Cascade Of Degeneration Research Articles

The relevance of high-intensity zones in degenerative disc disease.

The purpose of this study was to review the current understanding of high-intensity zones (HIZ) in the lumbar spine with particular attention to its imaging phenotype and clinical relevance. A review was conducted of studies related to HIZ. Particular attention was made to imaging phenotypes and classification, and its relationship with discogenic low back pain (LBP). The most current classification system of HIZ is based on location (anterior and posterior), morphology (round, fissure, vertical, rim, or giant types), and its appearance on both T1- and T2-weighted magnetic resonance imaging (MRI). HIZ are commonly manifested with disc degeneration. Hence, both conditions share similar risk factors such as the effect of frequent and prolonged disc loading. The clinical significance of HIZ however is not conclusive. Provocative discography is not sensitive (~ 70%) for eliciting a concordant pain response. Population-based studies have conflicting results regarding the prevalence (14-63%) of HIZ and its correlation with LBP. HIZ are likely a risk factor for discogenic LBP. However, its etiology and pathophysiology are not well understood. Some clinical studies suggest a link between its occurrence and LBP. However, the results are not consistent as a result of studies which are underpowered and based on heterogeneous study populations, lacking control groups, and without standardized imaging phenotypes. HIZ may be an important pain biomarker that should be further studied. With more modern MRI technology and a detailed classification system, future large-scale population studies will improve our knowledge on its role in the disc degeneration cascade and development of LBP.

Axonal degeneration induced by glutamate excitotoxicity is mediated by necroptosis.

Neuronal excitotoxicity induced by glutamate leads to cell death and functional impairment in a variety of central nervous system pathologies. Glutamate-mediated excitotoxicity triggers neuronal apoptosis in the cell soma as well as degeneration of axons and dendrites by a process associated with Ca2+ increase and mitochondrial dysfunction. Importantly, degeneration of axons initiated by diverse stimuli, including excitotoxicity, has been proposed as an important pathological event leading to functional impairment in neurodegenerative conditions. Here, we demonstrate that excitotoxicity-induced axonal degeneration proceeds by a mechanism dependent on the necroptotic kinases RIPK1 and RIPK3, and the necroptotic mediator MLKL. Inhibition of RIPK1, RIPK3 or MLKL prevents key steps in the axonal degeneration cascade, including mitochondrial depolarization, the opening of the permeability transition pore and Ca2+ dysregulation in the axon. Interestingly, the same excitotoxic stimuli lead to apoptosis in the cell soma, demonstrating the co-activation of two independent degenerative mechanisms in different compartments of the same cell. The identification of necroptosis as a key mechanism of axonal degeneration after excitotoxicity is an important initial step in the development of novel therapeutic strategies for nervous system disorders.

Osteoarthritis and intervertebral disc degeneration: Quite different, quite similar.

Intervertebral disc degeneration describes the vicious cycle of the deterioration of intervertebral discs and can eventually result in degenerative disc disease (DDD), which is accompanied by low‐back pain, the musculoskeletal disorder with the largest socioeconomic impact world‐wide. In more severe stages, intervertebral disc degeneration is accompanied by loss of joint space, subchondral sclerosis, and osteophytes, similar to osteoarthritis (OA) in the articular joint. Inspired by this resemblance, we investigated the analogy between human intervertebral discs and articular joints. Although embryonic origin and anatomy suggest substantial differences between the two types of joint, some features of cell physiology and extracellular matrix in the nucleus pulposus and articular cartilage share numerous parallels. Moreover, there are great similarities in the response to mechanical loading and the matrix‐degrading factors involved in the cascade of degeneration in both tissues. This suggests that the local environment of the cell is more important to its behavior than embryonic origin. Nevertheless, OA is widely regarded as a true disease, while intervertebral disc degeneration is often regarded as a radiological finding and DDD is undervalued as a cause of chronic low‐back pain by clinicians, patients and society. Emphasizing the similarities rather than the differences between the two diseases may create more awareness in the clinic, improve diagnostics in DDD, and provide cross‐fertilization of clinicians and scientists involved in both intervertebral disc degeneration and OA.

A Microstructural Investigation of Disc Disruption Induced by Low Frequency Cyclic Loading.

