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Development of spinal deformities in the tight-skin mouse.

ABSTRACT: Tight-skin (TSK) mice are commonly used as an animal model to study the pathogenesis of Marfan syndrome (MFS), but little is known of their skeletal phenotype and in particular of the development of the spinal deformities, common in MFS. Here we examined growth of the axial skeletons of TSK and wild-type(B6) mice during their period of rapid growth. The whole bodies of mice, 4-12 weeks of age, were scanned after sacrifice, by micro-computed tomography (microCT). We reconstructed three-dimensional models of the spine and ribs, and measured vertebral body heights and rib lengths using the Mac-based image-processing software "OsiriX". Although the TSK mice were smaller than the B6 mice at 4 weeks, they experienced an early growth spurt and by 8 weeks the height, but not the width, of the vertebral body was significantly greater in the TSK mice than the B6 mice. Measurement of the angles of scoliotic and kyphotic curves post-mortem in the mice was problematic, hence we measured changes that develop in skeletal elements in these disorders. As a marker of kyphosis, we measured anterior wedging of the vertebral bodies; as a marker for scoliosis we measured asymmetries in rib length. We found, unlike in the B6 mice where the pattern was diffuse, wedging in TSK mice was directly related to spinal level and peaked steeply at the thoracolumbar junction. There was also significant asymmetry in length of the ribs in the TSK mice, but not in the B6 mice. The TSK mice thus appear to exhibit spinal deformities seen in MFS and could be a useful model for gaining understanding of the mechanisms of development of scoliosis and kyphosis in this disorder.

SUBMITTER: Li B

PROVIDER: S-EPMC5605766 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Development of spinal deformities in the tight-skin mouse.

Li Bing B Urban Jill Pg JP Yu Jing J

Bone research 20170221

Tight-skin (TSK) mice are commonly used as an animal model to study the pathogenesis of Marfan syndrome (MFS), but little is known of their skeletal phenotype and in particular of the development of the spinal deformities, common in MFS. Here we examined growth of the axial skeletons of TSK and wild-type(B6) mice during their period of rapid growth. The whole bodies of mice, 4-12 weeks of age, were scanned after sacrifice, by micro-computed tomography (microCT). We reconstructed three-dimensiona ...[more]

PMID: 28944086

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Project description:STUDY DESIGN: Systematic review. OBJECTIVE: To determine the effectiveness of using electromyography (EMG) during intraoperative pedicle screw placement in patients with thoracic deformity. METHODS: A systematic review of the English-language literature was undertaken for articles published between 1970 and July 2011. For our first question, we identified all articles that were designed to evaluate the diagnostic test characteristics (ie, measures of validity such as sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV]) of EMG for thoracic deformities in adolescent and adult patients. For our second question, we attempted to identify all articles that reported complication rates (pedicle wall breach or new neurological event) after pedicle screw placement in the same population comparing patients who did and did not undergo intraoperative EMG. Articles were excluded if they did not report or give raw data to calculate at least one of the four primary diagnostic test characteristics: sensitivity, specificity, PPV, or NPV for study question one. Articles were excluded if they did not have a "no EMG" control group for study question two. Other exclusions were reviews, editorials, case reports, non-English written studies, and animal studies. We rated the overall body of evidence with respect to each key question using a modified Grades of Recommendation Assessment, Development and Evaluation (GRADE) system for diagnostic and therapeutic studies. RESULTS: The overall strength of evidence evaluating the diagnostic characteristics was low due to inconsistent findings between studies and uncertainty of the impact of false-negatives. The fairly low sensitivity may lead to a high-false negative rate. It is unclear what the impact of false-negatives would be since no neurological injuries were identified in the studies summarized. A higher specificity would suggest a fairly low false-positive rate; however, the rates could be as high as 30%. If sudden changes in treatment are required in the absence of any adverse event, this could be considered a limitation of such testing. The overall strength of evidence for evaluating the efficacy of EMG compared with no EMG was insufficient because of literature shortage on this topic. CONCLUSION: The overall strength of evidence evaluating the diagnostic characteristics was low due to inconsistent findings between studies and uncertainty of the impact of false-negatives. Given the low sensitivity and potential high rate of false-negatives, pedicle wall breaches may occur, without EMG notification. These undetected breaches may lead to loose or weak screw position which may lead to neurovascular complications during or after a translation-rotation maneuver, especially in rigid deformities. The higher sensitivity would suggest a lower rate of false-positives. We recommend considering the use of intraoperative EMG-monitoring method to help identify potential complications based upon available technology, personal experiences and preferences; however, surgeons should keep in mind that false-positive results may lead to increased surgery time and increased blood loss. The surgeon should not depend solely on EMG since it can also render false-negatives.

