bone mineral density (p=0.001) and significantly greater cortical bone mineral content than normal mice. Toluidine blue staining of the intervertebral disc between L4-L5 reveals loss of proteoglycan staining in the hyaline end plates and inner annulus fibrosus of the knockout mice. Loss of cartilage staining in the caudal end plate of L4 is due to ossification of the end plate in the myostatin-deficient animals. Results from this study suggest that increased muscle mass in mice lacking myostatin is associated with increased bone mass as well as degenerative changes in the intervertebral disc.

  8. Narrowing of lumbar spinal canal predicts chronic low back pain more accurately than intervertebral disc degeneration: a magnetic resonance imaging study in young Finnish male conscripts.

    PubMed

    Visuri, Tuomo; Ulaska, Jaana; Eskelin, Marja; Pulkkinen, Pekka

    2005-11-01

    The objective of this magnetic resonance imaging study was to evaluate the role of degenerative changes, developmental spinal stenosis, and compression of spinal nerve roots in chronic low back (CLBP) and radicular pain in Finnish conscripts. The degree of degeneration, protrusion, and herniation of the intervertebral discs and stenosis of the nerve root canals was evaluated, and the midsagittal diameter and cross-sectional area of the lumbar vertebrae canal were measured in 108 conscripts with CLBP and 90 asymptomatic controls. The midsagittal diameters at L1-L4 levels were significantly smaller in the patients with CLBP than in the controls. Moreover, degeneration of the L4/5 disc and protrusion or herniation of the L5/S1 disc and stenosis of the nerve root canals at level L5/S1 were more frequent among the CLBP patients. Multifactorial analysis of the magnetic resonance imaging findings provided a total explanatory rate of only 33%. Narrowing of the vertebral canal in the anteroposterior direction was more likely to produce CLBP and radiating pain than intervertebral disc degeneration or narrowing of the intervertebral nerve root canals.

  9. The elastic fibre network of the human lumbar anulus fibrosus: architecture, mechanical function and potential role in the progression of intervertebral disc degeneration

    PubMed Central

    Fazzalari, Nicola L.

    2009-01-01

    Elastic fibres are critical constituents of dynamic biological structures that functionally require elasticity and resilience. The network of elastic fibres in the anulus fibrosus of the intervertebral disc is extensive, however until recently, the majority of histological, biochemical and biomechanical studies have focussed on the roles of other extracellular matrix constituents such as collagens and proteoglycans. The resulting lack of detailed descriptions of elastic fibre network architecture and mechanical function has limited understanding of the potentially important contribution made by elastic fibres to healthy disc function and their possible roles in the progression of disc degeneration. In addition, it has made it difficult to postulate what the consequences of elastic fibre related disorders would be for intervertebral disc behaviour, and to develop treatments accordingly. In this paper, we review recent and historical studies which have examined both the structure and the function of the human lumbar anulus fibrosus elastic fibre network, provide a synergistic discussion in an attempt to clarify its potentially critical contribution both to normal intervertebral disc behaviour and the processes relating to its degeneration, and recommend critical areas for future research. PMID:19263091

  10. IL-21 Is Positively Associated with Intervertebral Disc Degeneration by Interaction with TNF-α Through the JAK-STAT Signaling Pathway.

    PubMed

    Chen, Bin; Liu, Yi; Zhang, YuanQiang; Li, JingKun; Cheng, KaiYuan; Cheng, Lei

    2017-04-01

    This study was conducted in order to investigate the function of IL-21 in intervertebral disc degeneration. The serum concentration of IL-21 in patients with lumbar disc herniation (LDH) was examined by ELISA. Immunohistochemistry and western blot analysis were performed to detect the expression of IL-21, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-7), and tumor necrosis factor alpha (TNF-α) in degenerated intervertebral disc (IVD) tissues of human and rat. Moreover, nucleus pulposus (NP) cells were treated with 0, 10, 100, and 1000 ng/mL of IL-21 cytokine with and without AG490. TNF-α, ADAMTS-7, and matrix metalloproteinases-13 (MMP-13) mRNA expression was determined by RT-PCR. The expression of signal transducers and activators of transcription, STAT-1, STAT-3, and STAT-5b, was detected by western blot. IL-21 concentration level is higher in the degenerated group and positively correlates with the visual analog score (VAS). IL-21, ADAMTS-7, and TNF-α can be detected in the degenerative NP tissues in both human and rat degenerated NP tissues. The mRNA expression of ADAMTS-7, TNF-α, and MMP-13 was enhanced after stimulation with IL-21. Compared to control, STAT-1, STAT-3, and STAT-5b expression was also enhanced after IL-21 treatment, with STAT-3 being the most significantly enhanced; furthermore, expression was significantly reduced after treatment with AG490. The mRNA expression of TNF-α was markedly reduced after treatment with AG490 compared to treatment with IL-21 only. IL-21 is involved in the pathological development of IVD degeneration and IL-21 could aggravate IVD degeneration by stimulating TNF-α through the STAT signaling pathway.

  11. TGFβ regulates Galectin-3 expression through canonical Smad3 signaling pathway in nucleus pulposus cells: implications in intervertebral disc degeneration.

    PubMed

    Tian, Ye; Yuan, Wen; Li, Jun; Wang, Hua; Hunt, Maxwell G; Liu, Chao; Shapiro, Irving M; Risbud, Makarand V

    2016-03-01

    Galectin-3 is highly expressed in notochordal nucleus pulposus (NP) and thought to play important physiological roles; however, regulation of its expression remains largely unexplored. The aim of the study was to investigate if TGFβ regulates Galectin-3 expression in NP cells. TGFβ treatment resulted in decreased Galectin-3 expression. Bioinformatic analysis using JASPAR and MatInspector databases cross-referenced with published ChIP-Seq data showed nine locations of highly probable Smad3 binding in the LGALS3 proximal promoter. In NP cells, TGFβ treatment resulted in decreased activity of reporters harboring several 5' deletions of the proximal Galectin-3 promoter. While transfection of NP cells with constitutively active (CA)-ALK5 resulted in decreased promoter activity, DN-ALK5 blocked the suppressive effect of TGFβ on the promoter. The suppressive effect of Smad3 on the Galectin-3 promoter was confirmed using gain- and loss-of-function studies. Transfection with DN-Smad3 or Smad7 blocked TGFβ mediated suppression of promoter activity. We also measured Galectin-3 promoter activity in Smad3 null and wild type cells. Noteworthy, promoter activity was suppressed by TGFβ only in wild type cells. Likewise, stable silencing of Smad3 in NP cells using sh-Smad3 significantly blocked TGFβ-dependent decrease in Galectin-3 expression. Treatment of human NP cells isolated from tissues with different grades of degeneration showed that Galectin-3 expression was responsive to TGF-β-mediated suppression. Importantly, Galectin-3 synergized effects of TNF-α on inflammatory gene expression by NP cells. Together these studies suggest that TGFβ, through Smad3 controls Galectin-3 expression in NP cells and may have implications in the intervertebral disc degeneration.

  12. Kaempferol slows intervertebral disc degeneration by modifying LPS-induced osteogenesis/adipogenesis imbalance and inflammation response in BMSCs.

    PubMed

    Zhu, Jun; Tang, Haoyu; Zhang, Zhenhua; Zhang, Yong; Qiu, Chengfeng; Zhang, Ling; Huang, Pinge; Li, Feng

    2017-02-01

    Intervertebral disc (IVD) degeneration is a common disease that represents a significant cause of socio-economic problems. Bone marrow-derived mesenchymal stem cells (BMSCs) are a potential autologous stem cell source for the nucleus pulposus regeneration. Kaempferol has been reported to exert protective effects against both osteoporosis and obesity. This study explored the effect of kaempferol on BMSCs differentiation and inflammation. The results demonstrated that kaempferol did not show any cytotoxicity at concentrations of 20, 60 and 100μM. Kaempferol enhanced cell viability by counteracting the lipopolysaccharide (LPS)-induced cell apoptosis and increasing cell proliferation. Western blot analysis of mitosis-associated nuclear antigen (Ki67) and proliferation cell nuclear antigen (PCNA) further confirmed the increased effect of kaempferol on LPS-induced decreased viability of BMSCs. Besides, kaempferol elevated LPS-induced reduced level of chondrogenic markers (SOX-9, Collagen II and Aggrecan), decreased the level of matrix-degrading enzymes, i.e., matrix metalloprotease (MMP)-3 and MMP-13, suggesting the osteogenesis of BMSC under kaempferol treatment. On the other hand, kaempferol enhanced LPS-induced decreased expression of lipid catabolism-related genes, i.e., carnitine palmitoyl transferase-1 (CPT-1). Kaempferol also suppressed the expression of lipid anabolism-related genes, i.e., peroxisome proliferators-activated receptor-γ (PPAR-γ). The Oil red O staining further convinced the inhibition effect of kaempferol on BMSCs adipogenesis. In addition, kaempferol alleviated inflammatory by reducing the level of pro-inflammatory cytokines (i.e., interleukin (IL)-6) and increasing anti-inflammatory cytokine (IL-10) via inhibiting the nucleus translocation of nuclear transcription factor (NF)-κB p65. Taken together, our research indicated that kaempferol may serve as a novel target for treatment of IVD degeneration.

  13. Short Link N Stimulates Intervertebral Disc Repair in a Novel Long-Term Organ Culture Model that Includes the Bony Vertebrae.

    PubMed

    AlGarni, Nizar; Grant, Michael P; Epure, Laura M; Salem, Omar; Bokhari, Rakan; Antoniou, John; Mwale, Fackson

    2016-11-01

    Link N (DHLSDNYTLDHDRAIH) is a peptide that occurs naturally in the intervertebral discs (IVDs) and cartilage as a result of proteolytic cleavage of Link protein. Several studies have identified Link N as a growth factor capable of stimulating matrix synthesis in these tissues. We have recently discovered that annulus fibrosus cells can release an enzyme (possibly cathepsin K) that can further cleave Link N resulting in an eight amino acid peptide, we called short Link N (sLink N). Separately, we recently developed and validated an organ culture model that has the vertebrae attached (vIVDs; IVD with intact vertebrae). The aims of this study were (i) to examine if sLink N has the potential to repair early degenerate discs and (ii) to determine if this new model can be used to test potential drugs for disc repair. To determine if sLink N was able to stimulate repair of the degenerate disc, vIVDs with trypsin-induced degeneration (DG) were used. After 4 weeks of culture, the proteoglycan content measured as glycosaminoglycans was stimulated by sLink N in the degenerated discs, and the staining of proteoglycan was observed throughout the tissue irrespective of its proximity to the cells. The quantity of extractable type II collagen and aggrecan was also increased when the degenerate discs were treated with sLink N. Taken together, the results suggest that sLink N can increase key disc matrix molecules, namely type II collagen and aggrecan. Thus sLink N is an attractive peptide for tissue engineering and regeneration of the disc due to its anabolic effects. Finally, we show the feasibility of using the long-term whole organ culture system with adjacent intact vertebrae for studying the DG and regeneration of the IVD.

  14. Modeling of rotating disc contactor (RDC) column

    NASA Astrophysics Data System (ADS)

    Ismail, Wan Nurul Aiffah; Zakaria, Siti Aisyah; Noor, Nor Fashihah Mohd; Sulong, Ibrahim; Arshad, Khairil Anuar

    2014-12-01

    Liquid-liquid extraction is one of the most important separation processes. Different kinds of liquid-liquid extractor such as Rotating Disc Contactor (RDC) Column being used in industries. The study of liquid-liquid extraction in an RDC column has become a very important subject to be discussed not just among chemical engineers but mathematician as well. In this research, the modeling of small diameter RDC column using the chemical system involving cumene/isobutryric asid/water are analyzed by the method of Artificial Neural Network (ANN). In the previous research, we begin the process of analyzed the data using methods of design of the experiments (DOE) to identify which factor and their interaction factor are significant and to determine the percentage of contribution of the variance for each factor. From the result obtained, we continue the research by discussed the development and validation of an artificial neural network model in estimating the concentration of continuous and concentration of dispersed outlet for an RDC column. It is expected that an efficient and reliable model will be formed to predict RDC column performance as an alternative to speed up the simulation process.

  15. Genetic polymorphisms of interleukin-1 alpha and the vitamin d receptor in mexican mestizo patients with intervertebral disc degeneration.

    PubMed

    Cervin Serrano, Salvador; González Villareal, Dalia; Aguilar-Medina, Maribel; Romero-Navarro, Jose Guillermo; Romero Quintana, Jose Geovanni; Arámbula Meraz, Eliakym; Osuna Ramírez, Ignacio; Picos-Cárdenas, Veronica; Granados, Julio; Estrada-García, Iris; Sánchez-Schmitz, Guzman; Ramos-Payán, Rosalío

    2014-01-01

    Intervertebral disc degeneration (IDD) is the most common diagnosis in patients with back pain, a leading cause of musculoskeletal disability worldwide. Several conditions, such as occupational activities, gender, age, and obesity, have been associated with IDD. However, the development of this disease has strong genetic determinants. In this study, we explore the possible association between rs1800587 (c.-949C>T) of interleukin-1 alpha (IL1A) and rs2228570 (c.2T>V) and rs731236 (c.1056T>C) of vitamin D receptor (VDR) gene polymorphisms and the development of IDD in northwestern Mexican Mestizo population. Gene polymorphisms were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism, in two groups matched by age and gender: patients with symptomatic lumbar IDD (n = 100) and subjects with normal lumbar-spine MRI-scans (n = 100). Distribution of the mutated alleles in patients and controls was 27.0% versus 28.0% (P = 0.455) for T of rs1800587 (IL1A); 53.0% versus 58.0% (P = 0.183) for V of rs2228570 (VDR); and 18.0% versus 21.0% (P = 0.262) for C of rs731236 (VDR). Our results showed no association between the studied polymorphisms and IDD in this population. This is the first report on the contribution of gene polymorphisms on IDD in a Mexican population.

  16. Genetic Polymorphisms of Interleukin-1 Alpha and the Vitamin D Receptor in Mexican Mestizo Patients with Intervertebral Disc Degeneration

    PubMed Central

    Cervin Serrano, Salvador; González Villareal, Dalia; Aguilar-Medina, Maribel; Romero-Navarro, Jose Guillermo; Romero Quintana, Jose Geovanni; Arámbula Meraz, Eliakym; Osuna Ramírez, Ignacio; Picos-Cárdenas, Veronica; Granados, Julio; Estrada-García, Iris; Sánchez-Schmitz, Guzman; Ramos-Payán, Rosalío

    2014-01-01

    Intervertebral disc degeneration (IDD) is the most common diagnosis in patients with back pain, a leading cause of musculoskeletal disability worldwide. Several conditions, such as occupational activities, gender, age, and obesity, have been associated with IDD. However, the development of this disease has strong genetic determinants. In this study, we explore the possible association between rs1800587 (c.-949C>T) of interleukin-1 alpha (IL1A) and rs2228570 (c.2T>V) and rs731236 (c.1056T>C) of vitamin D receptor (VDR) gene polymorphisms and the development of IDD in northwestern Mexican Mestizo population. Gene polymorphisms were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism, in two groups matched by age and gender: patients with symptomatic lumbar IDD (n = 100) and subjects with normal lumbar-spine MRI-scans (n = 100). Distribution of the mutated alleles in patients and controls was 27.0% versus 28.0% (P = 0.455) for T of rs1800587 (IL1A); 53.0% versus 58.0% (P = 0.183) for V of rs2228570 (VDR); and 18.0% versus 21.0% (P = 0.262) for C of rs731236 (VDR). Our results showed no association between the studied polymorphisms and IDD in this population. This is the first report on the contribution of gene polymorphisms on IDD in a Mexican population. PMID:25506053

  17. Degenerated intervertebral disc prolapse and its association of collagen I alpha 1 Spl gene polymorphism: A preliminary case control study of Indian population

    PubMed Central

    Anjankar, Shailendra D; Poornima, Subhadra; Raju, Subodh; Jaleel, MA; Bhiladvala, Dilnavaz; Hasan, Qurratulain

    2015-01-01

    Background: Degenerated disc disease (DDD) is a common disorder responsible for increased morbidity in a productive age group. Its etiology is multifactorial and genetic factors have been predominantly implicated. Disc prolapse results due to tear in the annulus, which is a fibrous structure composed largely of type I collagen. Functional polymorphism at the Sp1 site of the collagen I alpha 1 (COL1A1) gene has shown a positive association with DDD in Dutch and Greek populations. The purpose of this study was to assess COL1A1 Sp1 gene polymorphism in the Indian population. Materials and Methods: Fifty clinically and radiologically proven patients with disc prolapse requiring surgery were included as cases and 50 healthy, age-matched volunteers served as controls. After isolating DNA from their blood sample, genotyping for COL1A1 polymorphism (rs1800012) was performed and identified as GG, GT, and TT. Results: The mean age and body mass index in cases and controls were similar. 76% of the patients were males. The most common site of disc degeneration was L4–L5 (36%), followed by L5–S1 (34%). Homozygous–GG, heterozygous GT, and homozygous TT genotypes were seen in 38 (76%), 10 (20%) and 2 (4%) cases respectively, controls had similar percentage of genotypes as well. The alleles in cases and the control group showed no significant difference (P = 0.6744) and followed the Hardy–Weinberg Equilibrium in the study population. Conclusion: The COL1A1 (rs1800012) is in Hardy–Weinberg equilibrium in the present subset of Indian population. But taken as a single factor, it was not found to be associated with DDD in this preliminary study. Disc degeneration is multifactorial and also anticipated to be a result of multiple genes involvement and gene-gene interaction. PMID:26806964

  18. Parametric modeling of the intervertebral disc space in 3D: application to CT images of the lumbar spine.

    PubMed

    Korez, Robert; Likar, Boštjan; Pernuš, Franjo; Vrtovec, Tomaž

    2014-10-01

    Gradual degeneration of intervertebral discs of the lumbar spine is one of the most common causes of low back pain. Although conservative treatment for low back pain may provide relief to most individuals, surgical intervention may be required for individuals with significant continuing symptoms, which is usually performed by replacing the degenerated intervertebral disc with an artificial implant. For designing implants with good bone contact and continuous force distribution, the morphology of the intervertebral disc space and vertebral body endplates is of considerable importance. In this study, we propose a method for parametric modeling of the intervertebral disc space in three dimensions (3D) and show its application to computed tomography (CT) images of the lumbar spine. The initial 3D model of the intervertebral disc space is generated according to the superquadric approach and therefore represented by a truncated elliptical cone, which is initialized by parameters obtained from 3D models of adjacent vertebral bodies. In an optimization procedure, the 3D model of the intervertebral disc space is incrementally deformed by adding parameters that provide a more detailed morphometric description of the observed shape, and aligned to the observed intervertebral disc space in the 3D image. By applying the proposed method to CT images of 20 lumbar spines, the shape and pose of each of the 100 intervertebral disc spaces were represented by a 3D parametric model. The resulting mean (±standard deviation) accuracy of modeling was 1.06±0.98mm in terms of radial Euclidean distance against manually defined ground truth points, with the corresponding success rate of 93% (i.e. 93 out of 100 intervertebral disc spaces were modeled successfully). As the resulting 3D models provide a description of the shape of intervertebral disc spaces in a complete parametric form, morphometric analysis was straightforwardly enabled and allowed the computation of the corresponding

  19. Gas Modelling in the Disc of HD 163296

    NASA Technical Reports Server (NTRS)

    Tilling, I.; Woitke, P.; Meeus, G.; Mora, A.; Montesinos, B.; Riviere-Marichalar, P.; Eiroa, C.; Thi, W. -F.; Isella, A.; Roberge, A.; Martin-Zaidi, C.; Kamp, I.; Pinte, C.; Sandell, G.; Vacca, W. D.; Menard, F.; Mendigutia, I.; Duchene, G.; Dent, W. R. F.; Aresu, G.; Meijerink, R.; Spaans, M.

    2011-01-01

    We present detailed model fits to observations of the disc around the Herbig Ae star HD 163296. This well-studied object has an age of approx. 4Myr, with evidence of a circumstellar disc extending out to approx. 540AU. We use the radiation thermo-chemical disc code ProDiMo to model the gas and dust in the circumstellar disc of HD 163296, and attempt to determine the disc properties by fitting to observational line and continuum data. These include new Herschel/PACS observations obtained as part of the open-time key program GASPS (Gas in Protoplanetary Systems), consisting of a detection of the [Oi] 63 m line and upper limits for several other far infrared lines. We complement this with continuum data and ground-based observations of the CO-12 3-2, 2-1 and CO-13 J=1-0 line transitions, as well as the H2 S(1) transition. We explore the effects of stellar ultraviolet variability and dust settling on the line emission, and on the derived disc properties. Our fitting efforts lead to derived gas/dust ratios in the range 9-100, depending on the assumptions made. We note that the line fluxes are sensitive in general to the degree of dust settling in the disc, with an increase in line flux for settled models. This is most pronounced in lines which are formed in the warm gas in the inner disc, but the low excitation molecular lines are also affected. This has serious implications for attempts to derive the disc gas mass from line observations. We derive fractional PAH abundances between 0.007 and 0.04 relative to ISM levels. Using a stellar and UV excess input spectrum based on a detailed analysis of observations, we find that the all observations are consistent with the previously assumed disc geometry

  20. OPG rs2073617 polymorphism is associated with upregulated OPG protein expression and an increased risk of intervertebral disc degeneration

    PubMed Central

    Xue, Jing-Bo; Zhan, Xin-Li; Wang, Wen-Jun; Yan, Yi-Guo; Liu, Chong

    2016-01-01

    The present study aimed to investigate the associations between three distinct osteoprotegerin (OPG) gene polymorphisms and the risk of intervertebral disc degeneration (IDD). A total of 200 IDD patients and 200 healthy controls were recruited from the Department of Spine Surgery at the First Affiliated Hospital of the University of South China (Hengyang, China) between January 2013 and May 2014. The allele, genotype and haplotype frequency distributions of three OPG polymorphisms in the study and control populations were analyzed by polymerase chain reaction prior to restriction fragment length polymorphism or high resolution melting assays. In addition, serum OPG levels were measured via an ELISA. The genotype and allele frequencies of the OPG rs2073617 polymorphisms were significantly higher in the IDD patients, as compared with the control group (P<0.05). Furthermore, carriers of the C allele exhibited a higher risk of IDD, as compared with carriers of the T allele (P<0.001). Conversely, the genotype and allele frequencies of the two other gene polymorphisms, rs2073618 and rs3102735, showed no significant differences between the patients and controls (P>0.05). The serum OPG levels were significantly higher in IDD patients with TT, TC and CC genotypes at the OPG rs2073617 polymorphism, as compared with the control group (P<0.05). Logistic-regression analysis suggested that high serum levels of OPG were positively correlated with IDD risk, whereas the T-C-A, T-G-A and T-G-G haplotypes were negatively correlated with IDD risk (P<0.05). Furthermore, the G-T-G haplotype was associated with protection against IDD (P=0.008), whereas the G-C-G haplotype was associated with an elevated susceptibility to IDD (P=0.007). The results of the present study suggested that OPG rs2073617 polymorphisms and upregulated serum levels of OPG were associated with an increased risk of IDD, whereas the T-C-A, T-G-A and T-G-G haplotypes were protective factors for IDD. The results of the

  1. Mutation of a Drosophila gamma tubulin ring complex subunit encoded by discs degenerate-4 differentially disrupts centrosomal protein localization

    PubMed Central

    Barbosa, Vitor; Yamamoto, Rochele R.; Henderson, Daryl S.; Glover, David M.

    2000-01-01

    We have cloned the Drosophila gene discs degenerate-4 (dd4) and find that it encodes a component of the γ-tubulin ring complex (γTuRC) homologous to Spc98 of budding yeast. This provides the first opportunity to study decreased function of a member of the γ-tubulin ring complex, other than γ-tubulin itself, in a metazoan cell. γ-tubulin is no longer at the centrosomes but is dispersed throughout dd4 cells and yet bipolar metaphase spindles do form, although these have a dramatically decreased density of microtubules. Centrosomin (CNN) remains in broad discrete bodies but only at the focused poles of such spindles, whereas Asp (abnormal spindle protein) is always present at the presumptive minus ends of microtubules, whether or not they are focused. This is consistent with the proposed role of Asp in coordinating the nucleation of mitotic microtubule organizing centers. The centrosome associated protein CP190 is partially lost from the spindle poles in dd4 cells supporting a weak interaction with γ-tubulin, and the displaced protein accumulates in the vicinity of chromosomes. Electron microscopy indicates not only that the poles of dd4 cells have irregular amounts of pericentriolar material, but also that they can have abnormal centrioles. In six dd4 cells subjected to serial sectioning centrioles were missing from one of the two poles. This suggests that in addition to its role in nucleating cytoplasmic and spindle microtubules, the γTuRC is also essential to the structure of centrioles and the separation of centrosomes. PMID:11124805

  2. Drosophila melanogaster as a Model of Muscle Degeneration Disorders.

    PubMed

    Kreipke, R E; Kwon, Y V; Shcherbata, H R; Ruohola-Baker, H

    2017-01-01

    Drosophila melanogaster provides a powerful platform with which researchers can dissect complex genetic questions and biochemical pathways relevant to a vast array of human diseases and disorders. Of particular interest, much work has been done with flies to elucidate the molecular mechanisms underlying muscle degeneration diseases. The fly is particularly useful for modeling muscle degeneration disorders because there are no identified satellite muscle cells to repair adult muscle following injury. This allows for the identification of endogenous processes of muscle degeneration as discrete events, distinguishable from phenotypes due to the lack of stem cell-based regeneration. In this review, we will discuss the ways in which the fruit fly provides a powerful platform with which to study human muscle degeneration disorders.

  3. In vitro assessment of biomaterial-induced remodeling of subchondral and cancellous bone for the early intervention of joint degeneration with focus on the spinal disc

    NASA Astrophysics Data System (ADS)

    McCanless, Jonathan D.

    Osteoarthritis-associated pain of the spinal disc, knee, and hip derives from degeneration of cartilagenous tissues in these joints. Traditional therapies have focused on these cartilage (and disc specific nucleus pulposus) changes as a means of treatment through tissue grafting, regenerative synthetic implants, non-regenerative space filling implants, arthroplasty, and arthrodesis. Although such approaches may seem apparent upon initial consideration of joint degeneration, tissue pathology has shown changes in the underlying bone and vascular bed precede the onset of cartilaginous changes. It is hypothesized that these changes precedent joint degeneration and as such may provide a route for early prevention. The current work proposes an injectable biomaterial-based therapy within these subchondral and cancellous bone regions as a means of preventing or reversing osteoarthritis. Two human concentrated platelet releasate-containing alginate hydrogel/beta-tricalcium phosphate composites have been developed for this potential biomaterial application. The undertaking of assessing these materials through bench-, in vitro, and ex vivo work is described herein. These studies showed the capability of the biomaterials to initiate a wound healing response in monocytes, angiogenic and differentiation behavior in immature endothelial cells, and early osteochondral differentiation in mesenchymal stem cells. These cellular activities are associated with fracture healing and endochondral bone formation, demonstrating the potential of the biomaterials to induce osseous and vascular tissue remodeling underlying osteoarthritic joints as a novel therapy for a disease with rapidly growing healthcare costs.

  4. Development of Animal Models of Local Retinal Degeneration

    PubMed Central

    Lorach, Henri; Kung, Jennifer; Beier, Corinne; Mandel, Yossi; Dalal, Roopa; Huie, Philip; Wang, Jenny; Lee, Seungjun; Sher, Alexander; Jones, Bryan William; Palanker, Daniel

    2015-01-01

    Purpose Development of nongenetic animal models of local retinal degeneration is essential for studies of retinal pathologies, such as chronic retinal detachment or age-related macular degeneration. We present two different methods to induce a highly localized retinal degeneration with precise onset time, that can be applied to a broad range of species in laboratory use. Methods A 30-μm thin polymer sheet was implanted subretinally in wild-type (WT) rats. The effects of chronic retinal separation from the RPE were studied using histology and immunohistochemistry. Another approach is applicable to species with avascular retina, such as rabbits, where the photoreceptors and RPE were thermally ablated over large areas, using a high power scanning laser. Results Photoreceptors above the subretinal implant in rats degenerated over time, with 80% of the outer nuclear layer disappearing within a month, and the rest by 3 months. Similar loss was obtained by selective photocoagulation with a scanning laser. Cells in the inner nuclear layer and ganglion cell layer were preserved in both cases. However, there were signs of rewiring and decrease in the size of the bipolar cell terminals in the damaged areas. Conclusions Both methods induce highly reproducible degeneration of photoreceptors over a defined area, with complete preservation of the inner retinal neurons during the 3-month follow-up. They provide a reliable platform for studies of local retinal degeneration and development of therapeutic strategies in a wide variety of species. PMID:26207299

  5. Spinning disc atomisation process: Modelling and computations

    NASA Astrophysics Data System (ADS)

    Li, Yuan; Sisoev, Grigory; Shikhmurzaev, Yulii

    2016-11-01

    The atomisation of liquids using a spinning disc (SDA), where the centrifugal force is used to generate a continuous flow, with the liquid eventually disintegrating into drops which, on solidification, become particles, is a key element in many technologies. Examples of such technologies range from powder manufacturing in metallurgy to various biomedical applications. In order to be able to control the SDA process, it is necessary to understand it as a whole, from the feeding of the liquid and the wave pattern developing on the disc to the disintegration of the liquid film into filaments and these into drops. The SDA process has been the subject of a number of experimental studies and some elements of it, notably the film on a spinning disc and the dynamics of the jets streaming out from it, have been investigated theoretically. However, to date there have been no studies of the process as a whole, including, most importantly, the transition zone where the film that has already developed a certain wave pattern disintegrates into jets that spiral out. The present work reports some results of an ongoing project aimed at producing a definitive map of regimes occurring in the SDA process and their outcome.

  6. Polarimetric Models of Circumstellar Discs Including Aggregate Dust Grains

    NASA Astrophysics Data System (ADS)

    Mohan, Mahesh

    The work conducted in this thesis examines the nature of circumstellar discs by investigating irradiance and polarization of scattered light. Two circumstellar discs are investigated. Firstly, H-band high contrast imaging data on the transitional disc of the Herbig Ae/Be star HD169142 are presented. The images were obtained through the polarimetric differential imaging (PDI) technique on the Very Large Telescope (VLT) using the adaptive optics system NACO. Our observations use longer exposure times, allowing us to examine the edges of the disc. Analysis of the observations shows distinct signs of polarization due to circumstellar material, but due to excessive saturation and adaptive optics errors further information on the disc could not be inferred. The HD169142 disc is then modelled using the 3D radiative transfer code Hyperion. Initial models were constructed using a two disc structure, however recent PDI has shown the existence of an annular gap. In addition to this the annular gap is found not to be devoid of dust. This then led to the construction of a four-component disc structure. Estimates of the mass of dust in the gap (2.10E-6 Msun) are made as well as for the planet (1.53E-5 Msun (0.016 Mjupiter)) suspected to be responsible for causing the gap. The predicted polarization was also estimated for the disc, peaking at ~14 percent. The use of realistic dust grains (ballistic aggregate particles) in Monte Carlo code is also examined. The fortran code DDSCAT is used to calculate the scattering properties for aggregates which are used to replace the spherical grain models used by the radiative transfer code Hyperion. Currently, Hyperion uses four independent elements to define the scattering matrix, therefore the use of rotational averaging and a 50/50 percent population of grains and their enantiomers were explored to reduce the number of contributing scattering elements from DDSCAT. A python script was created to extract the scattering data from the DDSCAT

  7. Global existence for a degenerate haptotaxis model of cancer invasion

    NASA Astrophysics Data System (ADS)

    Zhigun, Anna; Surulescu, Christina; Uatay, Aydar

    2016-12-01

    We propose and study a strongly coupled PDE-ODE system with tissue-dependent degenerate diffusion and haptotaxis that can serve as a model prototype for cancer cell invasion through the extracellular matrix. We prove the global existence of weak solutions and illustrate the model behavior by numerical simulations for a two-dimensional setting.

  8. Mouse models for studies of retinal degeneration and diseases

    PubMed Central

    Chang, Bo

    2013-01-01

    Summary Mouse models, with their well-developed genetics and similarity to human physiology and anatomy, serve as powerful tools with which to investigate the etiology of human retinal degeneration. Mutant mice also provide reproducible, experimental systems for elucidating pathways of normal development and function. Here, I describe the tools used in the discoveries of many retinal degeneration models, including indirect ophthalmoscopy (to look at the fundus appearance), fundus photography and fluorescein angiography (to document the fundus appearance), electroretinography (to check retinal function) as well as the heritability test (for genetic characterization). PMID:23150358

  9. The noncoding RNA linc-ADAMTS5 cooperates with RREB1 to protect from intervertebral disc degeneration through inhibiting ADAMTS5 expression.

    PubMed

    Wang, Kun; Song, Yu; Liu, Wei; Wu, Xinghuo; Zhang, Yukun; Li, Shuai; Kang, Liang; Tu, Ji; Zhao, Kangcheng; Hua, Wenbin; Yang, Cao

    2017-03-24

    Previous studies have indicated the important roles of ADAMTS5 in intervertebral disc degeneration. However, the mechanisms that regulate ADAMTS5 expression in nuclear pulposus (NP) cells remain largely unknown. Evidence suggests that intergenic transcription may be associated with genes that encode transcriptional regulators. Here, we identified a long intergenic noncoding RNA, linc-ADAMTS5, that was transcribed in the opposite direction of ADAMTS5. In this study, through mining computational algorithm programs, and public available data sets, we identified Ras responsive element binding protein 1 (RREB1) as a crucial transcription factor regulating the expression of ADAMTS5 in NP cells. RNA pull-down, RNA immunoprecipitation, in vitro binding assays, and gain- and loss-of-function studies indicated that a physical interaction between linc-ADAMTS5 and splicing factor proline/glutamine-rich (SFPQ) facilitated the recruitment of RREB1 to binding sites within the ADAMTS5 promoter to induce chromatin remodeling. This resulted in subdued ADAMTS5 levels in cultured NP cells involving histone deacetylases. In clinical NP tissues, linc-ADAMTS5 and RREB1 were correlated negatively with ADAMTS5 expression. Taken together, these results demonstrate that RREB1 cooperates with noncoding RNA linc-ADAMTS5 to inhibit ADAMTS5 expression, thereby affecting degeneration of the extracellular matrix of the intervertebral disc.

  10. Photochemical-dynamical models of externally FUV irradiated protoplanetary discs

    NASA Astrophysics Data System (ADS)

    Haworth, Thomas J.; Boubert, Douglas; Facchini, Stefano; Bisbas, Thomas G.; Clarke, Cathie J.

    2016-12-01

    There is growing theoretical and observational evidence that protoplanetary disc evolution may be significantly affected by the canonical levels of far-ultraviolet (FUV) radiation found in a star-forming environment, leading to substantial stripping of material from the disc outer edge even in the absence of nearby massive stars. In this paper, we perform the first full radiation hydrodynamic simulations of the flow from the outer rim of protoplanetary discs externally irradiated by such intermediate strength FUV fields, including direct modelling of the photon-dominated region which is required to accurately compute the thermal properties. We find excellent agreement between our models and the semi-analytic models of Facchini et al. (2016) for the profile of the flow itself, as well as the mass-loss rate and location of their `critical radius'. This both validates their results (which differed significantly from prior semi-analytic estimates) and our new numerical method, the latter of which can now be applied to elements of the problem that the semi-analytic approaches are incapable of modelling. We also obtain the composition of the flow, but given the simple geometry of our models we can only hint at some diagnostics for future observations of externally irradiated discs at this stage. We also discuss the potential for these models as benchmarks for future photochemical-dynamical codes.

  11. The presence of local mesenchymal progenitor cells in human degenerated intervertebral discs and possibilities to influence these in vitro: a descriptive study in humans.

    PubMed

    Brisby, Helena; Papadimitriou, Nikolaos; Brantsing, Camilla; Bergh, Peter; Lindahl, Anders; Barreto Henriksson, Helena

    2013-03-01

    Low back pain is common and degenerated discs (DDs) are believed to be a major cause. In non-degenerated intervertebral discs (IVDs) presence of stem/progenitor cells was recently reported in different mammals (rabbit, rat, pig). Understanding processes of disc degeneration and regenerative mechanisms within DDs is important. The aim of the study was to examine the presence of local stem/progenitor cells in human DDs and if these cell populations could respond to paracrine stimulation in vitro. Tissue biopsies from the IVD region (L3-S1) were collected from 15 patients, age 34-69 years, undergoing surgery (spinal fusion) and mesenchymal stem cells (MSCs) (iliac crest) from 2 donors. Non-DD cells were collected from 1 donor (scoliosis) and chordoma tissue was obtained from (positive control, stem cell markers) 2 donors. The IVD biopsies were investigated for gene and protein expression of: OCT3/4, CD105, CD90, STRO-1, and NOTCH1. DD cell cultures (pellet mass) were performed with conditioned media from MSCs and non-degenerated IVD cells. Pellets were investigated after 7, 14, 28 days for the same stem cell markers as above. Gene expression of OCT3/4 and STRO-1 was detected in 13/15 patient samples, CD105 in 14/15 samples, and CD90 and NOTCH1 were detected 15/15 samples. Immunohistochemistry analysis supported findings on the protein level, in cells sparsely distributed in DDs tissues. DDs cell cultures displayed more undifferentiated appearance with increased expression of CD105, CD90, STRO-1, OCT3/4, NOTCH1, and JAGGED1, which was observed when cultured in conditioned cell culture media from MSCs compared to cell cultures cultured with conditioned media from non-DD cells. Expression of OCT3/4 (multipotency marker) and NOTCH1 (regulator of cell fate), MSC-markers, CD105, CD90, and STRO-1, indicate that primitive cell populations are present within DDs. Furthermore, the possibility to influence cells from DDs by paracrine signaling /soluble factors from MSCs and from

  12. From birth to death of protoplanetary discs: modelling their formation, evolution and dispersal

    NASA Astrophysics Data System (ADS)

    Kimura, Shigeo S.; Kunitomo, Masanobu; Takahashi, Sanemichi Z.

    2016-09-01

    The formation, evolution and dispersal processes of protoplanetary discs are investigated and the disc lifetime is estimated. The gravitational collapse of a pre-stellar core forms both a central star and a protoplanetary disc. The central star grows by accretion from the disc and irradiation by the central star heats up the disc and generates a thermal wind, which results in the disc's dispersal. Using the one-dimensional diffusion equation, we calculate the evolution of protoplanetary discs numerically. To calculate the disc evolution from formation to dispersal, we add source and sink terms that represent gas accretion from pre-stellar cores and photoevaporation, respectively. We find that the disc lifetimes of typical pre-stellar cores are around 2-4 million years (Myr). A pre-stellar core with high angular momentum forms a larger disc with a long lifetime, while a disc around an X-ray-luminous star has a short lifetime. Integrating disc lifetimes under various masses and angular velocities of pre-stellar cores and X-ray luminosities of young stellar objects, we obtain the disc fraction at a given stellar age and mean lifetime of the disc. Our model indicates that the mean lifetime of a protoplanetary disc is 3.7 Myr, which is consistent with the observational estimate from young stellar clusters. We also find that the dispersion of X-ray luminosity is needed to reproduce the observed disc fraction.

  13. Collisional modelling of the debris disc around HIP 17439

    NASA Astrophysics Data System (ADS)

    Schüppler, Ch.; Löhne, T.; Krivov, A. V.; Ertel, S.; Marshall, J. P.; Eiroa, C.

    2014-07-01

    We present an analysis of the debris disc around the nearby K2 V star HIP 17439. In the context of the Herschel DUNES key programme, the disc was observed and spatially resolved in the far-IR with the Herschel PACS and SPIRE instruments. In a previous study, we assumed that the size and radial distribution of the circumstellar dust are independent power laws. There, several scenarios capable of explaining the observations were suggested after exploring a very broad range of possible model parameters. In this paper, we perform a follow-up in-depth collisional modelling of these scenarios to further distinguish between them. In our models we consider collisions, direct radiation pressure, and drag forces, which are the actual physical processes operating in debris discs. We find that all scenarios discussed in the first paper are physically reasonable and can reproduce the observed spectral energy distribution along with the PACS surface brightness profiles reasonably well. In one model, the dust is produced beyond 120 au in a narrow planetesimal belt and is transported inwards by Poynting-Robertson and stellar wind drag. Good agreement with the observed radial profiles would require stellar winds by about an order of magnitude stronger than the solar value, which is not confirmed - although not ruled out - by observations. Another model consists of two spatially separated planetesimal belts, a warm inner and a cold outer one. This scenario would probably imply the presence of planets clearing the gap between the two components. Finally, we show qualitatively that the observations can be explained by assuming the dust is produced in a single, but broad planetesimal disc with a surface density of solids rising outwards, as expected for an extended disc that experiences a natural inside-out collisional depletion. Prospects of distinguishing between the competing scenarios by future observations are discussed.

  14. Radiative transfer modelling of parsec-scale dusty warped discs

    NASA Astrophysics Data System (ADS)

    Jud, H.; Schartmann, M.; Mould, J.; Burtscher, L.; Tristram, K. R. W.

    2017-02-01

    Warped discs have been found on (sub-)parsec scale in some nearby Seyfert nuclei, identified by their maser emission. Using dust radiative transfer simulations, we explore their observational signatures in the infrared in order to find out whether they can partly replace the molecular torus. Strong variations of the brightness distributions are found, depending on the orientation of the warp with respect to the line of sight. Whereas images at short wavelengths typically show a disc-like and a point source component, the warp itself only becomes visible at far-infrared wavelengths. A similar variety is visible in the shapes of the spectral energy distributions. Especially for close to edge-on views, the models show silicate feature strengths ranging from deep absorption to strong emission for variations of the lines of sight towards the warp. To test the applicability of our model, we use the case of the Circinus galaxy, where infrared interferometry has revealed a highly elongated emission component matching a warped maser disc in orientation and size. Our model is for the first time able to present a physical explanation for the observed dust morphology as coming from the active galactic nuclei heated dust. As opposed to available torus models, a warped disc morphology produces a variety of silicate feature shapes for grazing lines of sight, close to an edge-on view. This could be an attractive alternative to a claimed change of the dust composition for the case of the nearby Seyfert 2 galaxy NGC 1068, which harbours a warped maser disc as well.

  15. Selective rod degeneration and partial cone inactivation characterize an iodoacetic acid model of Swine retinal degeneration.

    PubMed

    Wang, Wei; Fernandez de Castro, Juan; Vukmanic, Eric; Zhou, Liang; Emery, Douglas; Demarco, Paul J; Kaplan, Henry J; Dean, Douglas C

    2011-10-07

    PURPOSE. Transgenic pigs carrying a mutant human rhodopsin transgene have been developed as a large animal model of retinitis pigmentosa (RP). This model displays some key features of human RP, but the time course of disease progression makes this model costly, time consuming, and difficult to study because of the size of the animals at end-stage disease. Here, the authors evaluate an iodoacetic acid (IAA) model of photoreceptor degeneration in the pig as an alternative model that shares features of the transgenic pig and human RP. METHODS. IAA blocks glycolysis, thereby inhibiting photoreceptor function. The effect of the intravenous injection of IAA on swine rod and cone photoreceptor viability and morphology was followed by histologic evaluation of different regions of the retina using hematoxylin and eosin and immunostaining. Rod and cone function was analyzed by full-field electroretinography and multifocal electroretinography. RESULTS. IAA led to specific loss of rods in a central-to-peripheral retinal gradient. Although cones were resistant, they showed shortened outer segments, loss of bipolar cell synaptic connections, and a diminished flicker ERG, hallmarks of transition to cone dysfunction in RP patients. CONCLUSIONS. IAA provides an alternative rod-dominant model of retinal damage that shares a surprising number of features with the pig transgenic model of RP and with human RP. This IAA model is cost-effective and rapid, ensuring that the size of the animals does not become prohibitive for end-stage evaluation or therapeutic intervention.

  16. On degenerate models of cosmic inflation

    SciTech Connect

    Gwyn, Rhiannon; Palma, Gonzalo A.; Sakellariadou, Mairi; Sypsas, Spyros E-mail: gpalmaquilod@ing.uchile.cl E-mail: s.sypsas@apctp.org

    2014-10-01

    In this article we discuss the role of current and future CMB measurements in pinning down the model of inflation responsible for the generation of primordial curvature perturbations. By considering a parameterization of the effective field theory of inflation with a modified dispersion relation arising from heavy fields, we derive the dependence of cosmological observables on the scale of heavy physics Λ{sub UV}. Specifically, we show how the f{sub NL} non-linearity parameters are related to the phase velocity of curvature perturbations at horizon exit, which is parameterized by Λ{sub UV}. BICEP2 and PLANCK findings are shown to be consistent with a value Λ{sub UV} ∼ Λ{sub GUT}. However, we find a degeneracy in the parameter space of inflationary models that can only be resolved with a detailed knowledge of the shape of the non-Gaussian bispectrum.

  17. A 20-year-old female with Hirayama disease complicated with dysplasia of the cervical vertebrae and degeneration of intervertebral discs

    PubMed Central

    Hashimoto, Masaya; Yoshioka, Masayuki; Sakimoto, Yoshihiro; Suzuki, Masahiko

    2012-01-01

    A 20-year-old female patient was presented with a 1-year history of progressive weakness of the left hand. Examination on admission showed atrophy of the muscles of the left forearm, cold paralysis and minipolymyoclonus. MR images of the cervical cord showed anterior transfer of the cervical cord on anterior flexion and cervical cord compression at the site of cervical kyphosis, confirming the diagnosis of Hirayama disease. Many features of the present case are unusual: the patient is a female (who are rarely afflicted by this disease), with cervical kyphosis and a history of exercise involving cervical vertebral loading, suggesting a potential involvement of the latter two factors in the disease onset. The findings suggest that cervical vertebral dysplasia and intervertebral disc degeneration may influence cervical kyphosis, and be involved in the onset of Hirayama disease. PMID:23144342

  18. Degeneration of the Y chromosome in evolutionary aging models

    NASA Astrophysics Data System (ADS)

    Lobo, M. P.; Onody, R. N.

    2005-06-01

    The Y chromosomes are genetically degenerated and do not recombine with their matching partners X. Recombination of XX pairs is pointed out as the key factor for the Y chromosome degeneration. However, there is an additional evolutionary force driving sex-chromosomes evolution. Here we show this mechanism by means of two different evolutionary models, in which sex chromosomes with non-recombining XX and XY pairs of chromosomes is considered. Our results show three curious effects. First, we observed that even when both XX and XY pairs of chromosomes do not recombine, the Y chromosomes still degenerate. Second, the accumulation of mutations on Y chromosomes followed a completely different pattern then those accumulated on X chromosomes. And third, the models may differ with respect to sexual proportion. These findings suggest that a more primeval mechanism rules the evolution of Y chromosomes due exclusively to the sex-chromosomes asymmetry itself, i.e., the fact that Y chromosomes never experience female bodies. Over aeons, natural selection favored X chromosomes spontaneously, even if at the very beginning of evolution, both XX and XY pairs of chromosomes did not recombine.

  19. From Disc Wind Models to Observations of TTauri Microjets

    NASA Astrophysics Data System (ADS)

    Ferreira, Jonathan; Casse, Fabien; Garcia, Paulo; Darren, O'brien; Sylvie, Cabrit; Catherine, Dougados; Pesenti, Nicolas; Luc, Binette

    Two decades after their discovery jets from accreting young stars still represent a major challenge for theorists. Several theoretical scenarii have been proposed but only models involving large scale magnetic fields have proved capable of producing self-collimated jets. However the launching region remains unknown: is it the star the surrounding accretion disc or their interaction zone? Progresses in high angular resolution offer now the opportunity to test the various proposed models. I will first review the results on magnetized disc winds based on the only MHD model describing self-consistently these accretion-ejection structures. Then I will show how the thermal and ionization states of the outflowing matter can be consistently computed once the dominant heating source has been chosen (ambipolar diffusion alfven wave damping or some local mechanical heating). A set of observational predictions (emission maps line fluxes/ratios and line profiles) for selected optical forbidden lines can then be calculated. As an illustration I will compare these predictions with new sub-arcsecond spectroimaging observations of the DG Tau and RW Aur jets and discuss the constraints they set on disc winds in TTauri stars.

  20. Radiative neutrino mass model with degenerate right-handed neutrinos

    NASA Astrophysics Data System (ADS)

    Kashiwase, Shoichi; Suematsu, Daijiro

    2016-03-01

    The radiative neutrino mass model can relate neutrino masses and dark matter at a TeV scale. If we apply this model to thermal leptogenesis, we need to consider resonant leptogenesis at that scale. It requires both finely degenerate masses for the right-handed neutrinos and a tiny neutrino Yukawa coupling. We propose an extension of the model with a U(1) gauge symmetry, in which these conditions are shown to be simultaneously realized through a TeV scale symmetry breaking. Moreover, this extension can bring about a small quartic scalar coupling between the Higgs doublet scalar and an inert doublet scalar which characterizes the radiative neutrino mass generation. It also is the origin of the Z_2 symmetry which guarantees the stability of dark matter. Several assumptions which are independently supposed in the original model are closely connected through this extension.

  1. Diagram theory for the twofold-degenerate Anderson impurity model

    NASA Astrophysics Data System (ADS)

    Moskalenko, V. A.; Dohotaru, L. A.; Digor, D. F.; Cebotari, I. D.

    2014-02-01

    We develop a diagram technique for investigating the twofold-degenerate Anderson impurity model in the normal state with the strong electronic correlations of d electrons of the impurity ion taken into account. We discuss the properties of the Slater-Kanamori model of d electrons. After finding the eigenfunctions and eigenvalues of all 16 local states, we determine the local one-particle propagator. We construct the perturbation theory around the atomic limit of the impurity ion and obtain a Dyson-type equation establishing the relation between the impurity electron propagator and the normal correlation function. As a result of summing infinite series of ladder diagrams, we obtain an approximation for the correlation function.

  2. Clinical and radiological outcome of anterior–posterior fusion versus transforaminal lumbar interbody fusion for symptomatic disc degeneration: a retrospective comparative study of 133 patients

    PubMed Central

    Schwender, James D.; Safriel, Yair; Gilbert, Thomas J.; Mehbod, Amir A.; Denis, Francis; Transfeldt, Ensor E.; Wroblewski, Jill M.

    2009-01-01

    Abundant data are available for direct anterior/posterior spine fusion (APF) and some for transforaminal lumbar interbody fusion (TLIF), but only few studies from one institution compares the two techniques. One-hundred and thirty-three patients were retrospectively analyzed, 68 having APF and 65 having TLIF. All patients had symptomatic disc degeneration of the lumbar spine. Only those with one or two-level surgeries were included. Clinical chart and radiologic reviews were done, fusion solidity assessed, and functional outcomes determined by pre- and postoperative SF-36 and postoperative Oswestry Disability Index (ODI), and a satisfaction questionnaire. The minimum follow-up was 24 months. The mean operating room time and hospital length of stay were less in the TLIF group. The blood loss was slightly less in the TLIF group (409 vs. 480 cc.). Intra-operative complications were higher in the APF group, mostly due to vein lacerations in the anterior retroperitoneal approach. Postoperative complications were higher in the TLIF group due to graft material extruding against the nerve root or wound drainage. The pseudarthrosis rate was statistically equal (APF 17.6% and TLIF 23.1%) and was higher than most published reports. Significant improvements were noted in both groups for the SF-36 questionnaires. The mean ODI scores at follow-up were 33.5 for the APF and 39.5 for the TLIF group. The patient satisfaction rate was equal for the two groups. PMID:19125304

  3. Subretinal transplantation of bone marrow mesenchymal stem cells delays retinal degeneration in the RCS rat model of retinal degeneration.