Microstructural investigation of low frequency cyclic loading and flexing of the lumbar disc. To explore micro-level structural damage in motion segments subjected to low frequency repetitive loading and flexing at sub-acute loads. Cumulative exposure to mechanical load has been implicated in low back pain and injury. The mechanical pathways by which cyclic loading physically affects spine tissues remain unclear, in part due to the absence of high quality microstructural evidence. The study utilized seven intact ovine lumbar spines and from each spine one motion segment was used as a control, two others were cyclically loaded. Ten motion segments were subjected to 5000 cycles at 0.5 Hz with a peak load corresponding to ∼30% of that required to achieve failure. An additional small group of segments subjected to 10,000 or 30,000 cycles was similarly analyzed. Following chemical fixation and decalcification samples were cryosectioned along one of the oblique fiber angles and imaged in their fully hydrated state using differential interference contrast optical microscopy. Structural damage obtained from the images was organized into an algebraic shell for analysis. At 5000 cycles the disc damage was limited to inner wall distortions, evidence of stress concentrations at bridging-lamellae attachments, and small delaminations. The high-cycle discs tested exhibited significant mid-wall damage. There was no evidence of nuclear material being displaced. At this low frequency and without the application of sustained loading or a more severe loading regime, or maintaining a constant flexion with repetitive loading, it seems unlikely that actual nuclear migration occurs. It is possible that the inner-annular damage shown in the low dose group could disrupt pathways for nutrient diffusion leading to earlier cell death and matrix degradation, thus contributing to a cascade of degeneration. N/A.

The Relevance of Iron in the Pathogenesis of Multiple System Atrophy: A Viewpoint.

Iron is essential for cellular development and maintenance of multiple physiological processes in the central nervous system. The disturbance of its homeostasis leads to abnormal iron deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Iron toxicity has been established in the pathogenesis of Parkinson’s disease; however, its contribution to multiple system atrophy (MSA) remains elusive. MSA is characterized by cytoplasmic inclusions of misfolded α-synuclein (α-SYN) in oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs). Remarkably, the oligodendrocytes possess high amounts of iron, which together with GCI pathology make a contribution toward MSA pathogenesis likely. Consistent with this observation, the GCI density is associated with neurodegeneration in central autonomic networks as well as olivopontocerebellar and striatonigral pathways. Iron converts native α-SYN into a β-sheet conformation and promotes its aggregation either directly or via increasing levels of oxidative stress. Interestingly, α-SYN possesses ferrireductase activity and α-SYN expression underlies iron mediated translational control via RNA stem loop structures. Despite a correlation between progressive putaminal atrophy and iron accumulation as well as clinical decline, it remains unclear whether pathologic iron accumulation in MSA is a secondary event in the cascade of neuronal degeneration rather than a primary cause. This review summarizes the current knowledge of iron in MSA and gives evidence for perturbed iron homeostasis as a potential pathogenic factor in MSA-associated neurodegeneration.

A systematic method for constructing discrete Painlevé equations in the degeneration cascade of the E8 group

We present a systematic and quite elementary method for constructing discrete Painlevé equations in the degeneration cascade for E8(1). Starting from the invariant for the autonomous limit of the E8(1) equation one wishes to study, the method relies on choosing simple homographies that will cast this invariant into certain judiciously chosen canonical forms. These new invariants lead to mappings the deautonomisations of which allow us to build up the entire degeneration cascade of the original mapping. We explain the method on three examples, two symmetric mappings and an asymmetric one, and we discuss the link between our results and the known geometric structure of these mappings.

Temporomandibular Joint Arthroscopy in the Pediatric Population

The temporomandibular joint has an essential role in the growth and development of the facial skeleton. In the pediatric patient, the temporomandibular joint may suffer mechanical or inflammatory disease that can propagate a cascade of joint degeneration. Significant derangements of the pediatric temporomandibular joint can lead to abnormalities in growth and facial morphology, necessitating extensive surgical intervention.

Intervertebral Disk Degeneration and Repair.

Intervertebral disk (IVD) degeneration is a natural progression of the aging process. Degenerative disk disease (DDD) is a pathologic condition associated with IVD that has been associated with chronic back pain. There are a variety of different mechanisms of DDD (genetic, mechanical, exposure). Each of these pathways leads to a final common result of unbalancing the anabolic and catabolic environment of the extracellular matrix in favor of catabolism. Attempts have been made to gain an understanding of the process of IVD degeneration with in Vitro studies. These models help our understanding of the disease process, but are limited as they do not come close to replicating the complexities that exist with an in Vivo model. Animal models have been developed to help us gain further understanding of the degenerative cascade of IVD degeneration In Vivo and test experimental treatment modalities to either prevent or reverse the process of DDD. Many modalities for treatment of DDD have been developed including therapeutic protein injections, stem cell injections, gene therapy, and tissue engineering. These interventions have had promising outcomes in animal models. Several of these modalities have been attempted in human trials, with early outcomes having promising results. Further, increasing our understanding of the degenerative process is essential to the development of new therapeutic interventions and the optimization of existing treatment protocols. Despite limited data, biological therapies are a promising treatment modality for DDD that could impact our future management of low back pain.

SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation

Axon injury in response to trauma or disease stimulates a self-destruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD+ and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD+ loss and axon degeneration. Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD+ loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD+ loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.

Strongly asymmetric discrete Painlevé equations: The multiplicative case

We examine a class of multiplicative discrete Painlevé equations which may possess a strongly asymmetric form. When the latter occurs, the equation is written as a system of two equations the right hand sides of which have different functional forms. The present investigation focuses upon two canonical families of the Quispel-Roberts-Thompson classification which contain equations associated with the affine Weyl groups D5(1) and E6(1) (or groups appearing lower in the degeneration cascade of these two). Many new discrete Painlevé equations with strongly asymmetric forms are obtained.

Elliptic and multiplicative discrete Painlevé equations from the affine Weyl group E8

Pursuing our study of discrete Painlevé equations associated with the affine Weyl group , we present our results on multiplicative and elliptic equations. Our method is based on the trihomographic representation of discrete Painlevé equations, which was shown to be equally rich as the more customary representations. The relation of equations to ones associated with affine Weyl groups situated in the degeneration cascade of is also presented, since it constitutes a precious aid for the derivation of the systems.

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

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.

Advances in the diagnosis of degenerated lumbar discs and their possible clinical application

One possible source of chronic low back pain is a degenerated intervertebral disc. In this review, various diagnostic methods for the assessment of the presence of degenerative changes are described. These include clinical MRI, a number of novel MRI techniques and nuclear magnetic resonance spectroscopy. Non-systematic literature review. Clinical MRI is the most commonly employed technique to determine the general "health status" of the intervertebral disc. Novel MRI techniques, such as quantitative MRI, T1ρ MRI, sodium MRI and nuclear magnetic resonance spectroscopy, are more sensitive in quantifying the biochemical changes of disc degeneration, as measured by alteration in collagen structure, as well as water and proteoglycan loss. As potential future diagnostic alternatives, miniature sensors are currently being developed to measure parameters associated with the disc degeneration cascade, such as intradiscal pressure and PG concentration. However, none of the methods listed above show sufficient specificity to identify a degenerated disc as the actual source of the pain. Provocative discography is the only test aimed at a direct diagnosis of discogenic pain, but it has a high false positive rate and there is some evidence of long-term adverse effects. Imaging techniques have also been tested for this purpose, but their validity has not been confirmed and they do appear to be problematic. A reliable diagnostic tool that could help a clinician to determine if a disc is the source of the pain in patients with chronic LBP is still not available. New MRI techniques are under investigation that could result in a significant improvement over current methods, particularly as they can allow monitoring, not only of morphological but also of biochemical changes.

Cyclic compression-induced p38 activation and subsequent MMP13 expression requires Rho/ROCK activity in bovine cartilage explants

Excessive mechanical stress on the cartilage causes the degradation of the matrix, leading to the osteoarthritis (OA). Matrix metalloproteinases 13 (MMP13) is a major catalytic enzyme in OA and p38 plays an important role in its induction. However, precise pathway inducing p38 activation has not been elucidated. We hypothesized here that the small GTPase Rho and its effector ROCK might function in upper part of the mechanical stress-induced matrix degeneration pathway. Bovine metacarpal phalangeal articular cartilage explants were loaded with 1MPa dynamic compression for 6h with or without a ROCK specific inhibitor Y27632 or/and a p38 specific inhibitor SB202190. Then p38 phosphorylation and MMP13 expression were assessed by western blot or/and quantitative RT-PCR. Rho-activity was measured by pull-down assay using glutathione S-transferase fusion protein of Rho binding domain. Cyclic compression caused Rho activation, p38 phosphorylation and MMP13 expression. Both Y27632 and SB202190 were found to block the mechanical stress-enhanced p38 phosphorylation and subsequent MMP13 expression. The present results show that p38 phosphorylation and MMP13 expression are regulated by Rho/ROCK activation, and support the potential novel pathway that Rho/ROCK is in the upper part of the mechanical stress-induced matrix degeneration cascade in cartilage comprised of p38 and MMP13.

