THE ROLES OF ORTHOPAEDIC PATHOLOGY AND GENETIC DETERMINANTS IN EQUINE CERVICAL STENOTIC MYELOPATHY

Cervical stenotic myelopathy (CSM) is an important musculoskeletal and neurologic disease of the horse. Clinical disease occurs due to malformations of the vertebrae in the neck causing stenosis of the cervical vertebral canal and subsequent spinal cord compression. The disease is multifactorial in nature, therefore a clearer understanding of the etiology and pathogenesis of CSM will allow for improved management and therapeutic practices. This thesis examines issues of equine CSM diagnosis, skeletal tissue pathology, and inherited genetic determinants utilizing advances in biomedical imaging technologies and equine genomics. Magnetic resonance imaging (MRI) data provided a more complete assessment of the cervical column through image acquisition in multiple planes. First, MRI was compared to standing cervical radiographs for detection of stenosis. Using canal area or the cord canal area ratio, MRI more accurately predicted sites of compression in CSM cases. Secondly, articular process skeletal pathology localized on MRI was found to be more frequent and severe in CSM horses compared to controls. In addition, lesions were generalized throughout the cervical column and not limited to the spinal cord compression sites. A subset of lesions identified on MRI was evaluated using micro-CT and histopathology. Osteochondrosis, osseous cyst-like structures, fibrous tissue replacement of bone, and osteosclerosis were observed. These lesions support likely developmental aberrations of vertebral bone and cartilage maturation with secondary biomechanical influences. Bone cyst-like structures are a novel finding in this disease. Finally, the long-standing question of the contribution of genetic determinants to CSM was investigated using a genome wide association study (GWAS). Multiple significant loci were identified supporting the influence of a complex genetic trait in clinical disease. A simple Mendelian trait controlled by one gene is unlikely given the detection of variants across multiple chromosomes. Major contributions from this research include documentation of articular process bone and cartilage pathology in horses with CSM, support for abnormal cervical vertebrae development being an important contributing factor in the etiology and/or pathogenesis of equine CSM, and evidence that multiple genetic loci contribute to the CSM disease phenotype

Multi-Surface Simplex Spine Segmentation for Spine Surgery Simulation and Planning

This research proposes to develop a knowledge-based multi-surface simplex deformable model for segmentation of healthy as well as pathological lumbar spine data. It aims to provide a more accurate and robust segmentation scheme for identification of intervertebral disc pathologies to assist with spine surgery planning. A robust technique that combines multi-surface and shape statistics-aware variants of the deformable simplex model is presented. Statistical shape variation within the dataset has been captured by application of principal component analysis and incorporated during the segmentation process to refine results. In the case where shape statistics hinder detection of the pathological region, user-assistance is allowed to disable the prior shape influence during deformation. Results have been validated against user-assisted expert segmentation

A Survey on Deep Learning in Medical Image Analysis

Deep learning algorithms, in particular convolutional networks, have rapidly become a methodology of choice for analyzing medical images. This paper reviews the major deep learning concepts pertinent to medical image analysis and summarizes over 300 contributions to the field, most of which appeared in the last year. We survey the use of deep learning for image classification, object detection, segmentation, registration, and other tasks and provide concise overviews of studies per application area. Open challenges and directions for future research are discussed.Comment: Revised survey includes expanded discussion section and reworked introductory section on common deep architectures. Added missed papers from before Feb 1st 201

UMFC #66 A Comprehensive Case Report

University of Montana Forensic Case #66 has been used as a teaching tool for many years. Little written information is available on the origin of this case. Information on the date of recovery is not available, nor are the circumstances surrounding the recovery. My goal in this report is to understand more about this case, particularly age at death, ancestry, and pathology. This case is particularly intriguing because it presents a textbook example of osteomyelitis, a pathological condition. Additionally, it is of significance to the history of the area because of its recovery in the state of Montana. As a current graduate student in the University of Montana Forensic Anthropology Department, I have the great opportunity to examine this case. This paper presents the results of a detailed comprehensive analysis incorporating current methods to further the knowledge concerning UMFC #66. Since the time of discovery there has been speculation on the ancestry of this case. In some previous analyses the ancestry has been ascribed to the peoples of Africa, and in others to the peoples of Asia or the Americas. Based my interpretation of the data collected, I conclude that this person was of Native American descent. I estimate this person’s age at between of 37 and 53 at the time of death. Osteomyelitis has greatly affected the left femur and adjacent bones. This caused a skeletal deformation of the ribs, possibly associated with lying on the side for extended periods of time. Cause of death can only be attributed to osteomyelitis since there is no other pathology or trauma indicating otherwise

Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

The type I collagenopathies are a group of heterogeneous connective tissue disorders, that are caused by mutations in the genes encoding type I collagen and include specific forms of osteogenesis imperfecta (OI) and the Ehlers-Danlos syndrome (EDS). These disorders present with a broad disease spectrum and large clinical variability of which the underlying genetic basis is still poorly understood. In this study, we systematically analyzed skeletal phenotypes in a large set of zebrafish, with diverse mutations in the genes encoding type I collagen, representing different genetic forms of human OI, and a zebrafish model resembling human EDS, which harbors a number of soft connective tissues defects, typical of EDS. Furthermore, we provide insight into how zebrafish and human type I collagen are compositionally and functionally related, which is relevant in the interpretation of human type I collagen-related disease models. Our studies reveal a high degree of intergenotype variability in phenotypic expressivity that closely correlates with associated OI severity. Furthermore, we demonstrate the potential for select mutations to give rise to phenotypic variability, mirroring the clinical variability associated with human disease pathology. Therefore, our work suggests the future potential for zebrafish to aid in identifying unknown genetic modifiers and mechanisms underlying the phenotypic variability in OI and related disorders. This will improve diagnostic strategies and enable the discovery of new targetable pathways for pharmacological intervention

Low Back Pain Pathogenesis and Treatment

Low back pain is a common disorder which affects the lumbar spine, and is associated with substantial morbidity for about 80% of the general population at some stages during their lives. Although low back pain usually is a self-limiting disorder that improves spontaneously over time, the etiology of low back pain is generally unknown and the diagnostic label, "non-specific low back pain", is frequently given. This book contains reviews and original articles with emphasis on pathogenesis and treatment of low back pain except for the rehabilitative aspect. Consisting of three sections, the first section of the book has a focus on pathogenesis of low back pain, while the second and third sections are on the treatment including conservative and surgical procedure, respectively

Dystrophic calcification and heterotopic ossification in fibrocartilaginous tissues of the spine in diffuse idiopathic skeletal hyperostosis (DISH)

© 2020, The Author(s). Diffuse idiopathic skeletal hyperostosis (DISH) is a prevalent noninflammatory spondyloarthropathy characterized by ectopic mineral formation along the anterolateral aspect of the vertebral column, yet little is known about its underlying pathogenesis. Our objective was to evaluate the histopathological features and composition of ectopic mineral within spinal tissues affected by DISH in humans. Thoracic spine segments from six embalmed cadaveric donors (one female and five males; median age 82 years) meeting the radiographic diagnostic criteria for DISH were evaluated using radiological, histological, and physical analyses. Overall, the histological features of ectopic mineralization at individual motion segments were heterogeneous, including regions of heterotopic ossification and dystrophic calcification. Heterotopic ossifications were characterized by woven and lamellar bone, multifocal areas of metaplastic cartilage, and bony bridges along the anterior aspect of the intervertebral disc space. Dystrophic calcifications were characterized by an amorphous appearance, a high content of calcium and phosphorus, an X-ray diffraction pattern matching that of hydroxyapatite, and radiodensities exceeding that of cortical bone. Dystrophic calcifications were found within the anterior longitudinal ligament and annulus fibrosus in motion segments both meeting and not meeting the radiographic criteria for DISH. In summary, our findings indicate that in DISH, ectopic mineral forms along the anterior aspect of the spine by both heterotopic ossification and dystrophic calcification of fibrocartilaginous tissues. Although both types of ectopic mineralization are captured by current radiographic criteria for DISH, dystrophic calcification may reflect a distinct disease process or an early stage in the pathogenesis of DISH

Phenotypic and genotypic characterization of a myelopathy in pugs : A journey from ’wobbly pugs’ to pug dog myelopathy