    PubMed

    Inoue, Yuji; Iriyama, Aya; Ueno, Shuji; Takahashi, Hidenori; Kondo, Mineo; Tamaki, Yasuhiro; Araie, Makoto; Yanagi, Yasuo

    2007-08-01

    Because there is no effective treatment for this retinal degeneration, potential application of cell-based therapy has attracted considerable attention. Several investigations support that bone marrow mesenchymal stem cells (MSCs) can be used for a broad spectrum of indications. Bone marrow MSCs exert their therapeutic effect in part by secreting trophic factors to promote cell survival. The current study investigates whether bone marrow MSCs secrete factor(s) to promote photoreceptor cell survival and whether subretinal transplantation of bone marrow MSCs promotes photoreceptor survival in a retinal degeneration model using Royal College of Surgeons (RCS) rats. In vitro, using mouse retinal cell culture, it was demonstrated that the conditioned medium of the MSCs delays photoreceptor cell apoptosis, suggesting that the secreted factor(s) from the MSCs promote photoreceptor cell survival. In vivo, the MSCs were injected into the subretinal space of the RCS rats and histological analysis, real-time RT-PCR and electrophysiological analysis demonstrated that the subretinal transplantation of MSCs delays retinal degeneration and preserves retinal function in the RCS rats. These results suggest that MSC is a useful cell source for cell-replacement therapy for some forms of retinal degeneration.

  4. Design and fabrication of 3D-printed anatomically shaped lumbar cage for intervertebral disc (IVD) degeneration treatment.

    PubMed

    Serra, T; Capelli, C; Toumpaniari, R; Orriss, I R; Leong, J J H; Dalgarno, K; Kalaskar, D M

    2016-07-19

    Spinal fusion is the gold standard surgical procedure for degenerative spinal conditions when conservative therapies have been unsuccessful in rehabilitation of patients. Novel strategies are required to improve biocompatibility and osseointegration of traditionally used materials for lumbar cages. Furthermore, new design and technologies are needed to bridge the gap due to the shortage of optimal implant sizes to fill the intervertebral disc defect. Within this context, additive manufacturing technology presents an excellent opportunity to fabricate ergonomic shape medical implants. The goal of this study is to design and manufacture a 3D-printed lumbar cage for lumbar interbody fusion. Optimisations of the proposed implant design and its printing parameters were achieved via in silico analysis. The final construct was characterised via scanning electron microscopy, contact angle, x-ray micro computed tomography (μCT), atomic force microscopy, and compressive test. Preliminary in vitro cell culture tests such as morphological assessment and metabolic activities were performed to access biocompatibility of 3D-printed constructs. Results of in silico analysis provided a useful platform to test preliminary cage design and to find an optimal value of filling density for 3D printing process. Surface characterisation confirmed a uniform coating of nHAp with nanoscale topography. Mechanical evaluation showed mechanical properties of final cage design similar to that of trabecular bone. Preliminary cell culture results showed promising results in terms of cell growth and activity confirming biocompatibility of constructs. Thus for the first time, design optimisation based on computational and experimental analysis combined with the 3D-printing technique for intervertebral fusion cage has been reported in a single study. 3D-printing is a promising technique for medical applications and this study paves the way for future development of customised implants in spinal

  5. The life cycles of Be viscous decretion discs: time-dependent modelling of infrared continuum observations

    NASA Astrophysics Data System (ADS)

    Vieira, R. G.; Carciofi, A. C.; Bjorkman, J. E.; Rivinius, Th.; Baade, D.; Rímulo, L. R.

    2017-01-01

    We apply the viscous decretion disc (VDD) model to interpret the infrared disc continuum emission of 80 Be stars observed in different epochs. In this way, we determined 169 specific disc structures, namely their density scale, ρ0, and exponent, n. We found that the n values range mainly between 1.5 and 3.5, and ρ0 varies between 10-12 and 10-10 g cm-3, with a peak close to the lower value. Our large sample also allowed us to firmly establish that the discs around early-type stars are denser than in late-type stars. Additionally, we estimated the disc mass decretion rates and found that they range between 10-12 and 10-9 M⊙ yr-1. These values are compatible with recent stellar evolution models of fast-rotating stars. One of the main findings of this work is a correlation between the ρ0 and n values. In order to find out whether these relations can be traced back to the evolution of discs or have some other origin, we used the VDD model to calculate temporal sequences under different assumptions for the time profile of the disc mass injection. The results support the hypothesis that the observed distribution of disc properties is due to a common evolutionary path. In particular, our results suggest that the time-scale for disc growth, during which the disc is being actively fed by mass injection episodes, is shorter than the time-scale for disc dissipation, when the disc is no longer fed by the star and dissipates as a result of the viscous diffusion of the disc material.

  6. Cellular models and therapies for age-related macular degeneration

    PubMed Central

    Forest, David L.; Johnson, Lincoln V.; Clegg, Dennis O.

    2015-01-01

    ABSTRACT Age-related macular degeneration (AMD) is a complex neurodegenerative visual disorder that causes profound physical and psychosocial effects. Visual impairment in AMD is caused by the loss of retinal pigmented epithelium (RPE) cells and the light-sensitive photoreceptor cells that they support. There is currently no effective treatment for the most common form of this disease (dry AMD). A new approach to treating AMD involves the transplantation of RPE cells derived from either human embryonic or induced pluripotent stem cells. Multiple clinical trials are being initiated using a variety of cell therapies. Although many animal models are available for AMD research, most do not recapitulate all aspects of the disease, hampering progress. However, the use of cultured RPE cells in AMD research is well established and, indeed, some of the more recently described RPE-based models show promise for investigating the molecular mechanisms of AMD and for screening drug candidates. Here, we discuss innovative cell-culture models of AMD and emerging stem-cell-based therapies for the treatment of this vision-robbing disease. PMID:26035859

  7. Building disc structure and galaxy properties through angular momentum: the DARK SAGE semi-analytic model

    NASA Astrophysics Data System (ADS)

    Stevens, Adam R. H.; Croton, Darren J.; Mutch, Simon J.

    2016-09-01

    We present the new semi-analytic model of galaxy evolution, DARK SAGE, a heavily modified version of the publicly available SAGE code. The model is designed for detailed evolution of galactic discs. We evolve discs in a series of annuli with fixed specific angular momentum, which allows us to make predictions for the radial and angular-momentum structure of galaxies. Most physical processes, including all channels of star formation and associated feedback, are performed in these annuli. We present the surface density profiles of our model spiral galaxies, both as a function of radius and specific angular momentum, and find that the discs naturally build a pseudo-bulge-like component. Our main results are focused on predictions relating to the integrated mass-specific angular momentum relation of stellar discs. The model produces a distinct sequence between these properties in remarkable agreement with recent observational literature. We investigate the impact Toomre disc instabilities have on shaping this sequence and find they are crucial for regulating both the mass and spin of discs. Without instabilities, high-mass discs would be systematically deficient in specific angular momentum by a factor of ˜2.5, with increased scatter. Instabilities also appear to drive the direction in which the mass-spin sequence of spiral galaxy discs evolves. With them, we find galaxies of fixed mass have higher specific angular momentum at later epochs.

  8. A Simple ``Sticky Disc'' Model for Crystalline and Amorphous Networks

    NASA Astrophysics Data System (ADS)

    Huerta, Adrian; Chubynsky, Nikita; Naumis, Gerardo; Thorpe, Michael

    2005-03-01

    Using Monte Carlo simulations, we study the structural and thermodynamic behavior of a simple one component network forming model made up of ``sticky discs.'' Central and bond bending forces was included, modeling such interactions as a simple square well radial and angular three body term in the potential respectively. The main feature of this model is the ability to form crystalline and amorphous networks upon cooling, similar to that obtained using the so called WWW methodology to describe the network of some vitreous structures [1]. With the ``pebble game'' algorithm [2], we evaluate the number of degrees of freedom and the amount of stress in both the amorphous and crystalline structures. We discuss the connection between the configurational entropy (associated with the topology) and the degrees of freedom. Other effects such as elasticity of these structures are also discussed. 1. Wooten, F., Winer, K. and Weaire, D., Phys. Rev. Lett., 54 1392- 1395 (1985). 2. Jacobs, D.J. and Thorpe, M.F., Phys. Rev. Lett., 75 4051- 4054 (1995).

  9. Tamoxifen Provides Structural and Functional Rescue in Murine Models of Photoreceptor Degeneration.

    PubMed

    Wang, Xu; Zhao, Lian; Zhang, Yikui; Ma, Wenxin; Gonzalez, Shaimar R; Fan, Jianguo; Kretschmer, Friedrich; Badea, Tudor C; Qian, Hao-Hua; Wong, Wai T

    2017-03-22

    Photoreceptor degeneration is a cause of irreversible vision loss in incurable blinding retinal diseases including retinitis pigmentosa (RP) and atrophic age-related macular degeneration. We found in two separate mouse models of photoreceptor degeneration that tamoxifen, a selective estrogen receptor modulator and a drug previously linked with retinal toxicity, paradoxically provided potent neuroprotective effects. In a light-induced degeneration model, tamoxifen prevented onset of photoreceptor apoptosis and atrophy and maintained near-normal levels of electroretinographic responses. Rescue effects were correlated with decreased microglial activation and inflammatory cytokine production in the retina in vivo and a reduction of microglia-mediated toxicity to photoreceptors in vitro, indicating a microglia-mediated mechanism of rescue. Tamoxifen also rescued degeneration in a genetic (Pde6b(rd10)) model of RP, significantly improving retinal structure, electrophysiological responses, and visual behavior. These prominent neuroprotective effects warrant the consideration of tamoxifen as a drug suitable for being repurposed to treat photoreceptor degenerative disease.SIGNIFICANCE STATEMENT Photoreceptor degeneration is a cause of irreversible blindness in a number of retinal diseases such as retinitis pigmentosa (RP) and atrophic age-related macular degeneration. Tamoxifen, a selective estrogen receptor modulator approved for the treatment of breast cancer and previously linked to a low incidence of retinal toxicity, was unexpectedly found to exert marked protective effects against photoreceptor degeneration. Structural and functional protective effects were found for an acute model of light-induced photoreceptor injury and for a genetic model for RP. The mechanism of protection involved the modulation of microglial activation and the production of inflammatory cytokines, highlighting the role of inflammatory mechanisms in photoreceptor degeneration. Tamoxifen may be

  10. The Paracrine Effect of Degenerated Disc Cells on Healthy Human Nucleus Pulposus Cells Is Mediated by MAPK and NF-κB Pathways and Can Be Reduced by TGF-β1.

    PubMed

    Cai, Feng; Zhu, Lei; Wang, Feng; Shi, Rui; Xie, Xin-Hui; Hong, Xin; Wang, Xiao-Hu; Wu, Xiao-Tao

    2017-02-01

    Inflammation is thought to have a major role in the pathogenesis of disc degeneration. Studies have shown that nucleus pulposus cells (NPCs) respond to one or two specific cytokines by regulating cell proliferation or matrix synthesis. However, the effects of a cocktail of factors secreted by degenerated disc cells on transplanted exogenous healthy NPCs remain unknown. Concentrations of multiple cytokines in degenerated disc tissue-conditioned medium (dCM) were measured using enzyme-linked immunosorbent assay (ELISA). 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and Ki67 immunofluorescence staining were used to evaluate the proliferation of cells in dCM. The function of exogenous NPCs cultured in dCM was evaluated by examining catabolic markers (ADAMTS-4, ADAMTS-5, MMP-1, MMP-3, and MMP-13), anabolic markers (TIMP-1, TIMP-2, and TIMP-3), and the extracellular matrix protein-aggrecan (ACAN) and collagen II (COL2)-expression with real time polymerase chain reaction (RT-PCR). Mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathway activation was observed using Western blotting. Finally, we examined the role of transforming growth factor (TGF)-β1 in reducing dCM-mediated exogenous NPC dysfunction. Levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, interferon-γ (IFN-γ), and prostaglandin E2 (PGE2) were higher and TGF-β1 levels were lower in dCM compared with the control medium. Treatment with dCM increased the proliferation of healthy NPCs. NPCs exhibited significantly higher expression of ADAMTS-4, ADAMTS-5, MMP-1, MMP-3, and MMP-13 and decreased TIMP-2, ACAN, and COL2 expression in the dCM group in a dose- and time-dependent manner. Treatment with dCM moderately increased TIMP-1 expression and had no effect on TIMP-3 mRNA levels. The MAPK and NF-κB pathways were implicated in dCM-mediated responses of healthy NPCs. TGF-β1 partially reversed the d

  11. Thermal Modeling of Disc Brake Rotor in Frictional Contact

    NASA Astrophysics Data System (ADS)

    Ali, Belhocine; Ghazaly, Nouby Mahdi

    2013-01-01

    Safety aspect in automotive engineering has been considered as a number one priority in development of new vehicle. Each single system has been studied and developed in order to meet safety requirement. Instead of having air bag, good suspension systems, good handling and safe cornering, there is one most critical system in the vehicle which is brake systems. The objective of this work is to investigate and analyze the temperature distribution of rotor disc during braking operation using ANSYS Multiphysics. The work uses the finite element analysis techniques to predict the temperature distribution on the full and ventilated brake disc and to identify the critical temperature of the rotor. The analysis also gives us, the heat flux distribution for the two discs.

  12. Effects of Transplantation of hTIMP1-Expressing Bone Marrow Mesenchymal Stem Cells on the Extracellular Matrix of Degenerative Intervertebral Discs in an in vivo Rabbit Model.

    PubMed

    Yi, Zhou; Guanjun, Tu; Lin, Cong; Zifeng, Pei

    2014-04-08

    Study Design. Prospective, randomized controlled animal study.Objective. To observe ECM changes in degenerative IVD after transplantation of bone marrow mesenchymal stem cells (BMSCs) virally transfected with a construct expressing human tissue inhibitor of metalloproteinase 1 (hTIMP-1), and to discuss the feasibility of using this approach to treat intervertebral disc degeneration (IDD).Summary of Background Data. Intervertebral disc (IVD) degeneration is characterized by decreased cell numbers, bioactivity of the nucleus pulposus (NP), and remodeled extracellular matrix (ECM). Exogenous genes can be targeted into cells to produce inhibition of ECM degradation and increase ECM content in IVDs, and thereby potentially stop or reverse degenerative processes and modify disc structure.Methods. BMSCs were isolated from a pure New-Zealand rabbit and identified by flow cytometry. Transgenic BMSCs were acquired by transfection with a recombinant adenovirus vector carrying the hTIMP-1 gene. Animal models of IDD were established by annulus puncture and then given intra-NP injections according to their random assignment into three groups: (1) a transgenic BMSC transplantation (TgBT) group that received BMSCs transfected with an hTIMP-1-expressing adenovirus vector; (2) a BMSC transplantation (BT) group that received unaltered BMSCs; and (3) a control (PCon) group that received cell-free phosphate-buffered saline. Degree of degeneration was evaluated 12 wks after modeling. ECM content was quantified using immunohistochemistry (IHC) and spectrophotography. Expression of hTIMP-1 was observed via quantitative PCR, western blot, and IHC.Results. Significantly fewer degenerative changes and increased ECM content were observed in the TBT and BT groups compared to PCon animals (P < .05). The TBT group had greater ECM content than did the BT group (P < .05), as well as higher levels of hTIMP-1 mRNA and protein.Conclusions. Transplantation of BMSCs transfected with hTIMP-1 can

  13. A two-fluid model for black-hole accretion flows: particle acceleration and disc structure

    NASA Astrophysics Data System (ADS)

    Lee, Jason P.; Becker, Peter A.

    2017-02-01

    Hot, tenuous advection-dominated accretion flows around black holes are ideal sites for the Fermi acceleration of relativistic particles at standing shock waves in the accretion disc. Previous work has demonstrated that the shock-acceleration process can be efficient enough to power the observed, strong outflows in radio-loud active galaxies such as M87. However, the dynamical effect (back-reaction) on the flow, exerted by the pressure of the relativistic particles, has not been previously considered, and this effect can have a significant influence on the disc structure. We reexamine the problem by developing a new, two-fluid model for the structure of the accretion disc that includes the dynamical effect of the relativistic particle pressure, combined with the pressure of the background (thermal) gas. The new model is analogous to the two-fluid model of cosmic ray acceleration in supernova-driven shock waves. As part of the model, we also develop a new set of shock jump conditions, which are solved along with the hydrodynamic conservation equations to determine the structure of the accretion disc. The solutions include the formation of a mildly relativistic outflow (jet) at the shock radius, driven by the relativistic particles accelerated in the disc. One of our main conclusions is that in the context of the new two-fluid accretion model, global smooth (shock-free) solutions do not exist, and the disc must always contain a standing shock wave, at least in the inviscid case considered here.

  14. High-resolution optical coherence tomography in mouse models of genetic and induced retinal degeneration

    NASA Astrophysics Data System (ADS)

    Cimalla, Peter; Carido, Madalena; Pran Babu, Sheik; Santos-Ferreira, Tiago; Gaertner, Maria; Kordowich, Simon; Wittig, Dierk; Ader, Marius; Karl, Mike; Koch, Edmund

    2013-06-01

    For the study of disease mechanisms and the development of novel therapeutic strategies for retinal pathologies in human, rodent models play an important role. Nowadays, optical coherence tomography (OCT) allows three-dimensional investigation of retinal events over time. However, a detailed analysis of how different retinal degenerations are reflected in OCT images is still lacking in the biomedical field. Therefore, we use OCT to visualize retinal degeneration in specific mouse models in order to study disease progression in vivo and improve image interpretation of this noninvasive modality. We use a self-developed spectral domain OCT system for simultaneous dual-band imaging in the 0.8 μm- and 1.3 μm-wavelength range - the two most common spectral bands in biomedical OCT. A fiber-coupled ophthalmic scanning unit allows flexible imaging of the eye with a high axial resolution of 3 - 4 μm in tissue. Four different mouse models consisting of one genetic (rhodopsin-deficient and three induced retinal degenerations (sodium iodate-induced damage, light-induced photoreceptor damage and Kainate neurotoxin damage) were investigated. OCT imaging was performed daily or weekly, depending on the specific degeneration model, over a time period of up to 9 weeks. Individual retinal layers that were affected by the specific degeneration could successfully be identified and monitored over the observation time period. Therefore, longitudinal OCT studies deliver reliable information about the retinal microstructure and the time course of retinal degeneration processes in vivo.

  15. Magnetorotationally driven wind cycles in local disc models

    NASA Astrophysics Data System (ADS)

    Riols, A.; Ogilvie, G. I.; Latter, H.; Ross, J. P.

    2016-12-01

    Jets, from the protostellar to the AGN context, have been extensively studied but their connection to the turbulent dynamics of the underlying accretion disc is poorly understood. Following a similar approach to Lesur, Fereira & Ogilvie, we examine the role of the magnetorotational instability (MRI) in the production and acceleration of outflows from discs. Via a suite of 1D shearing-box simulations of stratified discs, we show that magnetocentrifugal winds exhibit cyclic activity with a period of 10-20 Ω-1, a few times the orbital period. The cycle seems to be more vigorous for strong vertical field; it is robust to the variation of relevant parameters and independent of numerical details. The convergence of these solutions (in particular the mass-loss rate) with vertical box size is also studied. By considering a sequence of magnetohydrostatic equilibria and their stability, the periodic activity may be understood as the succession of the following phases: (a) a dominant MRI channel mode, (b) strong magnetic field generation, (c) consequent wind launching, and ultimately (d) vertical expulsion of the excess magnetic field by the expanding and accelerating gas associated with the wind. We discuss potential connections between this behaviour and observed time-variability in disc-jet systems.

  16. Numerical Modeling of Tidal Effects in Polytropic Accretion Discs

    NASA Technical Reports Server (NTRS)

    Godon, P.

    1996-01-01

    A two-dimensional time-dependent hybrid Fourier-Chebyshev method of collocation is developed and used for the study of tidal effects in accretion discs, under the assumption of a polytropic equation of state and a standard alpha viscosity prescription.

  17. Modeling the Compact Disc Read System in Lab

    ERIC Educational Resources Information Center

    Hinaus, Brad; Veum, Mick

    2009-01-01

    One of the great, engaging aspects of physics is its application to everyday technology. The compact disc player is an example of one such technology that applies fundamental principles from optics in order to efficiently store and quickly retrieve information. We have created a lab in which students use simple optical components to assemble a…

  18. The pseudo-photosphere model for the continuum emission of gaseous discs

    NASA Astrophysics Data System (ADS)

    Vieira, R. G.; Carciofi, A. C.; Bjorkman, J. E.

    2015-12-01

    We investigate the continuum emission of viscous decretion discs around Be stars in this paper. The results obtained from non-LTE (local thermodynamic equilibrium) radiative transfer models show two regimes in the disc surface brightness profile: an inner optically thick region, which behaves as a pseudo-photosphere with a wavelength-dependent size, and an optically thin tenuous outer part, which contributes with about a third of the total flux. The isophotal shape of the surface brightness is well described by elliptical contours with an axial ratio b/a = cos i for inclinations i < 75°. Based on these properties, a semi-analytical model was developed to describe the continuum emission of gaseous discs. It provides fluxes and spectral slopes at the infrared within an accuracy of 10 and 5 per cent, respectively, when compared to the numerical results. The model indicates that the infrared spectral slope is mainly determined by both the density radial slope and the disc flaring exponent, being practically independent of disc inclination and base density. As a first application, the density structure of 15 Be stars was investigated, based on the infrared flux excess, and the results compared to previous determinations in the literature. Our results indicate that the decretion rates are in the range of 10-12-10-9 M⊙ yr-1, which is at least two orders of magnitude smaller than the previous outflowing disc model predictions.

  19. A finite element model of the L4-L5-S1 human spine segment including the heterogeneity and anisotropy of the discs.

    PubMed

    Jaramillo, Hector E; Gómez, Lessby; García, Jose J

    2015-01-01

    With the aim to study disc degeneration and the risk of injury during occupational activities, a new finite element (FE) model of the L4-L5-S1 segment of the human spine was developed based on the anthropometry of a typical Colombian worker. Beginning with medical images, the programs CATIA and SOLIDWORKS were used to generate and assemble the vertebrae and create the soft structures of the segment. The software ABAQUS was used to run the analyses, which included a detailed model calibration using the experimental step-wise reduction data for the L4-L5 component, while the L5-S1 segment was calibrated in the intact condition. The range of motion curves, the intradiscal pressure and the lateral bulging under pure moments were considered for the calibration. As opposed to other FE models that include the L5-S1 disc, the model developed in this study considered the regional variations and anisotropy of the annulus as well as a realistic description of the nucleus geometry, which allowed an improved representation of experimental data during the validation process. Hence, the model can be used to analyze the stress and strain distributions in the L4-L5 and L5-S1 discs of workers performing activities such as lifting and carrying tasks.

  20. The circumstellar disc in the Bok globule CB 26. Multi-wavelength observations and modelling of the dust disc and envelope

    NASA Astrophysics Data System (ADS)

    Sauter, J.; Wolf, S.; Launhardt, R.; Padgett, D. L.; Stapelfeldt, K. R.; Pinte, C.; Duchêne, G.; Ménard, F.; McCabe, C.-E.; Pontoppidan, K.; Dunham, M.; Bourke, T. L.; Chen, J.-H.

    2009-10-01

    Context: Circumstellar discs are expected to be the nursery of planets. Grain growth within such discs is the first step in the planet formation process. The Bok globule CB 26 harbours such a young disc. Aims: We present a detailed model of the edge-on circumstellar disc and its envelope in the Bok globule CB 26. Methods: The model is based on HST near-infrared maps in the I, J, H, and K bands, OVRO and SMA radio maps at 1.1 mm, 1.3 mm and 2.7 mm, and the spectral energy distribution (SED) from 0.9 {μ m} to 3 mm. New photometric and spectroscopic data from the Spitzer Space Telescope and the Caltech Submilimeter Observatory are also part of our analysis. Using the self-consistent radiative transfer code MC3D, the model we construct is able to discriminate between parameter sets and dust properties of both envelope and disc. Results: We find that the data are fit by a disc that has an inner hole with a radius of 45±5 AU. Based on a dust model including silicate and graphite, the maximum grain size needed to reproduce the spectral millimetre index is 2.5 {μ m}. Features seen in the near-infrared images, dominated by scattered light, can be described as a result of a rotating envelope. Conclusions: Successful employment of ISM dust in both the disc and envelope hint that grain growth may not yet play a significant role for the appearance of this system. A large inner hole implies that CB 26 is a circumbinary disc.

  1. Probabilistic Fatigue Life Prediction of Turbine Disc Considering Model Parameter Uncertainty

    NASA Astrophysics Data System (ADS)

    He, Liping; Yu, Le; Zhu, Shun-Peng; Ding, Liangliang; Huang, Hong-Zhong

    2016-06-01

    Aiming to improve the predictive ability of Walker model for fatigue life prediction and taking the turbine disc alloy GH4133 as the application example, this paper investigates a new approach for probabilistic fatigue life prediction when considering parameter uncertainty inherent in the life prediction model. Firstly, experimental data are used to update the model parameters using Bayes' theorem, so as to obtain the posterior probability distribution functions of two parameters of the Walker model, as well to achieve the probabilistic life prediction model for turbine disc. During the updating process, Markov Chain Monte Carlo (MCMC) technique is used to generate samples of the given distribution and estimating the parameters distinctly. After that, the turbine disc life is predicted using the probabilistic Walker model based on Monte Carlo simulation technique. The experimental results indicate that: (1) after using the small sample test data obtained from turbine disc, parameter uncertainty of the Walker model can be quantified and the corresponding probabilistic model for fatigue life prediction can be established using Bayes' theorem; (2) there exists obvious dispersion of life data for turbine disc when predicting fatigue life in practical engineering application.

  2. Retinal Changes in an ATP-Induced Model of Retinal Degeneration.

    PubMed

    Aplin, Felix P; Vessey, Kirstan A; Luu, Chi D; Guymer, Robyn H; Shepherd, Robert K; Fletcher, Erica L

    2016-01-01

    In rodents and felines, intravitreal administration of adenosine triphosphate (ATP) has been shown to induce photoreceptor death providing a tractable model of retinal degeneration in these species. This study investigated the long term effects of photoreceptor loss in an ATP induced feline model of retinal degeneration. Six normal sighted felines were unilaterally blinded using intravitreal ATP injections and assessed using electroretinography (ERG) and optical coherence tomography (OCT). At 30 h (n = 3) or 12 weeks (n = 3) post-injection, the animals were euthanized and the eyes enucleated. Retinae were sectioned and labeled using immunohistochemistry for markers of cell death, neural remodeling and gliosis. Ongoing cell death and retinal degeneration was observed in the outer retina at both 30 h and 12 weeks following unilateral ATP injection. Markers of mid to late-stage retinal remodeling such as cell displacement and aberrant neurite growth were observed in the inner retina at 12 weeks post-injection. Ganglion cells appeared to remain intact in ATP injected eyes. Müller cell gliosis was observed throughout the inner and outer retina, in some parts completely enveloping and/or displacing the surviving neural tissue. Our data suggests that the ATP injected feline retina continues to undergo progressive retinal degeneration and exhibits abnormalities consistent with a description of retinal remodeling commonly seen in other models of retinal degeneration. These findings validate the use of intravitreal ATP injection in feline as a large animal model of retinal degeneration which may aid in development of therapies aiming to restore visual function after photoreceptor degeneration.

  3. Retinal Changes in an ATP-Induced Model of Retinal Degeneration

    PubMed Central

    Aplin, Felix P.; Vessey, Kirstan A.; Luu, Chi D.; Guymer, Robyn H.; Shepherd, Robert K.; Fletcher, Erica L.

    2016-01-01

    In rodents and felines, intravitreal administration of adenosine triphosphate (ATP) has been shown to induce photoreceptor death providing a tractable model of retinal degeneration in these species. This study investigated the long term effects of photoreceptor loss in an ATP induced feline model of retinal degeneration. Six normal sighted felines were unilaterally blinded using intravitreal ATP injections and assessed using electroretinography (ERG) and optical coherence tomography (OCT). At 30 h (n = 3) or 12 weeks (n = 3) post-injection, the animals were euthanized and the eyes enucleated. Retinae were sectioned and labeled using immunohistochemistry for markers of cell death, neural remodeling and gliosis. Ongoing cell death and retinal degeneration was observed in the outer retina at both 30 h and 12 weeks following unilateral ATP injection. Markers of mid to late-stage retinal remodeling such as cell displacement and aberrant neurite growth were observed in the inner retina at 12 weeks post-injection. Ganglion cells appeared to remain intact in ATP injected eyes. Müller cell gliosis was observed throughout the inner and outer retina, in some parts completely enveloping and/or displacing the surviving neural tissue. Our data suggests that the ATP injected feline retina continues to undergo progressive retinal degeneration and exhibits abnormalities consistent with a description of retinal remodeling commonly seen in other models of retinal degeneration. These findings validate the use of intravitreal ATP injection in feline as a large animal model of retinal degeneration which may aid in development of therapies aiming to restore visual function after photoreceptor degeneration. PMID:27199678

  4. Simulating the sensitivity of cell nutritive environment to composition changes within the intervertebral disc

    NASA Astrophysics Data System (ADS)

    Wills, C. Ruiz; Malandrino, A.; van Rijsbergen, MM.; Lacroix, D.; Ito, K.; Noailly, J.

    2016-05-01

    Altered nutrition in the intervertebral disc affects cell viability and can generate catabolic cascades contributing to extracellular matrix (ECM) degradation. Such degradation is expected to affect couplings between disc mechanics and nutrition, contributing to accelerate degenerative processes. However, the relation of ECM changes to major biophysical events within the loaded disc remains unclear. A L4-L5 disc finite element model including the nucleus (NP), annulus (AF) and endplates was used and coupled to a transport-cell viability model. Solute concentrations and cell viability were evaluated along the mid-sagittal plane path. A design of experiment (DOE) was performed. DOE parameters corresponded to AF and NP biochemical tissue measurements in discs with different degeneration grades. Cell viability was not affected by any parameter combinations defined. Nonetheless, the initial water content was the parameter that affected the most the solute contents, especially glucose. Calculations showed that altered NP composition could negatively affect AF cell nutrition. Results suggested that AF and NP tissue degeneration are not critical to nutrition-related cell viability at early-stage of disc degeneration. However, small ECM degenerative changes may alter significantly disc nutrition under mechanical loads. Coupling disc mechano-transport simulations and enzyme expression studies could allow identifying spatiotemporal sequences related to tissue catabolism.

  5. The Bosma effect revisited. I. HI and stellar disc scaling models

    NASA Astrophysics Data System (ADS)

    Hessman, F. V.; Ziebart, M.

    2011-08-01

    Context. The observed proportionality between the centripetal contribution of the dynamically insignificant HI gas in the discs of spiral galaxies and the dominant contribution of dark matter (DM) - the "Bosma effect" - has been repeatedly mentioned in the literature but largely ignored. Since this phenomenology, if statistically significant, tells us something about the relationship between the visible baryonic and invisible DM, it is important to re-examine the reality of this effect using formal tests and more modern data. Aims: We have re-examined the evidence for the Bosma effect, either by scaling the contribution of the HI gas alone or by using both the observed stellar disc and HI gas as proxies. Methods: We have calculated Bosma effect models for 17 galaxies in The HI Nearby Galaxy Survey data set. The results are compared with two models for exotic cold DM: internally consistent cosmological Navarro-Frenk-White (NFW) models with constrained compactness parameters, and "universal rotation curve" (URC) models using fully unconstrained Burkert density profiles. Results: Fits to spiral galaxy rotation curves computed using just HI scaling are inadequate, despite the clear proportionality seen in the outer discs. The poor performance is obviously related to the prominent decrease in the HI surface density in regions of high stellar surface density, where HI has been converted into molecules and stars. The Bosma models that partially correct for this physical effect using the stellar discs as additional proxies are statistically nearly as good as the URC models and clearly better than the NFW ones. Conclusions: We confirm the correlation between the centripetal effects of DM and that of the interstellar medium of spiral galaxies. The efficacy of "maximal disc" models is explained as the natural consequence of "classic" Bosma models which include the stellar disc as a proxy in regions of reduced atomic gas. The perception that the Bosma effect could be due to

  6. Precipitation Model Validation in 3rd Generation Aeroturbine Disc Alloys

    NASA Technical Reports Server (NTRS)

    Olson, G. B.; Jou, H.-J.; Jung, J.; Sebastian, J. T.; Misra, A.; Locci, I.; Hull, D.

    2008-01-01

    In support of application of the DARPA-AIM methodology to the accelerated hybrid thermal process optimization of 3rd generation aeroturbine disc alloys with quantified uncertainty, equilibrium and diffusion couple experiments have identified available fundamental thermodynamic and mobility databases of sufficient accuracy. Using coherent interfacial energies quantified by Single-Sensor DTA nucleation undercooling measurements, PrecipiCalc(TM) simulations of nonisothermal precipitation in both supersolvus and subsolvus treated samples show good agreement with measured gamma particle sizes and compositions. Observed longterm isothermal coarsening behavior defines requirements for further refinement of elastic misfit energy and treatment of the parallel evolution of incoherent precipitation at grain boundaries.

  7. In vivo dynamic stiffness of the porcine lumbar spine exposed to cyclic loading: influence of load and degeneration.

    PubMed

    Kaigle, A; Ekström, L; Holm, S; Rostedt, M; Hansson, T

    1998-02-01

    The dynamic axial stiffness of the L2-3 motion segment subjected to vibratory loading under intact and injured states of the intervertebral disc was studied using an in vivo porcine model. Three groups of animals with the following states of the intervertebral discs were studied: intact disc, acutely injured disc, and degenerated disc. A miniaturized servo-hydraulic exciter was used to sinusoidally vibrate the motion segment from 0.05 to 25 Hz under a compressive load with a peak value of either 100 or 200 N. The dynamic axial stiffness of the intervertebral disc was calculated at 1-Hz intervals over the frequency range. The results showed that the dynamic axial stiffness was frequency dependent. A positive relationship was found between an increase in mean dynamic stiffness and load magnitude. An increase in mean stiffness with successive exposures at the same load magnitude was observed, despite the allowance of a recovery period between loading. The greatest difference was noted between the first and second load sets. No significant change in stiffness was found due to an acute disc injury, whereas a significant increase in mean stiffness was found for the degenerated disc group as compared with the intact group. The form of the frequency response curve, however, remained relatively unaltered regardless of the degenerated state of the disc. With heavier loads, repeated loading, and/or disc degeneration, the stiffness of the intervertebral disc increases. An increase in stiffness can mean a reduction in the amount of allowable motion within the motion segment or a potentially harmful increase in force to obtain the desired motion. This may locally result in greater stresses due to an altered ability of the disc to distribute loads.

  8. LIM mineralization protein-1 suppresses TNF-α induced intervertebral disc degeneration by maintaining nucleus pulposus extracellular matrix production and inhibiting matrix metalloproteinases expression.

    PubMed

    Liu, Hui; Pan, Hehai; Yang, Hao; Wang, Jianru; Zhang, Kuibo; Li, Xiang; Wang, Hua; Ding, Wenbin; Li, Bingxue; Zheng, Zhaomin

    2015-03-01

    Imbalanced metabolism of Nucleus pulposus (NP) extracellular matrix (ECM) is closely correlated to Intervertebral Disc Degenerative Disease. LIM mineralization protein-1 (LMP-1) has been proven to induce sulfated glycosaminoglycan (sGAG) production in NP and have an anti-inflammatory effect in pre-osteoclast. However, whether it has any effect on the NP ECM production and degradation under inflammatory stimulation has not been studied. In the current study, a TNF-α induced cell model was established in vitro. Lentivirus encoding LMP-1 (LV-LMP-1) and short heparin LMP-1 (LV-shLMP-1) were constructed to overexpress and knockdown LMP-1 expression in NP cells. LMP-1 mRNA level was regulated in a dose-dependent manner after transfection. LV-LMP-1 increased whereas LV-shLMP-1 decreased collagen II, aggrecan, versican expression, and sGAG production. LV-LMP-1 abolished while LV-shLMP-1 aggravated TNF-α mediated down-regulation of the above matrix genes via ERK1/2 activation. Moreover, LV-LMP-1 abrogated TNF-α induced MMP-3 and MMP-13 expression via inhibiting p65 translocation and MMP-3 and MMP-13 promoter activity. These results indicated that LMP-1 had an ECM production maintenance effect under inflammatory stimulation. This effect was via up-regulation of matrix genes expression at least partially through ERK1/2 activation, and down-regulation of MMPs expression through NF-κB inhibition.

  9. Investigation of intervertebral disc degeneration using multivariate FTIR spectroscopic imaging† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c5fd00160a Click here for additional data file.

    PubMed Central

    Peeters, Mirte; Detiger, Suzanne E. L.; Helder, Marco N.; Smit, Theo H.; Le Maitre, Christine L.; Sammon, Chris

    2016-01-01

    Traditionally tissue samples are analysed using protein or enzyme specific stains on serial sections to build up a picture of the distribution of components contained within them. In this study we investigated the potential of multivariate curve resolution-alternating least squares (MCR-ALS) to deconvolute 2nd derivative spectra of Fourier transform infrared (FTIR) microscopic images measured in transflectance mode of goat and human paraffin embedded intervertebral disc (IVD) tissue sections, to see if this methodology can provide analogous information to that provided by immunohistochemical stains and bioassays but from a single section. MCR-ALS analysis of non-degenerate and enzymatically in vivo degenerated goat IVDs reveals five matrix components displaying distribution maps matching histological stains for collagen, elastin and proteoglycan (PG), as well as immunohistochemical stains for collagen type I and II. Interestingly, two components exhibiting characteristic spectral and distribution profiles of proteoglycans were found, and relative component/tissue maps of these components (labelled PG1 and PG2) showed distinct distributions in non-degenerate versus mildly degenerate goat samples. MCR-ALS analysis of human IVD sections resulted in comparable spectral profiles to those observed in the goat samples, highlighting the inter species transferability of the presented methodology. Multivariate FTIR image analysis of a set of 43 goat IVD sections allowed the extraction of semi-quantitative information from component/tissue gradients taken across the IVD width of collagen type I, collagen type II, PG1 and PG2. Regional component/tissue parameters were calculated and significant correlations were found between histological grades of degeneration and PG parameters (PG1: p = 0.0003, PG2: p < 0.0001); glycosaminoglycan (GAG) content and PGs (PG1: p = 0.0055, PG2: p = 0.0001); and MRI T2* measurements and PGs (PG1: p = 0.0021, PG2: p < 0.0001). Additionally

  10. MODELING NIGROSTRIATAL DEGENERATION IN ORGANOTYPIC CULTURES, A NEW EX VIVO MODEL OF PARKINSON’S DISEASE

    PubMed Central

    DAVIAUD, N.; GARBAYO, E.; LAUTRAM, N.; FRANCONI, F.; LEMAIRE, L.; PEREZ-PINZON, M.; MONTERO-MENEI, C. N.

    2014-01-01

    Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder afflicting 2% of the population older than 65 years worldwide. Recently, brain organotypic slices have been used to model neurodegenerative disorders, including PD. They conserve brain three-dimensional architecture, synaptic connectivity and its microenvironment. This model has allowed researchers a simple and rapid method to observe cellular interactions and mechanisms. In the present study, we developed an organotypic PD model from rat brains that includes all the areas involved in the nigrostriatal pathway in a single slice preparation, without using neurotoxins to induce the dopaminergic lesion. The mechanical transection of the nigrostriatal pathway obtained during slice preparation induced PD-like histopathology. Progressive nigrostriatal degeneration was monitored combining innovative approaches, such as diffusion tensor magnetic resonance imaging (DT-RMI) to follow fiber degeneration and mass spectrometry to quantify striatal dopamine content, together with bright-field and fluorescence microscopy imaging. A substantia nigra dopaminergic cell number decrease was observed by immunohistochemistry against rat tyrosine hydroxylase (TH) reaching 80% after 2 days in culture associated with a 30% decrease of striatal TH-positive fiber density, a 15% loss of striatal dopamine content quantified by mass spectrometry and a 70% reduction of nigrostriatal fiber fractional anisotropy quantified by DT-RMI. In addition, a significant decline of medium spiny neuron density was observed from days 7 to 16. These sagittal organotypic slices could be used to study the early stage of PD, namely dopaminergic degeneration, and the late stage of the pathology with dopaminergic and GABAergic neuron loss. This novel model might improve the understanding of PD and may represent a promising tool to refine the evaluation of new therapeutic approaches. PMID:24161279

  11. Disc erosion in Models 103 and 104 of Beall mitral valve prostheses

    PubMed Central

    Gómez, Ricardo; Verduras, María José; Lopez-Quintana, Alfonso; Riera, Luis; Zerolo, Ignacio; Martinez-Bordiu, Cristóbal

    1981-01-01

    Three cases of severe disc variance and erosion of the Teflon-disc Beall mitral valve prosthesis (Models 103 and 104) are reported. In two patients, the Beall mitral valves were excised and replaced with two Björk-Shiley mitral valves. The remaining patient did not survive, and at autopsy, the lens was found at the aortic bifurcation level. Because of this potentially lethal complication, careful follow-up of patients with Beall mitral valve prostheses (Models 103 and 104) is recommended. Images PMID:15216211

  12. The effect of sustained compression on oxygen metabolic transport in the intervertebral disc decreases with degenerative changes.

    PubMed

    Malandrino, Andrea; Noailly, Jérôme; Lacroix, Damien

    2011-08-01

    Intervertebral disc metabolic transport is essential to the functional spine and provides the cells with the nutrients necessary to tissue maintenance. Disc degenerative changes alter the tissue mechanics, but interactions between mechanical loading and disc transport are still an open issue. A poromechanical finite element model of the human disc was coupled with oxygen and lactate transport models. Deformations and fluid flow were linked to transport predictions by including strain-dependent diffusion and advection. The two solute transport models were also coupled to account for cell metabolism. With this approach, the relevance of metabolic and mechano-transport couplings were assessed in the healthy disc under loading-recovery daily compression. Disc height, cell density and material degenerative changes were parametrically simulated to study their influence on the calculated solute concentrations. The effects of load frequency and amplitude were also studied in the healthy disc by considering short periods of cyclic compression. Results indicate that external loads influence the oxygen and lactate regional distributions within the disc when large volume changes modify diffusion distances and diffusivities, especially when healthy disc properties are simulated. Advection was negligible under both sustained and cyclic compression. Simulating degeneration, mechanical changes inhibited the mechanical effect on transport while disc height, fluid content, nucleus pressure and overall cell density reductions affected significantly transport predictions. For the healthy disc, nutrient concentration patterns depended mostly on the time of sustained compression and recovery. The relevant effect of cell density on the metabolic transport indicates the disturbance of cell number as a possible onset for disc degeneration via alteration of the metabolic balance. Results also suggest that healthy disc properties have a positive effect of loading on metabolic transport. Such

  13. Molecular Mechanisms of Biological Aging in Intervertebral Discs

    PubMed Central

    Vo, Nam V.; Hartman, Robert A.; Patil, Prashanti R.; Risbud, Makarand V.; Kletsas, Dimitris; Iatridis, James C.; Hoyland, Judith A.; Le Maitre, Christine L.; Sowa, Gwendolyn A.; Kang, James D.

    2016-01-01

    Advanced age is the greatest risk factor for the majority of human ailments, including spine-related chronic disability and back pain, which stem from age-associated intervertebral disc degeneration (IDD). Given the rapid global rise in the aging population, understanding the biology of intervertebral disc aging in order to develop effective therapeutic interventions to combat the adverse effects of aging on disc health is now imperative. Fortunately, recent advances in aging research have begun to shed light on the basic biological process of aging. Here we review some of these insights and organize the complex process of disc aging into three different phases to guide research efforts to understand the biology of disc aging. The objective of this review is to provide an overview of the current knowledge and the recent progress made to elucidate specific molecular mechanisms underlying disc aging. In particular, studies over the last few years have uncovered cellular senescence and genomic instability as important drivers of disc aging. Supporting evidence comes from DNA repair-deficient animal models that show increased disc cellular senescence and accelerated disc aging. Additionally, stress-induced senescent cells have now been well documented to secrete catabolic factors, which can negatively impact the physiology of neighboring cells and ECM. These along with other molecular drivers of aging are reviewed in depth to shed crucial insights into the underlying mechanisms of age-related disc degeneration. We also highlight molecular targets for novel therapies and emerging candidate therapeutics that may mitigate age-associated IDD. PMID:26890203

  14. Analytical model of electron transport in polycrystalline, degenerately doped ZnO films

    SciTech Connect

    Bikowski, André Ellmer, Klaus

    2014-10-14

    An analytical description of the charge carrier transport, valid for non-degenerated and degenerated semiconductors, was developed, critically reviewed, and fitted to the temperature-dependent Hall mobility data of magnetron sputtered, degenerately doped ZnO:Al films. Our extended model for grain boundary scattering in semiconductors of arbitrary degeneracy is based on previous models from literature and suitable to describe the Hall mobility of the carriers as a function of the free carrier concentration and the temperature at the same time. It is mathematically simple enough for a fast fit procedure, which is not possible with most of the previous models. Applying a combined transport model consisting of ionized impurity scattering, phonon scattering, and grain boundary scattering in degenerate semiconductors, we were able to determine the trap density at the grain boundaries Nₜ ≈ 3×10¹³ to 5×10¹³cm⁻² and the deformation potential E{sub ac} in the range of 5 eV to 9 eV depending on the details of the transport model.

  15. Evaluation of load transfer characteristics of a dynamic stabilization device on disc loading under compression.

    PubMed

    Zhang, Qing Hang; Zhou, Yuan Li; Petit, Dominique; Teo, Ee Chon

    2009-06-01

    In the current study, finite element analyses were conducted to examine the biomechanical capability of a newly design dynamic stabilization system, FlexPLUS, to restore the load transmission of degenerated intervertebral L4-L5 lumbar motion segment spine under compression. Detailed three-dimensional FE models of L4-L5 motion segment and the FlexPLUS were developed. Compressive loading up to 1000N was applied to the intact L4-L5 model, the L4-L5 models with slight and moderate degenerated disc, and the implanted L4-L5 model. Further more, the load transmission characteristics of Dynesys and a rigid rod was also simulated for comparison. The resultant load-displacement curves and the load transferred through annulus under various conditions were compared. The predicted axial displacement of L4 top surface against applied compressive force of the intact L4-L5 model agreed well with experimental data. The predicted results showed that degenerated disc has significant effect on the lumbar segment load bearing capacity. Not only the stiffness of the segment was greatly increased, the uniform nature of the disc stress distribution was also altered. The FlexPLUS can effectively reduce the disc loading of degenerated model. Although the non-uniform load distribution pattern through annulus was not improved, the overall stress magnitude was greatly reduced to the level of intact model for grade II degeneration.

  16. A 1-D model of the nonlinear dynamics of the human lumbar intervertebral disc

    NASA Astrophysics Data System (ADS)

    Marini, Giacomo; Huber, Gerd; Püschel, Klaus; Ferguson, Stephen J.

    2017-01-01

    Lumped parameter models of the spine have been developed to investigate its response to whole body vibration. However, these models assume the behaviour of the intervertebral disc to be linear-elastic. Recently, the authors have reported on the nonlinear dynamic behaviour of the human lumbar intervertebral disc. This response was shown to be dependent on the applied preload and amplitude of the stimuli. However, the mechanical properties of a standard linear elastic model are not dependent on the current deformation state of the system. The aim of this study was therefore to develop a model that is able to describe the axial, nonlinear quasi-static response and to predict the nonlinear dynamic characteristics of the disc. The ability to adapt the model to an individual disc's response was a specific focus of the study, with model validation performed against prior experimental data. The influence of the numerical parameters used in the simulations was investigated. The developed model exhibited an axial quasi-static and dynamic response, which agreed well with the corresponding experiments. However, the model needs further improvement to capture additional peculiar characteristics of the system dynamics, such as the change of mean point of oscillation exhibited by the specimens when oscillating in the region of nonlinear resonance. Reference time steps were identified for specific integration scheme. The study has demonstrated that taking into account the nonlinear-elastic behaviour typical of the intervertebral disc results in a predicted system oscillation much closer to the physiological response than that provided by linear-elastic models. For dynamic analysis, the use of standard linear-elastic models should be avoided, or restricted to study cases where the amplitude of the stimuli is relatively small.

  17. Linear moose model with pairs of degenerate gauge boson triplets

    NASA Astrophysics Data System (ADS)

    Casalbuoni, Roberto; Coradeschi, Francesco; de Curtis, Stefania; Dominici, Daniele

    2008-05-01

    The possibility of a strongly interacting electroweak symmetry breaking sector, as opposed to the weakly interacting light Higgs of the standard model, is not yet ruled out by experiments. In this paper we make an extensive study of a deconstructed model (or “moose” model) providing an effective description of such a strong symmetry breaking sector, and show its compatibility with experimental data for a wide portion of the model parameter space. The model is a direct generalization of the previously proposed D-BESS model.

  18. Linear moose model with pairs of degenerate gauge boson triplets

    SciTech Connect

    Casalbuoni, Roberto; Coradeschi, Francesco; De Curtis, Stefania; Dominici, Daniele

    2008-05-01

    The possibility of a strongly interacting electroweak symmetry breaking sector, as opposed to the weakly interacting light Higgs of the standard model, is not yet ruled out by experiments. In this paper we make an extensive study of a deconstructed model (or ''moose'' model) providing an effective description of such a strong symmetry breaking sector, and show its compatibility with experimental data for a wide portion of the model parameter space. The model is a direct generalization of the previously proposed D-BESS model.

  19. Mechanical testing and modelling of carbon-carbon composites for aircraft disc brakes

    NASA Astrophysics Data System (ADS)

    Bradley, Luke R.