In Vitro Response of Human Chondrocytes to a Combination of Growth Factors and a Proteinase Inhibitor

Degenerative disk disease is an accelerating cascade of tissue degeneration in the intervertebral disk. A harsh catabolic environment perpetuates the degeneration of the intervertebral disk. Tissue engineering-based techniques offer effective treatment to slow the progression of degenerative disk disease and regenerate intervertebral disk tissue. The purpose of this study was to assess the efficacy of a regenerative therapy for degenerative disk disease by treating human chondrocytes with anabolic growth factors and a proteinase inhibitor. The use of both proved effective in upregulating important extracellular matrix markers of human chondrocytes. These successful in vitro results have implications for the regeneration of the intervertebral disk.

Null controllability of degenerate parabolic cascade systems

In this paper, we study the null controllability of degenerate semilinear cascade parabolic systems with one control force. The key tool is the Carleman estimates developed recently for degenerate one dimension parabolic equations. We develop a Carleman estimate for these systems and then an observability inequality for the linear adjoint system. We conclude by linearization and fixed point arguments.

Image-based Screening Identifies Novel Roles for IκB Kinase and Glycogen Synthase Kinase 3 in Axonal Degeneration

Axon degeneration is an active, evolutionarily conserved self-destruction program by which compromised axons fragment in response to varied insults. Unlike programmed cell death, axon degeneration is poorly understood. We have combined robotic liquid handling with automated microscopy and image analysis to create a robust screening platform to measure axon degeneration in mammalian primary neuronal cultures. Using this assay, we performed an unbiased screen of 480 bioactive compounds, identifying 11 that reproducibly delay fragmentation of severed axons in vitro, including two inhibitors of glycogen synthase kinase 3 and two inhibitors of IκB kinase. Knockdown of each of these targets by shRNA lentivirus also delays axon degeneration in vitro, further supporting their role in the axon degeneration program.

The relevance of iron in the pathogenesis of Parkinson’s disease

Alterations of iron levels in the brain has been observed and documented in a number of neurodegenerative disorders including Parkinson's disease (PD). The elevated nigral iron levels observed in PD may reflect a dysfunction of brain iron homeostasis. Under normal physiological conditions excess iron can be sequestrated in ferritin and neuromelanin. Alternatively, the excess iron may represent a component of brain iron deposition associated with ageing. The aetiology of idiopathic PD largely remains an enigma. However, intensive investigations have provided a host of putative mechanisms that might contribute to the pathogenesis underlying the characteristic degeneration of the dopaminergic neurons in the substantia nigra (SN). The mechanisms proposed include oxidative (and nitrative) stress, inflammation, excitotoxicity, mitochondrial dysfunction, altered proteolysis and finally apoptotic induced cell death. Iron-mediated cellular destruction is mediated primarily via reactive oxygen or/and nitrogen species induced oxidative stress. Furthermore, these pathogenic mechanisms appear to be closely interlinked to the cascade of events leading to cellular death. There are conflicting reports about the stage during disease progression at which nigral iron change occurs in PD. Some have found that there are no changes in iron content SN in asymptomatic incidental Lewy body disease, suggesting it may represent a secondary event in the cascade of neuronal degeneration. In contrast, others have found an elevation of iron in SN in pre-clinical stages. These discrepancies may be attributed to the occurrence of different sub-groups of the disease. This concurs with the notion that PD represents a group of related diseases with a number of potential pathogenic pathways.

Stationary entanglement inN-atom subradiant degenerate cascade systems

We address ultracold $N$-atom degenerate cascade systems and show that stationary subradiant states, already observed in the semiclassical regime, also exist in a fully quantum regime and for a small number of atoms. We explicitly evaluate the amount of stationary entanglement for the two-atom configuration and show full inseparability for the three-atom case. We also show that a continuous variable description of the systems is not suitable to detect entanglement due to the non-Gaussianity of subradiant states.

Age-related differences in white matter microstructure: Region-specific patterns of diffusivity

We collected MRI diffusion tensor imaging data from 80 younger (20–32 years) and 63 older (60–71 years) healthy adults. Tract-based spatial statistics (TBSS) analysis revealed that white matter integrity, as indicated by decreased fractional anisotropy (FA), was disrupted in numerous structures in older compared to younger adults. These regions displayed five distinct region-specific patterns of age-related differences in other diffusivity properties: (1) increases in both radial and mean diffusivity; (2) increases in radial diffusivity; (3) no differences in parameters other than FA; (4) a decrease in axial and an increase in radial diffusivity; and (5) a decrease in axial and mean diffusivity. These patterns suggest different biological underpinnings of age-related decline in FA, such as demyelination, Wallerian degeneration, gliosis, and severe fiber loss, and may represent stages in a cascade of age-related degeneration in white matter microstructure. This first simultaneous description of age-related differences in FA, mean, axial, and radial diffusivity requires histological and functional validation as well as analyses of intermediate age groups and longitudinal samples.