Spinal cord disease, myelopathy, in dogs have several aetiologies, all characterised by their clinical presentation. Pugs with a thoracolumbar myelopathy (PDM) differ from most dogs by developing a form of myelopathy that shows little clinical variability. Most pugs with PDM show slowly progressive paraparesis and ataxia, absence of obvious spinal pain and a high prevalence of incontinence.  The overall aims of the thesis were to investigate the prevalence of PDM, to clinically and pathologically characterize this unique disorder in pugs and to explore underlying aetiologies. The importance of congenital vertebral malformations (CVMs) was examined using advanced diagnostic imaging. A potential contribution of an autoimmune aetiology was studied by analysing biomarkers in blood and cerebrospinal fluid. The necrotizing meningoencephalitis (NME) susceptibility dog leucocyte (DLA) class II risk was assessed and a genetic contribution to PDM was investigated by molecular genetics.  In summary, gait abnormalities were common in Swedish pugs and the character of the abnormal gait suggesting an underlying spinal cord disorder. The lack of association between presence, or type, of CVMs in the thoracolumbar vertebral column and neurological deficits, paraparesis and ataxia, suggested that other or additional factors were important for the development of PDM. Neuropathological examination showed that the clinical disease, PDM, was caused by the formation of profound meningeal fibrosis that interfered with the vascular supply to the spinal cord as well as caused obstruction of cerebrospinal fluid (CSF) flow with subsequent parenchymal spinal cord destruction. In addition a considerable number of PDM pugs presented with inflammation in the central nervous system. A contribution of the immunological system on the development of PDM was supported by the finding of anti-GFAP autoantibodies in the CSF of pugs with PDM. Our results also indicated that the DLA class II risk haplotype for necrotizing meningoencephalitis (NME), even in a heterozygous state, may cause a more severe PDM phenotype. The potential relevance of multiple candidate genes to the pathogenesis of PDM, including those implicated with bone homeostasis, the differentiation of cartilage, inflammation and fibrotic scar tissue formation, should be confirmed in future studies

Equine cervical pain and dysfunction

2021 Fall.Includes bibliographical references.Cervical pain and dysfunction in horses has become more recognized in recent years. However, a horse may present with a long list of different clinical syndromes and the examination findings can be confusing, resulting in difficulty effectively treating the horse. This frequently leads to frustration by the owner, as well as the veterinarian charged with helping the horse. This body of work aims to enlighten the reader of the dearth of understanding of cervical pain and dysfunction, to highlight how dangerous behavior may be related to cervical pain, and describe the course and development of future research. There is a paucity of peer-reviewed equine literature available describing cervical pain and dysfunction in the horse. The first chapter is designed to provide a synopsis of the current state of understanding of the disease processes, diagnostic capabilities, and possible treatment strategies available to manage cervical pain and dysfunction in horses. The second chapter describes a series of horses displaying unwanted behavior that became dangerous to the rider and often times to the horse itself. The included horses all had moderate to severe ganglionitis at multiple vertebral levels. Ganglionitis has been associated with neuropathic pain in other species, and is believed to be causing a state of neuropathic pain in this series of horses. This study highlights the need for deeper understanding of pain behavior in horses. Chapter 3 describes a prospective evaluation of cervical pain and dysfunction in 12 horses. Recombinant equine interleukin-1β (reIL-1β) has been used as an acute synovitis model within the appendicular skeleton and was utilized in this study to create transient synovitis at the cervical articulation of C5-C6. This study evaluated the clinical, biomechanical and ultrasonographic features in horses with a known source of neck pain. Acute synovitis of the articular process joint (APJ) induced clinical signs of myofascial pain and neck stiffness with variable degrees of forelimb lameness. Ultrasonographic evidence of the presence and severity of APJ effusion could be readily identified and tracked over time. Utilizing this model in the future could further add to our understanding of the clinical presentations in horses experiencing cervical pain and dysfunction. Through this collection of work, we have developed collaborations to investigate many unanswered questions that have been raised. We will look to define pathways related to neuropathic pain mechanisms in order to ultimately improve the quality of life, not only for our equine patients, but potentially of other veterinary species and even the human population experiencing chronic pain

Vertebral compression fractures managed with brace: risk factors for progression

The aim of this study is to identify risk factors for vertebral compression fracture (VCF) progression in patients treated conservatively with a brace. Then, a case–control study was designed. All patients over 50 years old with diagnosis of thoracic or lumbar VCF (T5 to L5) in absence of underlying oncological process, treated conservatively with brace, and consecutively attended at our department from January 2017 to June 2021 were retrospectively selected for analysis. Patients missed for follow-up or dead during the frst 3 months of follow-up were excluded. Five hundred and eighty-two consecutive patients were recorded. Incomplete follow-up excluded 74 patients and other 19 died in the frst three months after diagnosis, so 489 cases were fnally analyzed. Median follow-up was 21 (IQR 13;30) weeks. Increased collapse of the vertebral body was found in 29.9% of VCFs with a median time to progression of 9 (IQR 7;13) weeks. Male gender (OR 1.6), type A3 fracture of the AOSpine classifcation (OR 2.7), thoracolumbar junction location (OR 1.7), and incorrect use of the brace (OR 3.5) were identifed as independent risk factors for progression after multivariable analysis. Male gender, type A3 fracture of the AOSpine classifcation, thoracolumbar junction location, and incorrect use of the brace were identifed as independent risk factors for VCF progression, which resulted in worse pain control, when treated with brace. Thus, other treatments such as percutaneous vertebral augmentation could be considered to avoid progression in selected cases, since collapse rate has been demonstrated lower with these procedure