    The objective of this study is to improve the understanding of the stress distributions and failure mechanisms experienced by carbon-carbon composite aircraft brake discs using finite element (FE) analyses. The project has been carried out in association with Dunlop Aerospace as an EPSRC CASE studentship. It therefore focuses on the carbon-carbon composite brake disc material produced by Dunlop Aerospace, although it is envisaged that the approach will have broader applications for modelling and mechanical testing of carbon-carbon composites in general. The disc brake material is a laminated carbon-carbon composite comprised of poly(acrylonitrile) (PAN) derived carbon fibres in a chemical vapour infiltration (CVI) deposited matrix, in which the reinforcement is present in both continuous fibre and chopped fibre forms. To pave the way for the finite element analysis, a comprehensive study of the mechanical properties of the carbon-carbon composite material was carried out. This focused largely, but not entirely, on model composite materials formulated using structural elements of the disc brake material. The strengths and moduli of these materials were measured in tension, compression and shear in several orientations. It was found that the stress-strain behaviour of the materials were linear in directions where there was some continuous fibre reinforcement, but non-linear when this was not the case. In all orientations, some degree of non-linearity was observed in the shear stress-strain response of the materials. However, this non-linearity was generally not large enough to pose a problem for the estimation of elastic moduli. Evidence was found for negative Poisson's ratio behaviour in some orientations of the material in tension. Additionally, the through-thickness properties of the composite, including interlaminar shear strength, were shown to be positively related to bulk density. The in-plane properties were mostly unrelated to bulk density over the range of

  20. Continuum and line modelling of discs around young stars. II. Line diagnostics for GASPS from the DENT grid

    NASA Astrophysics Data System (ADS)

    Kamp, I.; Woitke, P.; Pinte, C.; Tilling, I.; Thi, W.-F.; Menard, F.; Duchene, G.; Augereau, J.-C.

    2011-08-01

    Aims: We want to understand the chemistry and physics of discs on the basis of a large unbiased and statistically relevant grid of disc models. One of the main goals is to explore the diagnostic power of various gas emission lines and line ratios for deriving main disc parameters such as the gas mass. Methods: We explored the results of the DENT grid (Disk Evolution with Neat Theory) that consists of 300 000 disc models with 11 free parameters. Through a statistical analysis, we searched for correlations and trends in an effort to find tools for disc diagnostic. Results: All calculated quantities like species masses, temperatures, continuum, and line fluxes differ by several orders of magnitude across the entire parameter space. The broad distribution of these quantities as a function of input parameters shows the limitation of using a prototype T Tauri or Herbig Ae/Be disc model. The statistical analysis of the DENT grid shows that CO gas is rarely the dominant carbon reservoir in discs. Models with large inner radii (10 times the dust condensation radius) and/or shallow surface density gradients lack massive gas-phase water reservoirs. Also, 60% of the discs have gas temperatures averaged over the oxygen mass in the range between 15 and 70 K; the average gas temperatures for CO and O differ by less than a factor two. Our study of the observational diagnostics shows that the [C ii] 158 μm fine structure line flux is very sensitive to the stellar UV flux and presence of a UV excess, and that it traces the outer disc radius (Rout). In the submm, the CO low J rotational lines also trace Rout. Low [O i] 63/145 line ratios (disc models without UV excess. A combination of the [O i] 63 line and low J CO lines correlates with several disc properties, such as the average O i gas temperature in

  1. ICT and e-Governance: A Conceptual Model of e-DISC

    NASA Astrophysics Data System (ADS)

    Tejasvee, Sanjay; Sarangdevot, S. S.; Gahlot, Devendra; Gour, Vishal; Sandal, Shruti

    2010-11-01

    One of the most important objectives of e-governance is, proper distribution and delivery of government information and services to the citizens. By progression in resources of information technology, great opportunities comes to the government for serve information and services to the citizens and public sector in better manner. This paper intends to examine and explore the conceptual model of e-DISC (Effective Deliverance of Information and Services to the Citizens) The purpose of this paper is to gain a better understanding of e-government in India with the concept of e-DISC with ICTs and how to deal with challenges and barriers for successful e-DISC model with accuracy. The obtained results prove that the utilizing and by increasing interest in the new electronic, information, and communication technologies (ICTs) and e-DISC model in recent time, government improved the quality of e-governance and delivery of information and services and acknowledged the awareness of the system is also valuable.

  2. Retinal degeneration in animal models with a defective visual cycle

    PubMed Central

    Maeda, Akiko; Palczewski, Krzysztof

    2014-01-01

    Continuous generation of visual chromophore through the visual (retinoid) cycle is essential to maintain eyesight and retinal heath. Impairments in this cycle and related pathways adversely affect vision. In this review, we summarize the chemical reactions of vitamin A metabolites involved in the retinoid cycle and describe animal models of associated human diseases. Development of potential therapies for retinal disorders in these animal models is also introduced. PMID:25210527

  3. Influence of high-permeability discs in an axisymmetric model of the Cadarache dynamo experiment

    NASA Astrophysics Data System (ADS)

    Giesecke, A.; Nore, C.; Stefani, F.; Gerbeth, G.; Léorat, J.; Herreman, W.; Luddens, F.; Guermond, J.-L.

    2012-05-01

    Numerical simulations of the kinematic induction equation are performed on a model configuration of the Cadarache von-Kármán-sodium dynamo experiment. The effect of a localized axisymmetric distribution of relative permeability μr that represents soft iron material within the conducting fluid flow is investigated. The critical magnetic Reynolds number Rmc for dynamo action of the first non-axisymmetric mode roughly scales like Rmcμr - Rmc∞∝μ-1/2r, i.e. the threshold decreases as μr increases. This scaling law suggests a skin effect mechanism in the soft iron discs. More important with regard to the Cadarache dynamo experiment, we observe a purely toroidal axisymmetric mode localized in the high-permeability discs which becomes dominant for large μr. In this limit, the toroidal mode is close to the onset of dynamo action with a (negative) growth rate that is rather independent of the magnetic Reynolds number. We qualitatively explain this effect by paramagnetic pumping at the fluid/disc interface and propose a simplified model that quantitatively reproduces numerical results. The crucial role of the high-permeability discs in the mode selection in the Cadarache dynamo experiment cannot be inferred from computations using idealized pseudo-vacuum boundary conditions (H × n = 0).

  4. Yttrium oxide nanoparticles prevent photoreceptor death in a light-damage model of retinal degeneration.

    PubMed

    Mitra, Rajendra N; Merwin, Miles J; Han, Zongchao; Conley, Shannon M; Al-Ubaidi, Muayyad R; Naash, Muna I

    2014-10-01

    Photoreceptor (PR) cells are prone to accumulation of reactive oxygen species (ROS) and oxidative stress. An imbalance between the production of ROS and cellular antioxidant defenses contributes to PR degeneration and blindness in many different ocular disease states. Yttrium oxide (Y2O3) nanoparticles (NPs) are excellent free radical scavengers owing to their nonstoichiometric crystal defects. Here we utilize a murine light-stress model to test the efficacy of Y2O3 NPs (~10-14nm in diameter) in ameliorating retinal oxidative stress-associated degeneration. Our studies demonstrate that intravitreal injections of these NPs at doses ranging from 0.1 to 5.0µM 2 weeks before acute light stress protect PRs from degeneration. This protection is reflected both structurally (i.e., decreased light-associated thinning of the outer nuclear layer) and functionally (i.e., preservation of scotopic and photopic electroretinogram amplitudes). We also observe preservation of structure and function when NPs are delivered immediately after acute light stress, although the magnitude of the preservation is smaller, and only doses ranging from 1.0 to 5.0µM were effective. We show that the Y2O3 NPs are nontoxic and well tolerated after intravitreal delivery. Our results suggest that Y2O3 NPs have astonishing antioxidant benefits and, with further exploration, may be an excellent strategy for the treatment of oxidative stress associated with multiple forms of retinal degeneration.

  5. Loss of Ikbkap Causes Slow, Progressive Retinal Degeneration in a Mouse Model of Familial Dysautonomia

    PubMed Central

    Ramirez, Grisela

    2016-01-01

    Abstract Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that is caused by a mutation in the gene for inhibitor of kappa B kinase complex-associated protein (IKBKAP). Although FD patients suffer from multiple neuropathies, a major debilitation that affects their quality of life is progressive blindness. To determine the requirement for Ikbkap in the developing and adult retina, we generated Ikbkap conditional knockout (CKO) mice using a TUBA1a promoter-Cre (Tα1-Cre). In the retina, Tα1-Cre expression is detected predominantly in retinal ganglion cells (RGCs). At 6 months, significant loss of RGCs had occurred in the CKO retinas, with the greatest loss in the temporal retina, which is the same spatial phenotype observed in FD, Leber hereditary optic neuropathy, and dominant optic atrophy. Interestingly, the melanopsin-positive RGCs were resistant to degeneration. By 9 months, signs of photoreceptor degeneration were observed, which later progressed to panretinal degeneration, including RGC and photoreceptor loss, optic nerve thinning, Müller glial activation, and disruption of layers. Taking these results together, we conclude that although Ikbkap is not required for normal development of RGCs, its loss causes a slow, progressive RGC degeneration most severely in the temporal retina, which is later followed by indirect photoreceptor loss and complete retinal disorganization. This mouse model of FD is not only useful for identifying the mechanisms mediating retinal degeneration, but also provides a model system in which to attempt to test therapeutics that may mitigate the loss of vision in FD patients. PMID:27699209

  6. Longitudinal Changes in the Structure and Inflammatory Response of the Intervertebral Disc Due to Stab Injury in a Murine Organ Culture Model

    PubMed Central

    Abraham, Adam C.; Liu, Jennifer W.; Tang, Simon Y.

    2017-01-01

    Despite the significant public health impact of intervertebral disc (IVD) degeneration and low back pain, it remains challenging to investigate the multifactorial molecular mechanisms that drive the degenerative cascade. Organ culture model systems offer the advantage of allowing cells to live and interact with their native extracellular matrix, while simultaneously reducing the amount of biological variation and complexity present at the organismal level. Murine organ cultures in particular also allow the use of widely available genetically modified animals with molecular level reporters that would reveal insights on the degenerative cascade. Here, we utilize an organ culture system of murine lumbar functional spinal units where we are able to maintain the cellular, metabolic, and structural, and mechanical stability of the whole organ over a 21-day period. Furthermore, we describe a novel approach in organ culture by using tissues from animals with an NF-κB-luc reporter in combination with a mechanical injury model, and are able to show that proinflammatory factors and cytokines such as NF-κB and IL-6 produced by IVD cells can be monitored longitudinally during culture in a stab injury model. Taken together, we utilize a murine organ culture system that maintains the cellular and tissue level behavior of the intervertebral disc and apply it to transgenic animals that allow the monitoring of the inflammatory profile of IVDs. This approach could provide important insights on the molecular and metabolic mediators that regulate the homeostasis of the IVD. PMID:27273204

  7. From the channel model of an InSb-based superresolution optical disc system to impulse response and resolution limits.

    PubMed

    Hepper, Dietmar

    2011-06-10

    The signal model of a superresolution optical channel can be an efficient tool for developing components of an associated high-density optical disc system. While the behavior of the laser diode, aperture, lens, and detector are properly described, a general mathematical model of the superresolution disc itself has not yet been available until recently. Different approaches have been made to describe the properties of a mask layer, mainly based on temperature- or power-dependent nonlinear effects. A complete signal-based or phenomenological optical channel model--from non-return-to-zero inverted input to disc readout signal--has recently been developed including the reflectivity of a superresolution disc with InSb used for the mask layer. In this contribution, the model is now extended and applied to a moving disc including a land-and-pit structure, and results are compared with data read from real superresolution discs. Both impulse response and resolution limits are derived and discussed. Thus the model provides a bridge from physical to readout signal properties, which count after all. The presented approach allows judging of the suitability of a mask layer material for storage density enhancement already based on static experiments, i.e., even before developing an associated disc drive.

  8. From hidden symmetry to extra dimensions: A five-dimensional formulation of the degenerate BESS model

    NASA Astrophysics Data System (ADS)

    Coradeschi, Francesco; de Curtis, Stefania; Dominici, Daniele

    2010-07-01

    We consider the continuum limit of a moose model corresponding to a generalization to N sites of the degenerate BESS model. The five-dimensional formulation emerging in this limit is a realization of a RS1 type model with SU(2)L⊗SU(2)R in the bulk, broken by boundary conditions and a vacuum expectation value on the infrared brane. A low-energy effective Lagrangian is derived by means of the holographic technique and corresponding bounds on the model parameters are obtained.

  9. From hidden symmetry to extra dimensions: A five-dimensional formulation of the degenerate BESS model

    SciTech Connect

    Coradeschi, Francesco; De Curtis, Stefania; Dominici, Daniele

    2010-07-01

    We consider the continuum limit of a moose model corresponding to a generalization to N sites of the degenerate BESS model. The five-dimensional formulation emerging in this limit is a realization of a RS1 type model with SU(2){sub L} x SU(2){sub R} in the bulk, broken by boundary conditions and a vacuum expectation value on the infrared brane. A low-energy effective Lagrangian is derived by means of the holographic technique and corresponding bounds on the model parameters are obtained.

  10. Imbalanced Protein Expression Patterns of Anabolic, Catabolic, Anti-Catabolic and Inflammatory Cytokines in Degenerative Cervical Disc Cells: New Indications for Gene Therapeutic Treatments of Cervical Disc Diseases

    PubMed Central

    Mern, Demissew S.; Beierfuß, Anja; Fontana, Johann; Thomé, Claudius; Hegewald, Aldemar A.

    2014-01-01

    Degenerative disc disease (DDD) of the cervical spine is common after middle age and can cause loss of disc height with painful nerve impingement, bone and joint inflammation. Despite the clinical importance of these problems, in current publications the pathology of cervical disc degeneration has been studied merely from a morphologic view point using magnetic resonance imaging (MRI), without addressing the issue of biological treatment approaches. So far a wide range of endogenously expressed bioactive factors in degenerative cervical disc cells has not yet been investigated, despite its importance for gene therapeutic approaches. Although degenerative lumbar disc cells have been targeted by different biological treatment approaches, the quantities of disc cells and the concentrations of gene therapeutic factors used in animal models differ extremely. These indicate lack of experimentally acquired data regarding disc cell proliferation and levels of target proteins. Therefore, we analysed proliferation and endogenous expression levels of anabolic, catabolic, ant-catabolic, inflammatory cytokines and matrix proteins of degenerative cervical disc cells in three-dimensional cultures. Preoperative MRI grading of cervical discs was used, then grade III and IV nucleus pulposus (NP) tissues were isolated from 15 patients, operated due to cervical disc herniation. NP cells were cultured for four weeks with low-glucose in collagen I scaffold. Their proliferation rates were analysed using 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide. Their protein expression levels of 28 therapeutic targets were analysed using enzyme-linked immunosorbent assay. During progressive grades of degeneration NP cell proliferation rates were similar. Significantly decreased aggrecan and collagen II expressions (P<0.0001) were accompanied by accumulations of selective catabolic and inflammatory cytokines (disintegrin and metalloproteinase with thrombospondin motifs 4 and 5, matrix

  11. Cervical Total Disc Arthroplasty

    PubMed Central

    Basho, Rahul; Hood, Kenneth A.

    2012-01-01

    Symptomatic adjacent segment degeneration of the cervical spine remains problematic for patients and surgeons alike. Despite advances in surgical techniques and instrumentation, the solution remains elusive. Spurred by the success of total joint arthroplasty in hips and knees, surgeons and industry have turned to motion preservation devices in the cervical spine. By preserving motion at the diseased level, the hope is that adjacent segment degeneration can be prevented. Multiple cervical disc arthroplasty devices have come onto the market and completed Food and Drug Administration Investigational Device Exemption trials. Though some of the early results demonstrate equivalency of arthroplasty to fusion, compelling evidence of benefits in terms of symptomatic adjacent segment degeneration are lacking. In addition, non-industry-sponsored studies indicate that these devices are equivalent to fusion in terms of adjacent segment degeneration. Longer-term studies will eventually provide the definitive answer. PMID:24353955

  12. The rat intervertebral disk degeneration pain model: relationships between biological and structural alterations and pain

    PubMed Central

    2011-01-01

    Introduction Degeneration of the interverterbral disk is as a cause of low-back pain is increasing. To gain insight into relationships between biological processes, structural alterations and behavioral pain, we created an animal model in rats. Methods Disk degeneration was induced by removal of the nucleus pulposus (NP) from the lumbar disks (L4/L5 and L5/L6) of Sprague Dawley rats using a 0.5-mm-diameter microsurgical drill. The degree of primary hyperalgesia was assessed by using an algometer to measure pain upon external pressure on injured lumbar disks. Biochemical and histological assessments and radiographs of injured disks were used for evaluation. We investigated therapeutic modulation of chronic pain by administering pharmaceutical drugs in this animal model. Results After removal of the NP, pressure hyperalgesia developed over the lower back. Nine weeks after surgery we observed damaged or degenerated disks with proteoglycan loss and narrowing of disk height. These biological and structural changes in disks were closely related to the sustained pain hyperalgesia. A high dose of morphine (6.7 mg/kg) resulted in effective pain relief. However, high doses of pregabalin (20 mg/kg), a drug that has been used for treatment of chronic neuropathic pain, as well as the anti-inflammatory drugs celecoxib (50 mg/kg; a selective inhibitor of cyclooxygenase 2 (COX-2)) and ketorolac (20 mg/kg; an inhibitor of COX-1 and COX-2), did not have significant antihyperalgesic effects in our disk injury animal model. Conclusions Although similarities in gene expression profiles suggest potential overlap in chronic pain pathways linked to disk injury or neuropathy, drug-testing results suggest that pain pathways linked to these two chronic pain conditions are mechanistically distinct. Our findings provide a foundation for future research on new therapeutic interventions that can lead to improvements in the treatment of patients with back pain due to disk degeneration. PMID

  13. Intervertebral disc response to cyclic loading--an animal model.

    PubMed

    Ekström, L; Kaigle, A; Hult, E; Holm, S; Rostedt, M; Hansson, T

    1996-01-01

    The viscoelastic response of a lumbar motion segment loaded in cyclic compression was studied in an in vivo porcine model (N = 7). Using surgical techniques, a miniaturized servohydraulic exciter was attached to the L2-L3 motion segment via pedicle fixation. A dynamic loading scheme was implemented, which consisted of one hour of sinusoidal vibration at 5 Hz, 50 N peak load, followed by one hour of restitution at zero load and one hour of sinusoidal vibration at 5 Hz, 100 N peak load. The force and displacement responses of the motion segment were sampled at 25 Hz. The experimental data were used for evaluating the parameters of two viscoelastic models: a standard linear solid model (three-parameter) and a linear Burger's fluid model (four-parameter). In this study, the creep behaviour under sinusoidal vibration at 5 Hz closely resembled the creep behaviour under static loading observed in previous studies. Expanding the three-parameter solid model into a four-parameter fluid model made it possible to separate out a progressive linear displacement term. This deformation was not fully recovered during restitution and is therefore an indication of a specific effect caused by the cyclic loading. High variability was observed in the parameters determined from the 50 N experimental data, particularly for the elastic modulus E1. However, at the 100 N load level, significant differences between the models were found. Both models accurately predicted the creep response under the first 800 s of 100 N loading, as displayed by mean absolute errors for the calculated deformation data from the experimental data of 1.26 and 0.97 percent for the solid and fluid models respectively. The linear Burger's fluid model, however, yielded superior predictions particularly for the initial elastic response.

  14. Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration

    PubMed Central

    Sahaboglu, Ayse; Barth, Melanie; Secer, Enver; Amo, Eva M. del; Urtti, Arto; Arsenijevic, Yvan; Zrenner, Eberhart; Paquet-Durand, François

    2016-01-01

    The enzyme poly-ADP-ribose-polymerase (PARP) mediates DNA-repair and rearrangements of the nuclear chromatin. Generally, PARP activity is thought to promote cell survival and in recent years a number of PARP inhibitors have been clinically developed for cancer treatment. Paradoxically, PARP activity is also connected to many diseases including the untreatable blinding disease Retinitis Pigmentosa (RP), where PARP activity appears to drive the pathogenesis of photoreceptor loss. We tested the efficacy of three different PARP inhibitors to prevent photoreceptor loss in the rd1 mouse model for RP. In retinal explant cultures in vitro, olaparib had strong and long-lasting photoreceptor neuroprotective capacities. We demonstrated target engagement by showing that olaparib reduced photoreceptor accumulation of poly-ADP-ribosylated proteins. Remarkably, olaparib also reduced accumulation of cyclic-guanosine-monophosphate (cGMP), a characteristic marker for photoreceptor degeneration. Moreover, intravitreal injection of olaparib in rd1 animals diminished PARP activity and increased photoreceptor survival, confirming in vivo neuroprotection. This study affirms the role of PARP in inherited retinal degeneration and for the first time shows that a clinically approved PARP inhibitor can prevent photoreceptor degeneration in an RP model. The wealth of human clinical data available for olaparib highlights its strong potential for a rapid clinical translation into a novel RP treatment. PMID:28004814

  15. Models of collective cell spreading with variable cell aspect ratio: A motivation for degenerate diffusion models

    NASA Astrophysics Data System (ADS)

    Simpson, Matthew J.; Baker, Ruth E.; McCue, Scott W.

    2011-02-01

    Continuum diffusion models are often used to represent the collective motion of cell populations. Most previous studies have simply used linear diffusion to represent collective cell spreading, while others found that degenerate nonlinear diffusion provides a better match to experimental cell density profiles. In the cell modeling literature there is no guidance available with regard to which approach is more appropriate for representing the spreading of cell populations. Furthermore, there is no knowledge of particular experimental measurements that can be made to distinguish between situations where these two models are appropriate. Here we provide a link between individual-based and continuum models using a multiscale approach in which we analyze the collective motion of a population of interacting agents in a generalized lattice-based exclusion process. For round agents that occupy a single lattice site, we find that the relevant continuum description of the system is a linear diffusion equation, whereas for elongated rod-shaped agents that occupy L adjacent lattice sites we find that the relevant continuum description is connected to the porous media equation (PME). The exponent in the nonlinear diffusivity function is related to the aspect ratio of the agents. Our work provides a physical connection between modeling collective cell spreading and the use of either the linear diffusion equation or the PME to represent cell density profiles. Results suggest that when using continuum models to represent cell population spreading, we should take care to account for variations in the cell aspect ratio because different aspect ratios lead to different continuum models.

  16. The three-dimension model for the rock-breaking mechanism of disc cutter and analysis of rock-breaking forces

    NASA Astrophysics Data System (ADS)

    Zhang, Zhao-Huang; Sun, Fei

    2012-06-01

    To study the rock deformation with three-dimensional model under rolling forces of disc cutter, by carrying out the circular-grooving test with disc cutter rolling around on the rock, the rock mechanical behavior under rolling disc cutter is studied, the mechanical model of disc cutter rolling around the groove is established, and the theory of single-point and double-angle variables is proposed. Based on this theory, the physics equations and geometric equations of rock mechanical behavior under disc cutters of tunnel boring machine (TBM) are studied, and then the balance equations of interactive forces between disc cutter and rock are established. Accordingly, formulas about normal force, rolling force and side force of a disc cutter are derived, and their validity is studied by tests. Therefore, a new method and theory is proposed to study rock-breaking mechanism of disc cutters.

  17. Modelling accretion disc and stellar wind interactions: the case of Sgr A*

    NASA Astrophysics Data System (ADS)

    Christie, I. M.; Petropoulou, M.; Mimica, P.; Giannios, D.

    2016-07-01

    Sgr A* is an ideal target to study low-luminosity accreting systems. It has been recently proposed that properties of the accretion flow around Sgr A* can be probed through its interactions with the stellar wind of nearby massive stars belonging to the S-cluster. When a star intercepts the accretion disc, the ram and thermal pressures of the disc terminate the stellar wind leading to the formation of a bow shock structure. Here, a semi-analytical model is constructed which describes the geometry of the termination shock formed in the wind. With the employment of numerical hydrodynamic simulations, this model is both verified and extended to a region prone to Kelvin-Helmholtz instabilities. Because the characteristic wind and stellar velocities are in ˜108 cm s-1 range, the shocked wind may produce detectable X-rays via thermal bremsstrahlung emission. The application of this model to the pericentre passage of S2, the brightest member of the S-cluster, shows that the shocked wind produces roughly a month long X-ray flare with a peak luminosity of L ≈ 4 × 1033 erg s-1 for a stellar mass-loss rate, disc number density, and thermal pressure strength of dot{M}_w= 10^{-7} M_{⊙} yr^{-1}, nd = 105 cm-3, and α = 0.1, respectively. This peak luminosity is comparable to the quiescent X-ray emission detected from Sgr A* and is within the detection capabilities of current X-ray observatories. Its detection could constrain the density and thickness of the disc at a distance of ˜3000 gravitational radii from the supermassive black hole.

  18. Investigating the Andromeda stream - I. Simple analytic bulge-disc-halo model for M31

    NASA Astrophysics Data System (ADS)

    Geehan, J. J.; Fardal, M. A.; Babul, A.; Guhathakurta, P.

    2006-03-01

    This paper is the first in a series which studies interactions between M31 and its satellites, including the origin of the giant southern stream. We construct accurate yet simple analytic models for the potential of the M31 galaxy to provide an easy basis for the calculation of orbits in M31's halo. We use a Navarro, Frenk and White (NFW) dark halo, an exponential disc, a Hernquist bulge, and a central black hole point mass to describe the galaxy potential. We constrain the parameters of these functions by comparing to existing surface-brightness, velocity-dispersion, and rotation-curve measurements of M31. Our description provides a good fit to the observations, and agrees well with more sophisticated modelling of M31. While in many respects the parameter set is well constrained, there is substantial uncertainty in the outer halo potential and a near-degeneracy between the disc and halo components, producing a large, nearly two-dimensional allowed region in parameter space. We limit the allowed region using theoretical expectations for the halo concentration, baryonic content, and stellar mass-to-light ratio (M/LR), finding a smaller region where the parameters are physically plausible. Our proposed mass model for M31 has Mbulge= 3.2 × 1010Msolar, Mdisc= 7.2 × 1010Msolar, and M200= 7.1 × 1011Msolar, with uncorrected (for internal and foreground extinction) mass-to-light ratios of M/LR= 3.9 and 3.3 for the bulge and disc, respectively. We present some illustrative test-particle orbits for the progenitor of the stellar stream in our galaxy potential, highlighting the effects of the remaining uncertainty in the disc and halo masses.

  19. Modelling accretion disc and stellar wind interactions: the case of Sgr A.

    PubMed

    Christie, I M; Petropoulou, M; Mimica, P; Giannios, D

    2016-07-01

    Sgr A* is an ideal target to study low-luminosity accreting systems. It has been recently proposed that properties of the accretion flow around Sgr A* can be probed through its interactions with the stellar wind of nearby massive stars belonging to the S-cluster. When a star intercepts the accretion disc, the ram and thermal pressures of the disc terminate the stellar wind leading to the formation of a bow shock structure. Here, a semi-analytical model is constructed which describes the geometry of the termination shock formed in the wind. With the employment of numerical hydrodynamic simulations, this model is both verified and extended to a region prone to Kelvin-Helmholtz instabilities. Because the characteristic wind and stellar velocities are in ∼10(8) cm s(-1) range, the shocked wind may produce detectable X-rays via thermal bremsstrahlung emission. The application of this model to the pericentre passage of S2, the brightest member of the S-cluster, shows that the shocked wind produces roughly a month long X-ray flare with a peak luminosity of L ≈ 4 × 10(33) erg s(-1) for a stellar mass-loss rate, disc number density, and thermal pressure strength of [Formula: see text], nd = 10(5) cm(-3), and α = 0.1, respectively. This peak luminosity is comparable to the quiescent X-ray emission detected from Sgr A* and is within the detection capabilities of current X-ray observatories. Its detection could constrain the density and thickness of the disc at a distance of ∼3000 gravitational radii from the supermassive black hole.

  20. A new model of retinal photoreceptor cell degeneration induced by a chemical hypoxia-mimicking agent, cobalt chloride.

    PubMed

    Hara, Akira; Niwa, Masayuki; Aoki, Hitomi; Kumada, Masako; Kunisada, Takahiro; Oyama, Takeru; Yamamoto, Tetsuya; Kozawa, Osamu; Mori, Hideki

    2006-09-13

    Retinal photoreceptor cell degeneration was induced by cobalt chloride, a chemical hypoxia-mimicking agent in rodents. Time course and dose-response of photoreceptor cell degeneration in mouse retina after intravitreal injection of cobalt chloride were examined by conventional histological analysis by hematoxylin and eosin staining and in situ terminal dUTP-biotin nick end labeling of DNA fragments (TUNEL) method with the use of paraffin-embedded sections. The dose-response of photoreceptor cell degeneration in rat retina was also examined. Photoreceptor cells progressively degenerated with time and under dose-response relationship. The suitable dose of cobalt chloride for the selective photoreceptor cell degeneration in mice is 10-12 nmol intravitreal injection at the volume of 2 microl. The retinal morphology of the mice 2 weeks after the 10-12 nmol intravitreal injection was similar to that of retinal degeneration in the mutant rd mouse. Retinal damage of total retinal layers was induced by an excessive dose of cobalt chloride. The progression of retinal damage after cobalt chloride injection, measured morphologically, was completed at 1 week. However, nuclear DNA fragmentation, mainly detected at outer nuclear layer by TUNEL, peaked at 48 h after 12 nmol cobalt chloride injection. Thus, the selective photoreceptor cell degeneration induced by cobalt chloride follows DNA fragmentation at outer nuclear layer. The photoreceptor cell degeneration is established optionally by cobalt chloride without use of the retinal degeneration mutant animals. Thus, we have described the development of a new model of retinal photoreceptor cell degeneration induced by a chemical hypoxia-mimicking agent.

  1. Strontium ranelate reduces cartilage degeneration and subchondral bone remodeling in rat osteoarthritis model

    PubMed Central

    Yu, De-gang; Ding, Hui-feng; Mao, Yuan-qing; Liu, Ming; Yu, Bo; Zhao, Xin; Wang, Xiao-qing; Li, Yang; Liu, Guang-wang; Nie, Shao-bo; Liu, Shen; Zhu, Zhen-an

    2013-01-01

    Aim: To investigate whether strontium ranelate (SR), a new antiosteoporotic agent, could attenuate cartilage degeneration and subchondral bone remodeling in osteoarthritis (OA). Methods: Medial meniscal tear (MMT) operation was performed in adult SD rats to induce OA. SR (625 or 1800 mg·kg−1·d−1) was administered via gavage for 3 or 6 weeks. After the animals were sacrificed, articular cartilage degeneration was evaluated using toluidine blue O staining, SOX9 immunohistochemistry and TUNEL assay. The changes in microarchitecture indices and tissue mineral density (TMD), chemical composition (mineral-to-collagen ratio), and intrinsic mechanical properties of the subchondral bones were measured using micro-CT scanning, confocal Raman microspectroscopy and nanoindentation testing, respectively. Results: The high-dose SR significantly attenuated cartilage matrix and chondrocyte loss at 6 weeks, and decreased chondrocyte apoptosis, improved the expression of SOX9, a critical transcription factor responsible for the expression of anabolic genes type II collagen and aggrecan, at both 3 and 6 weeks. Meanwhile, the high-dose SR also significantly attenuated the subchondral bone remodeling at both 3 and 6 weeks, as shown by the improved microarchitecture indices, TMD, mineral-to-collagen ratio and intrinsic mechanical properties. In contrast, the low-dose SR did not significantly change all the detection indices of cartilage and bone at both 3 and 6 weeks. Conclusion: The high-dose SR treatment can reduce articular cartilage degeneration and subchondral bone remodeling in the rat MMT model of OA. PMID:23334238

  2. Glucosamine sulfate effect on the degenerated patellar cartilage: preliminary findings by pharmacokinetic magnetic resonance modeling.

    PubMed

    Martí-Bonmatí, Luis; Sanz-Requena, Roberto; Rodrigo, José Luis; Alberich-Bayarri, Angel; Carot, José Miguel

    2009-06-01

    Normal and degenerated cartilages have different magnetic resonance (MR) capillary permeability (K(trans)) and interstitial interchangeable volume (v(e)). Our hypothesis was that glucosamine sulfate treatment modifies these neovascularity abnormalities in osteoarthritis. Sixteen patients with patella degeneration, randomly distributed into glucosamine or control groups, underwent two 1.5-Tesla dynamic contrast-enhanced MR imaging studies (treatment initiation and after 6 months). The pain visual analog scale (VAS) and American Knee Society (AKS) score were used. A two-compartment pharmacokinetic model was used. Percentages of variations (postreatment-pretreatment/pretreatment) were compared (t-test for independent data). In the glucosamine group, pain and functional outcomes statistically improved (VAS: 7.3 +/- 1.1 to 3.6 +/- 1.3, p < 0.001; AKS: 18.6 +/- 6.9 to 42.9 +/- 2.7, p < 0.01). Glucosamine significantly increased K(trans) at 6 months (-54.4 +/- 21.2% vs 126.7 +/- 56.9%, p < 0.001, control vs glucosamine). In conclusion, glucosamine sulfate decreases pain while improving functional outcome in patients with cartilage degeneration. Glucosamine sulfate increases K(trans), allowing its proposal as a surrogate imaging biomarker after 6 months of treatment.

  3. A toy model for magnetic connection in black hole accretion disc

    NASA Astrophysics Data System (ADS)

    Wang, Ding-Xiong; Ye, Yong-Chun; Li, Yang; Liu, Dong-Mei

    2007-01-01

    A toy model for magnetic connection in black hole (BH) accretion disc is discussed based on a poloidal magnetic field generated by a single electric current flowing around a Kerr BH in the equatorial plane. We discuss the effects of the coexistence of two kinds of magnetic connection (MC) arising, respectively, from (1) the closed field lines connecting the BH horizon with the disc (henceforth MCHD) and (2) the closed field lines connecting the plunging region with the disc (henceforth MCPD). The magnetic field configuration is constrained by conservation of magnetic flux and a criterion of the screw instability of the magnetic field. Two parameters λ and αm are introduced to describe our model instead of resolving the complicated magnetohydrodynamic equations. Compared with MCHD, energy and angular momentum of the plunging particles are extracted via MCPD more effectively, provided that the BH spin is not very high. It turns out that negative energy can be delivered to the BH by the plunging particles without violating the second law of BH thermodynamics, however it cannot be realized via MCPD in a stable way.

  4. Analysis of the RPE sheet in the rd10 retinal degeneration model

    SciTech Connect

    Jiang, Yi

    2011-01-04

    The normal RPE sheet in the C57Bl/6J mouse is subclassified into two major tiling patterns: A regular generally hexagonal array covering most of the surface and a 'soft network' near the ciliary body made of irregularly shaped cells. Physics models predict these two patterns based on contractility and elasticity of the RPE cell, and strength of cellular adhesion between cells. We hypothesized and identified major changes in RPE regular hexagonal tiling pattern in rdl0 compared to C57BL/6J mice. RPE sheet damage was extensive but occurred in rd10 later than expected, after most retinal degeneration. RPE sheet changes occur in zones with a bullseye pattern. In the posterior zone around the optic nerve RPE cells take on larger irregular and varied shapes to form an intact monolayer. In mid periphery, there is a higher than normal density of cells that progress into involuted layers of RPE under the retina. The periphery remains mostly normal until late stages of degeneration. The number of neighboring cells varies widely depending on zone and progression. RPE morphology continues to deteriorate long after the photoreceptors have degenerated. The RPE cells are bystanders to the rd10 degeneration within photo receptors, and the collateral damage to the RPE sheet resembles stimulation of migration or chemotaxis. Quantitative measures of the tiling patterns and histopathology detected here, scripted in a pipeline written in Perl and Cell Profiler (an open source Matlab plugin), are directly applicable to RPE sheet images from noninvasive fundus autofluorescence (FAF), adaptive optics confocal scanning laser ophthalmoscope (AO-cSLO), and spectral domain optical coherence tomography (SD-OCT) of patients with early stage AMD or RP.

  5. Interleukin-6 and interleukin-6 receptor expression, localization, and involvement in pain-sensing neuron activation in a mouse intervertebral disc injury model.

    PubMed

    Sainoh, Takeshi; Orita, Sumihisa; Miyagi, Masayuki; Sakuma, Yoshihiro; Yamauchi, Kazuyo; Suzuki, Miyako; Kubota, Go; Oikawa, Yasuhiro; Inage, Kazuhide; Sato, Jun; Fujimoto, Kazuki; Shiga, Yasuhiro; Inoue, Gen; Aoki, Yasuchika; Takahashi, Kazuhisa; Ohtori, Seiji

    2015-10-01

    The pathological mechanism of intractable low back pain is unclear. However, intervertebral disc (IVD) degeneration is a primary cause of low back pain, and pain-related mediators, such as interleukin-6 (IL-6), have been correlated with discogenic pain. The objective of this study is to elucidate the mechanism of local IL-6 and IL-6 receptor (IL-6R) expression after IVD injury as well as determine the involvement of IL-6/IL-6 signaling in discogenic pain. To do this, quantitative and immunohistological analyses in a mouse model of IVD injury were performed. Firstly, we measured the local expression levels of IL-6 and IL-6R in IVDs by enzyme-linked immunosorbent assay (ELISA). Secondly, we immunohistochemically confirmed their localization in injured IVDs. Lastly, we evaluated the effects of intradiscal injection of an IL-6 inhibitor by evaluating pain-related protein, calcitonin gene-related peptide (CGRP), expression in dorsal root ganglia (DRG) neurons that innervate IVDs. Injured IVDs showed increased production of IL-6 and IL-6R. IL-6 and IL-6R expression in the injured IVD were predominantly localized in the annulus fibrosus and endplate, and intradiscal injection of the IL-6 inhibitor suppressed CGRP expression in the DRG neurons. These results show that IL-6 and IL-6R expression levels are responsive to IVD injury and that inhibition of IL-6/IL-6R signaling may be a promising analgesic treatment for degenerative disc diseases.

  6. Drosophila Imaginal Discs as a Model of Epithelial Wound Repair and Regeneration

    PubMed Central

    Smith-Bolton, Rachel

    2016-01-01

    Significance: The Drosophila larval imaginal discs, which form the adult fly during metamorphosis, are an established model system for the study of epithelial tissue damage. The disc proper is a simple columnar epithelium, but it contains complex patterning and cell-fate specification, and is genetically tractable. These features enable unbiased genetic screens to identify genes involved in all aspects of the wound response, from sensing damage to wound closure, initiation of regeneration, and re-establishment of proper cell fates. Identification of the genes that facilitate epithelial wound closure and regeneration will enable development of more sophisticated wound treatments for clinical use. Recent Advances: Imaginal disc epithelia can be damaged in many different ways, including fragmentation, induction of cell death, and irradiation. Recent work has demonstrated that the tissue's response to damage varies depending on how the wound was induced. Here, we summarize the different responses activated in these epithelial tissues after the different types of damage. Critical Issues: These studies highlight that not all wounds elicit the same response from the surrounding tissue. A complete understanding of the various wound-healing mechanisms in Drosophila will be a first step in understanding how to manage damaged human tissues and optimize healing in different clinical contexts. Future Directions: Further work is necessary to understand the similarities and differences among an epithelial tissue's responses to different insults. Ongoing studies will identify the genes and pathways employed by injured imaginal discs. Thus, work in this genetically tractable system complements work in more conventional wound-healing models. PMID:27274435

  7. Simulating realistic disc galaxies with a novel sub-resolution ISM model

    NASA Astrophysics Data System (ADS)

    Murante, Giuseppe; Monaco, Pierluigi; Borgani, Stefano; Tornatore, Luca; Dolag, Klaus; Goz, David

    2015-02-01

    We present results of cosmological simulations of disc galaxies carried out with the GADGET-3 TreePM+SPH code, where star formation and stellar feedback are described using our MUlti Phase Particle Integrator model. This description is based on a simple multiphase model of the interstellar medium at unresolved scales, where mass and energy flows among the components are explicitly followed by solving a system of ordinary differential equations. Thermal energy from supernovae is injected into the local hot phase, so as to avoid that it is promptly radiated away. A kinetic feedback prescription generates the massive outflows needed to avoid the overproduction of stars. We use two sets of zoomed-in initial conditions of isolated cosmological haloes with masses (2-3) × 1012 M⊙, both available at several resolution levels. In all cases we obtain spiral galaxies with small bulge-over-total stellar mass ratios (B/T ˜ 0.2), extended stellar and gas discs, flat rotation curves and realistic values of stellar masses. Gas profiles are relatively flat, molecular gas is found to dominate at the centre of galaxies, with star formation rates following the observed Schmidt-Kennicutt relation. Stars kinematically belonging to the bulge form early, while disc stars show a clear inside-out formation pattern and mostly form after redshift z = 2. However, the baryon conversion efficiencies in our simulations differ from the relation given by Moster et al. at a 3σ level, thus indicating that our stellar discs are still too massive for the dark matter halo in which they reside. Results are found to be remarkably stable against resolution. This further demonstrates the feasibility of carrying out simulations producing a realistic population of galaxies within representative cosmological volumes, at a relatively modest resolution.

  8. A wind-driving disc model for the mm-wavelength polarization structure of HL Tau

    NASA Astrophysics Data System (ADS)

    Matsakos, Titos; Tzeferacos, Petros; Königl, Arieh

    2016-12-01

    The recent advent of spatially resolved mm- and cm-wavelength polarimetry in protostellar accretion discs could help clarify the role of magnetic fields in the angular momentum transport in these systems. The best case to date is that of HL Tau, where the inability to produce a good fit to the 1.25-mm data with a combination of vertical and azimuthal magnetic field components was interpreted as implying that centrifugally driven winds (CDWs) are probably not a significant transport mechanism on the ˜102 au scale probed by the observations. Using synthetic polarization maps of heuristic single-field-component discs and of a post-processed simulation of a wind-driving disc, we demonstrate that a much better fit to the data can be obtained if the radial field component, a hallmark of the CDW mechanism, dominates in the polarized emission region. A similar inference was previously made in modelling the far-infrared polarization map of the pc-scale dust ring in the Galactic Centre. To reconcile this interpretation with theoretical models of protostellar discs, which indicate that the wind is launched from a comparatively high elevation above the mid-plane, we propose that most of the polarized emission originates - with a high ( ≳ 10 per cent) intrinsic degree of polarization - in small ( ≲ 0.1 mm) grains that remain suspended above the mid-plane, and that the bulk of the mm-wavelength emission is produced - with low intrinsic polarization - by larger grains that have settled to the mid-plane.

  9. A Milky Way with a massive, centrally concentrated thick disc: new Galactic mass models for orbit computations

    NASA Astrophysics Data System (ADS)

    Pouliasis, E.; Di Matteo, P.; Haywood, M.

    2017-02-01

    In this work, two new axisymmetric models for the Galactic mass distribution are presented. Motivated by recent results, these two models include the contribution of a stellar thin disc and of a thick disc, as massive as the thin counterpart but with a shorter scale-length. Both models satisfy a number of observational constraints: stellar densities at the solar vicinity, thin and thick disc scale lengths and heights, rotation curve(s), and the absolute value of the perpendicular force Kz as a function of distance to the Galactic centre. We numerically integrate into these new models the motion of all Galactic globular clusters for which distances, proper motions, and radial velocities are available, and the orbits of about one thousand stars in the solar vicinity. The retrieved orbital characteristics are compared to those obtained by integrating the clusters and stellar orbits in pure thin disc models. We find that, due to the possible presence of a thick disc, the computed orbital parameters of disc stars can vary by as much as 30-40%. We also show that the systematic uncertainties that affect the rotation curve still plague computed orbital parameters of globular clusters by similar amounts.

  10. Modelling the inner debris disc of HR 8799

    NASA Astrophysics Data System (ADS)

    Contro, B.; Horner, J.; Wittenmyer, R. A.; Marshall, J. P.; Hinse, T. C.

    2016-11-01

    In many ways, the HR 8799 planetary system strongly resembles our own. It features four giant planets and two debris belts, analogues to the Asteroid and Edgeworth-Kuiper belts. Here, we present the results of dynamical simulations of HR8799's inner debris belt, to study its structure and collisional environment. Our results suggest that HR 8799's inner belt is highly structured, with gaps between regions of dynamical stability. The belt is likely constrained between sharp inner and outer edges, located at ˜6 and ˜8 au, respectively. Its inner edge coincides with a broad gap cleared by the 4:1 mean-motion resonance with HR 8799e. Within the belt, planetesimals are undergoing a process of collisional attrition like that observed in the Asteroid belt. However, whilst the mean collision velocity in the Asteroid belt exceeds 5 km s-1, the majority of collisions within HR 8799's inner belt occur with velocities of order 1.2 km s-1, or less. Despite this, they remain sufficiently energetic to be destructive - giving a source for the warm dust detected in the system. Interior to the inner belt, test particles remain dynamically unstirred, aside from narrow bands excited by distant high-order resonances with HR 8799e. This lack of stirring is consistent with earlier thermal modelling of HR 8799's infrared excess, which predicted little dust inside 6 au. The inner system is sufficiently stable and unstirred that the formation of telluric planets is feasible, although such planets would doubtless be subject to a punitive impact regime, given the intense collisional grinding required in the inner belt to generate the observed infrared excess.

  11. Discrete/Finite Element Modelling of Rock Cutting with a TBM Disc Cutter

    NASA Astrophysics Data System (ADS)

    Labra, Carlos; Rojek, Jerzy; Oñate, Eugenio

    2017-03-01

    This paper presents advanced computer simulation of rock cutting process typical for excavation works in civil engineering. Theoretical formulation of the hybrid discrete/finite element model has been presented. The discrete and finite element methods have been used in different subdomains of a rock sample according to expected material behaviour, the part which is fractured and damaged during cutting is discretized with the discrete elements while the other part is treated as a continuous body and it is modelled using the finite element method. In this way, an optimum model is created, enabling a proper representation of the physical phenomena during cutting and efficient numerical computation. The model has been applied to simulation of the laboratory test of rock cutting with a single TBM (tunnel boring machine) disc cutter. The micromechanical parameters have been determined using the dimensionless relationships between micro- and macroscopic parameters. A number of numerical simulations of the LCM test in the unrelieved and relieved cutting modes have been performed. Numerical results have been compared with available data from in-situ measurements in a real TBM as well as with the theoretical predictions showing quite a good agreement. The numerical model has provided a new insight into the cutting mechanism enabling us to investigate the stress and pressure distribution at the tool-rock interaction. Sensitivity analysis of rock cutting performed for different parameters including disc geometry, cutting velocity, disc penetration and spacing has shown that the presented numerical model is a suitable tool for the design and optimization of rock cutting process.

  12. Inner retinal change in a novel rd1-FTL mouse model of retinal degeneration

    PubMed Central

    Greferath, Ursula; Anderson, Emily E.; Jobling, Andrew I.; Vessey, Kirstan A.; Martinez, Gemma; de Iongh, Robb U.; Kalloniatis, Michael; Fletcher, Erica L.

    2015-01-01

    While photoreceptor loss is the most devastating result of inherited retinal degenerations such as retinitis pigmentosa, inner retinal neurons also undergo significant alteration. Detailing these changes has become important as many vision restorative therapies target the remaining neurons. In this study, the rd1-Fos-Tau-LacZ (rd1-FTL) mouse model was used to explore inner retinal change at a late stage of retinal degeneration, after the loss of photoreceptor nuclei. The rd1-FTL model carries a mutation in the phosphodiesterase gene, Pde6b, and an axonally targeted transgenic beta galactosidase reporter system under the control of the c-fos promoter. Retinae of transgenic rd1-FTL mice and control FTL animals aged 2–12 months were processed for indirect fluorescence immunocytochemistry. At 2 months of age, a time when the majority of photoreceptor nuclei are lost, there was negligible c-fos reporter (FTL) expression, however, from 4 months, reporter expression was observed to increase within subpopulations of amacrine and ganglion cells within the central retina. These areas of inner retinal FTL expression coincided with regions that contained aberrant Müller cells. Specifically, these cells exhibited reduced glutamine synthetase and Kir4.1 immunolabelling, whilst showing evidence of proliferative gliosis (increased cyclinD1 and glial fibrillary acidic protein expression). These changes were limited to distinct regions where cone photoreceptor terminals were absent. Overall, these results highlight that distinct areas of the rd1-FTL central retina undergo significant glial alterations after cone photoreceptor loss. These areas coincide with up-regulation of the c-fos reporter in the inner retina, which may represent a change in neuronal function/plasticity. The rd1-FTL mouse is a useful model system to probe changes that occur in the inner retina at later stages of retinal degeneration. PMID:26283925

  13. Neuroprotective Effects of Voluntary Exercise in an Inherited Retinal Degeneration Mouse Model

    PubMed Central

    Hanif, Adam M.; Lawson, Eric C.; Prunty, Megan; Gogniat, Marissa; Aung, Moe H.; Chakraborty, Ranjay; Boatright, Jeffrey H.; Pardue, Machelle T.

    2015-01-01

    Purpose Our previous investigations showed that involuntary treadmill exercise is neuroprotective in a light-induced retinal degeneration mouse model, and it may act through activation of tropomyosin-related kinase B (TrkB) receptors. This study investigated whether voluntary running wheel exercise can be neuroprotective in an inheritable model of the retinal degenerative disease retinitis pigmentosa (RP), rd10 mice. Methods Breeding pairs of rd10 and C57BL/6J mice were given free-spinning (active) or locked (inactive) running wheels. Pups were weaned into separate cages with their parents' respective wheel types, and visual function was tested with ERG and a virtual optokinetic system at 4, 5, and 6 weeks of age. Offspring were killed at 6 weeks of age and retinal cross-sections were prepared for photoreceptor nuclei counting. Additionally, separate cohorts of active and inactive rd10 pups were injected daily for 14 days after eye opening with a selective TrkB receptor antagonist (ANA-12) or vehicle solution and assessed as described above. Results Mice in the rd10 active group exhibited significant preservation of visual acuity, cone nuclei, and total photoreceptor nuclei number. Injection with ANA-12 precluded the preservation of visual acuity and photoreceptor nuclei number in rd10 mice. Conclusions Voluntary running partially protected against the retinal degeneration and vision loss that otherwise occurs in the rd10 mouse model of RP. This protection was prevented by injection of ANA-12, suggesting that TrkB activation mediates exercise's preservation of the retina. Exercise may serve as an effective, clinically translational intervention against retinal degeneration. PMID:26567796

  14. Effects of Subretinal Gene Transfer at Different Time Points in a Mouse Model of Retinal Degeneration

    PubMed Central

    Dai, Xufeng; Zhang, Hua; Han, Juanjuan; He, Ying; Zhang, Yangyang; Qi, Yan; Pang, Ji-jing

    2016-01-01

    Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is necessary for photoreceptors to generate an important lipid component of their membranes. The absence of LPCAT1 results in early and rapid rod and cone degeneration. Retinal degeneration 11 (rd11) mice carry a mutation in the Lpcat1 gene, and are an excellent model of early-onset rapid retinal degeneration (RD). To date, no reports have documented gene therapy administration in the rd11 mouse model at different ages. In this study, the AAV8 (Y733F)-smCBA-Lpcat1 vector was subretinally injected at postnatal day (P) 10, 14, 18, or 22. Four months after injection, immunohistochemistry and analysis of retinal morphology showed that treatment at P10 rescued about 82% of the wild-type retinal thickness. However, the diffusion of the vector and the resulting rescue were limited to an area around the injection site that was only 31% of the total retinal area. Injection at P14 resulted in vector diffusion that covered approximately 84% of the retina, and we found that gene therapy was more effective against RD when exposure to light was limited before and after treatment. We observed long-term preservation of electroretinogram (ERG) responses, and preservation of retinal structure, indicating that early treatment followed by limited light exposure can improve gene therapy effectiveness for the eyes of rd11 mice. Importantly, delayed treatment still partially preserved M-cones, but not S-cones, and M-cones in the rd11 retina appeared to have a longer window of opportunity for effective preservation with gene therapy. These results provide important information regarding the effects of subretinal gene therapy in the mouse model of LPCAT1-deficiency. PMID:27228218

  15. Retinal Ultrastructure of Murine Models of Dry Age-related Macular Degeneration (AMD)

    PubMed Central

    Ramkumar, Hema L.; Zhang, Jun; Chan, Chi-Chao

    2010-01-01

    Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. The pathology of dry AMD consists of degeneration of photoreceptors and the RPE, lipofuscin (A2E) accumulation, and drusen formation. Mice have been widely used for generating models that simulate human AMD features for investigating the pathogenesis, treatment and prevention of the disease. Although the mouse has no macula, focal atrophy of photorecptors and RPE, lipofuscin accumulation, and increased A2E can develop in aged mouse eyes. However, drusen are rarely seen in mice because of their simpler Bruch’s membrane and different process of lipofuscin extrusion compared with humans. Thus, analyzing basal deposits at the ultrastructural level and understanding the ultrastructural pathologic differences between various mouse AMD models are critical to comprehending the significance of research findings and response to possible therapeutic options for dry AMD. Based on the multifactorial pathogenesis of AMD, murine dry AMD models can be classified into three groups. First, genetically engineered mice that target genes related to juvenile macular dystrophies are the most common models, and they include abcr−/− (Stargardt disease), transgenic ELOVL4 (Stargardt-3 dominant inheritary disease), Efemp1R345W/R345W (Doyne honeycomb retinal dystrophy), and Timp3S156C/S156C (Sorsby fundus dystrophy) mice. Other murine models target genes relevant to AMD, including inflammatory genes such as Cfh−/−, Ccl2−/−, Ccr2−/−, Cx3cr1−/−, and Ccl2−/−/cx3cr1−/−, oxidative stress associated genes such as Sod1−/− and Sod2 knockdown, metabolic pathway genes such as neprilysin −/− (amyloid β), transgenic mcd/mcd (cathepsin D), Cp−/−/Heph−/Y (ferroxidase ceruloplasmin/hepaestin, iron metabolism), and transgenic ApoE4 on high fat and high cholesterol diet (lipid metabolism). Second, mice have also been immunologically

  16. Orbitally Degenerate Spin-1 Model for Insulating V{sub 2}O{sub 3}

    SciTech Connect

    Mila, F.; Shiina, R.; Zhang, F.-C.; Joshi, A.; Ma, M.; Anisimov, V.; Rice, T. M.