Project description:Background & aimsLoss of claudin 18 (CLDN18), a membrane-spanning tight junction protein, occurs during early stages of development of gastric cancer and associates with shorter survival times of patients. We investigated whether loss of CLDN18 occurs in mice that develop intraepithelial neoplasia with invasive glands due to infection with Helicobacter pylori, and whether loss is sufficient to promote the development of similar lesions in mice with or without H pylori infection.MethodsWe performed immunohistochemical analyses in levels of CLDN18 in archived tissues from B6:129 mice infected with H pylori for 6 to 15 months. We analyzed gastric tissues from B6:129S5-Cldn18tm1Lex/Mmucd mice, in which the CLDN18 gene was disrupted in gastric tissues (CLDN18-knockout mice), or from control mice with a full-length CLDN18 gene (CLDN18+/+; B6:129S5/SvEvBrd) or heterozygous disruption of CLDN18 (CLDN18+/-; B6:129S5/SvEvBrd) that were infected with H pylori SS1 or PMSS1 at 6 weeks of age and tissues collected for analysis at 20 and 30 weeks after infection. Tissues from CLDN18-knockout mice and control mice with full-length CLDN18 gene expression were also analyzed without infection at 7 weeks and 2 years after birth. Tissues from control and CLDN18-knockout mice were analyzed by electron microscopy, stained by conventional methods and analyzed for histopathology, prepared by laser capture microdissection and analyzed by RNAseq, and immunostained for lineage markers, proliferation markers, and stem cell markers and analyzed by super-resolution or conventional confocal microscopy.ResultsCLDN18 had a basolateral rather than apical tight junction localization in gastric epithelial cells. B6:129 mice infected with H pylori, which developed intraepithelial neoplasia with invasive glands, had increasing levels of CLDN18 loss over time compared with uninfected mice. In B6:129 mice infected with H pylori compared with uninfected mice, CLDN18 was first lost from most gastric glands followed by disrupted and reduced expression in the gastric neck and in surface cells. Gastric tissues from CLDN18-knockout mice had low levels of inflammation but increased cell proliferation, expressed markers of intestinalized proliferative spasmolytic polypeptide-expressing metaplasia, and had defects in signal transduction pathways including p53 and STAT signaling by 7 weeks after birth compared with full-length CLDN18 gene control mice. By 20 to 30 weeks after birth, gastric tissues from uninfected CLDN18-knockout mice developed intraepithelial neoplasia that invaded the submucosa; by 2 years, gastric tissues contained large and focally dysplastic polypoid tumors with invasive glands that invaded the serosa.ConclusionsH pylori infection of B6:129 mice reduced the expression of CLDN18 early in gastric cancer progression, similar to previous observations from human gastric tissues. CLDN18 regulates cell lineage differentiation and cellular signaling in mouse stomach; CLDN18-knockout mice develop intraepithelial neoplasia and then large and focally dysplastic polypoid tumors in the absence of H pylori infection.

Project description:This study aimed to identify the differentiating parameters of the spinal curves' 2D projections through a hierarchical classification of the 3D spinal curve in adolescent idiopathic scoliosis (AIS). A total number of 103 right thoracic left lumbar pre-operative AIS patients were included retrospectively and consecutively. A total number of 20 non-scoliotic adolescents were included as the control group. All patients had biplanar X-rays and 3D reconstructions of the spine. The 3D spinal curve was calculated by interpolating the center of vertebrae and was isotropically normalized. A hierarchical classification of the normalized spinal curves was developed to group the patients based on the similarity of their 3D spinal curve. The spinal curves' 2D projections and clinical spinal measurements in the three anatomical planes were then statistically compared between these groups and between the scoliotic subtypes and the non-scoliotic controls. A total of 5 patient groups of right thoracic left lumbar AIS patients were identified. The characteristics of the posterior-anterior and sagittal views of the spines were: Type 1: Normal sagittal profile and S shape axial view. T1 is leveled or tilted to the right in the posterior view. Type 2: Hypokyphotic and a V shape axial view. T1 is tilted to the left in the posterior view. Type 3: Hypokyphotic (only T5-T10) and frontal imbalance, S shape axial view. T1 is leveled or tilted to the right, and 3 frontal curves. Type 4: Flat sagittal profile (T1-L2), slight frontal imbalance with a V shape axial view, T1 tilted to the left. Type 5: flat sagittal profile and forward trunk shift with a proximal kyphosis and S shape axial view. T1 is leveled or tilted to the right. In conclusion, a hierarchical classification of the 3D scoliotic spine allowed identifying various distinguishing features of the spinal curves in patients with a right thoracic curve in an orderly fashion. The subtypes' characteristics resulting from this 3D classification can be identified from the pairs of the frontal and sagittal spinal curves i.e. X-rays in right thoracic AIS patients.

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Development of spinal deformities in the tight-skin mouse.

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Development of spinal deformities in the tight-skin mouse.

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