    2000-08-21

    Motivated by recent neutron, x-ray absorption, and resonant scattering experiments, we revisit the electronic structure of V{sub 2}O {sub 3} . We propose a model in which S=1 V{sup 3+} ions are coupled in the vertical V-V pairs forming twofold orbitally degenerate configurations with S=2 . Ferro-orbital ordering of the V-V pairs gives a description which is consistent with all experiments in the antiferromagnetic insulating phase. (c) 2000 The American Physical Society.

  17. Striatonigral Degeneration

    MedlinePlus

    ... disease, striatonigral degeneration is not responsive to levodopa. Dopamine and anticholinergics provide some benefit. Generally, treatment is ... disease, striatonigral degeneration is not responsive to levodopa. Dopamine and anticholinergics provide some benefit. Generally, treatment is ...

  18. Macular degeneration

    MedlinePlus Videos and Cool Tools

    ... at the center of the field of vision. Macular degeneration results from a partial breakdown of the insulating ... choroid layer of blood vessels behind the retina. Macular degeneration results in the loss of central vision only.

  19. Anterior cervical discectomy with fusion in patients with cervical disc degeneration: a prospective outcome study of 258 patients (181 fused with autologous bone graft and 77 fused with a PEEK cage)

    PubMed Central

    2010-01-01

    Background Anterior cervical discectomy with fusion (ACDF) is challenging with respect to both patient selection and choice of surgical procedure. The aim of this study was to evaluate the clinical outcome of ACDF, with respect to both patient selection and choice of surgical procedure: fusion with an autologous iliac crest graft (AICG) versus fusion with an artificial cage made of polyetheretherketone (PEEK). Methods This was a non-randomized prospective single-center outcome study of 258 patients who underwent ACDF for cervical disc degeneration (CDD). Fusion was attained with either tricortical AICG or PEEK cages without additional anterior plating, with treatment selected at surgeon's discretion. Radicular pain, neck-pain, headache and patient satisfaction with the treatment were scored using the visual analogue scale (VAS). Results The median age was 47.5 (28.3-82.8) years, and 44% of patients were female. 59% had single-level ACDF, 40% had two level ACDF and 1% had three-level ACDF. Of the patients, 181 were fused with AICG and 77 with a PEEK-cage. After surgery, the patients showed a significant reduction in radicular pain (ΔVAS = 3.05), neck pain (ΔVAS = 2.30) and headache (ΔVAS = 0.55). Six months after surgery, 48% of patients had returned to work: however 24% were still receiving workers' compensation. Using univariate and multivariate analyses we found that high preoperative pain intensity was significantly associated with a decrease in pain intensity after surgery, for all three pain categories. There were no significant correlations between pain relief and the following patient characteristics: fusion method (AICG or PEEK-cage), sex, age, number of levels fused, disc level fused, previous neck surgery (except for neck pain), previous neck trauma, or preoperative symptom duration. Two hundred out of the 256 (78%) patients evaluated the surgical result as successful. Only 27/256 (11%) classified the surgical result as a failure. Patient satisfaction

  20. RPGR-Associated Retinal Degeneration in Human X-Linked RP and a Murine Model

    PubMed Central

    Huang, Wei Chieh; Wright, Alan F.; Roman, Alejandro J.; Cideciyan, Artur V.; Manson, Forbes D.; Gewaily, Dina Y.; Schwartz, Sharon B.; Sadigh, Sam; Limberis, Maria P.; Bell, Peter; Wilson, James M.; Swaroop, Anand; Jacobson, Samuel G.

    2012-01-01

    Purpose. We investigated the retinal disease due to mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene in human patients and in an Rpgr conditional knockout (cko) mouse model. Methods. XLRP patients with RPGR-ORF15 mutations (n = 35, ages at first visit 5–72 years) had clinical examinations, and rod and cone perimetry. Rpgr-cko mice, in which the proximal promoter and first exon were deleted ubiquitously, were back-crossed onto a BALB/c background, and studied with optical coherence tomography and electroretinography (ERG). Retinal histopathology was performed on a subset. Results. Different patterns of rod and cone dysfunction were present in patients. Frequently, there were midperipheral losses with residual rod and cone function in central and peripheral retina. Longitudinal data indicated that central rod loss preceded peripheral rod losses. Central cone-only vision with no peripheral function was a late stage. Less commonly, patients had central rod and cone dysfunction, but preserved, albeit abnormal, midperipheral rod and cone vision. Rpgr-cko mice had progressive retinal degeneration detectable in the first months of life. ERGs indicated relatively equal rod and cone disease. At late stages, there was greater inferior versus superior retinal degeneration. Conclusions. RPGR mutations lead to progressive loss of rod and cone vision, but show different patterns of residual photoreceptor disease expression. Knowledge of the patterns should guide treatment strategies. Rpgr-cko mice had onset of degeneration at relatively young ages and progressive photoreceptor disease. The natural history in this model will permit preclinical proof-of-concept studies to be designed and such studies should advance progress toward human therapy. PMID:22807293

  1. Constitutive model for flake graphite cast iron automotive brake discs: induced anisotropic damage model under complex loadings

    NASA Astrophysics Data System (ADS)

    Augustins, L.; Billardon, R.; Hild, F.

    2016-09-01

    The present paper details an elasto-viscoplastic constitutive model for automotive brake discs made of flake graphite cast iron. In a companion paper (Augustins et al. in Contin Mech Thermodyn, 2015), the authors proposed a one-dimensional setting appropriate for representing the complex behavior of the material (i.e., asymmetry between tensile and compressive loadings) under anisothermal conditions. The generalization of this 1D model to 3D cases on a volume element and the associated challenges are addressed. A direct transposition is not possible, and an alternative solution without unilateral conditions is first proposed. Induced anisotropic damage and associated constitutive laws are then introduced. The transition from the volume element to the real structure and the numerical implementation require a specific basis change. Brake disc simulations with this constitutive model show that unilateral conditions are needed for the friction bands. A damage deactivation procedure is therefore defined.

  2. Global models of planetary system formation in radiatively-inefficient protoplanetary discs

    NASA Astrophysics Data System (ADS)

    Hellary, Phil; Nelson, Richard P.

    2012-02-01

    We present the results of N-body simulations of planetary system formation in radiatively-inefficient disc models, where positive corotation torques may counter the rapid inward migration of low-mass planets driven by Lindblad torques. The aim of this work is to examine the nature of planetary systems that arise from oligarchic growth in such discs. We adapt the commonly used Mercury-6 symplectic integrator by including simple prescriptions for planetary migration (types I and II), planetary atmospheres that enhance the probability of planetesimal accretion by protoplanets, gas accretion on to forming planetary cores, and gas disc dispersal. We perform a suite of simulations for a variety of disc models with power-law surface density and temperature profiles, with a focus on models in which unsaturated corotation torques can drive outward migration of protoplanets. In some models, we account for the quenching of corotation torques which arises when planetary orbits become eccentric. Approximately half of our simulations lead to the successful formation of gas giant planets with a broad range of masses and semimajor-axes. Giant planetary masses range from being approximately equal to that of Saturn up to approximately twice that of Jupiter. The semimajor-axes of these range from being ˜0.2 au up to ˜75 au, with disc models that drive stronger outward migration favouring the formation of longer period giant planets. Out of a total of 20 giant planets being formed in our simulation suite, we obtain three systems that contain two giants. No super-Earth or Neptune-mass planets were present in the final stages of our simulations, in contrast to the large abundance of such objects being discovered in observation surveys. This result arises because of rapid inward migration suffered by massive planetary cores that form early in the disc lifetime (for which the corotation torques saturate), combined with gas accretion on to massive cores which leads them to become gas

  3. Interpreting Degenerate Solutions in Unfolding by Use of the Vector Model and the Compensatory Distance Model

    ERIC Educational Resources Information Center

    Van Deun, K.; Groenen, P. J. F.; Heiser, W. J.; Busing, F. M. T. A.; Delbeke, L.

    2005-01-01

    In this paper, we reconsider the merits of unfolding solutions based on loss functions involving a normalization on the variance per subject. In the literature, solutions based on Stress-2 are often diagnosed to be degenerate in the majority of cases. Here, the focus lies on two frequently occurring types of degeneracies. The first type typically…

  4. Exclusion of the Unfolded Protein Response in Light-Induced Retinal Degeneration in the Canine T4R RHO Model of Autosomal Dominant Retinitis Pigmentosa

    PubMed Central

    Marsili, Stefania; Genini, Sem; Sudharsan, Raghavi; Gingrich, Jeremy; Aguirre, Gustavo D.; Beltran, William A.

    2015-01-01

    Purpose To examine the occurrence of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) following acute light damage in the naturally-occurring canine model of RHO-adRP (T4R RHO dog). Methods The left eyes of T4R RHO dogs were briefly light-exposed and retinas collected 3, 6 and 24 hours later. The contra-lateral eyes were shielded and used as controls. To evaluate the time course of cell death, histology and TUNEL assays were performed. Electron microscopy was used to examine ultrastructural alterations in photoreceptors at 15 min, 1 hour, and 6 hours after light exposure. Gene expression of markers of ER stress and UPR were assessed by RT-PCR, qRT-PCR and western blot at the 6 hour time-point. Calpain and caspase-3 activation were assessed at 1, 3 and 6 hours after exposure. Results A brief exposure to clinically-relevant levels of white light causes within minutes acute disruption of the rod outer segment disc membranes, followed by prominent ultrastructural alterations in the inner segments and the initiation of cell death by 6 hours. Activation of the PERK and IRE1 pathways, and downstream targets (BIP, CHOP) of the UPR was not observed. However increased transcription of caspase-12 and hsp70 occurred, as well as calpain activation, but not that of caspase-3. Conclusion The UPR is not activated in the early phase of light-induced photoreceptor cell death in the T4R RHO model. Instead, disruption in rods of disc and plasma membranes within minutes after light exposure followed by increase in calpain activity and caspase-12 expression suggests a different mechanism of degeneration. PMID:25695253

  5. Prize of the best thesis 2015: Study of debris discs through state-of-the-art numerical modelling

    NASA Astrophysics Data System (ADS)

    Kral, Q.; Thébault, P.

    2015-12-01

    This proceeding summarises the thesis entitled ``Study of debris discs with a new generation numerical model'' by Quentin Kral, for which he obtained the prize of the best thesis in 2015. The thesis brought major contributions to the field of debris disc modelling. The main achievement is to have created, almost ex-nihilo, the first truly self-consistent numerical model able to simultaneously follow the coupled collisional and dynamical evolutions of debris discs. Such a code has been thought as being the ``Holy Grail'' of disc modellers for the past decade, and while several codes with partial dynamics/collisions coupling have been presented, the code developed in this thesis, called ``LIDT-DD'' is the first to achieve a full coupling. The LIDT-DD model, which is the first of a new-generation of fully self-consistent debris disc models is able to handle both planetesimals and dust and create new fragments after each collision. The main idea of LIDT-DD development was to merge into one code two approaches that were so far used separately in disc modelling, that is, an N-body algorithm to investigate the dynamics, and a statistical scheme to explore the collisional evolution. This complex scheme is not straightforward to develop as there are major difficulties to overcome: 1) collisions in debris discs are highly destructive and produce clouds of small fragments after each single impact, 2) the smallest (and most numerous) of these fragments have a strongly size-dependent dynamics because of the radiation pressure, and 3) the dust usually observed in discs is precisely these smallest grains. These extreme constraints had so far prevented all previous attempts at developing self-consistent disc models to succeed. The thesis contains many examples of the use of LIDT-DD that are not yet published but the case of the collision between two asteroid-like bodies is studied in detail. In particular, LIDT-DD is able to predict the different stages that should be observed

  6. Astroglial redistribution of aquaporin 4 during spongy degeneration in a Canavan disease mouse model.

    PubMed

    Clarner, Tim; Wieczorek, Nicola; Krauspe, Barbara; Jansen, Katharina; Beyer, Cordian; Kipp, Markus

    2014-05-01

    Canavan disease is a spongiform leukodystrophy caused by an autosomal recessive mutation in the aspartoacylase gene. Deficiency of oligodendroglial aspartoacylase activity and a subsequent increase of its substrate N-acetylaspartate are the etiologic factors for the disease. N-acetylaspartate acts as a molecular water pump. Therefore, an osmotic-hydrostatic mechanism is thought to be involved in the development of the Canavan disease phenotype. Astrocytes express water transporters and are critically involved in regulating and maintaining water homeostasis in the brain. We used the ASPA(Nur7/Nur7) mouse model of Canavan disease to investigate whether a disturbance of water homeostasis might be involved in the disease's progression. Animals showed an age-dependent impairment of motor performance and spongy degeneration in various brain regions, among the basal ganglia, brain stem, and cerebellar white matter. Astrocyte activation was prominent in regions which displayed less tissue damage, such as the corpus callosum, cortex, mesencephalon, and stratum Purkinje of cerebellar lobe IV. Immunohistochemistry revealed alterations in the cellular distribution of the water channel aquaporin 4 in astrocytes of ASPA(Nur7/Nur7) mice. In control animals, aquaporin 4 was located exclusively in the astrocytic end feet. In contrast, in ASPA(Nur7/Nur7) mice, aquaporin 4 was located throughout the cytoplasm. These results indicate that astroglial regulation of water homeostasis might be involved in the partial prevention of spongy degeneration. These observations highlight aquaporin 4 as a potential therapeutic target for Canavan disease.

  7. Equilibrium star formation in a constant Q disc: model optimization and initial tests

    NASA Astrophysics Data System (ADS)

    Zheng, Zheng; Meurer, Gerhardt R.; Heckman, Timothy M.; Thilker, David A.; Zwaan, Martin A.

    2013-10-01

    We develop a model for the distribution of the interstellar medium (ISM) and star formation in galaxies based on recent studies that indicate that galactic discs stabilize to a constant stability parameter, which we combine with prescriptions of how the phases of the ISM are determined and for the star formation law (SFL). The model predicts the gas surface mass density and star formation intensity of a galaxy given its rotation curve, stellar surface mass density and the gas velocity dispersion. This model is tested on radial profiles of neutral and molecular ISM surface mass density and star formation intensity of 12 galaxies selected from the H I Nearby Galaxy Survey sample. Our tests focus on intermediate radii (0.3 to 1 times the optical radius) because there are insufficient data to test the outer discs and the fits are less accurate in detail in the centre. Nevertheless, the model produces reasonable agreement with the ISM mass and star formation rate integrated over the central region in all but one case. To optimize the model, we evaluate four recipes for the stability parameter, three recipes for apportioning the ISM into molecular and neutral components, and eight versions of the SFL. We find no clear-cut best prescription for the two-fluid (gas and stars) stability parameter Q2f and therefore for simplicity, we use the Wang and Silk approximation (QWS). We found that an empirical scaling between the molecular-to-neutral ISM ratio (Rmol) and the stellar surface mass density proposed by Leroy et al. works marginally better than the other two prescriptions for this ratio in predicting the ISM profiles, and noticeably better in predicting the star formation intensity from the ISM profiles produced by our model with the SFLs we tested. Thus, in the context of our modelled ISM profiles, the linear molecular SFL and the two-component SFL work better than the other prescriptions we tested. We incorporate these relations into our `constant Q disc' model.

  8. Conditional Induction of Oxidative Stress in RPE: A Mouse Model of Progressive Retinal Degeneration.

    PubMed

    Biswal, Manas R; Ildefonso, Cristhian J; Mao, Haoyu; Seo, Soo Jung; Wang, Zhaoyang; Li, Hong; Le, Yun Z; Lewin, Alfred S

    2016-01-01

    An appropriate animal model is essential to screening drugs or designing a treatment strategy for geographic atrophy. Since oxidative stress contributes to the pathological changes of the retinal pigment epithelium (RPE), we are reporting a new mouse AMD model of retinal degeneration by inducing mitochondrial oxidative stress in RPE. Sod2 the gene for manganese superoxide dismutase (MnSOD) was deleted in RPE layer using conditional knockout strategy. Fundus microscopy, SD-OCT and electroretinography were used to monitor retinal structure and function in living animals and microscopy was used to assess pathology post mortem. Tissue specific deletion of Sod2 caused elevated signs of oxidative stress, RPE dysfunction and showed some key features of AMD. Due to induction of oxidative stress, the conditional knockout mice show progressive reduction in ERG responses and thinning of outer nuclear layer (ONL) compared to non-induced littermates.

  9. Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.

    PubMed

    Nordström, Ulrika; Beauvais, Geneviève; Ghosh, Anamitra; Pulikkaparambil Sasidharan, Baby Chakrapani; Lundblad, Martin; Fuchs, Julia; Joshi, Rajiv L; Lipton, Jack W; Roholt, Andrew; Medicetty, Satish; Feinstein, Timothy N; Steiner, Jennifer A; Escobar Galvis, Martha L; Prochiantz, Alain; Brundin, Patrik

    2015-01-01

    Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely

  10. Neural Degeneration in the Retina of the Streptozotocin-Induced Type 1 Diabetes Model

    PubMed Central

    Ozawa, Yoko; Kurihara, Toshihide; Sasaki, Mariko; Ban, Norimitsu; Yuki, Kenya; Kubota, Shunsuke; Tsubota, Kazuo

    2011-01-01

    Diabetic retinopathy, a vision-threatening disease, has been regarded as a vascular disorder. However, impaired oscillatory potentials (OPs) in the electroretinogram (ERG) and visual dysfunction are recorded before severe vascular lesions appear. Here, we review the molecular mechanisms underlying the retinal neural degeneration observed in the streptozotocin-(STZ-) induced type 1 diabetes model. The renin-angiotensin system (RAS) and reactive oxygen species (ROS) both cause OP impairment and reduced levels of synaptophysin, a synaptic vesicle protein for neurotransmitter release, most likely through excessive protein degradation by the ubiquitin-proteasome system. ROS also decrease brain-derived neurotrophic factor (BDNF) and inner retinal neuronal cells. The influence of both RAS and ROS on synaptophysin suggests that RAS-ROS crosstalk occurs in the diabetic retina. Therefore, suppressors of RAS or ROS, such as angiotensin II type 1 receptor blockers or the antioxidant lutein, respectively, are potential candidates for neuroprotective and preventive therapies to improve the visual prognosis. PMID:22144984

  11. Peripheral Disc Margin Shape and Internal Disc Derangement: Imaging Correlation in Significantly Painful Discs Identified at Provocation Lumbar Discography

    PubMed Central

    Bartynski, W.S.; Rothfus, W.E.

    2012-01-01

    Summary Annular margin shape is used to characterize lumbar disc abnormality on CT/MR imaging studies. Abnormal discs also have internal derangement including annular degeneration and radial defects. The purpose of this study was to evaluate potential correlation between disc-margin shape and annular internal derangement on post-discogram CT in significantly painful discs encountered at provocation lumbar discography (PLD). Significantly painful discs were encountered at 126 levels in 86 patients (47 male, 39 female) studied by PLD where no prior surgery had been performed and response to intradiscal lidocaine after provocation resulted in either substantial/total relief or no improvement after lidocaine administration. Post-discogram CT and discogram imaging was evaluated for disc-margin characteristics (bulge/protrusion), features of disc internal derangement (radial annular defect [RD: radial tear/fissure/annular gap], annular degeneration) and presence/absence of discographic contrast leakage. In discs with focal protrusion, 50 of 63 (79%) demonstrated Grade 3 RD with 13 (21%) demonstrating severe degenerative change only. In discs with generalized-bulge-only, 48 of 63 (76%) demonstrated degenerative change only (primarily Dallas Grade 3) with 15 of 63 (24%) demonstrating a RD (Dallas Grade 3). Differences were highly statistically significant (p<0.001). Pain elimination with intra-discal lidocaine correlated with discographic contrast leakage (p<0.001). Disc-margin shape correlates with features of internal derangement in significantly painful discs encountered at PLD. Discs with focal protrusion typically demonstrate RD while generalized bulging discs typically demonstrated degenerative changes only (p<0.001). Disc-margin shape may provide an important imaging clue to the cause of chronic discogenic low back pain. PMID:22681741

  12. Analysis of cell viability in intervertebral disc: Effect of endplate permeability on cell population.

    PubMed

    Shirazi-Adl, A; Taheri, M; Urban, J P G

    2010-05-07

    Responsible for making and maintaining the extracellular matrix, the cells of intervertebral discs are supplied with essential nutrients by diffusion from the blood supply through mainly the cartilaginous endplates (CEPs) and disc tissue. Decrease in transport rate and increase in cellular activity may adversely disturb the intricate supply-demand balance leading ultimately to cell death and disc degeneration. The present numerical study aimed to introduce for the first time cell viability criteria into nonlinear coupled nutrition transport equations thereby evaluating the dynamic nutritional processes governing viable cell population and concentrations of oxygen, glucose and lactic acid in the disc as CEP exchange area dropped from a fully permeable condition to an almost impermeable one. A uniaxial model of an in vitro cell culture analogue of the disc is first employed to examine and validate cell viability criteria. An axisymmetric model of the disc with four distinct regions was subsequently used to investigate the survival of cells at different CEP exchange areas. In agreement with measurements, predictions of the diffusion chamber model demonstrated substantial cell death as essential nutrient concentrations fell to levels too low to support cells. Cells died away from the nutrient supply and at higher cell densities. In the disc model, the nucleus region being farthest away from supply sources was most affected; cell death initiated first as CEP exchange area dropped below approximately 40% and continued exponentially thereafter to depletion as CEP calcified further. In cases with loss of endplate permeability and/or disruptions therein, as well as changes in geometry and fall in diffusivity associated with fluid outflow, the nutrient concentrations could fall to levels inadequate to maintain cellular activity or viability, resulting in cell death and disc degeneration.

  13. Retinal remodeling in the Tg P347L rabbit, a large-eye model of retinal degeneration.

    PubMed

    Jones, B W; Kondo, M; Terasaki, H; Watt, C B; Rapp, K; Anderson, J; Lin, Y; Shaw, M V; Yang, J-H; Marc, R E

    2011-10-01

    Retinitis pigmentosa (RP) is an inherited blinding disease characterized by progressive loss of retinal photoreceptors. There are numerous rodent models of retinal degeneration, but most are poor platforms for interventions that will translate into clinical practice. The rabbit possesses a number of desirable qualities for a model of retinal disease including a large eye and an existing and substantial knowledge base in retinal circuitry, anatomy, and ophthalmology. We have analyzed degeneration, remodeling, and reprogramming in a rabbit model of retinal degeneration, expressing a rhodopsin proline 347 to leucine transgene in a TgP347L rabbit as a powerful model to study the pathophysiology and treatment of retinal degeneration. We show that disease progression in the TgP347L rabbit closely tracks human cone-sparing RP, including the cone-associated preservation of bipolar cell signaling and triggering of reprogramming. The relatively fast disease progression makes the TgP347L rabbit an excellent model for gene therapy, cell biological intervention, progenitor cell transplantation, surgical interventions, and bionic prosthetic studies.

  14. A Naturally-Derived Compound Schisandrin B Enhanced Light Sensation in the pde6c Zebrafish Model of Retinal Degeneration

    PubMed Central

    Zhang, Liyun; Xiang, Lue; Liu, Yiwen; Venkatraman, Prahatha; Chong, Leelyn; Cho, Jin; Bonilla, Sylvia; Jin, Zi-Bing; Pang, Chi Pui; Ko, Kam Ming; Ma, Ping

    2016-01-01

    Retinal degeneration is often progressive. This feature has provided a therapeutic window for intervention that may extend functional vision in patients. Even though this approach is feasible, few promising drug candidates are available. The scarcity of new drugs has motivated research to discover novel compounds through different sources. One such example is Schisandrin B (SchB), an active component isolated from the five-flavor fruit (Fructus Schisandrae) that is postulated in traditional Chinese medicines to exert prophylactic visual benefit. This SchB benefit was investigated in this study in pde6cw59, a zebrafish retinal-degeneration model. In this model, the pde6c gene (phosphodiesterase 6C, cGMP-specific, cone, alpha prime) carried a mutation which caused cone degeneration. This altered the local environment and caused the bystander rods to degenerate too. To test SchB on the pde6cw59 mutants, a treatment concentration was first determined that would not cause morphological defects, and would initiate known physiological response. Then, the mutants were treated with the optimized SchB concentration before the appearance of retinal degeneration at 3 days postfertilization (dpf). The light sensation of animals was evaluated at 6 dpf by the visual motor response (VMR), a visual startle that could be initiated by drastic light onset and offset. The results show that the VMR of pde6cw59 mutants towards light onset was enhanced by the SchB treatment, and that the initial phase of the enhancement was primarily mediated through the mutants’ eyes. Further immunostaining analysis indicates that the treatment specifically reduced the size of the abnormally large rods. These observations implicate an interesting hypothesis: that the morphologically-improved rods drive the observed VMR enhancement. Together, these investigations have identified a possible visual benefit of SchB on retinal degeneration, a benefit that can potentially be further developed to extend

  15. Validation and application of an intervertebral disc finite element model utilizing independently constructed tissue-level constitutive formulations that are nonlinear, anisotropic, and time-dependent.

    PubMed

    Jacobs, Nathan T; Cortes, Daniel H; Peloquin, John M; Vresilovic, Edward J; Elliott, Dawn M

    2014-08-22

    Finite element (FE) models are advantageous in the study of intervertebral disc mechanics as the stress-strain distributions can be determined throughout the tissue and the applied loading and material properties can be controlled and modified. However, the complicated nature of the disc presents a challenge in developing an accurate and predictive disc model, which has led to limitations in FE geometry, material constitutive models and properties, and model validation. The objective of this study was to develop a new FE model of the intervertebral disc, to validate the model's nonlinear and time-dependent responses without tuning or calibration, and to evaluate the effect of changes in nucleus pulposus (NP), cartilaginous endplate (CEP), and annulus fibrosus (AF) material properties on the disc mechanical response. The new FE disc model utilized an analytically-based geometry. The model was created from the mean shape of human L4/L5 discs, measured from high-resolution 3D MR images and averaged using signed distance functions. Structural hyperelastic constitutive models were used in conjunction with biphasic-swelling theory to obtain material properties from recent tissue tests in confined compression and uniaxial tension. The FE disc model predictions fit within the experimental range (mean ± 95% confidence interval) of the disc's nonlinear response for compressive slow loading ramp, creep, and stress-relaxation simulations. Changes in NP and CEP properties affected the neutral-zone displacement but had little effect on the final stiffness during slow-ramp compression loading. These results highlight the need to validate FE models using the disc's full nonlinear response in multiple loading scenarios.

  16. Validity of quasi-degenerate neutrino mass models and their predictions on baryogenesis

    NASA Astrophysics Data System (ADS)

    Francis, Ng. K.; Nimai Singh, N.

    2012-10-01

    Quasi-degenerate neutrino mass models (QDN) which can explain the current data on neutrino masses and mixings, are studied. In the first part, we study the effect of CP-phases on QDN mass matrix (mLL) obeying μ-τ symmetry in normal hierarchical (QD-NH) and inverted hierarchical (QD-IH) patterns. The numerical predictions are consistent with observed data on (i) solar mixing angle (θ12) which lies below tri-bimaximal (TBM) value, (ii) absolute neutrino masses consistent with 0νββ decay mass parameter (mee) and (iii) cosmological upper bound ∑i3mi. mLL is parameterized using only two unknown parameters (ɛ,η) within μ-τ symmetry. The second part deals with the estimation of observed baryon asymmetry of the universe (BAU) where we consider the Majorana CP violating phases (α,β) and the Dirac neutrino mass matrix (mLR). mLR is taken as either the charged lepton or the up quark mass matrix. α, β is derived from the heavy right-handed Majorana mass matrix MRR. MRR is generated from mLL and mLR through inversion of Type-I seesaw formula. The predictions for BAU are nearly consistent with observations for flavoured thermal leptogenesis scenario for Type-IA in both QD-NH and QD-IH models. We also observe some enhancement effects in flavour leptogenesis compared to non-flavour leptogenesis by a magnitude of order one. In non-thermal leptogenesis QD-NH Type-IA is the only model consistent with observed data on baryon asymmetry. QD-NH model appears to be more favourable than those of QD-IH. The predicted inflaton mass needed to produce the BAU is found to be Mϕ˜1010 GeV corresponding to the reheating temperature TR=106 GeV. The present analysis shows that the three absolute neutrino masses may exhibit quasi-degenerate pattern in nature.

  17. Hybrid cervical disc arthroplasty.

    PubMed

    Tu, Tsung-Hsi; Wu, Jau-Ching; Cheng, Henrich; Mummaneni, Praveen V

    2017-01-01

    For patients with multilevel cervical stenosis at nonadjacent segments, one of the traditional approaches has included a multilevel fusion of the abnormal segments as well as the intervening normal segment. In this video we demonstrate an alternative treatment plan with tailored use of a combination of anterior cervical discectomy and fusion (ACDF) and cervical disc arthroplasty (CDA) with an intervening skipped level. The authors present the case of a 72-year-old woman with myeloradiculopathy and a large disc herniation with facet joint degeneration at C3-4 and bulging disc at C5-6. After nonoperative treatment failed, she underwent a single-level ACDF at C3-4 and single-level arthroplasty at C5-6, which successfully relieved her symptoms. No intervention was performed at the normal intervening C4-5 segment. By using ACDF combined with arthroplasty, the authors have avoided a 3-level fusion for this patient and maintained the range of motion of 2 disc levels. The video can be found here: https://youtu.be/OrxcPUBvqLk .

  18. Insights from Genetic Model Systems of Retinal Degeneration: Role of Epsins in Retinal Angiogenesis and VEGFR2 Signaling

    PubMed Central

    Wu, Yong; Liu, Yanjun; Deng, Lin; Chen, Hong

    2017-01-01

    The retina is a light sensitive tissue that contains specialized photoreceptor cells called rods and cones which process visual signals. These signals are relayed to the brain through interneurons and the fibers of the optic nerve. The retina is susceptible to a variety of degenerative diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP) and other inherited retinal degenerations. In order to reveal the mechanism underlying these diseases and to find methods for the prevention/treatment of retinal degeneration, animal models have been generated to mimic human eye diseases. In this paper, several well-characterized and commonly used animal models are reviewed. Of particular interest are the contributions of these models to our understanding of the mechanisms of retinal degeneration and thereby providing novel treatment options including gene therapy, stem cell therapy, nanomedicine, and CRISPR/Cas9 genome editing. Role of newly-identified adaptor protein epsins from our laboratory is discussed in retinal angiogenesis and VEGFR2 signaling. PMID:28191500

  19. Can Exercise Positively Influence the Intervertebral Disc?

    PubMed

    Belavý, Daniel L; Albracht, Kirsten; Bruggemann, Gert-Peter; Vergroesen, Pieter-Paul A; van Dieën, Jaap H

    2016-04-01

    To better understand what kinds of sports and exercise could be beneficial for the intervertebral disc (IVD), we performed a review to synthesise the literature on IVD adaptation with loading and exercise. The state of the literature did not permit a systematic review; therefore, we performed a narrative review. The majority of the available data come from cell or whole-disc loading models and animal exercise models. However, some studies have examined the impact of specific sports on IVD degeneration in humans and acute exercise on disc size. Based on the data available in the literature, loading types that are likely beneficial to the IVD are dynamic, axial, at slow to moderate movement speeds, and of a magnitude experienced in walking and jogging. Static loading, torsional loading, flexion with compression, rapid loading, high-impact loading and explosive tasks are likely detrimental for the IVD. Reduced physical activity and disuse appear to be detrimental for the IVD. We also consider the impact of genetics and the likelihood of a 'critical period' for the effect of exercise in IVD development. The current review summarises the literature to increase awareness amongst exercise, rehabilitation and ergonomic professionals regarding IVD health and provides recommendations on future directions in research.

  20. Degenerate limit thermodynamics beyond leading order for models of dense matter

    SciTech Connect

    Constantinou, Constantinos; Muccioli, Brian; Prakash, Madappa; Lattimer, James M.

    2015-12-15

    Analytical formulas for next-to-leading order temperature corrections to the thermal state variables of interacting nucleons in bulk matter are derived in the degenerate limit. The formalism developed is applicable to a wide class of non-relativistic and relativistic models of hot and dense matter currently used in nuclear physics and astrophysics (supernovae, proto-neutron stars and neutron star mergers) as well as in condensed matter physics. We consider the general case of arbitrary dimensionality of momentum space and an arbitrary degree of relativity (for relativistic models). For non-relativistic zero-range interactions, knowledge of the Landau effective mass suffices to compute next-to-leading order effects, but for finite-range interactions, momentum derivatives of the Landau effective mass function up to second order are required. Results from our analytical formulas are compared with the exact results for zero- and finite-range potential and relativistic mean-field theoretical models. In all cases, inclusion of next-to-leading order temperature effects substantially extends the ranges of partial degeneracy for which the analytical treatment remains valid. Effects of many-body correlations that deserve further investigation are highlighted.

  1. The development of an experimental model of subretinal neovascularization in disciform macular degeneration.

    PubMed Central

    Ryan, S J

    1979-01-01

    A reproducible model of subretinal neovascularization has been developed, an important first step in the study of disciform macular degeneration. The methodology and clinical description of subretinal neovascularization in the primate have been provided and histopathologic and electron microscopic correlations included. This model provides a most promising and useful mechanism for the evaluation of the many different factors and hypotheses that have been proposed for the genesis of the disciform response. In humans, it probably has more relevance to the traumatically induced disciform process, particularly that after laser therapy, than to the senile degenerative process. The purpose of this investigation is to develop the animal model by which many different theories regarding the pathogenesis of the disciform response can be tested. These initial studies relate to ischemia, hemorrhage, the inflammatory response, and position in relation to the center of the vascular-free zone as factors important in the development and evolution of subretinal neovascularization. Images FIGURE 1 FIGURE 2 A FIGURE 2 B FIGURE 2 C FIGURE 2 D FIGURE 3 A FIGURE 3 B FIGURE 3 C FIGURE 3 D FIGURE 3 E FIGURE 4 A FIGURE 4 B FIGURE 7 A FIGURE 7 B FIGURE 7 C FIGURE 7 D FIGURE 7 E FIGURE 7 F FIGURE 8 A FIGURE 8 B FIGURE 8 C FIGURE 8 D FIGURE 8 E FIGURE 8 F FIGURE 8 G FIGURE 9 A FIGURE 9 B FIGURE 9 C FIGURE 9 D FIGURE 10 A FIGURE 10 B FIGURE 10 C PMID:94717

  2. Line-driven disc wind model for ultrafast outflows in active galactic nuclei - scaling with luminosity

    NASA Astrophysics Data System (ADS)

    Nomura, M.; Ohsuga, K.

    2017-03-01

    In order to reveal the origin of the ultrafast outflows (UFOs) that are frequently observed in active galactic nuclei (AGNs), we perform two-dimensional radiation hydrodynamics simulations of the line-driven disc winds, which are accelerated by the radiation force due to the spectral lines. The line-driven winds are successfully launched for the range of MBH = 106-9 M⊙ and ε = 0.1-0.5, and the resulting mass outflow rate (dot{M_w}), momentum flux (dot{p_w}), and kinetic luminosity (dot{E_w}) are in the region containing 90 per cent of the posterior probability distribution in the dot{M}_w-Lbol plane, dot{p}_w-Lbol plane, and dot{E}_w-Lbol plane shown in Gofford et al., where MBH is the black hole mass, ε is the Eddington ratio, and Lbol is the bolometric luminosity. The best-fitting relations in Gofford et al., d log dot{M_w}/d log {L_bol}˜ 0.9, d log dot{p_w}/d log {L_bol}˜ 1.2, and d log dot{E_w}/d log {L_bol}˜ 1.5, are roughly consistent with our results, d log dot{M_w}/d log {L_bol}˜ 9/8, d log dot{p_w}/d log {L_bol}˜ 10/8, and d log dot{E_w}/d log {L_bol}˜ 11/8. In addition, our model predicts that no UFO features are detected for the AGNs with ε ≲ 0.01, since the winds do not appear. Also, only AGNs with MBH ≲ 108 M⊙ exhibit the UFOs when ε ∼ 0.025. These predictions nicely agree with the X-ray observations. These results support that the line-driven disc wind is the origin of the UFOs.

  3. Tissue and urokinase plasminogen activators instigate the degeneration of retinal ganglion cells in a mouse model of glaucoma

    PubMed Central

    Chintala, Shravan K

    2015-01-01

    Elevated intraocular pressure (IOP) promotes the degeneration of retinal ganglion cells (RGCs) during the progression of Primary Open-Angle Glaucoma (POAG). However, the molecular mechanisms underpinning IOP-mediated degeneration of RGCs remain unclear. Therefore, by employing a mouse model of POAG, this study examined whether elevated IOP promotes the degeneration of RGCs by up-regulating tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) in the retina. IOP was elevated in mouse eyes by injecting fluorescent-microbeads into the anterior chamber. Once a week, for eight weeks, IOP in mouse eyes was measured by using Tono-Pen XL. At various time periods after injecting microbeads, proteolytic activity of tPA and uPA in retinal protein extracts was determined by fibrinogen/plasminogen zymography assays. Localization of tPA and uPA, and their receptor LRP-1 (low-density receptor-related protein-1) in the retina was determined by immunohistochemistry. RGCs’ degeneration was assessed by immunostaining with antibodies against Brn3a. Injection of microbeads into the anterior chamber led to a progressive elevation in IOP, increased the proteolytic activity of tPA and uPA in the retina, activated plasminogen into plasmin, and promoted a significant degeneration of RGCs. Elevated IOP up-regulated tPA and LRP-1 in RGCs, and uPA in astrocytes. At four weeks after injecting microbeads, RAP (receptor associated protein; 0.5 and 1.0 μM) or tPA-Stop (1.0 and 4.0 μM) was injected into the vitreous humor. Treatment of IOP-elevated eyes with RAP led to a significant decrease in proteolytic activity of both tPA and uPA, and a significant decrease in IOP-mediated degeneration of RGCs. Also, treatment of IOP-elevated eyes with tPA-Stop decreased the proteolytic activity of both tPA and uPA, and, in turn, significantly attenuated IOP-mediated degeneration of RGCs. Results presented in this study provide evidence that elevated IOP promotes the degeneration of

  4. BMP9/ALK1 inhibits neovascularization in mouse models of age-related macular degeneration

    PubMed Central

    Ntumba, Kalonji; Akla, Naoufal; Oh, S. Paul; Eichmann, Anne; Larrivée, Bruno

    2016-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness in aging populations of industrialized countries. The drawbacks of inhibitors of vascular endothelial growth factor (VEGFs) currently used for the treatment of AMD, which include resistance and potential serious side-effects, require the identification of new therapeutic targets to modulate angiogenesis. BMP9 signaling through the endothelial Alk1 serine-threonine kinase receptor modulates the response of endothelial cells to VEGF and promotes vessel quiescence and maturation during development. Here, we show that BMP9/Alk1 signaling inhibits neovessel formation in mouse models of pathological ocular angiogenesis relevant to AMD. Activating Alk1 signaling in laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) inhibited neovascularization and reduced the volume of vascular lesions. Alk1 signaling was also found to interfere with VEGF signaling in endothelial cells whereas BMP9 potentiated the inhibitory effects of VEGFR2 signaling blockade, both in OIR and laser-induced CNV. Together, our data show that targeting BMP9/Alk1 efficiently prevents the growth of neovessels in AMD models and introduce a new approach to improve conventional anti-VEGF therapies. PMID:27517154

  5. Imaging Axonal Degeneration and Repair in Preclinical Animal Models of Multiple Sclerosis

    PubMed Central

    Yandamuri, Soumya S.; Lane, Thomas E.

    2016-01-01

    Multiple sclerosis (MS) is a central nervous system (CNS) disease characterized by chronic neuroinflammation, demyelination, and axonal damage. Infiltration of activated lymphocytes and myeloid cells are thought to be primarily responsible for white matter damage and axonopathy. Over time, this neurologic damage manifests clinically as debilitating motor and cognitive symptoms. Existing MS therapies focus on symptom relief and delay of disease progression through reduction of neuroinflammation. However, long-term strategies to remyelinate, protect, or regenerate axons have remained elusive, posing a challenge to treating progressive forms of MS. Preclinical mouse models and techniques, such as immunohistochemistry, flow cytometry, and genomic and proteomic analysis have provided advances in our understanding of discrete time-points of pathology following disease induction. More recently, in vivo and in situ two-photon (2P) microscopy has made it possible to visualize continuous real-time cellular behavior and structural changes occurring within the CNS during neuropathology. Research utilizing 2P imaging to study axonopathy in neuroinflammatory demyelinating disease has focused on five areas: (1) axonal morphologic changes, (2) organelle transport and health, (3) relationship to inflammation, (4) neuronal excitotoxicity, and (5) regenerative therapies. 2P imaging may also be used to identify novel therapeutic targets via identification and clarification of dynamic cellular and molecular mechanisms of axonal regeneration and remyelination. Here, we review tools that have made 2P accessible for imaging neuropathologies and advances in our understanding of axonal degeneration and repair in preclinical models of demyelinating diseases. PMID:27242796

  6. Adalimumab Reduces Photoreceptor Cell Death in A Mouse Model of Retinal Degeneration

    PubMed Central

    Martínez-Fernández de la Cámara, Cristina; Hernández-Pinto, Alberto M.; Olivares-González, Lorena; Cuevas-Martín, Carmen; Sánchez-Aragó, María; Hervás, David; Salom, David; Cuezva, José M.; de la Rosa, Enrique J.; Millán, José M; Rodrigo, Regina

    2015-01-01

    Growing evidence suggests that inflammation is involved in the progression of retinitis pigmentosa (RP) both in patients and in animal models. The aim of this study was to investigate the effect of Adalimumab, a monoclonal anti-TNFα antibody, on retinal degeneration in a murine model of human autosomal recessive RP, the rd10 mice at postnatal day (P) 18. In our housing conditions, rd10 retinas were seriously damaged at P18. Adalimumab reduced photoreceptor cell death, as determined by scoring the number of TUNEL-positive cells. In addition, nuclear poly (ADP) ribose (PAR) content, an indirect measure of PAR polymerase (PARP) activity, was also reduced after treatment. The blockade of TNFα ameliorated reactive gliosis, as visualized by decreased GFAP and IBA1 immunolabelling (Müller cell and microglial markers, respectively) and decreased up-regulation of TNFα gene expression. Adalimumab also improved antioxidant response by restoring total antioxidant capacity and superoxide dismutase activity. Finally, we observed that Adalimumab normalized energetic and metabolic pattern in rd10 mouse retinas. Our study suggests that the TNFα blockade could be a successful therapeutic approach to increase photoreceptor survival during the progression of RP. Further studies are needed to characterize its effect along the progression of the disease. PMID:26170250

  7. Persistent inflammatory state after photoreceptor loss in an animal model of retinal degeneration

    PubMed Central

    Noailles, Agustina; Maneu, Victoria; Campello, Laura; Gómez-Vicente, Violeta; Lax, Pedro; Cuenca, Nicolás

    2016-01-01

    Microglia act as the resident immune cells of the central nervous system, including the retina. In response to damaging stimuli microglia adopt an activated state, which can progress into a phagocytic phenotype and play a potentially harmful role by eliciting the expression and release of pro-inflammatory cytokines. The aim of the present study was to assess longitudinal changes in microglia during retinal degeneration in the homozygous P23H rat, a model of dominant retinitis pigmentosa. Microglial phenotypes, morphology and density were analyzed by immunohistochemistry, flow cytometry, and cytokine antibody array. In addition, we performed electroretinograms to evaluate the retinal response. In the P23H retina, sclera, choroid and ciliary body, inflammatory cells increased in number compared with the control at all ages analyzed. As the rats became older, a higher number of amoeboid MHC-II+ cells were observed in the P23H retina, which correlated with an increase in the expression of pro-inflammatory cytokines. These findings suggest that, in the P23H model, retinal neuroinflammation persists throughout the rat’s life span even after photoreceptor depletion. Therefore, the inclusion of anti-inflammatory drugs at advanced stages of the neurodegenerative process may provide better retinal fitness so the remaining cells could still be used as targets of cellular or gene therapies. PMID:27624537

  8. Intervertebral disc biomechanical analysis using the finite element modeling based on medical images.

    PubMed

    Li, Haiyun; Wang, Zheng

    2006-01-01

    In this paper, a 3D geometric model of the intervertebral and lumbar disks has been presented, which integrated the spine CT and MRI data-based anatomical structure. Based on the geometric model, a 3D finite element model of an L1-L2 segment was created. Loads, which simulate the pressure from above were applied to the FEM, while a boundary condition describing the relative L1-L2 displacement is imposed on the FEM to account for 3D physiological states. The simulation calculation illustrates the stress and strain distribution and deformation of the spine. The method has two characteristics compared to previous studies: first, the finite element model of the lumbar are based on the data directly derived from medical images such as CTs and MRIs. Second, the result of analysis will be more accurate than using the data of geometric parameters. The FEM provides a promising tool in clinical diagnosis and for optimizing individual therapy in the intervertebral disc herniation.

  9. A mathematical model for describing the retinal nerve fiber bundle trajectories in the human eye: average course, variability, and influence of refraction, optic disc size and optic disc position.

    PubMed

    Jansonius, Nomdo M; Schiefer, Julia; Nevalainen, Jukka; Paetzold, Jens; Schiefer, Ulrich

    2012-12-01

    Previously we developed a mathematical model for describing the retinal nerve fiber bundle trajectories in the superior-temporal and inferior-temporal regions of the human retina, based on traced trajectories extracted from fundus photographs. Aims of the current study were to (i) validate the existing model, (ii) expand the model to the entire retina and (iii) determine the influence of refraction, optic disc size and optic disc position on the trajectories. A new set of fundus photographs was collected comprising 28 eyes of 28 subjects. From these 28 photographs, 625 trajectories were extracted. Trajectories in the temporal region of the retina were compared to the existing model. In this region, 347 of 399 trajectories (87%) were within the 95% central range of the existing model. The model was extended to the nasal region. With this extension, the model can now be applied to the entire retina that corresponds to the visual field as tested with standard automated perimetry (up to approximately 30° eccentricity). There was an asymmetry between the superior and inferior hemifields and a considerable location-specific inter-subject variability. In the nasal region, we found two "singularities", located roughly at the one and five o'clock positions for the right optic disc. Here, trajectories from relatively widespread areas of the retina converge. Associations between individual deviations from the model and refraction, optic disc size and optic disc position were studied with multiple linear regression. Refraction (P = 0.021) and possibly optic disc inclination (P = 0.09) influenced the trajectories in the superior-temporal region.

  10. Imaging rhodopsin degeneration in vivo in a new model of ocular ischemia in living mice

    PubMed Central

    Ren, Jiaqian; Chen, Yinching I.; Mackey, Ashley M.; Liu, Philip K.

    2016-01-01

    Delivery of antibodies to monitor key biomarkers of retinopathy in vivo represents a significant challenge because living cells do not take up immunoglobulins to cellular antigens. We met this challenge by developing novel contrast agents for retinopathy, which we used with magnetic resonance imaging (MRI). Biotinylated rabbit polyclonal to chick IgY (rIgPxcIgY) and phosphorylthioate-modified oligoDNA (sODN) with random sequence (bio-sODN-Ran) were conjugated with NeutrAvidin-activated superparamagnetic iron oxide nanoparticles (SPION). The resulting Ran-SPION-rIgPxcIgY carries chick polyclonal to microtubule-associated protein 2 (MAP2) as Ran-SPION-rIgP/cIgY-MAP2, or to rhodopsin (Rho) as anti-Rho-SPION-Ran. We examined the uptake of Ran-SPION-rIgP/cIgY-MAP2 or SPION-rIgP/cIgY-MAP2 in normal C57black6 mice (n = 3 each, 40 μg/kg, i.c.v.); we found retention of Ran-SPION-rIgP/cIgY-MAP2 using molecular contrast-enhanced MRI in vivo and validated neuronal uptake using Cy5-goat IgPxcIgY ex vivo. Applying this novel method to monitor retinopathy in a bilateral carotid artery occlusion-induced ocular ischemia, we observed pericytes (at d 2, using Gd-nestin, by eyedrop solution), significant photoreceptor degeneration (at d 20, using anti-Rho-SPION-Ran, eyedrops, P = 0.03, Student's t test), and gliosis in Müller cells (at 6 mo, using SPION–glial fibrillary acidic protein administered by intraperitoneal injection) in surviving mice (n ≥ 5). Molecular contrast-enhanced MRI results were confirmed by optical and electron microscopy. We conclude that chimera and molecular contrast-enhanced MRI provide sufficient sensitivity for monitoring retinopathy and for theranostic applications.—Ren, J., Chen, Y. I., Mackey, A. M., Liu, P. K. Imaging rhodopsin degeneration in vivo in a new model of ocular ischemia in living mice. PMID:26443823

  11. Small heat shock proteins mediate cell-autonomous and -nonautonomous protection in a Drosophila model for environmental-stress-induced degeneration.

    PubMed

    Kawasaki, Fumiko; Koonce, Noelle L; Guo, Linda; Fatima, Shahroz; Qiu, Catherine; Moon, Mackenzie T; Zheng, Yunzhen; Ordway, Richard W

    2016-09-01

    Cell and tissue degeneration, and the development of degenerative diseases, are influenced by genetic and environmental factors that affect protein misfolding and proteotoxicity. To better understand the role of the environment in degeneration, we developed a genetic model for heat shock (HS)-stress-induced degeneration in Drosophila This model exhibits a unique combination of features that enhance genetic analysis of degeneration and protection mechanisms involving environmental stress. These include cell-type-specific failure of proteostasis and degeneration in response to global stress, cell-nonautonomous interactions within a simple and accessible network of susceptible cell types, and precise temporal control over the induction of degeneration. In wild-type flies, HS stress causes selective loss of the flight ability and degeneration of three susceptible cell types comprising the flight motor: muscle, motor neurons and associated glia. Other motor behaviors persist and, accordingly, the corresponding cell types controlling leg motor function are resistant to degeneration. Flight motor degeneration was preceded by a failure of muscle proteostasis characterized by diffuse ubiquitinated protein aggregates. Moreover, muscle-specific overexpression of a small heat shock protein (HSP), HSP23, promoted proteostasis and protected muscle from HS stress. Notably, neurons and glia were protected as well, indicating that a small HSP can mediate cell-nonautonomous protection. Cell-autonomous protection of muscle was characterized by a distinct distribution of ubiquitinated proteins, including perinuclear localization and clearance of protein aggregates associated with the perinuclear microtubule network. This network was severely disrupted in wild-type preparations prior to degeneration, suggesting that it serves an important role in muscle proteostasis and protection. Finally, studies of resistant leg muscles revealed that they sustain proteostasis and the microtubule

  12. Small heat shock proteins mediate cell-autonomous and -nonautonomous protection in a Drosophila model for environmental-stress-induced degeneration

    PubMed Central

    Kawasaki, Fumiko; Koonce, Noelle L.; Guo, Linda; Fatima, Shahroz; Qiu, Catherine; Moon, Mackenzie T.; Zheng, Yunzhen

    2016-01-01

    ABSTRACT Cell and tissue degeneration, and the development of degenerative diseases, are influenced by genetic and environmental factors that affect protein misfolding and proteotoxicity. To better understand the role of the environment in degeneration, we developed a genetic model for heat shock (HS)-stress-induced degeneration in Drosophila. This model exhibits a unique combination of features that enhance genetic analysis of degeneration and protection mechanisms involving environmental stress. These include cell-type-specific failure of proteostasis and degeneration in response to global stress, cell-nonautonomous interactions within a simple and accessible network of susceptible cell types, and precise temporal control over the induction of degeneration. In wild-type flies, HS stress causes selective loss of the flight ability and degeneration of three susceptible cell types comprising the flight motor: muscle, motor neurons and associated glia. Other motor behaviors persist and, accordingly, the corresponding cell types controlling leg motor function are resistant to degeneration. Flight motor degeneration was preceded by a failure of muscle proteostasis characterized by diffuse ubiquitinated protein aggregates. Moreover, muscle-specific overexpression of a small heat shock protein (HSP), HSP23, promoted proteostasis and protected muscle from HS stress. Notably, neurons and glia were protected as well, indicating that a small HSP can mediate cell-nonautonomous protection. Cell-autonomous protection of muscle was characterized by a distinct distribution of ubiquitinated proteins, including perinuclear localization and clearance of protein aggregates associated with the perinuclear microtubule network. This network was severely disrupted in wild-type preparations prior to degeneration, suggesting that it serves an important role in muscle proteostasis and protection. Finally, studies of resistant leg muscles revealed that they sustain proteostasis and the

  13. AAV Mediated GDNF Secretion From Retinal Glia Slows Down Retinal Degeneration in a Rat Model of Retinitis Pigmentosa

    PubMed Central

    Dalkara, Deniz; Kolstad, Kathleen D; Guerin, Karen I; Hoffmann, Natalie V; Visel, Meike; Klimczak, Ryan R; Schaffer, David V; Flannery, John G

    2011-01-01

    Mutations in over 80 identified genes can induce apoptosis in photoreceptors, resulting in blindness with a prevalence of 1 in 3,000 individuals. This broad genetic heterogeneity of disease impacting a wide range of photoreceptor functions renders the design of gene-specific therapies for photoreceptor degeneration impractical and necessitates the development of mutation-independent treatments to slow photoreceptor cell death. One promising strategy for photoreceptor neuroprotection is neurotrophin secretion from Müller cells, the primary retinal glia. Müller glia are excellent targets for secreting neurotrophins as they span the entire tissue, ensheath all neuronal populations, are numerous, and persist through retinal degeneration. We previously engineered an adeno-associated virus (AAV) variant (ShH10) capable of efficient and selective glial cell transduction through intravitreal injection. ShH10-mediated glial-derived neurotrophic factor (GDNF) secretion from glia, generates high GDNF levels in treated retinas, leading to sustained functional rescue for over 5 months. This GDNF secretion from glia following intravitreal vector administration is a safe and effective means to slow the progression of retinal degeneration in a rat model of retinitis pigmentosa (RP) and shows significant promise as a gene therapy to treat human retinal degenerations. These findings also demonstrate for the first time that glia-mediated secretion of neurotrophins is a promising treatment that may be applicable to other neurodegenerative conditions. PMID:21522134

  14. Non-local correlation and quantum discord in two atoms in the non-degenerate model

    SciTech Connect

    Mohamed, A.-B.A.

    2012-12-15

    By using geometric quantum discord (GQD) and measurement-induced nonlocality (MIN), quantum correlation is investigated for two atoms in the non-degenerate two-photon Tavis-Cummings model. It is shown that there is no asymptotic decay for MIN while asymptotic decay exists for GQD. Quantum correlations can be strengthened by introducing the dipole-dipole interaction. The evolvement period of quantum correlation gets shorter with the increase in the dipole-dipole parameter. It is found that there exists not only quantum nonlocality without entanglement but also quantum nonlocality without quantum discord. Also, the MIN and GQD are raised rather than entanglement, and also with weak initial entanglement, there are MIN and entanglement in a interval of death quantum discord. - Highlights: Black-Right-Pointing-Pointer Geometric quantum discord (GQD) and measurement induced nonlocality (MIN) are used to investigate the correlations of two two-level atoms. Black-Right-Pointing-Pointer There is no asymptotic decay for MIN while asymptotic decay exists for GQD. Black-Right-Pointing-Pointer Quantum correlations can be strengthened by introducing the dipole-dipole interaction. Black-Right-Pointing-Pointer There exists not only quantum nonlocality without entanglement but also without discord. Black-Right-Pointing-Pointer Weak initial entanglement leads to MIN and entanglement in intervals of death discord.

  15. Neuoroprotective efficacies by KUS121, a VCP modulator, on animal models of retinal degeneration

    PubMed Central

    Hasegawa, Tomoko; Muraoka, Yuki; Ikeda, Hanako Ohashi; Tsuruyama, Tatsuaki; Kondo, Mineo; Terasaki, Hiroko; Kakizuka, Akira; Yoshimura, Nagahisa

    2016-01-01

    Retinitis pigmentosa (RP) is one of the leading causes of adult blindness and has no established therapy. We have shown that valosin-containing protein (VCP) modulators, Kyoto University Substances (KUSs), ameliorated abnormally low ATP levels by inhibiting the ATPase of VCP, thereby protected several types of cells, including retinal neurons, from cell death-inducing insults. In this study, we found that KUS121, one of the VCP modulators, effectively protects photoreceptors both morphologically and functionally, in two animal models of retinal degeneration, rd12 mice and RP rabbits with a rhodopsin (Pro347Leu) mutation. In rd12 mice, KUS121 suppressed the loss of photoreceptors, not only rods but also cones, as well as the visual function deterioration. Significant protective effects existed even when the medication was started in later stages of the disease. In RP rabbits, KUS121 suppressed thinning of the outer nuclear layer and maintained visual function. In the retinas treated with KUS121, suppression of endoplasmic reticulum stress, activation of mammalian target of rapamycin and suppression of disease-associated apoptosis were evident. The ability of KUS121 to protect photoreceptors, especially cones, even in later stages of the disease may contribute to the preservation of central vision in RP patients, which is important for quality of vision. PMID:27503804

  16. Oxidative Damage Compromises Energy Metabolism in the Axonal Degeneration Mouse Model of X-Adrenoleukodystrophy

    PubMed Central

    Galino, Jorge; Ruiz, Montserrat; Fourcade, Stéphane; Schlüter, Agatha; López-Erauskin, Jone; Guilera, Cristina; Jove, Mariona; Naudi, Alba; García-Arumí, Elena; Andreu, Antoni L.; Starkov, Anatoly A.; Pamplona, Reinald; Ferrer, Isidre; Portero-Otin, Manuel

    2011-01-01

    Abstract Aims Chronic metabolic impairment and oxidative stress are associated with the pathogenesis of axonal dysfunction in a growing number of neurodegenerative conditions. To investigate the intertwining of both noxious factors, we have chosen the mouse model of adrenoleukodystrophy (X-ALD), which exhibits axonal degeneration in spinal cords and motor disability. The disease is caused by loss of function of the ABCD1 transporter, involved in the import and degradation of very long-chain fatty acids (VLCFA) in peroxisomes. Oxidative stress due to VLCFA excess appears early in the neurodegenerative cascade. Results In this study, we demonstrate by redox proteomics that oxidative damage to proteins specifically affects five key enzymes of glycolysis and TCA (Tricarboxylic acid) cycle in spinal cords of Abcd1− mice and pyruvate kinase in human X-ALD fibroblasts. We also show that NADH and ATP levels are significantly diminished in these samples, together with decrease of pyruvate kinase activities and GSH levels, and increase of NADPH. Innovation Treating Abcd1− mice with the antioxidants N-acetylcysteine and α-lipoic acid (LA) prevents protein oxidation; preserves NADH, NADPH, ATP, and GSH levels; and normalizes pyruvate kinase activity, which implies that oxidative stress provoked by VLCFA results in bioenergetic dysfunction, at a presymptomatic stage. Conclusion Our results provide mechanistic insight into the beneficial effects of antioxidants and enhance the rationale for translation into clinical trials for X-adrenoleukodystrophy. Antioxid. Redox Signal. 15, 2095–2107. PMID:21453200

  17. Cost-Effectiveness Models in Age-Related Macular Degeneration: Issues and Challenges.

    PubMed

    Schmier, Jordana K; Hulme-Lowe, Carolyn K

    2016-03-01

    Age-related macular degeneration (AMD) is a common ophthalmic condition that can have few symptoms in its early stage but can progress to major visual impairment. While there are no treatments for early-stage AMD, there are multiple modalities of treatment for advanced disease. Given the increasing prevalence of the disease, there are dozens of analyses of cost effectiveness of AMD treatments, but methods and approaches vary broadly. The goal of this review was to identify, characterize, and critique published models in AMD and provide guidance for their interpretation. After a literature review was performed to identify studies, and exclusion criteria applied to limit the review to studies comparing treatments for AMD, we compared methods across the 36 studies meeting the review criteria. To some extent, variation was related to targeting different audiences or acknowledging the most appropriate population for a given treatment. However, the review identified potential areas of uncertainty and difficulty in interpretation, particularly regarding duration of observation periods and the importance of visual acuity as an endpoint or a proxy for patient-reported utilities. We urge thoughtful consideration of these study characteristics when comparing results.

  18. An Adaptive Integration Model of Vector Polyline to DEM Data Based on Spherical Degeneration Quadtree Grids

    NASA Astrophysics Data System (ADS)

    Zhao, X. S.; Wang, J. J.; Yuan, Z. Y.; Gao, Y.

    2013-10-01

    Traditional geometry-based approach can maintain the characteristics of vector data. However, complex interpolation calculations limit its applications in high resolution and multi-source spatial data integration at spherical scale in digital earth systems. To overcome this deficiency, an adaptive integration model of vector polyline and spherical DEM is presented. Firstly, Degenerate Quadtree Grid (DQG) which is one of the partition models for global discrete grids, is selected as a basic framework for the adaptive integration model. Secondly, a novel shift algorithm is put forward based on DQG proximity search. The main idea of shift algorithm is that the vector node in a DQG cell moves to the cell corner-point when the displayed area of the cell is smaller or equal to a pixel of screen in order to find a new vector polyline approximate to the original one, which avoids lots of interpolation calculations and achieves seamless integration. Detailed operation steps are elaborated and the complexity of algorithm is analyzed. Thirdly, a prototype system has been developed by using VC++ language and OpenGL 3D API. ASTER GDEM data and DCW roads data sets of Jiangxi province in China are selected to evaluate the performance. The result shows that time consumption of shift algorithm decreased about 76% than that of geometry-based approach. Analysis on the mean shift error from different dimensions has been implemented. In the end, the conclusions and future works in the integration of vector data and DEM based on discrete global grids are also given.

  19. Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration

    NASA Astrophysics Data System (ADS)

    Bora, Puran S.; Hu, Zhiwei; Tezel, Tongalp H.; Sohn, Jeong-Hyeon; Kang, Shin Goo; Cruz, Jose M. C.; Bora, Nalini S.; Garen, Alan; Kaplan, Henry J.

    2003-03-01

    Age-related macular degeneration (AMD) is the leading cause of blindness after age 55 in the industrialized world. Severe loss of central vision frequently occurs with the exudative (wet) form of AMD, as a result of the formation of a pathological choroidal neovasculature (CNV) that damages the macular region of the retina. We tested the effect of an immunotherapy procedure, which had been shown to destroy the pathological neovasculature in solid tumors, on the formation of laser-induced CNV in a mouse model simulating exudative AMD in humans. The procedure involves administering an Icon molecule that binds with high affinity and specificity to tissue factor (TF), resulting in the activation of a potent cytolytic immune response against cells expressing TF. The Icon binds selectively to TF on the vascular endothelium of a CNV in the mouse and pig models and also on the CNV of patients with exudative AMD. Here we show that the Icon dramatically reduces the frequency of CNV formation in the mouse model. After laser treatment to induce CNV formation, the mice were injected either with an adenoviral vector encoding the Icon, resulting in synthesis of the Icon by vector-infected mouse cells, or with the Icon protein. The route of injection was i.v. or intraocular. The efficacy of the Icon in preventing formation of laser-induced CNV depends on binding selectively to the CNV. Because the Icon binds selectively to the CNV in exudative AMD as well as to laser-induced CNV, the Icon might also be efficacious for treating patients with exudative AMD.

  20. Automated segmentation of optic disc region on retinal fundus photographs: Comparison of contour modeling and pixel classification methods.

    PubMed

    Muramatsu, Chisako; Nakagawa, Toshiaki; Sawada, Akira; Hatanaka, Yuji; Hara, Takeshi; Yamamoto, Tetsuya; Fujita, Hiroshi

    2011-01-01

    The automatic determination of the optic disc area in retinal fundus images can be useful for calculation of the cup-to-disc (CD) ratio in the glaucoma screening. We compared three different methods that employed active contour model (ACM), fuzzy c-mean (FCM) clustering, and artificial neural network (ANN) for the segmentation of the optic disc regions. The results of these methods were evaluated using new databases that included the images captured by different camera systems. The average measures of overlap between the disc regions determined by an ophthalmologist and by using the ACM (0.88 and 0.87 for two test datasets) and ANN (0.88 and 0.89) methods were slightly higher than that by using FCM (0.86 and 0.86) method. These results on the unknown datasets were comparable with those of the resubstitution test; this indicates the generalizability of these methods. The differences in the vertical diameters, which are often used for CD ratio calculation, determined by the proposed methods and based on the ophthalmologist's outlines were even smaller than those in the case of the measure of overlap. The proposed methods can be useful for automatic determination of CD ratios.

  1. Stem cell therapy for intervertebral disc regeneration: obstacles and solutions.

    PubMed

    Sakai, Daisuke; Andersson, Gunnar B J

    2015-04-01

    Intervertebral disc (IVD) degeneration is frequently associated with low back and neck pain, which accounts for disability worldwide. Despite the known outcomes of the IVD degeneration cascade, the treatment of IVD degeneration is limited in that available conservative and surgical treatments do not reverse the pathology or restore the IVD tissue. Regenerative medicine for IVD degeneration, by injection of IVD cells, chondrocytes or stem cells, has been extensively studied in the past decade in various animal models of induced IVD degeneration, and has progressed to clinical trials in the treatment of various spinal conditions. Despite preliminary results showing positive effects of cell-injection strategies for IVD regeneration, detailed basic research on IVD cells and their niche indicates that transplanted cells are unable to survive and adapt in the avascular niche of the IVD. For this therapeutic strategy to succeed, the indications for its use and the patients who would benefit need to be better defined. To surmount these obstacles, the solution will be identified only by focused research, both in the laboratory and in the clinic.

  2. Characteristics of rod regeneration in a novel zebrafish retinal degeneration model using N-methyl-N-nitrosourea (MNU).

    PubMed

    Tappeiner, Christoph; Balmer, Jasmin; Iglicki, Matias; Schuerch, Kaspar; Jazwinska, Anna; Enzmann, Volker; Tschopp, Markus

    2013-01-01

    Primary loss of photoreceptors caused by diseases such as retinitis pigmentosa is one of the main causes of blindness worldwide. To study such diseases, rodent models of N-methyl-N-nitrosourea (MNU)-induced retinal degeneration are widely used. As zebrafish (Danio rerio) are a popular model system for visual research that offers persistent retinal neurogenesis throughout the lifetime and retinal regeneration after severe damage, we have established a novel MNU-induced model in this species. Histology with staining for apoptosis (TUNEL), proliferation (PCNA), activated Müller glial cells (GFAP), rods (rhodopsin) and cones (zpr-1) were performed. A characteristic sequence of retinal changes was found. First, apoptosis of rod photoreceptors occurred 3 days after MNU treatment and resulted in a loss of rod cells. Consequently, proliferation started in the inner nuclear layer (INL) with a maximum at day 8, whereas in the outer nuclear layer (ONL) a maximum was observed at day 15. The proliferation in the ONL persisted to the end of the follow-up (3 months), interestingly, without ongoing rod cell death. We demonstrate that rod degeneration is a sufficient trigger for the induction of Müller glial cell activation, even if only a minimal number of rod cells undergo cell death. In conclusion, the use of MNU is a simple and feasible model for rod photoreceptor degeneration in the zebrafish that offers new insights into rod regeneration.

  3. Characteristics of Rod Regeneration in a Novel Zebrafish Retinal Degeneration Model Using N-Methyl-N-Nitrosourea (MNU)

    PubMed Central

    Tappeiner, Christoph; Balmer, Jasmin; Iglicki, Matias; Schuerch, Kaspar; Jazwinska, Anna; Enzmann, Volker; Tschopp, Markus

    2013-01-01

    Primary loss of photoreceptors caused by diseases such as retinitis pigmentosa is one of the main causes of blindness worldwide. To study such diseases, rodent models of N-methyl-N-nitrosourea (MNU)-induced retinal degeneration are widely used. As zebrafish (Danio rerio) are a popular model system for visual research that offers persistent retinal neurogenesis throughout the lifetime and retinal regeneration after severe damage, we have established a novel MNU-induced model in this species. Histology with staining for apoptosis (TUNEL), proliferation (PCNA), activated Müller glial cells (GFAP), rods (rhodopsin) and cones (zpr-1) were performed. A characteristic sequence of retinal changes was found. First, apoptosis of rod photoreceptors occurred 3 days after MNU treatment and resulted in a loss of rod cells. Consequently, proliferation started in the inner nuclear layer (INL) with a maximum at day 8, whereas in the outer nuclear layer (ONL) a maximum was observed at day 15. The proliferation in the ONL persisted to the end of the follow-up (3 months), interestingly, without ongoing rod cell death. We demonstrate that rod degeneration is a sufficient trigger for the induction of Müller glial cell activation, even if only a minimal number of rod cells undergo cell death. In conclusion, the use of MNU is a simple and feasible model for rod photoreceptor degeneration in the zebrafish that offers new insights into rod regeneration. PMID:23951079

  4. Hearing impairment in the P23H-1 retinal degeneration rat model

    PubMed Central

    Sotoca, Jorge V.; Alvarado, Juan C.; Fuentes-Santamaría, Verónica; Martinez-Galan, Juan R.; Caminos, Elena

    2014-01-01

    The transgenic P23H line 1 (P23H-1) rat expresses a variant of rhodopsin with a mutation that leads to loss of visual function. This rat strain is an experimental model usually employed to study photoreceptor degeneration. Although the mutated protein should not interfere with other sensory functions, observing severe loss of auditory reflexes in response to natural sounds led us to study auditory brain response (ABR) recording. Animals were separated into different hearing levels following the response to natural stimuli (hand clapping and kissing sounds). Of all the analyzed animals, 25.9% presented auditory loss before 50 days of age (P50) and 45% were totally deaf by P200. ABR recordings showed that all the rats had a higher hearing threshold than the control Sprague-Dawley (SD) rats, which was also higher than any other rat strains. The integrity of the central and peripheral auditory pathway was analyzed by histology and immunocytochemistry. In the cochlear nucleus (CN), statistical differences were found between SD and P23H-1 rats in VGluT1 distribution, but none were found when labeling all the CN synapses with anti-Syntaxin. This finding suggests anatomical and/or molecular abnormalities in the auditory downstream pathway. The inner ear of the hypoacusic P23H-1 rats showed several anatomical defects, including loss and disruption of hair cells and spiral ganglion neurons. All these results can explain, at least in part, how hearing impairment can occur in a high percentage of P23H-1 rats. P23H-1 rats may be considered an experimental model with visual and auditory dysfunctions in future research. PMID:25278831

  5. Mechanics of Actuated Disc Cutting

    NASA Astrophysics Data System (ADS)

    Dehkhoda, Sevda; Detournay, Emmanuel

    2017-02-01

    This paper investigates the mechanics of an actuated disc cutter with the objective of determining the average forces acting on the disc as a function of the parameters characterizing its motion. The specific problem considered is that of a disc cutter revolving off-centrically at constant angular velocity around a secondary axis rigidly attached to a cartridge, which is moving at constant velocity and undercutting rock at a constant depth. This model represents an idealization of a technology that has been implemented in a number of hard rock mechanical excavators with the goal of reducing the average thrust force to be provided by the excavation equipment. By assuming perfect conformance of the rock with the actuated disc as well as a prescribed motion of the disc (perfectly rigid machine), the evolution of the contact surface between the disc and the rock during one actuation of the disc can be computed. Coupled with simple cutter/rock interaction models that embody either a ductile or a brittle mode of fragmentation, these kinematical considerations lead to an estimate of the average force on the cartridge and of the partitioning of the energy imparted by the disc to the rock between the actuation mechanism of the disc and the translation of the cartridge on which the actuated disc is attached.

  6. Collective molecular dissipation on Navier-Stokes macroscopic scales: Accretion disc viscous modeling in SPH

    NASA Astrophysics Data System (ADS)

    Lanzafame, Giuseppe

    2015-02-01

    In the nonlinear Navier-Stokes viscous flow dynamics, physical damping is mathematically accomplished by a braking term in the momentum equation, corresponding to a heating term in the energy equation, both responsible of the conversion of mechanical energy into heat. In such two terms, it is essential the role of the viscous stress tensor, relative to contiguous macroscopic moving flow components, depending on the macroscopic viscosity coefficient ν. A working formulation for ν can always be found analytically, tuning some arbitrary parameters in the current known formulations, according to the geometry, morphology and physics of the flow. Instead, in this paper, we write an alternative hybrid formulation for ν, where molecular parameters are also included. Our expression for ν has a more physical interpretation of the internal damping in dilute gases because the macroscopic viscosity is related to the small scale molecular dissipation, not strictly dependent on the flow morphology, as well as it is free of any arbitrary parameter. Results for some basic 2D tests are shown in the smoothed particle hydrodynamics (SPH) framework. An application to the 3D accretion disc modeling for low mass cataclysmic variables is also discussed. Consequences of the macroscopic viscosity coefficient reformulation in a more strictly physical terms on the thermal conductivity coefficient for dilute gases are also discussed.

  7. Numerical exploration of the combined effect of nutrient supply, tissue condition and deformation in the intervertebral disc.

    PubMed

    Malandrino, Andrea; Noailly, Jérôme; Lacroix, Damien

    2014-04-11

    Novel strategies to heal discogenic low back pain could highly benefit from comprehensive biophysical studies that consider both mechanical and biological factors involved in intervertebral disc degeneration. A decrease in nutrient availability at the bone-disc interface has been indicated as a relevant risk factor and as a possible initiator of cell death processes. Mechanical behaviour of both healthy and degenerated discs could highly interact with cell death in these compromised situations. In the present study, a mechano-transport finite element model was used to investigate the nature of mechanical effects on cell death processes via load-induced metabolic transport variations. Cycles of static sustained compression were chosen to simulate daily human activity. Healthy and degenerated cases were simulated as well as a reduced supply of solutes and an increase in solute exchange area at the bone-disc interface. Results showed that a reduction in metabolite concentrations at the bone-disc boundaries induced cell death, even when the increased exchange area was simulated. Slight local mechanical enhancements of glucose in the disc centre were capable of decelerating cell death but occurred only with healthy mechanical properties. However, mechanical deformations were responsible for a worsening in terms of cell death in the inner annulus, a disadvantaged zone far from the boundary supply with both an increased cell demand and a strain-dependent decrease of diffusivity. Such adverse mechanical effects were more accentuated when degenerative properties were simulated. Overall, this study paves the way for the use of biophysical models for a more integrated understanding of intervertebral disc pathophysiology.

  8. Total disc replacement.

    PubMed

    Vital, J-M; Boissière, L

    2014-02-01

    Total disc replacement (TDR) (partial disc replacement will not be described) has been used in the lumbar spine since the 1980s, and more recently in the cervical spine. Although the biomechanical concepts are the same and both are inserted through an anterior approach, lumbar TDR is conventionally indicated for chronic low back pain, whereas cervical TDR is used for soft discal hernia resulting in cervicobrachial neuralgia. The insertion technique must be rigorous, with precise centering in the disc space, taking account of vascular anatomy, which is more complex in the lumbar region, particularly proximally to L5-S1. All of the numerous studies, including prospective randomized comparative trials, have demonstrated non-inferiority to fusion, or even short-term superiority regarding speed of improvement. The main implant-related complication is bridging heterotopic ossification with resulting loss of range of motion and increased rates of adjacent segment degeneration, although with an incidence lower than after arthrodesis. A sufficiently long follow-up, which has not yet been reached, will be necessary to establish definitively an advantage for TDR, particularly in the cervical spine.

  9. Finite element analysis predicts experimental failure patterns in vertebral bodies loaded via intervertebral discs up to large deformation.

    PubMed

    Clouthier, Allison L; Hosseini, Hadi S; Maquer, Ghislain; Zysset, Philippe K

    2015-06-01

    Vertebral compression fractures are becoming increasingly common. Patient-specific nonlinear finite element (FE) models have shown promise in predicting yield strength and damage pattern but have not been experimentally validated for clinically relevant vertebral fractures, which involve loading through intervertebral discs with varying degrees of degeneration up to large compressive strains. Therefore, stepwise axial compression was applied in vitro on segments and performed in silico on their FE equivalents using a nonlocal damage-plastic model including densification at large compression for bone and a time-independent hyperelastic model for the disc. The ability of the nonlinear FE models to predict the failure pattern in large compression was evaluated for three boundary conditions: healthy and degenerated intervertebral discs and embedded endplates. Bone compaction and fracture patterns were predicted using the local volume change as an indicator and the best correspondence was obtained for the healthy intervertebral discs. These preliminary results show that nonlinear finite element models enable prediction of bone localisation and compaction. To the best of our knowledge, this is the first study to predict the collapse of osteoporotic vertebral bodies up to large compression using realistic loading via the intervertebral discs.

  10. An accretion disc-irradiation hybrid model for the optical/UV variability in radio-quiet quasars

    NASA Astrophysics Data System (ADS)

    Liu, Hui; Li, Shuang-Liang; Gu, Minfeng; Guo, Hengxiao

    2016-10-01

    The optical/ultraviolet (UV) variability of quasars has been discovered to be correlated with other quasar properties, such as luminosity, black hole mass and rest-frame wavelength. However, the origin of variability has been a puzzle so far. In this work, we upgrade the accretion disc model, which assumed the variability is caused by the change of global mass accretion rate, by constraining the disc size to match the viscous time-scale of accretion disc to the variability time-scale observed and by including the irradiation/X-ray reprocessing to make the emitted spectrum become steeper. We find this hybrid model can reproduce the observed bluer-when-brighter trend quite well, which is used to validate the theoretical model by several works recently. The traditional correlation between the variability amplitude and rest-frame wavelength can also be well fitted by our model. In addition, a weak positive correlation between variability amplitude and black hole mass is present, qualitatively consistent with recent observations.

  11. Regional annulus fibre orientations used as a tool for the calibration of lumbar intervertebral disc finite element models.

    PubMed

    Malandrino, Andrea; Noailly, Jérôme; Lacroix, Damien

    2013-01-01

    The collagen network of the annulus fibrosus largely controls the functional biomechanics of the lumbar intervertebral discs (IVDs). Quantitative anatomical examinations have shown bundle orientation patterns, possibly coming from regional adaptations of the annulus mechanics. This study aimed to show that the regional differences in annulus mechanical behaviour could be reproduced by considering only fibre orientation changes. Using the finite element method, a lumbar annulus was modelled as a poro-hyperelastic material in which fibres were represented by a direction-dependent strain energy density term. Fibre orientations were calibrated to reproduce the annulus tensile behaviours measured for four different regions: posterior outer, anterior outer, posterior inner and anterior inner. The back-calculated fibre angles and regional patterns as well as the global disc behaviour were comparable with anatomical descriptions reported in the literature. It was concluded that annulus fibre variations might be an effective tool to calibrate lumbar spine IVD and segment models.

  12. A SINGLE DEGENERATE PROGENITOR MODEL FOR TYPE Ia SUPERNOVAE HIGHLY EXCEEDING THE CHANDRASEKHAR MASS LIMIT

    SciTech Connect

    Hachisu, Izumi; Kato, Mariko; Saio, Hideyuki; Nomoto, Ken'ichi E-mail: mariko@educ.cc.keio.ac.jp E-mail: nomoto@astron.s.u-tokyo.ac.jp

    2012-01-01

    Recent observations of Type Ia supernovae (SNe Ia) suggest that some of the progenitor white dwarfs (WDs) had masses up to 2.4-2.8 M{sub Sun }, highly exceeding the Chandrasekhar mass limit. We present a new single degenerate model for SN Ia progenitors, in which the WD mass possibly reaches 2.3-2.7 M{sub Sun }. Three binary evolution processes are incorporated: optically thick winds from mass-accreting WDs, mass stripping from the binary companion star by the WD winds, and WDs being supported by differential rotation. The WD mass can increase by accretion up to 2.3 (2.7) M{sub Sun} from the initial value of 1.1 (1.2) M{sub Sun }, consistent with high-luminosity SNe Ia, such as SN 2003fg, SN 2006gz, SN 2007if, and SN 2009dc. There are three characteristic mass ranges of exploding WDs. In the extreme massive case, differentially rotating WDs explode as an SN Ia soon after the WD mass exceeds 2.4 M{sub Sun} because of a secular instability at T/|W| {approx} 0.14. For the mid-mass range of M{sub WD} = 1.5-2.4 M{sub Sun }, it takes some time (spinning-down time) until carbon is ignited to induce an SN Ia explosion after the WD mass has reached maximum, because it needs a loss or redistribution of angular momentum. For the lower mass case of rigidly rotating WDs, M{sub WD} = 1.38-1.5 M{sub Sun }, the spinning-down time depends on the timescale of angular momentum loss from the WD. The difference in the spinning-down time may produce the 'prompt' and 'tardy' components. We also suggest that the very bright super-Chandrasekhar mass SNe Ia are born in a low-metallicity environment.

  13. P23H opsin knock-in mice reveal a novel step in retinal rod disc morphogenesis

    PubMed Central

    Sakami, Sanae; Kolesnikov, Alexander V.; Kefalov, Vladimir J.; Palczewski, Krzysztof

    2014-01-01

    Retinal rod photoreceptor cells have double membrane discs located in their outer segments (ROS) that are continuously formed proximally from connecting cilia (CC) and phagocytized distally by the retinal pigmented epithelium. The major component of these rod discs, the light-sensitive visual pigment rhodopsin (Rho), consists of an opsin protein linked to 11-cis-retinal. The P23H mutation of rod opsin (P23H opsin) is the most common cause of human blinding autosomal dominant retinitis pigmentosa (adRP). A mouse model of adRP with this mutation (RhoP23H/+) shows low levels of P23H opsin protein, partial misalignment of discs and progressive retinal degeneration. However, the impact of mutant P23H opsin on the formation of abnormal discs is unclear and it is still unknown whether this mutant pigment can mediate phototransduction. Using transretinal ERG recordings, we demonstrate that P23H mutant Rho can trigger phototransduction but RhoP23H/P23H rods are ∼17 000-fold less sensitive to light than Rho+/+ rods and produce abnormally fast photo-responses. By analyzing homozygous RhoP23H/P23H knock-in mice, we show that P23H opsin is transported to ciliary protrusions where it forms sagittally elongated discs. Transmission electron microscopy of postnatal day (PND) 14 RhoP23H/+ mouse retina revealed disordered sagittally oriented discs before the onset of retinal degeneration. Surprisingly, we also observed smaller, immature sagittally oriented discs in PND14 Rho+/− and Rho+/+ mice that were not seen in older animals. These findings provide fundamental insights into the pathogenesis of the P23H mutant opsin and reveal a novel early sagittally aligned disc formation step in normal ROS disc expansion. PMID:24214395

  14. A nonlinear model for magnetoacoustic waves in dense dissipative plasmas with degenerate electrons

    SciTech Connect

    Masood, W.; Jahangir, R.; Siddiq, M.; Eliasson, B.

    2014-10-15

    The properties of nonlinear fast magnetoacoustic waves in dense dissipative plasmas with degenerate electrons are studied theoretically in the framework of the Zabolotskaya-Khokhlov (ZK) equation for small but finite amplitude excitations. Shock-like solutions of the ZK equation are obtained and are applied to parameters relevant to white dwarf stars.

  15. Self-consistent Model Of Debris Discs Coupling Dynamics And Collisions

    NASA Astrophysics Data System (ADS)

    Kral, Quentin; Thebault, P.; Charnoz, S.

    2012-10-01

    I will present the first attempt at developing a fully self-consistent code coupling dynamics and collisions to study debris discs. So far, these two crucial mechanisms were studied separately, with N-body and statistical codes respectively, because of stringent computational constraints. In particular, incorporating collisional effects (especially destructive collisions) into an N-body scheme was deemed an impossible task because of the exponential increase of particles it would imply. We present here an alternative approach, based on the LIDT code developed by Charnoz et al.(2012) for protoplanetary discs, and strongly upgraded to account for the complexity of debris disc physics (high velocity collisions, radiation-pressure affected orbits, etc.). In this 3D Lagrangian-Eulerian code, grains of given size at a given location in a disc are grouped into "super-particles" (SPs), whose orbits are tracked with an N-body code and whose mutual collisions are treated using a particle-in-a-box scheme. To keep the number of super-particles from diverging, a reassignment routine reallocates redundant SPs to regions where they are needed. Our code is under development but already working for simple astrophysical cases. I will present some preliminary results for simple disc configurations, as well as some perspectives for the close-future.

  16. A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration.

    PubMed

    Chavali, Venkata R M; Khan, Naheed W; Cukras, Catherine A; Bartsch, Dirk-Uwe; Jablonski, Monica M; Ayyagari, Radha

    2011-05-15

    Late-onset retinal macular degeneration (L-ORD) is an autosomal dominant inherited disorder caused by a single missense mutation (S163R) in the CTRP5/C1QTNF5 protein. Early phenotypic features of L-ORD include: dark adaptation abnormalities, nyctalopia, and drusen deposits in the peripheral macular region. Apart from posterior segment abnormalities, these patients also develop abnormally long anterior lens zonules. In the sixth decade of life the rod and cone function declines, accompanied by electroretinogram (ERG) abnormalities. Some patients also develop choroidal neovascularization and glaucoma. In order to understand the disease pathology and mechanisms involved in retinal dystrophy, we generated a knock-in (Ctrp5(+/-)) mouse model carrying the disease-associated mutation in the mouse Ctrp5/C1QTNF5 gene. These mice develop slower rod-b wave recovery consistent with early dark adaptation abnormalities, accumulation of hyperautofluorescence spots, retinal pigment epithelium abnormalities, drusen, Bruch's membrane abnormalities, loss of photoreceptors, and retinal vascular leakage. The Ctrp5(+/-) mice, which have most of the pathological features of age-related macular degeneration, are unique and may serve as a valuable model both to understand the molecular pathology of late-onset retinal degeneration and to evaluate therapies.

  17. A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration

    PubMed Central

    Chavali, Venkata R.M.; Khan, Naheed W.; Cukras, Catherine A.; Bartsch, Dirk-Uwe; Jablonski, Monica M.; Ayyagari, Radha

    2011-01-01

    Late-onset retinal macular degeneration (L-ORD) is an autosomal dominant inherited disorder caused by a single missense mutation (S163R) in the CTRP5/C1QTNF5 protein. Early phenotypic features of L-ORD include: dark adaptation abnormalities, nyctalopia, and drusen deposits in the peripheral macular region. Apart from posterior segment abnormalities, these patients also develop abnormally long anterior lens zonules. In the sixth decade of life the rod and cone function declines, accompanied by electroretinogram (ERG) abnormalities. Some patients also develop choroidal neovascularization and glaucoma. In order to understand the disease pathology and mechanisms involved in retinal dystrophy, we generated a knock-in (Ctrp5+/−) mouse model carrying the disease-associated mutation in the mouse Ctrp5/C1QTNF5 gene. These mice develop slower rod-b wave recovery consistent with early dark adaptation abnormalities, accumulation of hyperautofluorescence spots, retinal pigment epithelium abnormalities, drusen, Bruch's membrane abnormalities, loss of photoreceptors, and retinal vascular leakage. The Ctrp5+/−mice, which have most of the pathological features of age-related macular degeneration, are unique and may serve as a valuable model both to understand the molecular pathology of late-onset retinal degeneration and to evaluate therapies. PMID:21349921

  18. Time-dependent models of accretion discs with nuclear burning following the tidal disruption of a white dwarf by a neutron star

    NASA Astrophysics Data System (ADS)

    Margalit, Ben; Metzger, Brian D.

    2016-09-01

    We construct time-dependent one-dimensional (vertically averaged) models of accretion discs produced by the tidal disruption of a white dwarf (WD) by a binary neutron star (NS) companion. Nuclear reactions in the disc mid-plane burn the WD matter to increasingly heavier elements at sequentially smaller radii, releasing substantial energy which can impact the disc dynamics. A model for disc outflows is employed, by which cooling from the outflow balances other sources of heating (viscous, nuclear) in regulating the Bernoulli parameter of the mid-plane to a fixed value ≲0. We perform a comprehensive parameter study of the compositional yields and velocity distributions of the disc outflows for WDs of different initial compositions. For C/O WDs, the radial composition profile of the disc evolves self-similarly in a quasi-steady-state manner, and is remarkably robust to model parameters. The nucleosynthesis in helium WD discs does not exhibit this behaviour, which instead depends sensitively on factors controlling the disc mid-plane density (e.g. the strength of the viscosity, α). By the end of the simulation, a substantial fraction of the WD mass is unbound in outflows at characteristic velocities of ˜109 cm s-1. The outflows from WD-NS merger discs contain 10-4-3 × 10-3 M⊙ of radioactive 56Ni, resulting in fast (˜ week long) dim (˜1040 erg s-1) optical transients; shock heating of the ejecta by late-time outflows may increase the peak luminosity to ˜1043 erg s-1. The accreted mass on to the NS is probably not sufficient to induce gravitational collapse, but may be capable of spinning up the NS to periods of ˜10 ms, illustrating the feasibility of this channel in forming isolated millisecond pulsars.

  19. Heat distribution in disc brake

    NASA Astrophysics Data System (ADS)

    Klimenda, Frantisek; Soukup, Josef; Kampo, Jan

    2016-06-01

    This article is deals by the thermal analysis of the disc brake with floating caliper. The issue is solved by numerically. The half 2D model is used for solution in program ADINA 8.8. Two brake discs without the ventilation are solved. One disc is made from cast iron and the second is made from stainless steel. Both materials are an isotropic. By acting the pressure force on the brake pads will be pressing the pads to the brake disc. Speed will be reduced (slowing down). On the contact surface generates the heat, which the disc and pads heats. In the next part of article is comparison the maximum temperature at the time of braking. The temperatures of both materials for brake disc (gray cast iron, stainless steel) are compares. The heat flux during braking for the both materials is shown.

  20. Hsp104 Suppresses Polyglutamine-Induced Degeneration Post Onset in a Drosophila MJD/SCA3 Model

    PubMed Central

    Cushman-Nick, Mimi; Bonini, Nancy M.; Shorter, James

    2013-01-01

    There are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ) disorders, including Spinocerebellar Ataxia Type-3 (SCA3). Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase from yeast, which is bafflingly absent from metazoa. Hsp104 suppressed eye degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, but unexpectedly enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 suppressed toxicity of MJD variants lacking a portion of the N-terminal deubiquitylase domain and full-length MJD variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 modalities. Importantly, in staging experiments, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression. PMID:24039611

  1. Platelet-derived growth factor (PDGF)-C inhibits neuroretinal apoptosis in a murine model of focal retinal degeneration.

    PubMed

    Wang, Yujuan; Abu-Asab, Mones S; Yu, Cheng-Rong; Tang, Zhongshu; Shen, Defen; Tuo, Jingsheng; Li, Xuri; Chan, Chi-Chao

    2014-06-01

    Platelet-derived growth factor (PDGF)-C is a member of the PDGF family and is critical for neuronal survival in the central nervous system. We studied the possible survival and antiapoptotic effects of PDGF-C on focal retinal lesions in Ccl2(-/-)/Cx3cr1(-/-) on C57BL/6N [Crb1(rd8)] (DKO rd8) background mice, a model for progressive and focal retinal degeneration. We found no difference in transcript and protein expression of PDGF-C in the retina between DKO rd8 mice and wild type (WT, C57BL/6N). Recombinant PDGF-CC protein (500 ng/eye) was injected intravitreally into the right eye of DKO rd8 mice with phosphate-buffered saline as controls into the left eye. The retinal effects of PDGF-C were assessed by fundoscopy, ocular histopathology, A2E levels, apoptotic molecule analysis, and direct flat mount retinal vascular labeling. We found that the PDGF-CC-treated eyes showed slower progression or attenuation of the focal retinal lesions, lesser photoreceptor and retinal pigment epithelial degeneration resulting in better-preserved photoreceptor structure. Lower expression of apoptotic molecules was detected in the PDGF-CC-treated eyes than in controls. In addition, no retinal neovascularization was observed after PDGF-CC treatment. Our results demonstrate that PDGF-C potently ameliorates photoreceptor degeneration via the suppression of apoptotic pathways without inducing retinal angiogenesis. The protective effects of PDGF-C suggest a novel alternative approach for potential age-related retinal degeneration treatment.

  2. Differential expression of genes involved in the degeneration and regeneration pathways in mouse models for muscular dystrophies.

    PubMed

    Onofre-Oliveira, P C G; Santos, A L F; Martins, P M; Ayub-Guerrieri, D; Vainzof, M

    2012-03-01

    The genetically determined muscular dystrophies are caused by mutations in genes coding for muscle proteins. Differences in the phenotypes are mainly the age of onset and velocity of progression. Muscle weakness is the consequence of myofiber degeneration due to an imbalance between successive cycles of degeneration/regeneration. While muscle fibers are lost, a replacement of the degraded muscle fibers by adipose and connective tissues occurs. Major investigation points are to elicit the involved pathophysiological mechanisms to elucidate how each mutation can lead to a specific degenerative process and how the regeneration is stimulated in each case. To answer these questions, we used four mouse models with different mutations causing muscular dystrophies, Dmd (mdx), SJL/J, Large (myd) and Lama2 (dy2J) /J, and compared the histological changes of regeneration and fibrosis to the expression of genes involved in those processes. For regeneration, the MyoD, Myf5 and myogenin genes related to the proliferation and differentiation of satellite cells were studied, while for degeneration, the TGF-β1 and Pro-collagen 1α2 genes, involved in the fibrotic cascade, were analyzed. The result suggests that TGF-β1 gene is activated in the dystrophic process in all the stages of degeneration, while the activation of the expression of the pro-collagen gene possibly occurs in mildest stages of this process. We also observed that each pathophysiological mechanism acted differently in the activation of regeneration, with distinctions in the induction of proliferation of satellite cells, but with no alterations in stimulation to differentiation. Dysfunction of satellite cells can, therefore, be an important additional mechanism of pathogenesis in the dystrophic muscle.

  3. The circumstellar disc of FS Tau B - a self-consistent model based on observations in the mid-infrared with NACO

    NASA Astrophysics Data System (ADS)

    Kirchschlager, Florian; Wolf, Sebastian; Madlener, David

    2016-10-01

    Protoplanetary discs are a byproduct of the star formation process. In the dense mid-plane of these discs, planetesimals and planets are expected to form. The first step in planet formation is the growth of dust particles from submicrometre-sized grains to macroscopic mm-sized aggregates. The grain growth is accompanied by radial drift and vertical segregation of the particles within the disc. To understand this essential evolutionary step, spatially resolved multi-wavelength observations as well as photometric data are necessary which reflect the properties of both disc and dust. We present the first spatially resolved image obtained with NACO at the VLT in the Lp band of the near edge-on protoplanetary disc FS Tau B. Based on this new image, a previously published Hubble image in H band and the spectral energy distribution from optical to millimetre wavelengths, we derive constraints on the spatial dust distribution and the progress of grain growth. For this purpose we perform a disc modelling using the radiative transfer code MC3D. Radial drift and vertical sedimentation of the dust are not considered. We find a best-fitting model which features a disc extending from 2 au to several hundreds au with a moderately decreasing surface density and Mdisc = 2.8 × 10-2 M⊙. The inclination amounts to i = 80°. Our findings indicate that substantial dust grain growth has taken place and that grains of a size equal to or larger than 1 mm are present in the disc. In conclusion, the parameters describing the vertical density distribution are better constrained than those describing the radial disc structure.

  4. Mass spectrometric analyses of phospholipids in the S334ter-3 rat model of retinal degeneration

    PubMed Central

    Chen, Caroline Y.; Lam, Byron L.; Bhattacharya, Sanjoy K.

    2014-01-01

    Purpose The purpose of this study was to profile the endogenous phospholipid species in the retinal tissue of the S334ter-3 rat model of retinal degeneration. Retinal tissue was collected from S334ter-3 rats at postnatal day (P) 20, P30, and P60, while control retinal samples were collected from Sprague-Dawley (SD) rats at the same time points for comparison. Methods Lipids were extracted using the Bligh and Dyer method, and resuspended in an acetonitrile/isopropanol (1:1) solution. For lipid analyses, a positive ion–mode precursor ion scan (PIS) was used for phosphatidylcholine (PC; product m/z of 184), a negative ion–mode neutral loss scan (NLS) was used for phosphatidylserine (PS; product m/z of 87.1), and a negative ion–mode PIS was used for phosphatidylinositol (PI; product m/z of 241) and phosphatidylethanolamine (PE; product m/z of 196); the analyses were carried out using a TSQ Quantum Access Max mass spectrometer. The samples were directly infused with a Triversa Nanomate using 1.6 kV and 0.4 psi of pressure for the positive ion mode, and 1.3 kV and 0.6 psi of pressure for the negative ion mode, and scanned for 2 min between 200 m/z and 1000 m/z. Ratiometric quantification was performed using quantitative standards for each lipid class. Results The comparative profiles of PC, PE, PS, and PI between S334ter-3 and control rats showed that there were several lipid species common to both groups, as well as several that were unique to the S334ter-3 group and vice versa. Conclusions It was found that the proportions of PC and PS were higher in the control retina compared to S334ter-3, and that the proportions of PE and PI were higher in the S334ter-3 retina compared to control. PMID:25489232

  5. Efficacy of Anti-NaV1.7 Antibody on the Sensory Nervous System in a Rat Model of Lumbar Intervertebral Disc Injury

    PubMed Central

    Nojima, Daisuke; Inage, Kazuhide; Sakuma, Yoshihiro; Sato, Jun; Orita, Sumihisa; Yamauchi, Kazuyo; Eguchi, Yawara; Ochiai, Nobuyasu; Kuniyoshi, Kazuki; Aoki, Yasuchika; Nakamura, Junichi; Miyagi, Masayuki; Suzuki, Miyako; Kubota, Gou; Sainoh, Takeshi; Fujimoto, Kazuki; Shiga, Yasuhiro; Abe, Koki; Kanamoto, Hirohito; Inoue, Gen; Takahashi, Kazuhisa

    2016-01-01

    Purpose The pathophysiology of discogenic low back pain is not fully understood. Tetrodotoxin-sensitive voltage-gated sodium (NaV) channels are associated with primary sensory nerve transmission, and the NaV1.7 channel has emerged as an analgesic target. Previously, we found increased NaV1.7 expression in dorsal root ganglion (DRG) neurons innervating injured discs. This study aimed to examine the effect of blocking NaV1.7 on sensory nerves after disc injury. Materials and Methods Rat DRG neurons innervating the L5/6 disc were labeled with Fluoro-Gold (FG) neurotracer. Twenty-four rats underwent intervertebral disc puncture (puncture group) and 12 rats underwent sham surgery (non-puncture group). The injury group was divided into a saline infusion group (puncture+saline group) and a NaV1.7 inhibition group, injected with anti-NaV1.7 antibody (puncture+anti-NaV1.7 group); n=12 per group. Seven and 14 days post-surgery, L1 to L6 DRGs were harvested and immunostained for calcitonin gene-related peptide (CGRP) (an inflammatory pain marker), and the proportion of CGRP-immunoreactive (IR) DRG neurons of all FG-positive neurons was evaluated. Results The ratio of CGRP-IR DRG neurons to total FG-labeled neurons in the puncture+saline group significantly increased at 7 and 14 days, compared with the non-puncture group, respectively (p<0.05). Application of anti-NaV1.7 into the disc significantly decreased the ratio of CGRP-IR DRG neurons to total FG-labeled neurons after disc puncture at 7 and 14 days (40% and 37%, respectively; p<0.05). Conclusion NaV1.7 antibody suppressed CGRP expression in disc DRG neurons. Anti-NaV1.7 antibody is a potential therapeutic target for pain control in patients with lumbar disc degeneration. PMID:26996577

  6. Remedy for fictive negative pressures in biphasic finite element models of the intervertebral disc during unloading.

    PubMed

    Schmidt, Hendrik; Galbusera, Fabio; Wilke, Hans-Joachim; Shirazi-Adl, Aboulfazl

    2011-03-01

    Previous biphasic finite element studies investigated the temporal response of a spinal segment under rather simplified loading conditions with no attention to unloading and recovery phases. Employment of existing constitutive relations in porous media yields rather large suction-type pore pressures in the disc as the load suddenly disappears. Such negative pressures are absent in vivo and are hence fictive. The aim of this study was to search for remedies to avoid the computation of negative pressures upon unloading. Partial saturation for the disc or a rest load (RL) higher than 400 N totally eliminated the negative pressures. Decreasing the voids ratio (VR) also led to a reduced negative pressure. When defining a partial saturated disc or using a lower VR in combination with a boundary pressure of 0.25 MPa and a RL of 350 N, no negative pressure was calculated. It appears that the constraint of full saturation and a high mobile fluid fraction of the disc tissues along with inadequate tissue properties are the likely causes of negative pressures during unloading.

  7. Collisional dust production in extrasolar discs: a new dynamical and photometric model

    NASA Astrophysics Data System (ADS)

    Thebault, P.; Augereau, J.-C.

    2003-05-01

    In most extrasolar discs, the observed dust is believed to be produced by collisional cascades starting at (at least) kilometre-sized planetesimals. The numerical studies of Thebault et al. (A&A 2003) have shown on a peculiar example, the inner Beta-Pictoris disc, that the collisional size distribution from micron-sized grains to planetesimals might significantly depart from the classical dN α r-3.5dr power law. The main reason for this departure is the specific behaviour of the smallest grains, i.e. stellar radiation blow-out size limit and highly eccentric orbits, which indirectly affects the whole size distribution. We extend our approach to the more general case of any collisionaly produced dust disc. We consider mutualy interacting concentric annuli with a collisionaly evolving size distribution ranging from the blow-out size to 50 km objects. Realistic grain optical properties are taken into account in order to derive scattered light and thermal images. Complete S.E.D. profiles are also derived and compared to observational data. Preliminary results are presented for the β -Pic system and for other well known discs.

  8. Vertebral degenerative disc disease severity evaluation using random forest classification

    NASA Astrophysics Data System (ADS)

    Munoz, Hector E.; Yao, Jianhua; Burns, Joseph E.; Pham, Yasuyuki; Stieger, James; Summers, Ronald M.

    2014-03-01

    Degenerative disc disease (DDD) develops in the spine as vertebral discs degenerate and osseous excrescences or outgrowths naturally form to restabilize unstable segments of the spine. These osseous excrescences, or osteophytes, may progress or stabilize in size as the spine reaches a new equilibrium point. We have previously created a CAD system that detects DDD. This paper presents a new system to determine the severity of DDD of individual vertebral levels. This will be useful to monitor the progress of developing DDD, as rapid growth may indicate that there is a greater stabilization problem that should be addressed. The existing DDD CAD system extracts the spine from CT images and segments the cortical shell of individual levels with a dual-surface model. The cortical shell is unwrapped, and is analyzed to detect the hyperdense regions of DDD. Three radiologists scored the severity of DDD of each disc space of 46 CT scans. Radiologists' scores and features generated from CAD detections were used to train a random forest classifier. The classifier then assessed the severity of DDD at each vertebral disc level. The agreement between the computer severity score and the average radiologist's score had a quadratic weighted Cohen's kappa of 0.64.

  9. Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration

    PubMed Central

    Shirai, Hiroshi; Mandai, Michiko; Matsushita, Keizo; Kuwahara, Atsushi; Yonemura, Shigenobu; Nakano, Tokushige; Assawachananont, Juthaporn; Kimura, Toru; Saito, Koichi; Terasaki, Hiroko; Eiraku, Mototsugu; Sasai, Yoshiki; Takahashi, Masayo

    2016-01-01

    Retinal transplantation therapy for retinitis pigmentosa is increasingly of interest due to accumulating evidence of transplantation efficacy from animal studies and development of techniques for the differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells into retinal tissues or cells. In this study, we aimed to assess the potential clinical utility of hESC-derived retinal tissues (hESC-retina) using newly developed primate models of retinal degeneration to obtain preparatory information regarding the potential clinical utility of these hESC-retinas in transplantation therapy. hESC-retinas were first transplanted subretinally into nude rats with or without retinal degeneration to confirm their competency as a graft to mature to form highly specified outer segment structure and to integrate after transplantation. Two focal selective photoreceptor degeneration models were then developed in monkeys by subretinal injection of cobalt chloride or 577-nm optically pumped semiconductor laser photocoagulation. The utility of the developed models and a practicality of visual acuity test developed for monkeys were evaluated. Finally, feasibility of hESC-retina transplantation was assessed in the developed monkey models under practical surgical procedure and postoperational examinations. Grafted hESC-retina was observed differentiating into a range of retinal cell types, including rod and cone photoreceptors that developed structured outer nuclear layers after transplantation. Further, immunohistochemical analyses suggested the formation of host–graft synaptic connections. The findings of this study demonstrate the clinical feasibility of hESC-retina transplantation and provide the practical tools for the optimization of transplantation strategies for future clinical applications. PMID:26699487

  10. Human organotypic retinal cultures (HORCs) as a chronic experimental model for investigation of retinal ganglion cell degeneration.

    PubMed

    Osborne, Andrew; Hopes, Marina; Wright, Phillip; Broadway, David C; Sanderson, Julie

    2016-02-01

    There is a growing need for models of human diseases that utilise native, donated human tissue in order to model disease processes and develop novel therapeutic strategies. In this paper we assessed the suitability of adult human retinal explants as a potential model of chronic retinal ganglion cell (RGC) degeneration. Our results confirmed that RGC markers commonly used in rodent studies (NeuN, βIII Tubulin and Thy-1) were appropriate for labelling human RGCs and followed the expected differential expression patterns across, as well as throughout, the macular and para-macular regions of the retina. Furthermore, we showed that neither donor age nor post-mortem time (within 24 h) significantly affected the initial expression levels of RGC markers. In addition, the feasibility of using human post mortem donor tissue as a long-term model of RGC degeneration was determined with RGC protein being detectable up to 4 weeks in culture with an associated decline in RGC mRNA and significant, progressive, apoptotic labelling of NeuN(+) cells. Differences in RGC apoptosis might have been influenced by medium compositions indicating that media constituents could play a role in supporting axotomised RGCs. We propose that using ex vivo human explants may prove to be a useful model for testing the effectiveness of neuroprotective strategies.

  11. Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs

    PubMed Central

    Nasto, Luigi A.; Wang, Dong; Robinson, Andria R.; Clauson, Cheryl L.; Ngo, Kevin; Dong, Qing; Roughley, Peter; Epperly, Michael; Huq, Saiful M.; Pola, Enrico; Sowa, Gwendolyn; Robbins, Paul D.; Kang, James; Niedernhofer, Laura J.; Vo, Nam V.

    2013-01-01

    Intervertebral disc degeneration (IDD) is the leading cause of debilitating spinal disorders such as chronic lower back pain. Aging is the greatest risk factor for IDD. Previously, we demonstrated IDD in a murine model of a progeroid syndrome caused by reduced expression of a key DNA repair enzyme. This led us to hypothesize that DNA damage promotes IDD. To test our hypothesis, we chronically exposed adult wild-type (Wt) and DNA repair-deficient Ercc1−/Δ mice to the cancer therapeutic agent mechlorethamine (MEC) or ionization radiation (IR) to induce DNA damage and measured the impact on disc structure. Proteoglycan, a major structural matrix constituent of the disc, was reduced 3-5x in the discs of MEC- and IR-exposed animals compared to untreated controls. Expression of the protease ADAMTS4 and aggrecan proteolytic fragments were significantly increased. Additionally, new PG synthesis was reduced 2-3x in MEC- and IR-treated discs compared to untreated controls. Both cellular senescence and apoptosis were increased in discs of treated animals. The effects were more severe in the DNA repair-deficient Ercc1−/Δ mice than in Wt littermates. Local irradiation of the vertebra in Wt mice elicited a similar reduction in PG. These data demonstrate that genotoxic stress drives degenerative changes associated with IDD. PMID:23262094

  12. A Porcine Animal Model for Early Meniscal Degeneration – Analysis of Histology, Gene Expression and Magnetic Resonance Imaging Six Months after Resection of the Anterior Cruciate Ligament

    PubMed Central

    Kreinest, Michael; Reisig, Gregor; Ströbel, Philipp; Dinter, Dietmar; Attenberger, Ulrike; Lipp, Peter; Schwarz, Markus

    2016-01-01

    Background/Objective The menisci of the mammalian knee joint balance the incongruence between femoral condyle and tibial plateau and thus menisci absorb and distribute high loads. Degeneration processes of the menisci lead to pain syndromes in the knee joint. The origin of such degenerative processes on meniscal tissue is rarely understood and may be described best as an imbalance of anabolic and catabolic metabolism. A standardized animal model of meniscal degeneration is needed for further studies. The aim of the current study was to develop a porcine animal model with early meniscal degeneration. Material and Methods Resection of the anterior cruciate ligament (ACLR) was performed on the left knee joints of eight Göttingen minipigs. A sham operation was carried out on the right knee joint. The grade of degeneration was determined 26 weeks after the operation using histology and magnetic resonance imaging (MRI). Furthermore, the expression of 14 genes which code for extracellular matrix proteins, catabolic matrix metalloproteinases and inflammation mediators were analyzed. Results Degenerative changes were detected by a histological analysis of the medial meniscus after ACLR. These changes were not detected by MRI. In terms of their gene expression profile, these degenerated medial menisci showed a significantly increased expression of COL1A1. Conclusion This paper describes a new animal model for early secondary meniscal degeneration in the Göttingen minipig. Histopathological evidence of the degenerative changes could be described. This early degenerative changes could not be seen by NMR imaging. PMID:27434644

  13. Viscoelastic finite element analysis of the cervical intervertebral discs in conjunction with a multi-body dynamic model of the human head and neck.

    PubMed

    Esat, V; Acar, M

    2009-02-01

    This article presents the effects of the frontal and rear-end impact loadings on the cervical spine components by using a multi-body dynamic model of the head and neck, and a viscoelastic finite element (FE) model of the six cervical intervertebral discs. A three-dimensional multi-body model of the human head and neck is used to simulate 15 g frontal and 8.5 g rear-end impacts. The load history at each intervertebral joint from the predictions of the multi-body model is used as dynamic loading boundary conditions for the FE model of the intervertebral discs. The results from the multi-body model simulations, such as the intervertebral disc loadings in the form of compressive, tensile, and shear forces and moments, and from the FE analysis such as the von Mises stresses in the intervertebral discs are analysed. This study shows that the proposed approach that uses dynamic loading conditions from the multi-body model as input to the FE model has the potential to investigate the kinetics and the kinematics of the cervical spine and its components together with the biomechanical response of the intervertebral discs under the complex dynamic loading history.

  14. How Does Lumbar Degenerative Disc Disease Affect the Disc Deformation at the Cephalic Levels In Vivo?

    PubMed Central

    Wang, Shaobai; Xia, Qun; Passias, Peter; Li, Weishi; Wood, Kirkham; Li, Guoan

    2013-01-01

    Study Design Case-control study. Objective . To evaluate the effect of lumbar degenerative disc disease (DDD) on the disc deformation at the adjacent level and at the level one above the adjacent level during end ranges of lumbar motion. Summary of Background Data It has been reported that in patients with DDD, the intervertebral discs adjacent to the diseased levels have a greater tendency to degenerate. Although altered biomechanics have been suggested to be the causative factors, few data have been reported on the deformation characteristics of the adjacent discs in patients with DDD. Methods Ten symptomatic patients with discogenic low back pain between L4 and S1 and with healthy discs at the cephalic segments were involved. Eight healthy subjects recruited in our previous studies were used as a reference comparison. The in vivo kinematics of L3–L4 (the cephalic adjacent level to the degenerated discs) and L2–L3 (the level one above the adjacent level) lumbar discs of both groups were obtained using a combined magnetic resonance imaging and dual fluoroscopic imaging technique at functional postures. Deformation characteristics, in terms of areas of minimal deformation (defined as less than 5%), deformations at the center of the discs, and maximum tensile and shear deformations, were compared between the two groups at the two disc levels. Results In the patients with DDD, there were significantly smaller areas of minimal disc deformation at L3–L4 and L2–L3 than the healthy subjects (18% compared with 45% of the total disc area, on average). Both L2–L3 and L3–L4 discs underwent larger tensile and shear deformations in all postures than the healthy subjects. The maximum tensile deformations were higher by up to 23% (of the local disc height in standing) and the maximum shear deformations were higher by approximately 25% to 40% (of the local disc height in standing) compared with those of the healthy subjects. Conclusion Both the discs of the adjacent

  15. Reducing Endogenous α-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model

    PubMed Central

    Spencer, Brian; Desplats, Paula A.; Overk, Cassia R.; Valera-Martin, Elvira; Rissman, Robert A.; Wu, Chengbiao; Mante, Michael; Adame, Anthony; Florio, Jazmin; Rockenstein, Edward

    2016-01-01

    Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid β (Aβ) and microtubule associate protein tau, leading to the selective degeneration of neurons in the neocortex, limbic system, and nucleus basalis, among others. Recent studies have shown that α-synuclein (α-syn) also accumulates in the brains of patients with AD and interacts with Aβ and tau, forming toxic hetero-oligomers. Although the involvement of α-syn has been investigated extensively in Lewy body disease, less is known about the role of this synaptic protein in AD. Here, we found that reducing endogenous α-syn in an APP transgenic mouse model of AD prevented the degeneration of cholinergic neurons, ameliorated corresponding deficits, and recovered the levels of Rab3a and Rab5 proteins involved in intracellular transport and sorting of nerve growth factor and brain-derived neurotrophic factor. Together, these results suggest that α-syn might participate in mechanisms of vulnerability of selected neuronal populations in AD and that reducing α-syn might be a potential approach to protecting these populations from the toxic effects of Aβ. SIGNIFICANCE STATEMENT Reducing endogenous α-synuclein (α-syn) in an APP transgenic mouse model of Alzheimer's disease (AD) prevented the degeneration of cholinergic neurons, ameliorated corresponding deficits, and recovered the levels of Rab3a and Rab5 proteins involved in intracellular transport and sorting of nerve growth factor and brain-derived neurotrophic factor. These results suggest that α-syn might participate in mechanisms of vulnerability of selected neuronal populations in AD and that reducing α-syn might be a potential approach to protecting these populations from the toxic effects of amyloid β. PMID:27466341

  16. Riboflavin crosslinked high-density collagen gel for the repair of annular defects in intervertebral discs: An in vivo study.

    PubMed

    Grunert, Peter; Borde, Brandon H; Towne, Sara B; Moriguchi, Yu; Hudson, Katherine D; Bonassar, Lawrence J; Härtl, Roger

    2015-10-01

    Open annular defects compromise the ability of the annulus fibrosus to contain nuclear tissue in the disc space, and therefore lead to disc herniation with subsequent degenerative changes to the entire intervertebral disc. This study reports the use of riboflavin crosslinked high-density collagen gel for the repair of annular defects in a needle-punctured rat-tail model. High-density collagen has increased stiffness and greater hydraulic permeability than conventional low-density gels; riboflavin crosslinking further increases these properties. This study found that treating annular defects with crosslinked high-density collagen inhibited the progression of disc degeneration over 18 weeks compared to untreated control discs. Histological sections of FITC-labeled collagen gel revealed an early tight attachment to host annular tissue. The gel was subsequently infiltrated by host fibroblasts which remodeled it into a fibrous cap that bridged the outer disrupted annular fibers and partially repaired the defect. This repair tissue enhanced retention of nucleus pulposus tissue, maintained physiological disc hydration, and preserved hydraulic permeability, according to MRI, histological, and mechanical assessments. Degenerative changes were partially reversed in treated discs, as indicated by an increase in nucleus pulposus size and hydration between weeks 5 and 18. The collagen gel appeared to work as an instant sealant and by enhancing the intrinsic healing capabilities of the host tissue.

  17. Striatopallidonigral degeneration

    PubMed Central

    Bell, W. E.; McCormick, W. F.

    1971-01-01

    A 15-year-old girl is described with a sporadic, progressive illness manifested by unilateral limb rigidity and dystonia. Obvious dysarthria and some intellectual decline also were noted. Neuropathological findings included gross discoloration and shrinkage of the pallida and, microscopically, profound neuronal loss and gliosis of the caudata and putamena, with less severe neuronal loss from the pallida and substantia nigra. The disease bears some similarities to striatonigral degeneration, but certain clinical and morphological differences justify its consideration as a separate syndrome. ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5 PMID:5565467

  18. Degenerate ground states and multiple bifurcations in a two-dimensional q-state quantum Potts model.

    PubMed

    Dai, Yan-Wei; Cho, Sam Young; Batchelor, Murray T; Zhou, Huan-Qiang

    2014-06-01

    We numerically investigate the two-dimensional q-state quantum Potts model on the infinite square lattice by using the infinite projected entangled-pair state (iPEPS) algorithm. We show that the quantum fidelity, defined as an overlap measurement between an arbitrary reference state and the iPEPS ground state of the system, can detect q-fold degenerate ground states for the Z_{q} broken-symmetry phase. Accordingly, a multiple bifurcation of the quantum ground-state fidelity is shown to occur as the transverse magnetic field varies from the symmetry phase to the broken-symmetry phase, which means that a multiple-bifurcation point corresponds to a critical point. A (dis)continuous behavior of quantum fidelity at phase transition points characterizes a (dis)continuous phase transition. Similar to the characteristic behavior of the quantum fidelity, the magnetizations, as order parameters, obtained from the degenerate ground states exhibit multiple bifurcation at critical points. Each order parameter is also explicitly demonstrated to transform under the Z_{q} subgroup of the symmetry group of the Hamiltonian. We find that the q-state quantum Potts model on the square lattice undergoes a discontinuous (first-order) phase transition for q=3 and q=4 and a continuous phase transition for q=2 (the two-dimensional quantum transverse Ising model).

  19. Determination of the intervertebral disc space from CT images of the lumbar spine

    NASA Astrophysics Data System (ADS)

    Korez, Robert; Å tern, Darko; Likar, Boštjan; Pernuš, Franjo; Vrtovec, Tomaž

    2014-03-01

    Degenerative changes of the intervertebral disc are among the most common causes of low back pain, where for individuals with significant symptoms surgery may be needed. One of the interventions is the total disc replacement surgery, where the degenerated disc is replaced by an artificial implant. For designing implants with good bone contact and continuous force distribution, the morphology of the intervertebral disc space and vertebral body endplates is of considerable importance. In this study we propose a method for the determination of the intervertebral disc space from three-dimensional (3D) computed tomography (CT) images of the lumbar spine. The first step of the proposed method is the construction of a model of vertebral bodies in the lumbar spine. For this purpose, a chain of five elliptical cylinders is initialized in the 3D image and then deformed to resemble vertebral bodies by introducing 25 shape parameters. The parameters are obtained by aligning the chain to the vertebral bodies in the CT image according to image intensity and appearance information. The determination of the intervertebral disc space is finally achieved by finding the planes that fit the endplates of the obtained parametric 3D models, and placing points in the space between the planes of adjacent vertebrae that enable surface reconstruction of the intervertebral disc space. The morphometric analysis of images from 20 subjects yielded 11:3 +/- 2:6, 12:1 +/- 2:4, 12:8 +/- 2:0 and 12:9 +/- 2:7 cm3 in terms of L1-L2, L2-L3, L3-L4 and L4-L5 intervertebral disc space volume, respectively.

  20. Prediction of glycosaminoglycan synthesis in intervertebral disc under mechanical loading.

    PubMed

    Gao, Xin; Zhu, Qiaoqiao; Gu, Weiyong

    2016-09-06

    The loss of glycosaminoglycan (GAG) content is a major biochemical change during intervertebral disc (IVD) degeneration. Abnormal mechanical loading is one of the major factors causing disc degeneration. In this study, a multiscale mathematical model was developed to quantify the effect of mechanical loading on GAG synthesis. This model was based on a recently developed cell volume dependent GAG synthesis theory that predicts the variation of GAG synthesis rate of a cell under the influence of mechanical stimuli, and the biphasic theory that describes the deformation of IVD under mechanical loading. The GAG synthesis (at the cell level) was coupled with the mechanical loading (at the tissue level) via a cell-matrix unit approach which established a relationship between the variation of cell dilatation and the local tissue dilatation. This multiscale mathematical model was used to predict the effect of static load (creep load) on GAG synthesis in bovine tail discs. The predicted results are in the range of experimental results. This model was also used to investigate the effect of static (0.2MPa) and diurnal loads (0.1/0.3MPa and 0.15/0.25MPa in 12/12 hours shift with an average of 0.2MPa over a cycle) on GAG synthesis. It was found that static load and diurnal loads have different effects on GAG synthesis in a diurnal cycle, and the diurnal load effects depend on the amplitude of the load. The model is important to understand the effect of mechanical loading at the tissue level on GAG synthesis at the cellular level, as well as to optimize the mechanical loading in growing engineered tissue.

  1. Coevolution of binaries and circumbinary gaseous discs

    NASA Astrophysics Data System (ADS)

    Fleming, David P.; Quinn, Thomas R.

    2017-01-01

    The recent discoveries of circumbinary planets by Kepler raise questions for contemporary planet formation models. Understanding how these planets form requires characterizing their formation environment, the circumbinary protoplanetary disc and how the disc and binary interact and change as a result. The central binary excites resonances in the surrounding protoplanetary disc which drive evolution in both the binary orbital elements and in the disc. To probe how these interactions impact binary eccentricity and disc structure evolution, N-body smooth particle hydrodynamics simulations of gaseous protoplanetary discs surrounding binaries based on Kepler 38 were run for 104 binary periods for several initial binary eccentricities. We find that nearly circular binaries weakly couple to the disc via a parametric instability and excite disc eccentricity growth. Eccentric binaries strongly couple to the disc causing eccentricity growth for both the disc and binary. Discs around sufficiently eccentric binaries which strongly couple to the disc develop an m = 1 spiral wave launched from the 1:3 eccentric outer Lindblad resonance which corresponds to an alignment of gas particle longitude of periastrons. All systems display binary semimajor axis decay due to dissipation from the viscous disc.

  2. Tissue Engineering a Biological Repair Strategy for Lumbar Disc Herniation

    PubMed Central

    O'Connell, Grace D.; Leach, J. Kent; Klineberg, Eric O.

    2015-01-01

    Abstract The intervertebral disc is a critical part of the intersegmental soft tissue of the spinal column, providing flexibility and mobility, while absorbing large complex loads. Spinal disease, including disc herniation and degeneration, may be a significant contributor to low back pain. Clinically, disc herniations are treated with both nonoperative and operative methods. Operative treatment for disc herniation includes removal of the herniated material when neural compression occurs. While this strategy may have short-term advantages over nonoperative methods, the remaining disc material is not addressed and surgery for mild degeneration may have limited long-term advantage over nonoperative methods. Furthermore, disc herniation and surgery significantly alter the mechanical function of the disc joint, which may contribute to progression of degeneration in surrounding tissues. We reviewed recent advances in tissue engineering and regenerative medicine strategies that may have a significant impact on disc herniation repair. Our review on tissue engineering strategies focuses on cell-based and inductive methods, each commonly combined with material-based approaches. An ideal clinically relevant biological repair strategy will significantly reduce pain and repair and restore flexibility and motion of the spine. PMID:26634189

  3. Interrelation Between Oxidative Stress and Complement Activation in Models of Age-Related Macular Degeneration.

    PubMed

    Pujol-Lereis, Luciana M; Schäfer, Nicole; Kuhn, Laura B; Rohrer, Bärbel; Pauly, Diana

    2016-01-01

    Millions of individuals older than 50-years suffer from age-related macular degeneration (AMD). Associated with this multifactorial disease are polymorphisms of complement factor genes and a main environmental risk factor-oxidative stress. Until now the linkage between these risk factors for AMD has not been fully understood. Recent studies, integrating results on oxidative stress, complement activation, epidemiology and ocular pathology suggested the following sequence in AMD-etiology: initially, chronic oxidative stress results in modification of proteins and lipids in the posterior of the eye; these tissue alterations trigger chronic inflammation, involving the complement system; and finally, invasive immune cells facilitate pathology in the retina. Here, we summarize the results for animal studies which aim to elucidate this molecular interplay of oxidative events and tissue-specific complement activation in the eye.

  4. Cost-utility analysis modeling at 2-year follow-up for cervical disc arthroplasty versus anterior cervical discectomy and fusion: A single-center contribution to the randomized controlled trial

    PubMed Central

    Warren, Daniel; Andres, Tate; Hoelscher, Christian; Ricart-Hoffiz, Pedro; Bendo, John; Goldstein, Jeffrey

    2013-01-01

    Background Patients with cervical disc herniations resulting in radiculopathy or myelopathy from single level disease have traditionally been treated with Anterior Cervical Discectomy and Fusion (ACDF), yet Cervical Disc Arthroplasty (CDA) is a new alternative. Expert suggestion of reduced adjacent segment degeneration is a promising future result of CDA. A cost-utility analysis of these procedures with long-term follow-up has not been previously reported. Methods We reviewed single institution prospective data from a randomized trial comparing single-level ACDF and CDA in cervical disc disease. Both Medicare reimbursement schedules and actual hospital cost data for peri-operative care were separately reviewed and analyzed to estimate the cost of treatment of each patient. QALYs were calculated at 1 and 2 years based on NDI and SF-36 outcome scores, and incremental cost effectiveness ratio (ICER) analysis was performed to determine relative cost-effectiveness. Results Patients of both groups showed improvement in NDI and SF-36 outcome scores. Medicare reimbursement rates to the hospital were $11,747 and $10,015 for ACDF and CDA, respectively; these figures rose to $16,162 and $13,171 when including physician and anesthesiologist reimbursement. The estimated actual cost to the hospital of ACDF averaged $16,108, while CDA averaged $16,004 (p = 0.97); when including estimated physicians fees, total hospital costs came to $19,811 and $18,440, respectively. The cost/QALY analyses therefore varied widely with these discrepancies in cost values. The ICERs of ACDF vs CDA with Medicare reimbursements were $18,593 (NDI) and $19,940 (SF-36), while ICERs based on actual total hospital cost were $13,710 (NDI) and $9,140 (SF-36). Conclusions We confirm the efficacy of ACDF and CDA in the treatment of cervical disc disease, as our results suggest similar clinical outcomes at one and two year follow-up. The ICER suggests that the non-significant added benefit via ACDF comes at a

  5. Correlation between SD-OCT, immunocytochemistry and functional findings in an animal model of retinal degeneration

    PubMed Central

    Cuenca, Nicolás; Fernández-Sánchez, Laura; Sauvé, Yves; Segura, Francisco J.; Martínez-Navarrete, Gema; Tamarit, José Manuel; Fuentes-Broto, Lorena; Sanchez-Cano, Ana; Pinilla, Isabel

    2014-01-01

    Purpose: The P23H rhodopsin mutation is an autosomal dominant cause of retinitis pigmentosa (RP). The degeneration can be tracked using different anatomical and functional methods. In our case, we evaluated the anatomical changes using Spectral-Domain Optical Coherence Tomography (SD-OCT) and correlated the findings with retinal thickness values determined by immunocytochemistry.Methods: Pigmented rats heterozygous for the P23H mutation, with ages between P18 and P180 were studied. Function was assessed by means of optomotor testing and ERGs. Retinal thicknesses measurements, autofluorescence and fluorescein angiography were performed using Spectralis OCT. Retinas were studied by means of immunohistochemistry. Results: Between P30 and P180, visual acuity decreased from 0.500 to 0.182 cycles per degree (cyc/deg) and contrast sensitivity decreased from 54.56 to 2.98 for a spatial frequency of 0.089 cyc/deg. Only cone-driven b-wave responses reached developmental maturity. Flicker fusions were also comparable at P29 (42 Hz). Double flash-isolated rod-driven responses were already affected at P29. Photopic responses revealed deterioration after P29.A reduction in retinal thicknesses and morphological modifications were seen in OCT sections. Statistically significant differences were found in all evaluated thicknesses. Autofluorescence was seen in P23H rats as sparse dots. Immunocytochemistry showed a progressive decrease in the outer nuclear layer (ONL), and morphological changes. Although anatomical thickness measures were significantly lower than OCT values, there was a very strong correlation between the values measured by both techniques.Conclusions: In pigmented P23H rats, a progressive deterioration occurs in both retinal function and anatomy. Anatomical changes can be effectively evaluated using SD-OCT and immunocytochemistry, with a good correlation between their values, thus making SD-OCT an important tool for research in retinal degeneration. PMID:25565976

  6. Replacement Gene Therapy with a Human RPGRIP1 Sequence Slows Photoreceptor Degeneration in a Murine Model of Leber Congenital Amaurosis

    PubMed Central

    Pawlyk, Basil S.; Bulgakov, Oleg V.; Liu, Xiaoqing; Xu, Xiaoyun; Adamian, Michael; Sun, Xun; Khani, Shahrokh C.; Berson, Eliot L.; Sandberg, Michael A.

    2010-01-01

    Abstract RPGR-interacting protein-1 (RPGRIP1) is localized in the photoreceptor-connecting cilium, where it anchors the RPGR (retinitis pigmentosa GTPase regulator) protein, and its function is essential for photoreceptor maintenance. Genetic defect in RPGRIP1 is a known cause of Leber congenital amaurosis (LCA), a severe, early-onset form of retinal degeneration. We evaluated the efficacy of replacement gene therapy in a murine model of LCA carrying a targeted disruption of RPGRIP1. The replacement construct, packaged in an adeno-associated virus serotype 8 (AAV8) vector, used a rhodopsin kinase gene promoter to drive RPGRIP1 expression. Both promoter and transgene were of human origin. After subretinal delivery of the replacement gene in the mutant mice, human RPGRIP1 was expressed specifically in photoreceptors, localized correctly in the connecting cilia, and restored the normal localization of RPGR. Electroretinogram and histological examinations showed better preservation of rod and cone photoreceptor function and improved photoreceptor survival in the treated eyes. This study demonstrates the efficacy of human gene replacement therapy and validates a gene therapy design for future clinical trials in patients afflicted with this condition. Our results also have therapeutic implications for other forms of retinal degenerations attributable to a ciliary defect. PMID:20384479

  7. An ex vivo laser-induced spinal cord injury model to assess mechanisms of axonal degeneration in real-time.

    PubMed

    Okada, Starlyn L M; Stivers, Nicole S; Stys, Peter K; Stirling, David P

    2014-11-25

    Injured CNS axons fail to regenerate and often retract away from the injury site. Axons spared from the initial injury may later undergo secondary axonal degeneration. Lack of growth cone formation, regeneration, and loss of additional myelinated axonal projections within the spinal cord greatly limits neurological recovery following injury. To assess how central myelinated axons of the spinal cord respond to injury, we developed an ex vivo living spinal cord model utilizing transgenic mice that express yellow fluorescent protein in axons and a focal and highly reproducible laser-induced spinal cord injury to document the fate of axons and myelin (lipophilic fluorescent dye Nile Red) over time using two-photon excitation time-lapse microscopy. Dynamic processes such as acute axonal injury, axonal retraction, and myelin degeneration are best studied in real-time. However, the non-focal nature of contusion-based injuries and movement artifacts encountered during in vivo spinal cord imaging make differentiating primary and secondary axonal injury responses using high resolution microscopy challenging. The ex vivo spinal cord model described here mimics several aspects of clinically relevant contusion/compression-induced axonal pathologies including axonal swelling, spheroid formation, axonal transection, and peri-axonal swelling providing a useful model to study these dynamic processes in real-time. Major advantages of this model are excellent spatiotemporal resolution that allows differentiation between the primary insult that directly injures axons and secondary injury mechanisms; controlled infusion of reagents directly to the perfusate bathing the cord; precise alterations of the environmental milieu (e.g., calcium, sodium ions, known contributors to axonal injury, but near impossible to manipulate in vivo); and murine models also offer an advantage as they provide an opportunity to visualize and manipulate genetically identified cell populations and subcellular

  8. Macular degeneration (image)

    MedlinePlus

    Macular degeneration is a disease of the retina that affects the macula in the back of the eye. ... see fine details. There are two types of macular degeneration, dry and wet. Dry macular degeneration is more ...

  9. Wet Macular Degeneration

    MedlinePlus

    Wet macular degeneration Overview By Mayo Clinic Staff Wet macular degeneration is a chronic eye disease that causes blurred vision ... of the retina responsible for central vision. Wet macular degeneration is one of two types of age-related ...

  10. Dry Macular Degeneration

    MedlinePlus

    Dry macular degeneration Overview By Mayo Clinic Staff Dry macular degeneration is a common eye disorder among people over 65. ... vision in your direct line of sight. Dry macular degeneration may first develop in one eye and then ...

  11. Time-dependent loss of mitochondrial function precedes progressive histologic cartilage degeneration in a rabbit meniscal destabilization model.

    PubMed

    Goetz, Jessica E; Coleman, Mitchell C; Fredericks, Douglas C; Petersen, Emily; Martin, James A; McKinley, Todd O; Tochigi, Yuki

    2017-03-01

    The goals of this work were to characterize progression of osteoarthritic cartilage degeneration in a rabbit medial meniscus destabilization (MMD) model and then to use the model to identify pre-histologic disruptions in chondrocyte metabolism under chronically elevated joint contact stresses in vivo. To characterize PTOA progression, 24 rabbits received either MMD or sham surgery. Limb loading was analyzed preoperatively and at regular postoperative intervals using a Tekscan pressure-sensitive walkway. Animals were euthanized 8 (n = 8 MMD; n = 8 sham) or 26 weeks (n = 8 MMD) postoperatively for histological cartilage evaluation by an objective, semi-automated Mankin scoring routine. To examine pre-histologic pathology, MMD was performed on an additional 20 rabbits, euthanized 1 (n = 9) or 4 weeks (n = 10) postoperatively. Chondrocytes were harvested fresh for measurement of mitochondrial function, an intracellular indicator of pathology after mechanical injury. Both MMD and sham surgery caused slight decreases in limb loading which returned to preoperative levels after 2 weeks. Histologically apparent cartilage damage progressed from 8 to 26 weeks after MMD. Changes in chondrocyte respiration were variable at 1 week, but by 4 weeks postoperatively chondrocyte mitochondrial function was significantly reduced. Many human injuries that lead to PTOA are relatively mild, and the cell-level mechanisms leading to disease remain unclear. We have documented PTOA progression in an animal model of subtle joint injury under continued use, and demonstrated that this model provides a realistic environment for investigation of multi-stage cellular pathology that develops prior to overt tissue degeneration and which could be targeted for disease modifying treatments. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:590-599, 2017.

  12. The origin of UV-optical variability in AGN and test of disc models: XMM-Newton and ground-based observations of NGC 4395

    NASA Astrophysics Data System (ADS)

    McHardy, I. M.; Connolly, S. D.; Peterson, B. M.; Bieryla, A.; Chand, H.; Elvis, M. S.; Emmanoulopoulos, D.; Falco, E.; Gandhi, P.; Kaspi, S.; Latham, D.; Lira, P.; McCully, C.; Netzer, H.; Uemura, M.

    2016-05-01

    The origin of short timescale (weeks/months) variability of AGN, whether due to intrinsic disc variations or reprocessing of X-ray emission by a surrounding accretion disc, has been a puzzle for many years. However recently a number of observational programmes, particularly of NGC 5548 with Swift, have shown that the UV/optical variations lag behind the X-ray variations in a manner strongly supportive of X-ray reprocessing. Somewhat surprisingly, the implied size of the accretion disc is ∼3 times greater than expected from a standard, smooth, Shakura-Sunyaev thin disc model. Although the difference may be explained by a clumpy accretion disc, it is not clear whether the difference will occur in all AGN or whether it may change as, eg, a function of black hole mass, accretion rate, or disc temperature. Measurements of interband lags for most AGN require long timescale monitoring, which is hard to arrange. However for low mass (< 106 M⊙) AGN, the combination of XMM-Newton EPIC (X-rays) with the optical monitor in fast readout mode allows an X-ray/UV-optical lag to be measured within a single long observation. Here we summarise previous related observations and report on XMM-Newton observations of NGC 4395 (mass 100 times lower, accretion rate ∼20 times lower than for NGC 5548). We find that the UVW1 lags the X-rays by ∼ 470 s. Simultaneous observations at 6 different ground based observatories also allowed the g-band lag (∼ 800s) to be measured. These observations are in agreement with X-ray reprocessing but initial analysis suggests that, for NGC 4395, they do not differ markedly from the predictions of the standard thin disc model.

  13. Mean Kinetic Energy Budget of Wakes Within Model Wind Farms: Comparison of an Array of Model Wind Turbines and Porous Discs

    NASA Astrophysics Data System (ADS)

    Camp, E.; Cal, R. B.

    2015-12-01

    To optimize the power production of large wind farms, it is important to understand the flow within the wind turbine array as well as its interaction with the surrounding atmosphere. Computational simulations are often employed to study both the velocity field within and immediately above wind farms. In many computational studies, wind turbines are modeled as stationary, porous actuator discs. A wind tunnel study is done in order to compare the wakes within an array of porous discs and an equivalent array of model wind turbines. To characterize the wakes within a 4×3 model wind farm, stereoscopic particle image velocimetry (SPIV) is employed. SPIV measurements focus on the region along the centerline of the array upstream and downstream of the center turbine in the fourth row. The computed mean flow fields and turbulent stresses provide a basis to compare the near and far wakes of the turbines with those of the porous discs. The detailed analysis of the wakes for each case focus on the mean kinetic energy budget within the wakes. Examining the mean kinetic energy budget is done via computing the mean kinetic energy, flux of kinetic energy, and production of turbulence which are analogous to a measure of extracted power.

  14. Model for the architecture of caveolae based on a flexible, net-like assembly of Cavin1 and Caveolin discs.

    PubMed

    Stoeber, Miriam; Schellenberger, Pascale; Siebert, C Alistair; Leyrat, Cedric; Helenius, Ari; Grünewald, Kay

    2016-12-13

    Caveolae are invaginated plasma membrane domains involved in mechanosensing, signaling, endocytosis, and membrane homeostasis. Oligomers of membrane-embedded caveolins and peripherally attached cavins form the caveolar coat whose structure has remained elusive. Here, purified Cavin1 60S complexes were analyzed structurally in solution and after liposome reconstitution by electron cryotomography. Cavin1 adopted a flexible, net-like protein mesh able to form polyhedral lattices on phosphatidylserine-containing vesicles. Mutating the two coiled-coil domains in Cavin1 revealed that they mediate distinct assembly steps during 60S complex formation. The organization of the cavin coat corresponded to a polyhedral nano-net held together by coiled-coil segments. Positive residues around the C-terminal coiled-coil domain were required for membrane binding. Purified caveolin 8S oligomers assumed disc-shaped arrangements of sizes that are consistent with the discs occupying the faces in the caveolar polyhedra. Polygonal caveolar membrane profiles were revealed in tomograms of native caveolae inside cells. We propose a model with a regular dodecahedron as structural basis for the caveolae architecture.

  15. Model for the architecture of caveolae based on a flexible, net-like assembly of Cavin1 and Caveolin discs

    PubMed Central

    Stoeber, Miriam; Schellenberger, Pascale; Siebert, C. Alistair; Leyrat, Cedric; Helenius, Ari

    2016-01-01

    Caveolae are invaginated plasma membrane domains involved in mechanosensing, signaling, endocytosis, and membrane homeostasis. Oligomers of membrane-embedded caveolins and peripherally attached cavins form the caveolar coat whose structure has remained elusive. Here, purified Cavin1 60S complexes were analyzed structurally in solution and after liposome reconstitution by electron cryotomography. Cavin1 adopted a flexible, net-like protein mesh able to form polyhedral lattices on phosphatidylserine-containing vesicles. Mutating the two coiled-coil domains in Cavin1 revealed that they mediate distinct assembly steps during 60S complex formation. The organization of the cavin coat corresponded to a polyhedral nano-net held together by coiled-coil segments. Positive residues around the C-terminal coiled-coil domain were required for membrane binding. Purified caveolin 8S oligomers assumed disc-shaped arrangements of sizes that are consistent with the discs occupying the faces in the caveolar polyhedra. Polygonal caveolar membrane profiles were revealed in tomograms of native caveolae inside cells. We propose a model with a regular dodecahedron as structural basis for the caveolae architecture. PMID:27834731

  16. Physical activity ameliorates cartilage degeneration in a rat model of aging: a study on lubricin expression.

    PubMed

    Musumeci, G; Castrogiovanni, P; Trovato, F M; Imbesi, R; Giunta, S; Szychlinska, M A; Loreto, C; Castorina, S; Mobasheri, A

    2015-04-01

    Osteoarthritis (OA) is a common musculoskeletal disorder characterized by slow progression and joint tissue degeneration. Aging is one of the most prominent risk factors for the development and progression of OA. OA is not, however, an inevitable consequence of aging and age-related changes in the joint can be distinguished from those that are the result of joint injury or inflammatory disease. The question that remains is whether OA can be prevented by undertaking regular physical activity. Would moderate physical activity in the elderly cartilage (and lubricin expression) comparable to a sedentary healthy adult? In this study we used physical exercise in healthy young, adult, and aged rats to evaluate the expression of lubricin as a novel biomarker of chondrocyte senescence. Immunohistochemistry and western blotting were used to evaluate the expression of lubricin in articular cartilage, while enzyme-linked immunosorbent assay was used to quantify lubricin in synovial fluid. Morphological evaluation was done by histology to monitor possible tissue alterations. Our data suggest that moderate physical activity and normal mechanical joint loading in elderly rats improve tribology and lubricative properties of articular cartilage, promoting lubricin synthesis and its elevation in synovial fluid, thus preventing cartilage degradation compared with unexercised adult rats.

  17. Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy

    PubMed Central

    Morató, Laia; Galino, Jorge; Ruiz, Montserrat; Calingasan, Noel Ylagan; Starkov, Anatoly A.; Dumont, Magali; Naudí, Alba; Martínez, Juan José; Aubourg, Patrick; Portero-Otín, Manuel; Pamplona, Reinald; Galea, Elena; Beal, M. Flint; Ferrer, Isidre; Fourcade, Stéphane

    2013-01-01

    X-linked adrenoleukodystrophy is a neurometabolic disorder caused by inactivation of the peroxisomal ABCD1 transporter of very long-chain fatty acids. In mice, ABCD1 loss causes late onset axonal degeneration in the spinal cord in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. Increasing evidence indicates that oxidative stress and bioenergetic failure play major roles in the pathogenesis of X-linked adrenoleukodystrophy. In this study, we aimed to evaluate whether mitochondrial biogenesis is affected in X-linked adrenoleukodystrophy. We demonstrated that Abcd1 null mice show reduced mitochondrial DNA concomitant with downregulation of mitochondrial biogenesis pathway driven by PGC-1α/PPARγ and reduced expression of mitochondrial proteins cytochrome c, NDUFB8 and VDAC. Moreover, we show that the oral administration of pioglitazone, an agonist of PPARγ, restored mitochondrial content and expression of master regulators of biogenesis, neutralized oxidative damage to proteins and DNA, and reversed bioenergetic failure in terms of ATP levels, NAD+/NADH ratios, pyruvate kinase and glutathione reductase activities. Most importantly, the treatment halted locomotor disability and axonal damage in X-linked adrenoleukodystrophy mice. These results lend support to the use of pioglitazone in clinical trials with patients with adrenomyeloneuropathy and reveal novel molecular mechanisms of action of pioglitazone in neurodegeneration. Future studies should address the effects of this anti-diabetic drug on other axonopathies in which oxidative stress and mitochondrial dysfunction are contributing factors. PMID:23794606

  18. Temporo-spatial distribution of blood vessels in human lumbar intervertebral discs

    PubMed Central

    Schaaf, Rainer; Wälchli, Beat; Boos, Norbert

    2006-01-01

    While there is consensus in the literature that blood vessels are confined to the outer anulus fibrosus of normal adult intervertebral disc, debate continues whether there is a vascular in-growths into inner parts of the intervertebral disc during degeneration. We therefore tested the hypothesis that vascular in-growth is not a distinct feature of disc degeneration. The specific endothelial cell marker CD 31 (PECAM) was used to immunohistochemically investigate 42 paraffin-embedded complete mid-sagittal human intervertebral disc sections of various ages (0–86 years) and varying extent of histomorphological degeneration. Additionally, 20 surgical disc samples from individuals (26–69 years) were included in this study. In discs of fetal to infantile age, blood vessels perforated the cartilaginous end plate and extended into the inner and outer anulus fibrosus, but not into the nucleus pulposus. In adolescents and adults, no blood vessels were seen except for the outer zone of the anulus fibrosus adjacent to the insertion to ligaments. The cartilaginous end plate remained free of vessels, except for areas with circumscribed destruction of the end plate. In advanced disc degeneration, no vessels were observed except for those few cases with complete, scar-like disc destruction. However, some rim lesions and occasionally major clefts were surrounded by a small network of capillary blood vessels extending into deeper zones of the anulus fibrosus. A subsequent morphometric analysis, revealed slightly “deeper” blood vessel extension in juvenile/adolescent discs when compared to young, mature and senile adult individuals with significantly “deeper” extension in the posterior than anterior anulus. The analysis of the surgical specimens showed that only sparse capillary blood vessels which did not extend into the nucleus pulposus even in major disc disruption. Our results show that vascular invasion deeper than the periphery was not observed during disc

  19. Intervertebral disc properties: challenges for biodevices.

    PubMed

    Costi, John J; Freeman, Brian J C; Elliott, Dawn M

    2011-05-01

    Intervertebral disc biodevices that employ motion-preservation strategies (e.g., nucleus replacement, total disc replacement and posterior stabilization devices) are currently in use or in development. However, their long-term performance is unknown and only a small number of randomized controlled trials have been conducted. In this article, we discuss the following biodevices: interbody cages, nuclear pulposus replacements, total disc replacements and posterior dynamic stabilization devices, as well as future biological treatments. These biodevices restore some function to the motion segment; however, contrary to expectations, the risk of adjacent-level degeneration does not appear to have been reduced. The short-term challenge is to replicate the complex biomechanical function of the motion segment (e.g., biphasic, viscoelastic behavior and nonlinearity) to improve the quality of motion and minimize adjacent level problems, while ensuring biodevice longevity for the younger, more active patient. Biological strategies for regeneration and repair of disc tissue are being developed and these offer exciting opportunities (and challenges) for the longer term. Responsible introduction and rigorous assessment of these new technologies are required. In this article, we will describe the properties of the disc, explore biodevices currently in use for the surgical treatment of low back pain (with an emphasis on lumbar total disc replacement) and discuss future directions for biological treatments. Finally, we will assess the challenges ahead for the next generation of biodevices designed to replace the disc.

  20. Stem cells sources for intervertebral disc regeneration

    PubMed Central

    Vadalà, Gianluca; Russo, Fabrizio; Ambrosio, Luca; Loppini, Mattia; Denaro, Vincenzo

    2016-01-01

    Intervertebral disc regeneration field is rapidly growing since disc disorders represent a major health problem in industrialized countries with very few possible treatments. Indeed, current available therapies are symptomatic, and surgical procedures consist in disc removal and spinal fusion, which is not immune to regardable concerns about possible comorbidities, cost-effectiveness, secondary risks and long-lasting outcomes. This review paper aims to share recent advances in stem cell therapy for the treatment of intervertebral disc degeneration. In literature the potential use of different adult stem cells for intervertebral disc regeneration has already been reported. Bone marrow mesenchymal stromal/stem cells, adipose tissue derived stem cells, synovial stem cells, muscle-derived stem cells, olfactory neural stem cells, induced pluripotent stem cells, hematopoietic stem cells, disc stem cells, and embryonic stem cells have been studied for this purpose either in vitro or in vivo. Moreover, several engineered carriers (e.g., hydrogels), characterized by full biocompatibility and prompt biodegradation, have been designed and combined with different stem cell types in order to optimize the local and controlled delivery of cellular substrates in situ. The paper overviews the literature discussing the current status of our knowledge of the different stem cells types used as a cell-based therapy for disc regeneration. PMID:27247704

  1. Mechanical Vibrations Reduce the Intervertebral Disc Swelling and Muscle Atrophy from Bed Rest

    NASA Technical Reports Server (NTRS)

    Holguin, Nilsson; Muir, Jesse; Evans, Harlan J.; Qin, Yi-Xian; Rubin, Clinton; Wagshul, Mark; Judex, Stefan

    2007-01-01

    Loss of functional weight bearing, such as experienced during space flight or bed rest (BR), distorts intervertebral disc (IVD) and muscle morphology. IVDs are avascular structures consisting of cells that may derive their nutrition and waste removal from the load induced fluid flow into and out of the disc. A diurnal cycle is produced by forces related to weight bearing and muscular activity, and comprised of a supine and erect posture over a 24 hr period. A diurnal cycle will include a disc volume change of approx. 10-13%. However, in space there are little or no diurnal changes because of the microgravity, which removes the gravitational load and compressive forces to the back muscles. The BR model and the etiology of the disc swelling and muscle atrophy could provide insight into those subjects confined to bed for chronic disease/injury and aging. We hypothesize that extremely low-magnitude, high frequency mechanical vibrations will abate the disc degeneration and muscle loss associated with long-term BR.

  2. Nephronophthisis and retinal degeneration in tmem218-/- mice: a novel mouse model for Senior-Løken syndrome?

    PubMed

    Vogel, P; Gelfman, C M; Issa, T; Payne, B J; Hansen, G M; Read, R W; Jones, C; Pitcher, M R; Ding, Z-M; DaCosta, C M; Shadoan, M K; Vance, R B; Powell, D R

    2015-05-01

    Mice deficient in TMEM218 (Tmem218(-/-) ) were generated as part of an effort to identify and validate pharmaceutically tractable targets for drug development through large-scale phenotypic screening of knockout mice. Routine diagnostics, expression analysis, histopathology, and electroretinogram analyses completed on Tmem218(-/-) mice identified a previously unknown role for TMEM218 in the development and function of the kidney and eye. The major observed phenotypes in Tmem218(-/-) mice were progressive cystic kidney disease and retinal degeneration. The renal lesions were characterized by diffuse renal cyst development with tubulointerstitial nephropathy and disruption of tubular basement membranes in essentially normal-sized kidneys. The retinal lesions were characterized by slow-onset loss of photoreceptors, which resulted in reduced electroretinogram responses. These renal and retinal lesions are most similar to those associated with nephronophthisis (NPHP) and retinitis pigmentosa in humans. At least 10% of NPHP cases present with extrarenal conditions, which most often include retinal degeneration. Senior-Løken syndrome is characterized by the concurrent development of autosomal recessive NPHP and retinitis pigmentosa. Since mutations in the known NPHP genes collectively account for only about 30% of NPHP cases, it is possible that TMEM218 could be involved in the development of similar ciliopathies in humans. In reviewing all other reported mouse models of NPHP, we suggest that Tmem218(-/-) mice could provide a useful model for elucidating the pathogenesis of cilia-associated disease in both the kidney and the retina, as well as in developing and testing novel therapeutic strategies for Senior-Løken syndrome.

  3. Complement system dysregulation and inflammation in the retinal pigment epithelium of a mouse model for Stargardt macular degeneration.

    PubMed

    Radu, Roxana A; Hu, Jane; Yuan, Quan; Welch, Darcy L; Makshanoff, Jacob; Lloyd, Marcia; McMullen, Stephen; Travis, Gabriel H; Bok, Dean

    2011-05-27

    Accumulation of vitamin A-derived lipofuscin fluorophores in the retinal pigment epithelium (RPE) is a pathologic feature of recessive Stargardt macular dystrophy, a blinding disease caused by dysfunction or loss of the ABCA4 transporter in rods and cones. Age-related macular degeneration, a prevalent blinding disease of the elderly, is strongly associated with mutations in the genes for complement regulatory proteins (CRP), causing chronic inflammation of the RPE. Here we explore the possible relationship between lipofuscin accumulation and complement activation in vivo. Using the abca4(-/-) mouse model for recessive Stargardt, we investigated the role of lipofuscin fluorophores (A2E-lipofuscin) on oxidative stress and complement activation. We observed higher expression of oxidative-stress genes and elevated products of lipid peroxidation in eyes from abca4(-/-) versus wild-type mice. We also observed higher levels of complement-activation products in abca4(-/-) RPE cells. Unexpectedly, expression of multiple CRPs, which protect cells from attack by the complement system, were lower in abca4(-/-) versus wild-type RPE. To test whether acute exposure of healthy RPE cells to A2E-lipofuscin affects oxidative stress and expression of CRPs, we fed cultured fetal-derived human RPE cells with rod outer segments from wild-type or abca4(-/-) retinas. In contrast to RPE cells in abca4(-/-) mice, human RPE cells exposed to abca4(-/-) rod outer segments adaptively increased expression of both oxidative-stress and CRP genes. These results suggest that A2E accumulation causes oxidative stress, complement activation, and down-regulation of protective CRP in the Stargardt mouse model. Thus, Stargardt disease and age-related macular degeneration may both be caused by chronic inflammation of the RPE.

  4. BMP13 prevents the effects of annular injury in an ovine model.

    PubMed

    Wei, Aiqun; Williams, Lisa A; Bhargav, Divya; Shen, Bojiang; Kishen, Thomas; Duffy, Neil; Diwan, Ashish D

    2009-06-03

    Chronic back pain is a global health problem affecting millions of people worldwide and carries significant economic and social morbidities. Intervertebral disc damage and degeneration is a major cause of back pain, characterised by histological and biochemical changes that have been well documented in animal models. Recently there has been intense interest in early intervention in disc degeneration using growth factors or stem cell transplantation, to replenish the diseased tissues. Bone Morphogenetic Proteins (BMPs) have been approved for clinical use in augmenting spinal fusions, and may represent candidate molecules for intervertebral disc regeneration. BMP13 has an important role in embryonic development and recent genetic evidence shows a role in the development of the human spine. This study explores the effect of BMP13 on a damaged intervertebral disc in an ovine model of discal degeneration. We found that, when injected at the time of injury, BMP13 reversed or arrested histological changes that occurred in the control discs such as loss of extracellular matrix proteins. In addition, BMP13 injected discs retained greater hydration after 4 months, and possessed more cells in the NP. Taken together, BMP13 may be a potent clinical therapeutic agent when used early in the degeneration cascade to promote healthy disc tissue.

  5. Effect of Degeneration on Fluid–Solid Interaction within Intervertebral Disk Under Cyclic Loading – A Meta-Model Analysis of Finite Element Simulations

    PubMed Central

    Nikkhoo, Mohammad; Khalaf, Kinda; Kuo, Ya-Wen; Hsu, Yu-Chun; Haghpanahi, Mohammad; Parnianpour, Mohamad; Wang, Jaw-Lin

    2015-01-01

    The risk of low back pain resulted from cyclic loadings is greater than that resulted from prolonged static postures. Disk degeneration results in degradation of disk solid structures and decrease of water contents, which is caused by activation of matrix digestive enzymes. The mechanical responses resulted from internal solid–fluid interactions of degenerative disks to cyclic loadings are not well studied yet. The fluid–solid interactions in disks can be evaluated by mathematical models, especially the poroelastic finite element (FE) models. We developed a robust disk poroelastic FE model to analyze the effect of degeneration on solid–fluid interactions within disk subjected to cyclic loadings at different loading frequencies. A backward analysis combined with in vitro experiments was used to find the elastic modulus and hydraulic permeability of intact and enzyme-induced degenerated porcine disks. The results showed that the averaged peak-to-peak disk deformations during the in vitro cyclic tests were well fitted with limited FE simulations and a quadratic response surface regression for both disk groups. The results showed that higher loading frequency increased the intradiscal pressure, decreased the total fluid loss, and slightly increased the maximum axial stress within solid matrix. Enzyme-induced degeneration decreased the intradiscal pressure and total fluid loss, and barely changed the maximum axial stress within solid matrix. The increase of intradiscal pressure and total fluid loss with loading frequency was less sensitive after the frequency elevated to 0.1 Hz for the enzyme-induced degenerated disk. Based on this study, it is found that enzyme-induced degeneration decreases energy attenuation capability of disk, but less change the strength of disk. PMID:25674562

  6. Molecular Therapy for Degenerative Disc Disease: Clues from Secretome Analysis of the Notochordal Cell-Rich Nucleus Pulposus

    PubMed Central

    Matta, Ajay; Karim, M. Zia; Isenman, David E.; Erwin, W. Mark

    2017-01-01

    Degenerative disc disease (DDD) is associated with spinal pain often leading to long-term disability. However, the non-chondrodystrophic canine intervertebral disc is protected from the development of DDD, ostensibly due to its retention of notochordal cells (NC) in the nucleus pulposus (NP). In this study, we hypothesized that secretome analysis of the NC-rich NP will lead to the identification of key proteins that delay the onset of DDD. Using mass-spectrometry, we identified 303 proteins including components of TGFβ- and Wnt-signaling, anti-angiogeneic factors and proteins that inhibit axonal ingrowth in the bioactive fractions of serum free, notochordal cell derived conditioned medium (NCCM). Ingenuity Pathway Analysis revealed TGFβ1 and CTGF as major hubs in protein interaction networks. In vitro treatment with TGFβ1 and CTGF promoted the synthesis of healthy extra-cellular matrix proteins, increased cell proliferation and reduced cell death in human degenerative disc NP cells. A single intra-discal injection of recombinant TGFβ1 and CTGF proteins in a pre-clinical rat-tail disc injury model restored the NC and stem cell rich NP. In conclusion, we demonstrate the potential of TGFβ1 and CTGF to mitigate the progression of disc degeneration and the potential use of these molecules in a molecular therapy to treat the degenerative disc. PMID:28358123

  7. The dark phase intraocular pressure elevation and retinal ganglion cell degeneration in a rat model of experimental glaucoma.

    PubMed

    Kwong, Jacky M K; Vo, Nancy; Quan, Ann; Nam, Michael; Kyung, Haksu; Yu, Fei; Piri, Natik; Caprioli, Joseph

    2013-07-01

    Intraocular pressure (IOP) elevation is considered as a major risk factor causing the progression of vision deterioration in glaucoma. Although it is known that the IOP level changes widely throughout the day and night, how the dark or light phase IOP elevation contributes to retinal ganglion cell (RGC) degeneration is still largely unclear. To examine the profile of IOP, modified laser photocoagulation was applied to the trabecular meshwork of Brown Norway rats and both light and dark phase IOPs were monitored approximately 1-2 times a week. The relationship between IOP elevation and RGC degeneration was investigated while RGC body loss was analyzed with Rbpms immunolabeling on retinal wholemount and axonal injury in the optic nerve was semi-quantified. The baseline awake dark and light IOPs were 30.4 ± 2.7 and 20.2 ± 2.1 mmHg respectively. The average dark IOP was increased to 38.2 ± 3.2 mmHg for five weeks after the laser treatment on 270° trabecular meshwork. However, there was no significant loss of RGC body and axonal injury. After laser treatment on 330° trabecular meshwork, the dark and light IOPs were significantly increased to 43.8 ± 4.6 and 23 ± 3.7 mmHg respectively for 5 weeks. The cumulative dark and light IOP elevations were 277 ± 86 and 113 ± 50 mmHg days respectively while the cumulative total (light and dark) IOP elevation was 213 ± 114 mmHg days. After 5 weeks, regional RGC body loss of 29.5 ± 15.5% and moderate axonal injury were observed. Axonal injury and loss of RGC body had a high correlation with the cumulative total IOP elevation (R(2) = 0.60 and 0.65 respectively). There was an association between the cumulative dark IOP elevation and RGC body loss (R(2) = 0.37) and axonal injury (R(2) = 0.51) whereas the associations between neuronal damages and the cumulative light IOP elevation were weak (for RGC body loss, R(2) = 0.01; for axonal injury, R(2) = 0.26). Simple linear regression model

  8. Redundant disc

    NASA Technical Reports Server (NTRS)

    Barack, W. N.; Domas, P. A.; Beekman, S. W. (Inventor)

    1978-01-01

    A rotatable disc is described that consists of parallel plates tightly joined together for rotation about a hub. Each plate is provided with several angularly projecting spaced lands. The lands of each plate are interposed in alternating relationship between the lands of the next adjacent plate. In this manner, circumferential displacement of adjacent sectors in any one plate is prevented in the event that a crack develops. Each plate is redundantly sized so that, in event of structural failure of one plate, the remaining plates support a proportionate share of the load of the failed plate. The plates are prevented from separating laterally through the inclusion of generally radially extending splines which are inserted to interlock cooperating, circumferentially adjacent lands.

  9. Astrocytes and Müller Cell Alterations During Retinal Degeneration in a Transgenic Rat Model of Retinitis Pigmentosa

    PubMed Central

    Fernández-Sánchez, Laura; Lax, Pedro; Campello, Laura; Pinilla, Isabel; Cuenca, Nicolás

    2015-01-01

    Purpose: Retinitis pigmentosa includes a group of progressive retinal degenerative diseases that affect the structure and function of photoreceptors. Secondarily to the loss of photoreceptors, there is a reduction in retinal vascularization, which seems to influence the cellular degenerative process. Retinal macroglial cells, astrocytes, and Müller cells provide support for retinal neurons and are fundamental for maintaining normal retinal function. The aim of this study was to investigate the evolution of macroglial changes during retinal degeneration in P23H rats. Methods: Homozygous P23H line-3 rats aged from P18 to 18 months were used to study the evolution of the disease, and SD rats were used as controls. Immunolabeling with antibodies against GFAP, vimentin, and transducin were used to visualize macroglial cells and cone photoreceptors. Results: In P23H rats, increased GFAP labeling in Müller cells was observed as an early indicator of retinal gliosis. At 4 and 12 months of age, the apical processes of Müller cells in P23H rats clustered in firework-like structures, which were associated with ring-like shaped areas of cone degeneration in the outer nuclear layer. These structures were not observed at 16 months of age. The number of astrocytes was higher in P23H rats than in the SD matched controls at 4 and 12 months of age, supporting the idea of astrocyte proliferation. As the disease progressed, astrocytes exhibited a deteriorated morphology and marked hypertrophy. The increase in the complexity of the astrocytic processes correlated with greater connexin 43 expression and higher density of connexin 43 immunoreactive puncta within the ganglion cell layer (GCL) of P23H vs. SD rat retinas. Conclusions: In the P23H rat model of retinitis pigmentosa, the loss of photoreceptors triggers major changes in the number and morphology of glial cells affecting the inner retina. PMID:26733810

  10. Prevalence of Age-Related Changes in Ovine Lumbar Intervertebral Discs during Computed Tomography and Magnetic Resonance Imaging

    PubMed Central

    Nisolle, Jean-François; Bihin, Benoît; Kirschvink, Nathalie; Neveu, Fabienne; Clegg, Peter; Dugdale, Alexandra; Wang, Xiaoqing; Vandeweerd, Jean-Michel

    2016-01-01

    Ovine models are used to study intervertebral disc (IVD) degeneration. The objective of the current study was to assess the naturally occurring age-related changes of the IVD that can be diagnosed by CT and MRI in the lumbar spine of sheep. We used CT and T2-weighted MR images to score the IVD (L6S1 to L1L2) in 41 sheep (age, 6 mo to 11 y) that were euthanized for reasons not related to musculoskeletal disease. T2 mapping and measurement of T2 time of L6S1 to L2L3 were performed in 22 of the sheep. Degenerative changes manifested as early as 2 y of age and occurred at every IVD level. Discs were more severely damaged in older sheep. The age effect of the L6S1 IVD was larger than the average age effect for the other IVD. The current study provides evidence that lesions similar to those encountered in humans can be identified by CT and MRI in lumbar spine of sheep. Ideally, research animals should be assessed at the initiation of preclinical trials to determine the extent of prevalent degenerative changes. The ovine lumbosacral disc seems particularly prone to degeneration and might be a favorable anatomic site for studying IVD degeneration. PMID:27538861

  11. Effects of tissue-engineered articular disc implants on the biomechanical loading of the human temporomandibular joint in a three-dimensional finite element model.

    PubMed

    Al-Sukhun, Jehad; Ashammakhi, Nureddin; Penttila, Heikki

    2007-07-01

    The purpose of this study was to evaluate biomechanical loading of the temporomandibular joint when using a biodegradable laminate implant to replace the articular disc and to test the hypothesis that the use of the implant reduces stress distribution in the condyle, implant, and glenoid fossa. A finite element model of a female human mandible, including the temporomandibular joint, which had two standard endosseous implants inserted bilaterally in the premolar region, was constructed from computed tomography scan images using a commercially available finite element software. The disc, condyle, and glenoid fossa were arbitrarily divided into five regions: the anterior, posterior, medial, lateral, and central. The disc was then replaced with a poly-L/DL-lactide biodegradable laminate. The finite element model was then used to predict principal and Von Mises stresses. The use of poly-L/DL-lactide implant resulted in remarkable reduction in Von Mises stresses (approximately threefold) in the anterior, central, and medial regions of the mandibular condyle in comparison with slight to moderate stress reductions in the corresponding regions of the implant and glenoid fossa. The mandibular condyle also demonstrated the largest total displacement in all directions followed by the implant and glenoid fossa. The use of an alloplastic implant such as the bioresorbable, poly-L/DL-lactide laminate to replace the articular disc reduces loading of the mandibular condyle rather than the implant and glenoid fossa. These findings lead to support the hypothesis that the mandibular condyle more likely functions as a shock absorber than the disc. The use of bioresorbable laminate implants might prove an efficient technique to replace the articular disc and promote normal function of the temporomandibular joint.

  12. A macroscopic multi-mechanism based constitutive model for the thermo-mechanical cyclic degeneration of shape memory effect of NiTi shape memory alloy

    NASA Astrophysics Data System (ADS)

    Yu, Chao; Kang, Guozheng; Kan, Qianhua

    2017-01-01

    A macroscopic based multi-mechanism constitutive model is constructed in the framework of irreversible thermodynamics to describe the degeneration of shape memory effect occurring in the thermo-mechanical cyclic deformation of NiTi shape memory alloys (SMAs). Three phases, austenite A, twinned martensite Mt and detwinned martensite Md , as well as the phase transitions occurring between each pair of phases (A→ M t , Mt→ A , A→ M d , Md→ A , and Mt→ M d) are considered in the proposed model. Meanwhile, two kinds of inelastic deformation mechanisms, martensite transformation-induced plasticity and reorientation-induced plasticity, are used to explain the degeneration of shape memory effects of NiTi SMAs. The evolution equations of internal variables are proposed by attributing the degeneration of shape memory effect to the interaction between the three phases (A, Mt , and Md) and plastic deformation. Finally, the capability of the proposed model is verified by comparing the predictions with the experimental results of NiTi SMAs. It is shown that the degeneration of shape memory effect and its dependence on the loading level can be reasonably described by the proposed model.

  13. Subcortical dopaminergic deficits in a DISC1 mutant model: a study in direct reference to human molecular brain imaging

    PubMed Central

    Jaaro-Peled, Hanna; Niwa, Minae; Foss, Catherine A.; Murai, Rina; de los Reyes, Samantha; Kamiya, Atsushi; Mateo, Yolanda; O'Donnell, Patricio; Cascella, Nicola G.; Nabeshima, Toshitaka; Guilarte, Tomás R.; Pomper, Martin G.; Sawa, Akira

    2013-01-01

    Imaging of the human brain has been an invaluable aid in understanding neuropsychopharmacology and, in particular, the role of dopamine in the striatum in mental illness. Here, we report a study in a genetic mouse model for major mental illness guided by results from human brain imaging: a systematic study using small animal positron emission tomography (PET), autoradiography, microdialysis and molecular biology in a putative dominant-negative mutant DISC1 transgenic model. This mouse model showed augmented binding of radioligands to the dopamine D2 receptor (D2R) in the striatum as well as neurochemical and behavioral changes to methamphetamine administration. Previously we reported that this model displayed deficits in the forced swim test, a representative indicator of antidepressant efficacy. By combining the results of our two studies, we propose a working hypothesis for future studies that this model might represent a mixed condition of depression and psychosis. We hope that this study will also help bridge a major gap in translational psychiatry between basic characterization of animal models and clinico-pharmacological assessment of patients mainly through PET imaging. PMID:23314019

  14. Structural and Ultrastructural Analysis of the Cervical Discs of Young and Elderly Humans.

    PubMed

    Fontes, Ricardo Braganca de Vasconcellos; Baptista, Josemberg Silva; Rabbani, Said Rahnamaye; Traynelis, Vincent C; Liberti, Edson Aparecido

    2015-01-01

    Several studies describing the ultrastructure and extracellular matrix (ECM) of intervertebral discs (IVDs) involve animal models and specimens obtained from symptomatic individuals during surgery for degenerative disease or scoliosis, which may not necessarily correlate to changes secondary to normal aging in humans. These changes may also be segment-specific based on different load patterns throughout life. Our objective was to describe the ECM and collagen profile of cervical IVDs in young (G1 - <35 years) and elderly (G2 - >65 years) presumably-asymptomatic individuals. Thirty cervical discs per group were obtained during autopsies of presumably-asymptomatic individuals. IVDs were analyzed with MRI, a morphological grading scale, light microscopy, scanning electron microscopy (SEM) and immunohistochemistry (IHC) for collagen types I, II, III, IV, V, VI, IX and X. Macroscopic degenerative features such as loss of annulus-nucleus distinction and fissures were found in both groups and significantly more severe in G2 as expected. MRI could not detect all morphological changes when compared even with simple morphological inspection. The loose fibrocartilaginous G1 matrix was replaced by a denser ECM in G2 with predominantly cartilaginous characteristics, chondrocyte clusters and absent elastic fibers. SEM demonstrated persistence of an identifiable nucleus and Sharpey-type insertion of cervical annulus fibers even in highly-degenerated G2 specimens. All collagen types were detected in every disc sector except for collagen X, with the largest area stained by collagens II and IV. Collagen detection was significantly decreased in G2: although significant intradiscal differences were rare, changes may occur faster or earlier in the posterior annulus. These results demonstrate an extensive modification of the ECM with maintenance of basic ultrastructural features despite severe macroscopic degeneration. Collagen analysis supports there is not a "pathologic" collagen type

  15. Cervical disc arthroplasty: Pros and cons

    PubMed Central

    Moatz, Bradley; Tortolani, P. Justin

    2012-01-01

    Background: Cervical disc arthroplasty has emerged as a promising potential alternative to anterior cervical discectomy and fusion (ACDF) in appropriately selected patients. Despite a history of excellent outcomes after ACDF, the question as to whether a fusion leads to adjacent segment degeneration remains unanswered. Numerous US investigational device exemption trials comparing cervical arthroplasty to fusion have been conducted to answer this question. Methods: This study reviews the current research regarding cervical athroplasty, and emphasizes both the pros and cons of arthroplasty as compared with ACDF. Results: Early clinical outcomes show that cervical arthroplasty is as effective as the standard ACDF. However, this new technology is also associated with an expanding list of novel complications. Conclusion: Although there is no definitive evidence that cervical disc replacement reduces the incidence of adjacent segment degeneration, it does show other advantages; for example, faster return to work, and reduced need for postoperative bracing. PMID:22905327

  16. Prognosis of intervertebral disc loss from diagnosis of degenerative disc disease

    NASA Astrophysics Data System (ADS)

    Li, S.; Lin, A.; Tay, K.; Romano, W.; Osman, Said

    2015-03-01

    Degenerative Disc Disease (DDD) is one of the most common causes of low back pain, and is a major factor in limiting the quality of life of an individual usually as they enter older stages of life, the disc degeneration reduces the shock absorption available which in turn causes pain. Disc loss is one of the central processes in the pathogenesis of DDD. In this study, we investigated whether the image texture features quantified from magnetic resonance imaging (MRI) could be appropriate markers for diagnosis of DDD and prognosis of inter-vertebral disc loss. The main objective is to use simple image based biomarkers to perform prognosis of spinal diseases using non-invasive procedures. Our results from 65 subjects proved the higher success rates of the combination marker compared to the individual markers and in the future, we will extend the study to other spine regions to allow prognosis and diagnosis of DDD for a wider region.

  17. Detrimental Effects of Discectomy on Intervertebral Disc Biology can be Decelerated by Growth Factor Treatment during Surgery – A large animal organ culture model

    PubMed Central

    Illien-Jünger, S.; Lu, Y.; Purmessur, D.; Mayer, J.E.; Walter, B.A.; Roughley, P.J.; Qureshi, S.A.; Hecht, A.C.; Iatridis, J.C.

    2014-01-01

    BACKGROUND CONTEXT Lumbar discectomies are common surgical interventions that treat radiculopathy by removing herniated and loose intervertebral disc (IVD) tissues. However, remaining IVD tissue can continue to degenerate resulting in long-term clinical problems. Little information is available on the effects of discectomy on IVD biology. Currently no treatments exist that can suspend or reverse the degeneration of the remaining IVD. PURPOSE To improve knowledge how discectomy procedures influence IVD physiology and to assess the potential of growth-factor treatment as an augmentation during surgery STUDY DESIGN To determine effects of discectomy on IVDs with and without TGFβ3 augmentation using bovine IVD organ culture. METHODS This study determined effects of discectomy with and without TGFβ3 injection using 1, 6, and 19 days organ culture experiments. Treated IVDs were injected with 0.2μg TGFβ3 in 20μl PBS+BSA into several locations of the discectomy site. Cell viability, gene expression, nitric-oxide release, IVD height, aggrecan degradation, and proteoglycan content were determined. RESULTS Discectomy significantly increased cell death, aggrecan degradation and nitric-oxide release in healthy IVDs. TGFβ3 injection treatment prevented or mitigated those effects for the 19 days culture period. CONCLUSIONS Discectomy procedures induced cell death, catabolism and nitric-oxide production in healthy IVDs, and we conclude that post-discectomy degeneration is likely to be associated with cell death and matrix degradation. TGFβ3 injection augmented discectomy procedures by acting to protect IVD tissues by maintaining cell viability, limiting matrix degradation and suppressing nitric-oxide. We conclude that discectomy procedures can be improved with injectable therapies at the time of surgery although further in vivo and human studies are required. PMID:24768749

  18. On the Relative Relevance of Subject-Specific Geometries and Degeneration-Specific Mechanical Properties for the Study of Cell Death in Human Intervertebral Disk Models

    PubMed Central

    Malandrino, Andrea; Pozo, José M.; Castro-Mateos, Isaac; Frangi, Alejandro F.; van Rijsbergen, Marc M.; Ito, Keita; Wilke, Hans-Joachim; Dao, Tien Tuan; Ho Ba Tho, Marie-Christine; Noailly, Jérôme

    2015-01-01

    Capturing patient- or condition-specific intervertebral disk (IVD) properties in finite element models is outmost important in order to explore how biomechanical and biophysical processes may interact in spine diseases. However, disk degenerative changes are often modeled through equations similar to those employed for healthy organs, which might not be valid. As for the simulated effects of degenerative changes, they likely depend on specific disk geometries. Accordingly, we explored the ability of continuum tissue models to simulate disk degenerative changes. We further used the results in order to assess the interplay between these simulated changes and particular IVD morphologies, in relation to disk cell nutrition, a potentially important factor in disk tissue regulation. A protocol to derive patient-specific computational models from clinical images was applied to different spine specimens. In vitro, IVD creep tests were used to optimize poro-hyperelastic input material parameters in these models, in function of the IVD degeneration grade. The use of condition-specific tissue model parameters in the specimen-specific geometrical models was validated against independent kinematic measurements in vitro. Then, models were coupled to a transport-cell viability model in order to assess the respective effects of tissue degeneration and disk geometry on cell viability. While classic disk poro-mechanical models failed in representing known degenerative changes, additional simulation of tissue damage allowed model validation and gave degeneration-dependent material properties related to osmotic pressure and water loss, and to increased fibrosis. Surprisingly, nutrition-induced cell death was independent of the grade-dependent material properties, but was favored by increased diffusion distances in large IVDs. Our results suggest that in situ geometrical screening of IVD morphology might help to anticipate particular mechanisms of disk degeneration. PMID:25717471

  19. Circumplanetary discs around young giant planets: a comparison between core-accretion and disc instability

    NASA Astrophysics Data System (ADS)

    Szulágyi, J.; Mayer, L.; Quinn, T.

    2017-01-01

    Circumplanetary discs can be found around forming giant planets, regardless of whether core accretion or gravitational instability built the planet. We carried out state-of-the-art hydrodynamical simulations of the circumplanetary discs for both formation scenarios, using as similar initial conditions as possible to unveil possible intrinsic differences in the circumplanetary disc mass and temperature between the two formation mechanisms. We found that the circumplanetary discs' mass linearly scales with the circumstellar disc mass. Therefore, in an equally massive protoplanetary disc, the circumplanetary discs formed in the disc instability model can be only a factor of 8 more massive than their core-accretion counterparts. On the other hand, the bulk circumplanetary disc temperature differs by more than an order of magnitude between the two cases. The subdiscs around planets formed by gravitational instability have a characteristic temperature below 100 K, while the core-accretion circumplanetary discs are hot, with temperatures even greater than 1000 K when embedded in massive, optically thick protoplanetary discs. We explain how this difference can be understood as the natural result of the different formation mechanisms. We argue that the different temperatures should persist up to the point when a full-fledged gas giant forms via disc instability; hence, our result provides a convenient criterion for observations to distinguish between the two main formation scenarios by measuring the bulk temperature in the planet vicinity.

  20. Validation of Sodium MRI of Intervertebral Disc

    PubMed Central

    Wang, Chenyang; McArdle, Erin; Fenty, Matthew; Witschey, Walter; Elliott, Mark; Sochor, Matthew; Reddy, Ravinder; Borthakur, Arijitt

    2009-01-01

    Study Design This study demonstrated the diagnostic potential of sodium MRI for non-invasive quantification of PG in the intervertebral discs. Objective To determine the existence of a linear correlation between intervertebral disc [Na] measured from sodium MRI and [PG] measurement from DMMB assay. Summary of Background Data Previous studies have shown the possibility of quantifying [Na] in vivo using sodium MRI, however none has shown a direct linear correlation between [Na] measured from sodium MRI and [PG]. Methods 3D sodium MRI images of bovine discs were acquired and converted into [Na] maps. Samples were systematically removed from the discs for DMMB assay. The removal locations were photographically recorded and applied to the [Na] maps to extract the [Na] measurements for comparison. In vivo sodium MRI scans were also carried out on a pair of symptomatic and asymptomatic subjects. Results The linear regression fit of [Na] versus [PG] data yielded a significant linear correlation coefficient of 0.71. The in vivo sodium MRI image of the symptomatic subject showed significant [Na] decrease when compared to that of the asymptomatic subject. Conclusion Sodium MRI's specificity for PG in the intervertebral discs makes it a promising diagnostic tool for the earlier phase of disc degeneration. PMID:20147881

  1. Detection of the optic disc in fundus images by combining probability models.

    PubMed

    Harangi, Balazs; Hajdu, Andras

    2015-10-01

    In this paper, we propose a combination method for the automatic detection of the optic disc (OD) in fundus images based on ensembles of individual algorithms. We have studied and adapted some of the state-of-the-art OD detectors and finally organized them into a complex framework in order to maximize the accuracy of the localization of the OD. The detection of the OD can be considered as a single-object detection problem. This object can be localized with high accuracy by several algorithms extracting single candidates for the center of the OD and the final location can be defined using a single majority voting rule. To include more information to support the final decision, we can use member algorithms providing more candidates which can be ranked based on the confidence ordered by the algorithms. In this case, a spatial weighted graph is defined where the candidates are considered as its nodes, and the final OD position is determined in terms of finding a maximum-weighted clique. Now, we examine how to apply in our ensemble-based framework all the accessible information supplied by the member algorithms by making them return confidence values for each image pixel. These confidence values inform us about the probability that a given pixel is the center point of the object. We apply axiomatic and Bayesian approaches, as in the case of aggregation of judgments of experts in decision and risk analysis, to combine these confidence values. According to our experimental study, the accuracy of the localization of OD increases further. Besides single localization, this approach can be adapted for the precise detection of the boundary of the OD. Comparative experimental results are also given for several publicly available datasets.

  2. High-density channel model and detection method for signal readout from super-resolution near-field structure discs

    NASA Astrophysics Data System (ADS)

    Hosogai, Shota; Ansai, Tsutomu; Yoshinari, Takehisa; Tanabe, Takaya

    2016-09-01

    Although a readout method using the super-resolution near-field structure (super-RENS) effect can overcome diffraction limits, readout characteristics for greatly surpassed high-density conditions do not become clear, because a high-density channel function having a differential response property is superimposed on a normal readout function. We propose a high-density channel model to indicate the properties of the super-RENS effect directly. This model can be expressed as a differential response function using the finite impulse response (FIR) filter model. It expresses the super-RENS readout process, which is divided on the basis of recording densities such as high and normal Blu-ray Disc™ densities. We estimated the properties of super-RENS readout signals by comparison between theoretical expressions and experiments. Results show that good signal quality require readout signals having sharp peaks and smaller offsets. We also evaluated the channel model by adding an adaptive FIR filter and a Viterbi decoder by simulations. Results show that the super-RENS disc can achieve a fourfold higher recording density if the signal-to-noise ratio (S/N) is improved to 6 dB in the case of partial response (PR) (1 + D + D 2).

  3. Prediction of gauge couplings from anti-GUT and multi-degenerate vacuum: finetuning model suggests non-locality

    SciTech Connect

    Bennett, D. L.; Nielsen, H. B.

    1997-06-15

    We present our theoretical predictions for the three gauge coupling constants of the Standard Model (SM). For the famous finestructure constant our prediction is {alpha}{sup -1}=137{+-}9. These predictions are based on our Anti-Grand-Unified Theory (Anti-GUT) gauge group and the Multiple Point Criticality Principle (MPCP). Both Anti-GUT and MPCP are proposed as principles or laws underlying the SM. Both were originally suggested by our observation that the experimentally determined Standard Model Group (SMG) gauge couplings have non-generic patterns of values that could be explained by these two new principles. The observation that the gauge couplings assume values corresponding to a maximally degenerate vacuum lead to the MPCP. As the transitions between the different vacuua are first order, the MPCP provides a way of finetuning constants of Nature - without finetuned imput - in a manner reminescent of how temperature is 'finetuned' to 0 deg. C. In an equilibrated mixture of ice and water. In a 4-dimensional field theory, this mechanism for finetuning suggests a form of non-locality that, however, is phenomenologically tolerable because the only effect is the modification of the values of coupling constants. We argue that the time-machine type of paradoxes that plague non-local theories are avoided precisely when Nature obeys the MPCP.

  4. Quantitative assessment of age-related macular degeneration using parametric modeling of the leakage transfer function: preliminary results.

    PubMed

    Eldeeb, Safaa M; Abdelmoula, Walid M; Shah, Syed M; Fahmy, Ahmed S

    2012-01-01

    Age-related macular degeneration (AMD) is a major cause of blindness and visual impairment in older adults. The wet form of the disease is characterized by abnormal blood vessels forming a choroidal neovascular membrane (CNV), that result in destruction of normal architecture of the retina. Current evaluation and follow up of wet AMD include subjective evaluation of Fluorescein Angiograms (FA) to determine the activity of the lesion and monitor the progression or regression of the disease. However, this subjective evaluation prevents accurate monitoring of the disease progression or regression in response to a pharmacologic agent. In this work, we present a method that allows objective assessment of the activity of a CNV lesion which can be statistically compared across different patient and time points. The method is based on a hypothesis that the discrepancy in the time-intensity signals among the diseased and normal retinal areas are due to an implicit transfer function whose parameters can be used to characterize the retina. The method begins with parametric modeling of the temporal variation of the lesion and background intensities. Then, the values of the model parameters are used to evaluate the change in the activity of the disease. Preliminary results on five datasets show that the calculated parameters are highly correlated with the Visual Acuity (VA) of the patients.

  5. The quiescent phase of galactic disc growth

    NASA Astrophysics Data System (ADS)

    Aumer, Michael; Binney, James; Schönrich, Ralph

    2016-07-01

    We perform a series of controlled N-body simulations of growing disc galaxies within non-growing, live dark matter haloes of varying mass and concentration. Our initial conditions include either a low-mass disc or a compact bulge. New stellar particles are continuously added on near-circular orbits to the existing disc, so spiral structure is continuously excited. To study the effect of combined spiral and giant molecular cloud (GMC) heating on the discs, we introduce massive, short-lived particles that sample a GMC mass function. An isothermal gas component is introduced for a subset of the models. We perform a resolution study and vary parameters governing the GMC population, the histories of star formation and radial scale growth. Models with GMCs and standard values for the disc mass and halo density provide the right level of self-gravity to explain the age-velocity dispersion relation of the solar neighbourhood (Snhd). GMC heating generates remarkably exponential vertical profiles with scaleheights that are radially constant and agree with observations of galactic thin discs. GMCs are also capable of significantly delaying bar formation. The amount of spiral-induced radial migration agrees with what is required for the metallicity distribution of the Snhd. However, in our standard models, the outward-migrating populations are not hot enough vertically to create thick discs. Thick discs can form in models with high baryon fractions, but the corresponding bars are too long, the young stellar populations too hot and the discs flare considerably.

  6. Novel immunodeficient Pde6b rd1 mouse model of retinitis pigmentosa to investigate potential therapeutics and pathogenesis of retinal degeneration.

    PubMed

    Mishra, Alaknanda; Das, Barun; Nath, Madhu; Iyer, Srikanth; Kesarwani, Ashwani; Bhattacharjee, Jashdeep; Arindkar, Shailendra; Sahay, Preeti; Jain, Kshama; Sahu, Parul; Sinha, Prakriti; Velpandian, Thirumurthy; Nagarajan, Perumal; Upadhyay, Pramod

    2017-03-03

    Retinitis pigmentosa (RP) is a common retinal degeneration disease caused by mutation in any gene of the photo transduction cascade and results in photoreceptor dystrophy. Over decades, several animal models have been used to address the need for elucidation of effective therapeutics and factors regulating retinal degeneration to prohibit or renew the damaged retina. However, controversies over immune privilege of retina during cell transplantation and role of immune modulation during RP still remain largely uninvestigated due to lack of proper animal models. Therefore, in our present study, we have developed an immune compromised mouse model NOD.SCID- rd1 for retinitis pigmentosa (RP) by crossing CBA/J and NOD SCID mice and selecting homozygous double mutant animals for further breeding. Characterization of the newly developed RP model indicates similar retinal degeneration pattern as CBA/J with decreased apoptosis rate and rhodopsin loss. It also exhibits loss of T cells, B cells and NK cells. NOD.SCID- rd1model is extremely useful for xenogenic cell based therapeutics as indicated by higher cell integration capacity post transplantation. The dissection of underlying role of immune system in the progression of RP and effect of immune deficiency on immune privilege of eye has also been further elucidated using comparative qPCR studies of this model with immune competent RP model.

  7. DNA sensor model based on a carbon nanotube network in the degenerate limit

    NASA Astrophysics Data System (ADS)

    Abadi, H. Karimi Feiz; Webb, J. F.; Ahmadi, M. T.; Rahmani, M.; Saeidmanesh, M.; Khalid, M.; Ismail, R.

    2012-11-01

    An analytical model of a possible DNA sensor based on a carbon nanotube network that functions as a selective detector of DNA molecules is presented. The ability to implement label-free electronic detection using a DNA sensor based on a carbon nanotube network constitutes an important step towards low-cost, highly sensitive, simple and accurate molecular diagnostics. In particular, there is an urgent need for a simple method of detection of DNA molecules as this will provided a new and efficient way to diagnosis genetic or pathogenic diseases. Bio-compatibility and high sensitivity towards environmental perturbations make graphene nanomaterials a good choice for a sensing layer in an electronic DNA sensor. In this study, a conductance model of a DNA sensor based on a carbon nanotube network is suggested and the performance of the model is evaluated by calculating current-voltage characteristics.

  8. Mitochondrial alterations and oxidative stress in an acute transient mouse model of muscle degeneration: implications for muscular dystrophy and related muscle pathologies.

    PubMed

    Ramadasan-Nair, Renjini; Gayathri, Narayanappa; Mishra, Sudha; Sunitha, Balaraju; Mythri, Rajeswara Babu; Nalini, Atchayaram; Subbannayya, Yashwanth; Harsha, Hindalahalli Chandregowda; Kolthur-Seetharam, Ullas; Srinivas Bharath, Muchukunte Mukunda

    2014-01-03

    Muscular dystrophies (MDs) and inflammatory myopathies (IMs) are debilitating skeletal muscle disorders characterized by common pathological events including myodegeneration and inflammation. However, an experimental model representing both muscle pathologies and displaying most of the distinctive markers has not been characterized. We investigated the cardiotoxin (CTX)-mediated transient acute mouse model of muscle degeneration and compared the cardinal features with human MDs and IMs. The CTX model displayed degeneration, apoptosis, inflammation, loss of sarcolemmal complexes, sarcolemmal disruption, and ultrastructural changes characteristic of human MDs and IMs. Cell death caused by CTX involved calcium influx and mitochondrial damage both in murine C2C12 muscle cells and in mice. Mitochondrial proteomic analysis at the initial phase of degeneration in the model detected lowered expression of 80 mitochondrial proteins including subunits of respiratory complexes, ATP machinery, fatty acid metabolism, and Krebs cycle, which further decreased in expression during the peak degenerative phase. The mass spectrometry (MS) data were supported by enzyme assays, Western blot, and histochemistry. The CTX model also displayed markers of oxidative stress and a lowered glutathione reduced/oxidized ratio (GSH/GSSG) similar to MDs, human myopathies, and neurogenic atrophies. MS analysis identified 6 unique oxidized proteins from Duchenne muscular dystrophy samples (n = 6) (versus controls; n = 6), including two mitochondrial proteins. Interestingly, these mitochondrial proteins were down-regulated in the CTX model thereby linking oxidative stress and mitochondrial dysfunction. We conclude that mitochondrial alterations and oxidative damage significantly contribute to CTX-mediated muscle pathology with implications for human muscle diseases.

  9. LIDT-DD: A new self-consistent debris disc model that includes radiation pressure and couples dynamical and collisional evolution

    NASA Astrophysics Data System (ADS)

    Kral, Q.; Thébault, P.; Charnoz, S.

    2013-10-01

    Context. In most current debris disc models, the dynamical and the collisional evolutions are studied separately with N-body and statistical codes, respectively, because of stringent computational constraints. In particular, incorporating collisional effects (especially destructive collisions) into an N-body scheme has proven a very arduous task because of the exponential increase of particles it would imply. Aims: We present here LIDT-DD, the first code able to mix both approaches in a fully self-consistent way. Our aim is for it to be generic enough to be applied to any astrophysical case where we expect dynamics and collisions to be deeply interlocked with one another: planets in discs, violent massive breakups, destabilized planetesimal belts, bright exozodiacal discs, etc. Methods: The code takes its basic architecture from the LIDT3D algorithm for protoplanetary discs, but has been strongly modified and updated to handle the very constraining specificities of debris disc physics: high-velocity fragmenting collisions, radiation-pressure affected orbits, absence of gas that never relaxes initial conditions, etc. It has a 3D Lagrangian-Eulerian structure, where grains of a given size at a given location in a disc are grouped into super-particles or tracers whose orbits are evolved with an N-body code and whose mutual collisions are individually tracked and treated using a particle-in-a-box prescription designed to handle fragmenting impacts. To cope with the wide range of possible dynamics for same-sized particles at any given location in the disc, and in order not to lose important dynamical information, tracers are sorted and regrouped into dynamical families depending on their orbits. A complex reassignment routine that searches for redundant tracers in each family and reassignes them where they are needed, prevents the number of tracers from diverging. Results: The LIDT-DD code has been successfully tested on simplified cases for which robust results have

  10. Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration.

    PubMed

    Wang, Jing; Saul, Alan; Roon, Penny; Smith, Sylvia B

    2016-06-28

    Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6β(rd10) (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R(-/-) mice administered (+)-PTZ exhibited no cone preservation. (+)-PTZ treatment was associated with several beneficial cellular phenomena including attenuated reactive gliosis, reduced microglial activation, and decreased oxidative stress in mutant retinas. To our knowledge, this is the first report that activation of Sig1R attenuates inherited PRC loss. The findings may have far-reaching therapeutic implications for retinal neurodegenerative diseases.

  11. C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease*

    PubMed Central

    Ma, Li; Kaufman, Yardana; Zhang, Junhua; Washington, Ilyas

    2011-01-01

    Stargardt disease, also known as juvenile macular degeneration, occurs in approximately one in 10,000 people and results from genetic defects in the ABCA4 gene. The disease is characterized by premature accumulation of lipofuscin in the retinal pigment epithelium (RPE) of the eye and by vision loss. No cure or treatment is available. Although lipofuscin is considered a hallmark of Stargardt disease, its mechanism of formation and its role in disease pathogenesis are poorly understood. In this work we investigated the effects of long-term administration of deuterium-enriched vitamin A, C20-D3-vitamin A, on RPE lipofuscin deposition and eye function in a mouse model of Stargardt's disease. Results support the notion that lipofuscin forms partly as a result of the aberrant reactivity of vitamin A through the formation of vitamin A dimers, provide evidence that preventing vitamin A dimerization may slow disease related, retinal physiological changes and perhaps vision loss and suggest that administration of C20-D3-vitamin A may be a potential clinical strategy to ameliorate clinical symptoms resulting from ABCA4 genetic defects. PMID:21156790

  12. Terrestrial laser scanning and a degenerated cylinder model to determine gross morphological change of cadavers under conditions of natural decomposition.

    PubMed

    Zhang, Xiao; Glennie, Craig L; Bucheli, Sibyl R; Lindgren, Natalie K; Lynne, Aaron M

    2014-08-01

    Decomposition can be a highly variable process with stages that are difficult to quantify. Using high accuracy terrestrial laser scanning a repeated three-dimensional (3D) documentation of volumetric changes of a human body during early decomposition is recorded. To determine temporal volumetric variations as well as 3D distribution of the changed locations in the body over time, this paper introduces the use of multiple degenerated cylinder models to provide a reasonable approximation of body parts against which 3D change can be measured and visualized. An iterative closest point algorithm is used for 3D registration, and a method for determining volumetric change is presented. Comparison of the laser scanning estimates of volumetric change shows good agreement with repeated in-situ measurements of abdomen and limb circumference that were taken diurnally. The 3D visualizations of volumetric changes demonstrate that bloat is a process with a beginning, middle, and end rather than a state of presence or absence. Additionally, the 3D visualizations show conclusively that cadaver bloat is not isolated to the abdominal cavity, but also occurs in the limbs. Detailed quantification of the bloat stage of decay has the potential to alter how the beginning and end of bloat are determined by researchers and can provide further insight into the effects of the ecosystem on decomposition.

  13. Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

    PubMed Central

    Wang, Jing; Saul, Alan; Roon, Penny; Smith, Sylvia B.

    2016-01-01

    Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6βrd10 (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R−/− mice administered (+)-PTZ exhibited no cone preservation. (+)-PTZ treatment was associated with several beneficial cellular phenomena including attenuated reactive gliosis, reduced microglial activation, and decreased oxidative stress in mutant retinas. To our knowledge, this is the first report that activation of Sig1R attenuates inherited PRC loss. The findings may have far-reaching therapeutic implications for retinal neurodegenerative diseases. PMID:27298364

  14. Calcitonin attenuates cartilage degeneration and nociception in an experimental rat model of osteoarthritis: role of TGF-β in chondrocytes

    PubMed Central

    Wen, Zhi-Hong; Tang, Chi-Chieh; Chang, Yi-Chen; Huang, Shi-Ying; Lin, Yen-You; Hsieh, Shih-Peng; Lee, Hsin-Pai; Lin, Sung-Chun; Chen, Wu-Fu; Jean, Yen-Hsuan

    2016-01-01

    We investigated the role of the calcitonin (Miacalcin) in the progression of osteoarthritis (OA) and in nociceptive behavior in an experimental rat model of OA and osteoporosis. OA was induced by anterior cruciate ligament transection (ACLT) of the right knee and by bilateral ovariectomy (OVX) in Wistar rats. Nociceptive behaviors (secondary mechanical allodynia and weight-bearing distribution of the hind paws) were analyzed prior to surgery and every week, beginning at 12 weeks after surgery, up to 20 weeks. At 20 weeks, histopathological studies were performed on the cartilage of the knee joints. Immunohistochemical analysis was performed to examine the effect of calcitonin on transforming growth factor (TGF)-β1 expression in articular cartilage chondrocytes. Rats subjected to ACLT + OVX surgery showed obvious OA changes in the joints. Animals subjected to ACLT + OVX and treated with calcitonin showed significantly less cartilage degeneration and improved nociceptive tests compared with animals subjected to ACLT + OVX surgeries alone. Moreover, calcitonin increased TGF-β1 expression in chondrocytes in ACLT + OVX-affected cartilage. Subcutaneous injection of calcitonin (1) attenuated the development of OA, (2) concomitantly reduced nociception, and (3) modulated chondrocyte metabolism, possibly by increasing cellular TGF-β1 expression. PMID:27345362

  15. Numerical modeling of mid-infrared fiber optical parametric oscillator based on the degenerated FWM of tellurite photonic crystal fiber.

    PubMed

    Cheng, Huihui; Luo, Zhengqian; Ye, Chenchun; Huang, Yizhong; Liu, Chun; Cai, Zhiping

    2013-01-20

    Mid-infrared fiber optical parametric oscillators (MIR FOPOs) based on the degenerate four-wave mixing (DFWM) of tellurite photonic crystal fibers (PCFs) are proposed and modeled for the first time. Using the DFWM coupled-wave equations, numerical simulations are performed to analyze the effects of tellurite PCFs, single-resonant cavity, and pump source on the MIR FOPO performances. The numerical results show that: (1) although a longer tellurite PCF can decrease the pump threshold of MIR FOPOs to a few watts only, the high conversion-efficiency of MIR idler usually requires a short-length optimum PCF with low loss; (2) compared with the single-pass DFWM configurations of the MIR fiber sources published previously, the stable oscillation of signal light in single-resonant cavity can significantly promote the MIR idler output efficiency. With a suggested tellurite PCF as parametric gain medium, the theoretical prediction indicates that such a MIR FOPO could obtain a wide MIR-tunable range and a high conversion efficiency of more than 10%.

  16. Evolution of protoplanetary discs with magnetically driven disc winds

    NASA Astrophysics Data System (ADS)

    Suzuki, Takeru K.; Ogihara, Masahiro; Morbidelli, Alessandro; Crida, Aurélien; Guillot, Tristan

    2016-12-01

    Aims: We investigate the evolution of protoplanetary discs (PPDs) with magnetically driven disc winds and viscous heating. Methods: We considered an initially massive disc with 0.1 M⊙ to track the evolution from the early stage of PPDs. We solved the time evolution of surface density and temperature by taking into account viscous heating and the loss of mass and angular momentum by the disc winds within the framework of a standard α model for accretion discs. Our model parameters, turbulent viscosity, disc wind mass-loss, and disc wind torque, which were adopted from local magnetohydrodynamical simulations and constrained by the global energetics of the gravitational accretion, largely depends on the physical condition of PPDs, particularly on the evolution of the vertical magnetic flux in weakly ionized PPDs. Results: Although there are still uncertainties concerning the evolution of the vertical magnetic flux that remains, the surface densities show a large variety, depending on the combination of these three parameters, some of which are very different from the surface density expected from the standard accretion. When a PPD is in a wind-driven accretion state with the preserved vertical magnetic field, the radial dependence of the surface density can be positive in the inner region <1-10 au. The mass accretion rates are consistent with observations, even in the very low level of magnetohydrodynamical turbulence. Such a positive radial slope of the surface density strongly affects planet formation because it inhibits the inward drift or even causes the outward drift of pebble- to boulder-sized solid bodies, and it also slows down or even reversed the inward type-I migration of protoplanets. Conclusions: The variety of our calculated PPDs should yield a wide variety of exoplanet systems.

  17. Macular Degeneration Partnership

    MedlinePlus

    ... Age Related Macular Degeneration) Partnership Listen AMD Month Public Service Announcement To raise awareness of AMD, the Macular Degeneration Partnership (MDP) is distributing a public service announcement (PSA) nationwide. Seen through the eyes of a ...

  18. Degenerate Ising model for atomistic simulation of crystal-melt interfaces

    SciTech Connect

    Schebarchov, D.; Schulze, T. P.; Hendy, S. C.

    2014-02-21

    One of the simplest microscopic models for a thermally driven first-order phase transition is an Ising-type lattice system with nearest-neighbour interactions, an external field, and a degeneracy parameter. The underlying lattice and the interaction coupling constant control the anisotropic energy of the phase boundary, the field strength represents the bulk latent heat, and the degeneracy quantifies the difference in communal entropy between the two phases. We simulate the (stochastic) evolution of this minimal model by applying rejection-free canonical and microcanonical Monte Carlo algorithms, and we obtain caloric curves and heat capacity plots for square (2D) and face-centred cubic (3D) lattices with periodic boundary conditions. Since the model admits precise adjustment of bulk latent heat and communal entropy, neither of which affect the interface properties, we are able to tune the crystal nucleation barriers at a fixed degree of undercooling and verify a dimension-dependent scaling expected from classical nucleation theory. We also analyse the equilibrium crystal-melt coexistence in the microcanonical ensemble, where we detect negative heat capacities and find that this phenomenon is more pronounced when the interface is the dominant contributor to the total entropy. The negative branch of the heat capacity appears smooth only when the equilibrium interface-area-to-volume ratio is not constant but varies smoothly with the excitation energy. Finally, we simulate microcanonical crystal nucleation and subsequent relaxation to an equilibrium Wulff shape, demonstrating the model's utility in tracking crystal-melt interfaces at the atomistic level.

  19. A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration.

    PubMed

    López Del Amo, Víctor; Palomino-Schätzlein, Martina; Seco-Cervera, Marta; García-Giménez, José Luis; Pallardó, Federico Vicente; Pineda-Lucena, Antonio; Galindo, Máximo Ibo

    2017-03-01

    Charcot-Marie-Tooth disease is a rare peripheral neuropathy for which there is no specific treatment. Some forms of Charcot-Marie-Tooth are due to mutations in the GDAP1 gene. A striking feature of mutations in GDAP1 is that they have a variable clinical manifestation, according to disease onset and progression, histology and mode of inheritance. Studies in cellular and animal models have revealed a role of GDAP1 in mitochondrial morphology and distribution, calcium homeostasis and oxidative stress. To get a better understanding of the disease mechanism we have generated models of over-expression and RNA interference of the Drosophila Gdap1 gene. In order to get an overview about the changes that Gdap1 mutations cause in our disease model, we have combined a comprehensive determination of the metabolic profile in the flies by nuclear magnetic resonance spectroscopy with gene expression analyses and biophysical tests. Our results revealed that both up- and down-regulation of Gdap1 results in an early systemic inactivation of the insulin pathway before the onset of neuromuscular degeneration, followed by an accumulation of carbohydrates and an increase in the β-oxidation of lipids. Our findings are in line with emerging reports of energy metabolism impairments linked to different types of neural pathologies caused by defective mitochondrial function, which is not surprising given the central role of mitochondria in the control of energy metabolism. The relationship of mitochondrial dynamics with metabolism during neurodegeneration opens new avenues to understand the cause of the disease, and for the discovery of new biomarkers and treatments.

  20. Proto-planetary disc evolution and dispersal

    NASA Astrophysics Data System (ADS)

    Rosotti, Giovanni Pietro

    2015-05-01

    Planets form from gas and dust discs in orbit around young stars. The timescale for planet formation is constrained by the lifetime of these discs. The properties of the formed planetary systems depend thus on the evolution and final dispersal of the discs, which is the main topic of this thesis. Observations reveal the existence of a class of discs called "transitional", which lack dust in their inner regions. They are thought to be the last stage before the complete disc dispersal, and hence they may provide the key to understanding the mechanisms behind disc evolution. X-ray photoevaporation and planet formation have been studied as possible physical mechanisms responsible for the final dispersal of discs. However up to now, these two phenomena have been studied separately, neglecting any possible feedback or interaction. In this thesis we have investigated what is the interplay between these two processes. We show that the presence of a giant planet in a photo-evaporating disc can significantly shorten its lifetime, by cutting the inner regions from the mass reservoir in the exterior of the disc. This mechanism produces transition discs that for a given mass accretion rate have larger holes than in models considering only X-ray photo-evaporation, constituting a possible route to the formation of accreting transition discs with large holes. These discs are found in observations and still constitute a puzzle for the theory. Inclusion of the phenomenon called "thermal sweeping", a violent instability that can destroy a whole disc in as little as 10 4 years, shows that the outer disc left can be very short-lived (depending on the X-ray luminosity of the star), possibly explaining why very few non accreting transition discs are observed. However the mechanism does not seem to be efficient enough to reconcile with observations. In this thesis we also show that X-ray photo-evaporation naturally explains the observed correlation between stellar masses and accretion

  1. Automated kinematic modelling of warped galaxy discs in large H I surveys: 3D tilted-ring fitting of H I emission cubes

    NASA Astrophysics Data System (ADS)

    Kamphuis, P.; Józsa, G. I. G.; Oh, S.-. H.; Spekkens, K.; Urbancic, N.; Serra, P.; Koribalski, B. S.; Dettmar, R.-J.

    2015-09-01

    Kinematical parametrizations of disc galaxies, employing emission line observations, are indispensable tools for studying the formation and evolution of galaxies. Future large-scale H I surveys will resolve the discs of many thousands of galaxies, allowing a statistical analysis of their disc and halo kinematics, mass distribution and dark matter content. Here, we present an automated procedure which fits tilted-ring models to H I data cubes of individual, well-resolved galaxies. The method builds on the 3D Tilted Ring Fitting Code (TIRIFIC) and is called Fully Automated TIRIFIC (FAT). To assess the accuracy of the code, we apply it to a set of 52 artificial galaxies and 25 real galaxies from the Local Volume H I Survey (LVHIS). Using LVHIS data, we compare our 3D modelling to the 2D modelling methods DISKFIT and ROTCUR. A conservative result is that FAT accurately models the kinematics and the morphologies of galaxies with an extent of eight beams across the major axis in the inclination range 20°-90° without the need for priors such as disc inclination. When comparing to 2D methods we find that velocity fields cannot be used to determine inclinations in galaxies that are marginally resolved. We conclude that with the current code tilted-ring models can be produced in a fully automated fashion. This will be essential for future H I surveys, with the Square Kilometre Array and its pathfinders, which will allow us to model the gas kinematics of many thousands of well-resolved galaxies. Performance studies of FAT close to our conservative limits, as well as the introduction of more parametrized models will open up the possibility to study even less resolved galaxies.

  2. Lumbar disc herniation: Is there an association between histological and magnetic resonance imaging findings?

    PubMed Central

    Majeed, Shiju A; Seshadrinath, N Arun Kumar; Binoy, Kavitha Ravi; Raji, Laila

    2016-01-01

    Background: Although validated radiological scoring systems and histological scoring system of surgically removed degenerated disc are used in assessment of progression of intervertebral disc degeneration, there have not been many studies that integrate these two aspects of assessments. The data available in this respect are very limited. This clinical study was designed to find the correlation between quantitative radiological score (Pfirmann grading system and Modic changes [MC]) and quantitative histological degeneration score (HDS). Materials and Methods: A cohort of 77 patients (45 males, 32 females; mean age of 38 years [range 18–58 years]) who presented with complaints of discogenic pain or radiculopathy at single level were assessed radiologically. They were graded according to the radiological pattern. The surgically excised disc specimen was graded according to HDS. The degree of radiological changes were correlated with the degree of histological changes. Results: Though the overall HDS (0–15) did not show statistically significant correlation with Pfirmann grading system, there were positive association found between mucoid degeneration, chondrocyte proliferation with the Pfirmann grading and mucoid degeneration, which were statistically significant. Female sex also had a higher association with instability pattern. Conclusion: The study shows that the Pfirmann grading system, MCs and HDS can reliably be used as scoring systems for assessing lumbar disc degeneration. The radiological assessment can be used as a noninvasive tool to assess the probable change in content rather than the microstructure of a disc undergoing degeneration. PMID:27293282

  3. Inner retinal preservation in rat models of retinal degeneration implanted with subretinal photovoltaic arrays.

    PubMed

    Light, Jacob G; Fransen, James W; Adekunle, Adewumi N; Adkins, Alice; Pangeni, Gobinda; Loudin, James; Mathieson, Keith; Palanker, Daniel V; McCall, Maureen A; Pardue, Machelle T

    2014-11-01

    Photovoltaic arrays (PVA) implanted into the subretinal space of patients with retinitis pigmentosa (RP) are designed to electrically stimulate the remaining inner retinal circuitry in response to incident light, thereby recreating a visual signal when photoreceptor function declines or is lost. Preservation of inner retinal circuitry is critical to the fidelity of this transmitted signal to ganglion cells and beyond to higher visual targets. Post-implantation loss of retinal interneurons or excessive glial scarring could diminish and/or eliminate PVA-evoked signal transmission. As such, assessing the morphology of the inner retina in RP animal models with subretinal PVAs is an important step in defining biocompatibility and predicting success of signal transmission. In this study, we used immunohistochemical methods to qualitatively and quantitatively compare inner retinal morphology after the implantation of a PVA in two RP models: the Royal College of Surgeons (RCS) or transgenic S334ter-line 3 (S334ter-3) rhodopsin mutant rat. Two PVA designs were compared. In the RCS rat, we implanted devices in the subretinal space at 4 weeks of age and histologically examined them at 8 weeks of age and found inner retinal morphology preservation with both PVA devices. In the S334ter-3 rat, we implanted devices at 6-12 weeks of age and again, inner retinal morphology was generally preserved with either PVA design 16-26 weeks post-implantation. Specifically, the length of rod bipolar cells and numbers of cholinergic amacrine cells were maintained along with their characteristic inner plexiform lamination patterns. Throughout the implanted retinas we found nonspecific glial reaction, but none showed additional glial scarring at the implant site. Our results indicate that subretinally implanted PVAs are well-tolerated in rodent RP models and that the inner retinal circuitry is preserved, consistent with our published results showing implant-evoked signal transmission.

  4. Stress - Strain Response of the Human Spine Intervertebral Disc As an Anisotropic Body. Mathematical Modeling and Computation

    NASA Astrophysics Data System (ADS)

    Minárová, Mária; Sumec, Jozef

    2016-01-01

    The paper deals with the biomechanical investigation on the human lumbar intervertebral disc under the static load. The disc is regarded as a two - phased ambient consisting of a fibrous outer part called annulus fibrosis and a liquid inner part nucleus pulposus. Due to the fibrous structure, the annulus fibrosis can be treated by using a special case of anisotropy - transversal isotropy. In the paper the corresponding tensor of material constants is derived. The tensor consequently incomes to the constitutive equations determining the stress - strain relation in the material. In order to study the mechanical behaviour the disc is observed within the motion segment, the basic unit for motion tracing. The motion segment involves two neighbouring vertebrae and the intervertebral disc between them that connect them both. When constitutive equations are accomplished, they can be incorporated in the finite element analysis. The illustrative example of the intervertebral disc L2/L3, the disc between the second and the third lumbar vertebrae the lumbar part of spine, with its computer implementation is performed. Finally the comparison of the results of using anisotropic and homogenized approach is provided. The comparison illustrates the eligibility of such a kind of approach.

  5. FTY720 Attenuates 6-OHDA-Associated Dopaminergic Degeneration in Cellular and Mouse Parkinsonian Models.

    PubMed

    Ren, Manru; Han, Minxing; Wei, Xinbing; Guo, Ying; Shi, Huanying; Zhang, Xiumei; Perez, Ruth G; Lou, Haiyan

    2017-02-01

    FTY720 (fingolimod) is the first oral drug approved for treating relapsing-remitting forms of multiple sclerosis. It is also protective in other neurological models including ischemia, Alzheimer's disease, Huntington disease and Rett syndrome. However, whether it might protect in a 6-hydroxydopamine (6-OHDA) mouse model associated with the dopaminergic pathology of Parkinson's disease (PD), has not been explored. Therefore, in the present study, we investigated the effects of FTY720 on 6-OHDA-induced neurotoxicity in cell cultures and mice. Here we show that FTY720 protected against 6-OHDA cytotoxicity and apoptosis in SH-SY5Y cells. We also show that prior administration of FTY720 to 6-OHDA lesioned mice ameliorated both motor deficits and nigral dopaminergic neurotoxicity, while also reducing 6-OHDA-associated inflammation. The protective effects of FTY720 were associated with activation of AKT and ERK1/2 pro-survival pathways and an increase in brain derived neurotrophic factor (BDNF) expression in vitro and in vivo. These findings suggest that FTY720 holds promise as a PD therapeutic acting, at least in part, through AKT/ERK1/2/P-CREB-associated BDNF expression.

  6. Macular Degeneration: An Overview.

    ERIC Educational Resources Information Center

    Chalifoux, L. M.

    1991-01-01

    This article presents information on macular degeneration for professionals helping persons with this disease adjust to their visual loss. It covers types of macular degeneration, the etiology of the disease, and its treatment. Also considered are psychosocial problems and other difficulties that persons with age-related macular degeneration face.…

  7. Multiple Quantitative Trait Loci Modify Cochlear Hair Cell Degeneration in the Beethoven (Tmc1Bth) Mouse Model of Progressive Hearing Loss DFNA36

    PubMed Central

    Noguchi, Yoshihiro; Kurima, Kiyoto; Makishima, Tomoko; de Angelis, Martin Hrabé; Fuchs, Helmut; Frolenkov, Gregory; Kitamura, Ken; Griffith, Andrew J.

    2006-01-01

    Dominant mutations of transmembrane channel-like gene 1 (TMC1) cause progressive sensorineural hearing loss in humans and Beethoven (Tmc1Bth/+) mice. Here we show that Tmc1Bth/+ mice on a C3HeB/FeJ strain background have selective degeneration of inner hair cells while outer hair cells remain structurally and functionally intact. Inner hair cells primarily function as afferent sensory cells, whereas outer hair cells are electromotile amplifiers of auditory stimuli that can be functionally assessed by distortion product otoacoustic emission (DPOAE) analysis. When C3H-Tmc1Bth/Bth is crossed with either C57BL/6J or DBA/2J wild-type mice, F1 hybrid Tmc1Bth/+ progeny have increased hearing loss associated with increased degeneration of outer hair cells and diminution of DPOAE amplitudes but no difference in degeneration of inner hair cells. We mapped at least one quantitative trait locus (QTL), Tmc1m1, for DPOAE amplitude on chromosome 2 in [(C/B)F1 × C]N2-Tmc1Bth/+ backcross progeny, and three other QTL on chromosomes 11 (Tmc1m2), 12 (Tmc1m3), and 5 (Tmc1m4) in [(C/D)F1 × C]N2-Tmc1Bth/+ progeny. The polygenic basis of outer hair cell degeneration in Beethoven mice provides a model system for the dissection of common, complex hearing loss phenotypes, such as presbycusis, that involve outer hair cell degeneration in humans. PMID:16648588

  8. Multiple quantitative trait loci modify cochlear hair cell degeneration in the Beethoven (Tmc1Bth) mouse model of progressive hearing loss DFNA36.

    PubMed

    Noguchi, Yoshihiro; Kurima, Kiyoto; Makishima, Tomoko; de Angelis, Martin Hrabé; Fuchs, Helmut; Frolenkov, Gregory; Kitamura, Ken; Griffith, Andrew J

    2006-08-01

    Dominant mutations of transmembrane channel-like gene 1 (TMC1) cause progressive sensorineural hearing loss in humans and Beethoven (Tmc1Bth/+) mice. Here we show that Tmc1Bth/+ mice on a C3HeB/FeJ strain background have selective degeneration of inner hair cells while outer hair cells remain structurally and functionally intact. Inner hair cells primarily function as afferent sensory cells, whereas outer hair cells are electromotile amplifiers of auditory stimuli that can be functionally assessed by distortion product otoacoustic emission (DPOAE) analysis. When C3H-Tmc1Bth/Bth is crossed with either C57BL/6J or DBA/2J wild-type mice, F1 hybrid Tmc1Bth/+ progeny have increased hearing loss associated with increased degeneration of outer hair cells and diminution of DPOAE amplitudes but no difference in degeneration of inner hair cells. We mapped at least one quantitative trait locus (QTL), Tmc1m1, for DPOAE amplitude on chromosome 2 in [(C/B)F1xC]N2-Tmc1Bth/+ backcross progeny, and three other QTL on chromosomes 11 (Tmc1m2), 12 (Tmc1m3), and 5 (Tmc1m4) in [(C/D)F1xC]N2-Tmc1Bth/+ progeny. The polygenic basis of outer hair cell degeneration in Beethoven mice provides a model system for the dissection of common, complex hearing loss phenotypes, such as presbycusis, that involve outer hair cell degeneration in humans.

  9. Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration

    PubMed Central

    Garland, Donita L.; Fernandez-Godino, Rosario; Kaur, Inderjeet; Speicher, Kaye D.; Harnly, James M.; Lambris, John D.; Speicher, David W.; Pierce, Eric A.

    2014-01-01

    Macular degenerations, inherited and age related, are important causes of vision loss. Human genetic studies have suggested perturbation of the complement system is important in the pathogenesis of age-related macular degeneration. The mechanisms underlying the involvement of the complement system are not understood, although complement and inflammation have been implicated in drusen formation. Drusen are an early clinical hallmark of inherited and age-related forms of macular degeneration. We studied one of the earliest stages of macular degeneration which precedes and leads to the formation of drusen, i.e. the formation of basal deposits. The studies were done using a mouse model of the inherited macular dystrophy Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) which is caused by a p.Arg345Trp mutation in EFEMP1. The hallmark of DHRD/ML is the formation of drusen at an early age, and gene targeted Efemp1R345W/R345W mice develop extensive basal deposits. Proteomic analyses of Bruch's membrane/choroid and Bruch's membrane in the Efemp1R345W/R345W mice indicate that the basal deposits comprise normal extracellular matrix (ECM) components present in abnormal amounts. The proteomic analyses also identified significant changes in proteins with immune-related function, including complement components, in the diseased tissue samples. Genetic ablation of the complement response via generation of Efemp1R345W/R345W:C3−/− double-mutant mice inhibited the formation of basal deposits. The results demonstrate a critical role for the complement system in basal deposit formation, and suggest that complement-mediated recognition of abnormal ECM may participate in basal deposit formation in DHRD/ML and perhaps other macular degenerations. PMID:23943789

  10. Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration.

    PubMed

    Garland, Donita L; Fernandez-Godino, Rosario; Kaur, Inderjeet; Speicher, Kaye D; Harnly, James M; Lambris, John D; Speicher, David W; Pierce, Eric A

    2014-01-01

    Macular degenerations, inherited and age related, are important causes of vision loss. Human genetic studies have suggested perturbation of the complement system is important in the pathogenesis of age-related macular degeneration. The mechanisms underlying the involvement of the complement system are not understood, although complement and inflammation have been implicated in drusen formation. Drusen are an early clinical hallmark of inherited and age-related forms of macular degeneration. We studied one of the earliest stages of macular degeneration which precedes and leads to the formation of drusen, i.e. the formation of basal deposits. The studies were done using a mouse model of the inherited macular dystrophy Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) which is caused by a p.Arg345Trp mutation in EFEMP1. The hallmark of DHRD/ML is the formation of drusen at an early age, and gene targeted Efemp1(R345W/R345W) mice develop extensive basal deposits. Proteomic analyses of Bruch's membrane/choroid and Bruch's membrane in the Efemp1(R345W/R345W) mice indicate that the basal deposits comprise normal extracellular matrix (ECM) components present in abnormal amounts. The proteomic analyses also identified significant changes in proteins with immune-related function, including complement components, in the diseased tissue samples. Genetic ablation of the complement response via generation of Efemp1(R345W/R345W):C3(-/-) double-mutant mice inhibited the formation of basal deposits. The results demonstrate a critical role for the complement system in basal deposit formation, and suggest that complement-mediated recognition of abnormal ECM may participate in basal deposit formation in DHRD/ML and perhaps other macular degenerations.

  11. Exendin-4 Ameliorates Motor Neuron Degeneration in Cellular and Animal Models of Amyotrophic Lateral Sclerosis

    PubMed Central

    Li, Yazhou; Chigurupati, Srinivasulu; Holloway, Harold W.; Mughal, Mohamed; Tweedie, David; Bruestle, Daniel A.; Mattson, Mark P.; Wang, Yun; Harvey, Brandon K.; Ray, Balmiki; Lahiri, Debomoy K.; Greig, Nigel H.

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1), facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4) is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells) and in vivo (SOD1 G93A mutant mice) models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT) activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R) stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS. PMID:22384126

  12. Optical coherence tomography-guided retinal prosthesis design: model of degenerated retinal curvature and thickness for patient-specific devices.

    PubMed

    Opie, Nicholas L; Ayton, Lauren N; Apollo, Nicholas V; Ganesan, Kumaravelu; Guymer, Robyn H; Luu, Chi D

    2014-06-01

    Retinitis pigmentosa affects over 1.5 million people worldwide and is a leading cause of vision loss and blindness. While retinal prostheses have shown some success in restoring basic levels of vision, only generic, "one-size-fits-all" devices are currently being implanted. In this study, we used optical coherence tomography scans of the degenerated retina from 88 patients with retinitis pigmentosa to generate models of retinal thickness and curvature for the design of customized implants. We found the average retinal thickness at the fovea to be 152.9 ± 61.3 μm, increasing to a maximum retinal thickness of 250.9 ± 57.5 μm at a nasal eccentricity of 5°. These measures could be used to assist the development of custom-made penetrating electrodes to enhance and optimize epiretinal prostheses. From the retinal thickness measurements, we determined that the optimal length of penetrating electrodes to selectively stimulate retinal ganglion cell bodies and interneuron axons in the ganglion cell layer should be 30-100 μm, and to preferentially stimulate interneurons in the inner nuclear layer, electrodes should be 100-200 μm long. Electrodes greater than 200 μm long had the potential to penetrate through the retina into the choroid, which could cause devastating complications to the eye and should be avoided. The two- and three-dimensional models of retinal thickness developed in this study can be used to design patient-specific epiretinal implants that will help with safety and to optimize the efficacy of neuronal stimulation, ensuring the best functional performance of the device for patients.

  13. The high-throughput phenotyping of the viscoelastic behavior of whole mouse intervertebral discs using a novel method of dynamic mechanical testing.

    PubMed

    Liu, Jennifer W; Abraham, Adam C; Tang, Simon Y

    2015-07-16

    Intervertebral disc (IVD) degeneration is highly correlated with lower back pain, and thus understanding the mechanisms of IVD degeneration is critical for the treatment of this disease. Utilizing mouse models to probe the mechanisms of degeneration is especially attractive due to the ease of manipulating mouse models and the availability of transgenics. Yet characterizing the mechanical behavior of mice IVDs remain challenging due to their minute size (approximately 540 μm in height and 1080 μm(2) in cross sectional area). We have thus developed a simple method to dynamically characterize the mechanical properties of intact mouse IVDs. The IVDs were dissected with the endplates intact, and dynamically compressed in the axial direction at 1% and 5% peak strains at 1 Hz. Utilizing this novel approach, we examined the effects of in vitro ribosylation and trypsin digestion for 24 or 72 h on the viscoelastic behavior of the whole murine IVD. Trypsin treatment resulted in a decrease of proteoglycans and loss of disc height, while ribosylation had no effect on structure or proteoglycan composition. The 72 h ribosylation group exhibited a stiffening of the disc, and both treatments significantly reduced viscous behavior of the IVDs, with the effects being more pronounced at 5% strain. Here we demonstrate a novel high-throughput method to mechanically characterize murine IVDs and detect strain-dependent differences in the elastic and the viscous behavior of the treated IVDs due to ribose and trypsin treatments.

  14. Characterisation of a C1qtnf5 Ser163Arg Knock-In Mouse Model of Late-Onset Retinal Macular Degeneration

    PubMed Central

    Shu, Xinhua; Luhmann, Ulrich F. O.; Aleman, Tomas S.; Barker, Susan E.; Lennon, Alan; Tulloch, Brian; Chen, Mei; Xu, Heping; Jacobson, Samuel G.; Ali, Robin; Wright, Alan F.

    2011-01-01

    A single founder mutation resulting in a Ser163Arg substitution in the C1QTNF5 gene product causes autosomal dominant late-onset retinal macular degeneration (L-ORMD) in humans, which has clinical and pathological features resembling age-related macular degeneration. We generated and characterised a mouse “knock-in” model carrying the Ser163Arg mutation in the orthologous murine C1qtnf5 gene by site-directed mutagenesis and homologous recombination into mouse embryonic stem cells. Biochemical, immunological, electron microscopic, fundus autofluorescence, electroretinography and laser photocoagulation analyses were used to characterise the mouse model. Heterozygous and homozygous knock-in mice showed no significant abnormality in any of the above measures at time points up to 2 years. This result contrasts with another C1qtnf5 Ser163Arg knock-in mouse which showed most of the features of L-ORMD but differed in genetic background and targeting construct. PMID:22110650

  15. Characterisation of a C1qtnf5 Ser163Arg knock-in mouse model of late-onset retinal macular degeneration.

    PubMed

    Shu, Xinhua; Luhmann, Ulrich F O; Aleman, Tomas S; Barker, Susan E; Lennon, Alan; Tulloch, Brian; Chen, Mei; Xu, Heping; Jacobson, Samuel G; Ali, Robin; Wright, Alan F

    2011-01-01

    A single founder mutation resulting in a Ser163Arg substitution in the C1QTNF5 gene product causes autosomal dominant late-onset retinal macular degeneration (L-ORMD) in humans, which has clinical and pathological features resembling age-related macular degeneration. We generated and characterised a mouse "knock-in" model carrying the Ser163Arg mutation in the orthologous murine C1qtnf5 gene by site-directed mutagenesis and homologous recombination into mouse embryonic stem cells. Biochemical, immunological, electron microscopic, fundus autofluorescence, electroretinography and laser photocoagulation analyses were used to characterise the mouse model. Heterozygous and homozygous knock-in mice showed no significant abnormality in any of the above measures at time points up to 2 years. This result contrasts with another C1qtnf5 Ser163Arg knock-in mouse which showed most of the features of L-ORMD but differed in genetic background and targeting construct.

  16. Do clones degenerate over time? Explaining the genetic variability of asexuals through population genetic models

    PubMed Central

    2011-01-01

    Background Quest for understanding the nature of mechanisms governing the life span of clonal organisms lasts for several decades. Phylogenetic evidence for recent origins of most clones is usually interpreted as proof that clones suffer from gradual age-dependent fitness decay (e.g. Muller's ratchet). However, we have shown that a neutral drift can also qualitatively explain the observed distribution of clonal ages. This finding was followed by several attempts to distinguish the effects of neutral and non-neutral processes. Most recently, Neiman et al. 2009 (Ann N Y Acad Sci.:1168:185-200.) reviewed the distribution of asexual lineage ages estimated from a diverse array of taxa and concluded that neutral processes alone may not explain the observed data. Moreover, the authors inferred that similar types of mechanisms determine maximum asexual lineage ages in all asexual taxa. In this paper we review recent methods for distinguishing the effects of neutral and non-neutral processes and point at methodological problems related with them. Results and Discussion We found that contemporary analyses based on phylogenetic data are inadequate to provide any clear-cut answer about the nature and generality of processes affecting evolution of clones. As an alternative approach, we demonstrate that sequence variability in asexual populations is suitable to detect age-dependent selection against clonal lineages. We found that asexual taxa with relatively old clonal lineages are characterised by progressively stronger deviations from neutrality. Conclusions Our results demonstrate that some type of age-dependent selection against clones is generally operational in asexual animals, which cover a wide taxonomic range spanning from flatworms to vertebrates. However, we also found a notable difference between the data distribution predicted by available models of sequence evolution and those observed in empirical data. These findings point at the possibility that processes

  17. Radiologic Evaluation of Degeneration in Isthmic and Degenerative Spondylolisthesis

    PubMed Central

    Jeong, Hyun-Yoon; Sohn, Hong-Moon; Park, Sang-Ha

    2013-01-01

    Study Design A cross-sectional imaging study. Purpose The objective was to assess the degree of degeneration and the associated factors through imaging studies of the lesion segment and the adjacent superior and inferior segments of isthmic and degenerative spondylolisthesis. Overview of Literature Few articles existed for degeneration and related factors in isthmic and degenerative spondylolisthesis. Methods The subjects were 95 patients diagnosed with spondylolisthesis. Simple plain radiographs including flexion and extension and magnetic resonance imaging were used to investigate the degree of translation, disc degeneration, high intensity zone (HIZ) lesion, Schmorl's node (SN) and Modic changes. Results Advanced disc degeneration, grade 5, was shown to be significant in the index segment of the isthmic type (p=0.034). Overall, type 2 Modic change was most common in both groups and also, it was observed more in the isthmus group, specifically, the index segment compared to the degenerative group (p=0.03). For the SN, compared to the degenerative type, the isthmus type had a significantly high occurrence in the index segment (p=0.04). For the HIZ lesions, the isthmus type had a higher occurrence than the degenerative type, especially in the upper segment (p=0.03). Conclusions Most advanced disc degeneration, fifth degree, SN and Modic change occurred more frequently in the lesions of the isthmus type. HIZ lesions were observed more in the isthmus type, especially in the segment superior to the lesion. PMID:23508359

  18. Mathematical glimpse on the Y chromosome degeneration

    NASA Astrophysics Data System (ADS)

    Lobo, M. P.

    2006-04-01

    The Y chromosomes are genetically degenerate and do not recombine with their matching partners X. Non-recombination of XY pairs has been pointed out as the key factor for the degeneration of the Y chromosome. The aim here is to show that there is a mathematical asymmetry in sex chromosomes which leads to the degeneration of Y chromosomes even in the absence of XX and XY recombination. A model for sex-chromosome evolution in a stationary regime is proposed. The consequences of their asymmetry are analyzed and lead us to a couple of conclusions. First, Y chromosome degeneration shows up sqrt{2} more often than X chromosome degeneration. Second, if nature prohibits female mortalities from beeing exactly 50%, then Y chromosome degeneration is inevitable.

  19. Early dysfunction and progressive degeneration of the subthalamic nucleus in mouse models of Huntington's disease

    PubMed Central

    Atherton, Jeremy F; McIver, Eileen L; Mullen, Matthew RM; Wokosin, David L; Surmeier, D James; Bevan, Mark D

    2016-01-01

    The subthalamic nucleus (STN) is an element of cortico-basal ganglia-thalamo-cortical circuitry critical for action suppression. In Huntington's disease (HD) action suppression is impaired, resembling the effects of STN lesioning or inactivation. To explore this potential linkage, the STN was studied in BAC transgenic and Q175 knock-in mouse models of HD. At <2 and 6 months of age autonomous STN activity was impaired due to activation of KATP channels. STN neurons exhibited prolonged NMDA receptor-mediated synaptic currents, caused by a deficit in glutamate uptake, and elevated mitochondrial oxidant stress, which was ameliorated by NMDA receptor antagonism. STN activity was rescued by NMDA receptor antagonism or the break down of hydrogen peroxide. At 12 months of age approximately 30% of STN neurons had been lost, as in HD. Together, these data argue that dysfunction within the STN is an early feature of HD that may contribute to its expression and course. DOI: http://dx.doi.org/10.7554/eLife.21616.001 PMID:27995895

  20. Peritendinous elastase treatment induces tendon degeneration in rats: A potential model of tendinopathy in vivo.

    PubMed

    Wu, Yen-Ting; Wu, Po-Ting; Jou, I-Ming

    2016-03-01

    The purpose of this study was to investigate the role of elastase on tendinopathy, as well as to evaluate the potential for peritendinous injections of elastase into rats to cause tendinopathy. We first investigated the expression of elastase in the tendons of patients with tendinopathy, and then established the effects of elastase injection on the Achilles tendons of rats. Ultrasonographic and incapacitance testing was used to conduct tests for 8 weeks. Tendon tissues were collected for histological observation and protein levels of collagen type I and type III were detected using Western blotting. The percentage of elastase-positive cells increased in human specimens with grades II and III tendinopathy. The rat model demonstrated that the thickness of the tendon increased after elastase injection during Week 2-8. Hypercellularity and focal lesions were detected after Week 2. The expression of elastase was increased and elastin was decreased in Week 8. Collagen type I expression was decreased, but type III was increased in Week 4. These results suggested that elastase may be involved in the development of chronic tendinopathy, and that peritendinous injection of elastase may result in tendinopathy in rats.

  1. MECHANICAL DESIGN CRITERIA FOR INTERVERTEBRAL DISC TISSUE ENGINEERING

    PubMed Central

    Nerurkar, Nandan L.; Elliott, Dawn M.; Mauck, Robert L.

    2009-01-01

    Due to the inability of current clinical practices to restore function to degenerated intervertebral discs, the arena of disc tissue engineering has received substantial attention in recent years. Despite tremendous growth and progress in this field, translation to clinical implementation has been hindered by a lack of well-defined functional benchmarks. Because successful replacement of the disc is contingent upon replication of some or all of its complex mechanical behaviour, it is critically important that disc mechanics be well characterized in order to establish discrete functional goals for tissue engineering. In this review, the key functional signatures of the intervertebral disc are discussed and used to propose a series of native tissue benchmarks to guide the development of engineered replacement tissues. These benchmarks include measures of mechanical function under tensile, compressive and shear deformations for the disc and its substructures. In some cases, important functional measures are identified that have yet to be measured in the native tissue. Ultimately, native tissue benchmark values are compared to measurements that have been made on engineered disc tissues, identifying measures where functional equivalence was achieved, and others where there remain opportunities for advancement. Several excellent reviews exist regarding disc composition and structure, as well as recent tissue engineering strategies; therefore this review will remain focused on the functional aspects of disc tissue engineering. PMID:20080239

  2. Structure formation through self-gravitational instability in degenerate and non-degenerate anisotropic magnetized plasma

    NASA Astrophysics Data System (ADS)

    Sharma, Prerana

    2017-04-01

    The self-gravitational instability is examined for non-degenerate and degenerate magnetized plasma. In the case of non-degenerate collisionless magnetized plasma the pressure is considered as anisotropic while in the case of degenerate situations it is taken as isotropic. The effect of finite Larmor radius correction of non-degenerate ions and viscous dissipation is taken into account in both the cases. Firstly in non-degenerate anisotropic plasma the conventional magnetohydrodynamic model is used to construct basic set of equations within the framework of modified Chew-Goldberger and Low theory. Secondly, in the case of degenerate isotropic plasma, which is considered to be composed of degenerate electrons and non-degenerate ions, the model equations are constructed using quantum magneto hydrodynamic model. The dynamics of degenerate particles are governed by Bohm and exchange potentials. The general dispersion relations are derived for both degenerate and non-degenerate situations separately using linearized perturbation equations. The results are discussed analytically and numerically for various modes of propagation. In case of non degenerate strongly magnetized plasma the effects of stress tensor anisotropy dominate over the influence of FLR effects while the FLR effects prevail in the weak magnetic field region. In case of isotropic degenerate plasma the implications of exchange parameter on the Jeans mass have been estimated and it is found that the increase in exchange parameter increases the limit of Jeans mass. The Jeans length and Jeans mass have been estimated for the white dwarf stars as LJ ≈ 2.1 × 10^{11} m and MJ ≈ 5 × 10^{39} kg respectively assist the existence of super Chandrasekhar white dwarfs.

  3. Comparative analysis of the influence of Fructus Ligustri Lucidi on a rat lumbar disc herniation model.

    PubMed

    Han, Ya-Xin; Liang, Dong; Han, Xiao-Rui; Liang, De-Yong

    2015-07-01

    Lumbar disc herniation (LDH) is a term used for a group of conditions, including back pain, femoral nerve pain and sciatica. Currently available treatments and surgical options are insufficient for patients with LDH. Fructus Ligustri Lucidi (FLL) is a herb that is used for treating age-associated diseases. The results of the present study suggested that FLL may be used for treatment of patients with LDH. In the present study, matrix metalloproteinase-1, -3, -8 and -9 (MMP-1, -3, -8 and -9) protein and mRNA expression downregulation was observed in patients with LDH according to western blotting and reverse transcription-quantitative polymerase chain reaction. By contrast, upregulation of interleukin-2 (IL-2), IL-6, IL-8 and tumor necrosis factor-α (TNF-α) expression was observed in patients with LDH, according to an enzyme-linked immunosorbent assay. Mechanical allodynia was observed in rats with LDH not treated with FLL; however, not in FLL‑treated rats. IL-2, IL-6, IL-8 and TNF-α expression levels in the serum from untreated rats were significantly higher than that of the FLL‑treated rat models. Protein expression levels of MMPs in FLL-treated rats were lower than those in untreated rats. However, the mechanisms underlying the association between FLL and protein expression levels require further investigation.

  4. Functional connectivity modeling of consistent cortico-striatal degeneration in Huntington's disease

    PubMed Central

    Dogan, Imis; Eickhoff, Claudia R.; Fox, Peter T.; Laird, Angela R.; Schulz, Jörg B.; Eickhoff, Simon B.; Reetz, Kathrin

    2015-01-01

    Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by a complex neuropsychiatric phenotype. In a recent meta-analysis we identified core regions of consistent neurodegeneration in premanifest HD in the striatum and middle occipital gyrus (MOG). For early manifest HD convergent evidence of atrophy was most prominent in the striatum, motor cortex (M1) and inferior frontal junction (IFJ). The aim of the present study was to functionally characterize this topography of brain atrophy and to investigate differential connectivity patterns formed by consistent cortico-striatal atrophy regions in HD. Using areas of striatal and cortical atrophy at different disease stages as seeds, we performed task-free resting-state and task-based meta-analytic connectivity modeling (MACM). MACM utilizes the large data source of the BrainMap database and identifies significant areas of above-chance co-activation with the seed-region via the activation-likelihood-estimation approach. In order to delineate functional networks formed by cortical as well as striatal atrophy regions we computed the conjunction between the co-activation profiles of striatal and cortical seeds in the premanifest and manifest stages of HD, respectively. Functional characterization of the seeds was obtained using the behavioral meta-data of BrainMap. Cortico-striatal atrophy seeds of the premanifest stage of HD showed common co-activation with a rather cognitive network including the striatum, anterior insula, lateral prefrontal, premotor, supplementary motor and parietal regions. A similar but more pronounced co-activation pattern, additionally including the medial prefrontal cortex and thalamic nuclei was found with striatal and IFJ seeds at the manifest HD stage. The striatum and M1 were functionally connected mainly to premotor and sensorimotor areas, posterior insula, putamen and thalamus. Behavioral characterization of the seeds confirmed that experiments activating the MOG

  5. Accretion Discs Show Their True Colours

    NASA Astrophysics Data System (ADS)

    2008-07-01

    Quasars are the brilliant cores of remote galaxies, at the hearts of which lie supermassive black holes that can generate enough power to outshine the Sun a trillion times. These mighty power sources are fuelled by interstellar gas, thought to be sucked into the hole from a surrounding 'accretion disc'. A paper in this week's issue of the journal Nature, partly based on observations collected with ESO's Very Large Telescope, verifies a long-standing prediction about the intensely luminous radiation emitted by these accretion discs. Uncovering the disc ESO PR Photo 21/08 Uncovering the inner disc "Astronomers were puzzled by the fact that the best models of these discs couldn't quite be reconciled with some of the observations, in particular, with the fact that these discs did not appear as blue as they should be," explains lead-author Makoto Kishimoto. Such a discrepancy could be the signal that there was something very wrong with the models. With his colleagues, he investigated this discrepancy by studying the polarised light from six quasars. This enabled them to demonstrate that the disc spectrum is as blue as predicted. "The crucial observational difficulty here has been that the disc is surrounded by a much larger torus containing hot dust, whose light partly outshines that of the disc," says Kishimoto. "Because the light coming from the disc is scattered in the disc vicinity and thus polarised, by observing only polarised light from the quasars, one can uncover the buried light from the disc." In a similar way that a fisherman would wear polarised sunglasses to help get rid of the glare from the water surface and allow him to see more clearly under the water, the filter on the telescope allowed the astronomers to see beyond surrounding clouds of dust and gas to the blue colour of the disc in infrared light. The observations were done with the FORS and ISAAC instruments on one of the 8.2-m Unit Telescopes of ESO's Very Large Telescope, located in the Atacama

  6. Apparent diffusion coefficient in normal and abnormal pattern of intervertebral lumbar discs: initial experience☆

    PubMed Central

    Niu, Gang; Yu, Xuewen; Yang, Jian; Wang, Rong; Zhang, Shaojuan; Guo, Youmin

    2011-01-01

    The aim of the present study was to compare the relationship of morphologically defined non-bulging/herniated, bulging and herniated intervertebral lumbar discs with quantitative apparent diffusion coefficient (ADC). Thirty-two healthy volunteers and 28 patients with back pain or sciatica were examined by MRI. All intervertebral lumbar discs from L1 to S1 were classified according to morphological abnormality and degenerated grades. The ADC values of nucleus pulposus (NP) were measured and recorded. The significant differences about mean ADC values of NP were found between non-bulging/herniated discs and bulging discs as well as herniated discs (P < 0.05), whereas there were no significant differences in ADC values between bulging and herniated discs (P > 0.05). Moreover, statistically significant relationship was found in the mean ADC values of NP between “non-bulging/herniated and non-degenerated discs” and “non-bulging/herniated degenerated discs” as well as herniated discs (P < 0.05). Linear regression analysis between ADC value and disc level revealed an inverse correlation (r = -0.18). The ADC map of the NP is a potentially useful tool for the quantitative assessment of componential and molecular alterations accompanied with lumbar disc abnormalities. PMID:23554690

  7. Turbine disc sealing assembly

    DOEpatents

    Diakunchak, Ihor S.

    2013-03-05

    A disc seal assembly for use in a turbine engine. The disc seal assembly includes a plurality of outwardly extending sealing flange members that define a plurality of fluid pockets. The sealing flange members define a labyrinth flow path therebetween to limit leakage between a hot gas path and a disc cavity in the turbine engine.

  8. Inclusion of regional poroelastic material properties better predicts biomechanical behavior of lumbar discs subjected to dynamic loading.

    PubMed

    Williams, Jamie R; Natarajan, Raghu N; Andersson, Gunnar B J

    2007-01-01

    Understanding the relationship between repetitive lifting and the breakdown of disc tissue over several years of exposure is difficult to study in vivo and in vitro. The aim of this investigation was to develop a three-dimensional poroelastic finite element model of a lumbar motion segment that reflects the biological properties and behaviors of in vivo disc tissues including swelling pressure due to the proteoglycans and strain-dependent permeability and porosity. It was hypothesized that when modeling the annulus, prescribing tissue specific material properties will not be adequate for studying the in vivo loading and unloading behavior of the disc. Rather, regional variations of these properties, which are known to exist within the annulus, must also be included. Finite element predictions were compared to in vivo measurements published by Tyrrell et al. (1985) of percent change in total stature for two loading protocols, short-term creep loading and standing recovery and short-term cyclic loading with standing recovery. The model in which the regional variations of material properties in the annulus had been included provided an overall better prediction of the in vivo behavior as compared to the model in which the annulus properties were assumed to be homogenous. This model will now be used to study the relationship between repetitive lifting and disc degeneration.

  9. Design concepts in lumbar total disc arthroplasty

    PubMed Central

    Bellini, Chiara M.; Zweig, Thomas; Ferguson, Stephen; Raimondi, Manuela T.; Lamartina, Claudio; Brayda-Bruno, Marco; Fornari, Maurizio

    2008-01-01

    The implantation of lumbar disc prostheses based on different design concepts is widely accepted. This paper reviews currently available literature studies on the biomechanics of TDA in the lumbar spine, and is targeted at the evaluation of possible relationships between the aims of TDA and the geometrical, mechanical and material properties of the various available disc prostheses. Both theoretical and experimental studies were analyzed, by a PUBMED search (performed in February 2007, revised in January 2008), focusing on single level TDA. Both semi-constrained and unconstrained lumbar discs seem to be able to restore nearly physiological IAR locations and ROM values. However, both increased and decreased ROM was stated in some papers, unrelated to the clinical outcome. Segmental lordosis alterations after TDA were reported in most cases, for both constrained and unconstrained disc prostheses. An increase in the load through the facet joints was documented, for both semi-constrained and unconstrained artificial discs, but with some contrasting results. Semi-constrained devices may be able to share a greater part of the load, thus protecting the surrounding biological structure from overloading and possible early degeneration, but may be more susceptible to wear. The next level of development will be the biomechanical integration of compression across the motion segment. All these findings need to be supported by long-term clinical outcome studies. PMID:18946684

  10. Severe motor neuron degeneration in the spinal cord of the Tg2576 mouse model of Alzheimer disease.

    PubMed

    Seo, Ji-Seon; Leem, Yea-Hyun; Lee, Kang-Woo; Kim, Seung-Woo; Lee, Ja-Kyeong; Han, Pyung-Lim

    2010-01-01

    The transgenic mouse Tg2576 is widely used as a murine model of Alzheimer's disease (AD) and exhibits plaque pathogenesis in the brain and progressive memory impairments. Here we report that Tg2576 mice also have severe spinal cord deficits. At 10 months of age, Tg2576 mice showed a severe defect in the hindlimb extension reflex test and abnormal body trembling and hindlimb tremors when suspended by the tail. The frequency and severity of these abnormalities were overt at 10 months of age and became gradually worsened. On the foot-printing analysis, Tg2576 mice had shorter and narrower strides than the non-transgenic control. Histological analyses showed that neuronal cells including cholinergic neurons in the lumbar cord of Tg2576 mice were severely reduced in number. At 16 months of age, Tg2576 mice showed high levels of amyloid-beta accumulation in the spinal cord. Consistent with this, Tg2576 mice showed that lipid peroxidation levels were increased and mitochondrial metabolic activity were significantly reduced in the spinal cord. Administration of curcumin, a natural compound that has antioxidant properties, notably reversed motor function deficits of Tg2576 mice. The enhanced lipid peroxidation and neuronal loss in the lumbar cord was also partially suppressed by curcumin. Electron microscopic analysis revealed that the sciatic nerve fibers were severely reduced in number and were demyelinated in Tg2576 mice, which were partially rescued by curcumin. These results showed that Tg2576 mice display severe degeneration of motor neurons in the spinal cord and associated motor function deficits.

  11. miR-126 Regulation of Angiogenesis in Age-Related Macular Degeneration in CNV Mouse Model

    PubMed Central

    Wang, Lei; Lee, Amy Yi Wei; Wigg, Jonathan P.; Peshavariya, Hitesh; Liu, Ping; Zhang, Hong

    2016-01-01

    miR-126 has recently been implicated in modulating angiogenic factors in vascular development. Understandings its biological significance might enable development of therapeutic interventions for diseases like age-related macular degeneration (AMD). We aimed to determine the role of miR-126 in AMD using a laser-induced choroidal neovascularization (CNV) mouse model. CNV was induced by laser photocoagulation in C57BL/6 mice. The CNV mice were transfected with scrambled miR or miR-126 mimic. The expression of miR-126, vascular endothelial growth factor-A (VEGF-A), Kinase insert domain receptor (KDR) and Sprouty-related EVH1 domain-containing protein 1 (SPRED-1) in ocular tissues were analyzed by qPCR and Western blot. The overexpression effects of miR-126 were also proven on human microvascular endothelial cells (HMECs). miR-126 showed a significant decrease in CNV mice (p < 0.05). Both mRNA and protein levels of VEGF-A, KDR and SPRED-1 were upregulated with CNV; these changes were ameliorated by restoration of miR-126 (p < 0.05). CNV was reduced after miR-126 transfection. Transfection of miR-126 reduced the HMECs 2D-capillary-like tube formation (p < 0.01) and migration (p < 0.01). miR-126 has been shown to be a negative modulator of angiogenesis in the eye. All together these results high lights the therapeutic potential of miR-126 suggests that it may contribute as a putative therapeutic target for AMD in humans. PMID:27338342

  12. N-methyl-N-nitrosourea-induced neuronal cell death in a large animal model of retinal degeneration in vitro.

    PubMed

    Taylor, Linnéa; Arnér, Karin; Ghosh, Fredrik

    2016-07-01

    N-methyl-N-nitrosourea (MNU) has been reported to induce photoreceptor-specific degeneration with minimal inner retinal impact in small animals in vivo. Pending its use within a retinal transplantation paradigm, we here explore the effects of MNU on outer and inner retinal neurons and glia in an in vitro large animal model of retinal degeneration. The previously described degenerative culture explant model of adult porcine retina was used and compared with explants receiving 10 or 100 μg/ml MNU (MNU10 and MNU100) supplementation. All explants were kept for 5 days in vitro, and examined for morphology as well as for glial and neuronal immunohistochemical markers. Rhodopsin-labeled photoreceptors were present in all explants. The number of cone photoreceptors (transducin), rod bipolar cells (PKC) and horizontal cells (calbindin) was significantly lower in MNU treated explants (p < 0.001). Gliosis was attenuated in MNU10 treated explants, with expression of vimentin, glial fibrillary protein (GFAP), glutamine synthetase (GS), and bFGF comparable to in vivo controls. In corresponding MNU100 counterparts, the expression of Müller cell proteins was almost extinguished. We here show that MNU causes degeneration of outer and inner retinal neurons and glia in the adult porcine retina in vitro. MNU10 explants display attenuation of gliosis, despite decreased neuronal survival compared with untreated controls. Our results have impact on the use of MNU as a large animal photoreceptor degeneration model, on tissue engineering related to retinal transplantation, and on our understanding of gliosis related neuronal degenerative cell death.

  13. The implantation of non-cell-based materials to prevent the recurrent disc herniation: an in vivo porcine model using quantitative discomanometry examination

    PubMed Central

    Wang, Yao-Hung; Kuo, Tzong-Fu

    2007-01-01

    Recurrent disc herniation is frequently observed due to leakage of nucleus pulposus through injured anulus fibrosus. There is no effective treatment to prevent recurrent disc herniation yet. In this study, we proposed to implant non-cell-based materials into the porcine disc to stimulate the growth of fibrous tissue and thereby increase the disc functional integrity. The disc herniation was simulated by anular punctures using the spinal needles. Four clinically used implantation materials, i.e., gelfoam, platinum coil, bone cement and tissue glue, were delivered into the discs via percutaneous spinal needles. Two months after the surgery, the swine were killed. The degree of disc integrity of intact, naturally healed and implanted discs, was examined by quantitative discomanometry apparatus. We found the disc injury could not recover after 2 months of healing, and the disc implantation affected the degree of disc integrity. The disc integrity of gelfoam-implanted discs was better than that of coil-, bone cement-, and glue-implanted discs. The implantation of non-cell-based material was proved to be a potentially clinically applicable method to recover the integrity of injured discs and to prevent recurrent disc herniation. PMID:17252217

  14. Axonal degeneration, distal collateral branching and neuromuscular junction architecture alterations occur prior to symptom onset in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.

    PubMed

    Clark, Jayden A; Southam, Katherine A; Blizzard, Catherine A; King, Anna E; Dickson, Tracey C

    2016-10-01

    Degeneration of the distal axon and neuromuscular junction (NMJ) is considered a key and early feature of the pathology that accompanies motor neuron loss in people with amyotrophic lateral sclerosis (ALS). The mutant SOD1(G93A) mouse replicates many features of the disease, however the sequence of events resulting in degeneration of the neuromuscular circuitry remains unknown. Furthermore, despite widespread degenerative neuronal pathology throughout the spinal cord in this model, hindlimb motor function is lost before forelimb function. We investigated axons and NMJs in the hindlimb (gastrocnemius) and forelimb (extensor) muscles in the high copy number mutant SOD1(G93A)xYFP (yellow fluorescent protein) mouse. We found that distal axonal and NMJ alterations were present prior to previously reported functional symptom onset in this strain. Indeed, increased branch complexity as well as colocalisation between pre- and post-synaptic markers indicated widespread early axonal and NMJ alterations in the hindlimb. Immunohistochemical analysis demonstrated that the colocalisation of the scaffolding proteins nestin, LRP-4, dystrophin and rapsyn were diminished before post-synaptic receptors in the gastrocnemius, and the degree of loss differed between proteins. Analysis of the forelimb muscle revealed axonal and NMJ degeneration at a late, post symptomatic stage, as well as novel differences in NMJ morphology, with reduced complexity. Furthermore, post-synaptic scaffolding proteins were preserved in the forelimb compared with the hindlimb. Analysis of protein levels indicated an increase in LRP-4, dystrophin and rapsyn in post symptomatic skeletal muscle that may suggest ongoing attempts at repair. This study indicates that axonal and NMJ