A Study of the Influence of Sex on Genome Wide Methylation

Sex differences in methylation status have been observed in specific gene-disease studies and healthy methylation variation studies, but little work has been done to study the impact of sex on methylation at the genome wide locus-to-locus level or to determine methods for accounting for sex in genomic association studies. In this study we investigate the genomic sex effect on saliva DNA methylation of 197 subjects (54 females) using 20,493 CpG sites. Three methods, two-sample T-test, principle component analysis and independent component analysis, all successfully identify sex influences. The results show that sex not only influences the methylation of genes in the X chromosome but also in autosomes. 580 autosomal sites show strong differences between males and females. They are found to be highly involved in eight functional groups, including DNA transcription, RNA splicing, membrane, etc. Equally important is that we identify some methylation sites associated with not only sex, but also other phenotypes (age, smoking and drinking level, and cancer). Verification was done through an independent blood cell DNA methylation data (1298 CpG sites from a cancer panel array). The same genomic site-specific influence pattern and potential confounding effects with cancer were observed. The overlapping rate of identified sex affected genes between saliva and blood cell is 81% for X chromosome, and 8% for autosomes. Therefore, correction for sex is necessary. We propose a simple correction method based on independent component analysis, which is a data driven method and accommodates sample differences. Comparison before and after the correction suggests that the method is able to effectively remove the potentially confounding effects of sex, and leave other phenotypes untouched. As such, our method is able to disentangle the sex influence on a genome wide level, and paves the way to achieve more accurate association analyses in genome wide methylation studies

Primary Amyloidosis Presenting Intrahepatic Cholestasis and Fulminant Hepatic Failure

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Effects of the fusionless instrumentation on the disks and facet joints of the unfused segments: A pig model

PubMedID: 23812137Background: Growing rod (GR) is a state-of-the-art procedure favored when curvatures of the spine cannot be managed non-operatively in early-onset scoliosis. Although some postulate that multiple distractions and/or relative immobilization of the unfused segments affect the health of disk and facet joint (FJ) and cause degeneration and/or spontaneous fusion, this has not thoroughly been investigated. In this study, changes in the un-fused segment after a spine-based fusionless instrumentation (SBFI) are investigated and compared with the control (CG) and instrumented fusion (IF) groups. Methods: A total of 13 piglets, 10 to 14 weeks of age, were used. SBFI and IF were performed on 7 and 3 piglets, respectively, and 3 formed the CG. In SBFI, lengthening procedures of 5mm were applied once monthly for 3 months, and, after 4 months, all piglets were euthanized. Histologic sections of the unfused disks and FJ were analyzed, and morphometric histologic analysis was performed. Results: On the basis of the Gries criteria, unfused disk median grades were 1, 2, and 4 for control, SBFI, and IF, respectively, that revealed a statistical difference (P < 0.001). Unfused FJ median grades were 1 and 2 for control and SBFI, respectively, that revealed a statistical difference (P < 0.001). The mean hyper-trophic zone (HZ) heights were 69.78, 84.20, and 66.14 mm; HZ chondrocyte cell widths were 19.03, 18.76, and 17.36 mm; and HZ chondrocyte cell heights were 15.01, 15.04, and 12.42 mm in the CG, SBFI, and IF groups, respectively. Statistically, for HZ heights, SBFI was different compared with CG and IF (P < 0.001), and, for HZ chondrocyte cell widths and heights, IF was different compared with CG and SBFI (P < 0.001). Conclusions: Morphometric analysis in this study supports the findings that SBFI preserves the growth potential of the spine. Furthermore, changes in the HZ heights show that distractive forces stimulate the apophyseal growth of the axial skeleton describing how the growth rate of the spine in GR might surpass the normal growth rate. Overall, although some degenerative changes are observed, SBFI and repeated distractions alone are not solely responsible for FJ arthrosis and disk degeneration, given that they are structurally preserved. Clinical Relevance: GR and regular lengthening procedures do not impair disk health and preserve the growth potential of the spine if it is applied with a meticulous technique. Copyright © 2013 by Lippincott Williams & Wilkins

Igg4-Related Sclerosing Disease With Mesenteric And Retroperitoneal Involvement

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Fusionless instrumentation in growing spine and adjacent segment problems: An experimental study in immature pigs

PubMedID: 24285274STUDY DESIGN.: Experimental study. OBJECTIVE.: To compare the effects of fusionless instrumentation (FI) and instrumented fusion (IF) on the adjacent segment in an immature pig model. SUMMARY OF BACKGROUND DATA.: Observations reveal proximal junctional kyphosis after FI. Possible reasons are stress concentration, repeated distractive forces, and/or soft tissue damage done in the index surgery. It was speculated that FI can decrease stressors to the junctional area by preserving the spinal mobility in some manner; however, this has not been proven to date. METHODS.: Thirteen piglets of 10- to 14-week age were used. FI and IF were performed on 7 and 3 piglets, respectively, and 3 piglets formed the control group. Control piglets did not undergo any surgical procedures. T11-L4 instrumentation, decortication, and grafting were applied to IF piglets. In FI groups, however, L1-L2 was left uninstrumented and unfused using T11-T12 and L3-L4 levels as anchors to the growing construct. A total of 4 lengthening procedures were performed: 1 in the index operation and 3 more, once in each lengthening procedure monthly, for 3 months. Four months after the index operations, all piglets were killed and the adjacent segment motion capabilities, disc, and facets were evaluated with radiographical, magnetic resonance imaging, biomechanical, and histological analyses. RESULTS.: Comparison of proximal junctional Cobb angles of the postindex (mean: 21, range: 17-27) and presacrification (mean: 21, range: 11-31) radiographs in the FI group revealed no difference (P> 0.05). In magnetic resonance imaging, both surgical group proximal adjacent discs showed degeneration to some degree that was statistically indifferent (P = 0.903). Biomechanical evaluation revealed restriction of adjacent segment motion in all directions for both groups; however, this negative effect was significantly less in FI group (P < 0.01). Degeneration observed in histological evaluation in adjacent discs and facets of FI group was significantly lower (P = 0.00). CONCLUSION.: In this quadruped straight spine model, in comparison with IF applications, FI is closer to normal physiology even after several lengthening procedures regarding the adjacent segment discs, facet joints, and motion, when interpreting the radiological, biomechanical, and histological results altogether. © 2013, Lippincott Williams & Wilkins

Recurrent novel HMGA2-NCOR2 fusions characterize a subset of keratin-positive giant cell-rich soft tissue tumors

Giant cell tumors of soft tissue (GCT-ST) are rare low-grade neoplasms that were at one time thought to represent the soft tissue counterparts of GCT of bone (GCT-B) but are now known to lack the H3F3 mutations characteristic of osseous GCT. We present six distinctive giant cell-rich soft tissue neoplasms that expressed keratins and carried a recurrent HMGA2-NCOR2 gene fusion. Patients were five females and one male aged 14–60 years (median, 29). All presented with superficial (subcutaneous) masses that were removed by conservative marginal (3) or wide (2) local excision. The tumors originated in the upper extremity (2), lower extremity (2), head/neck (1), and trunk (1). Five patients with follow-up (median, 21 months; range, 14–168) remained disease-free. Grossly, all tumors were well-demarcated but not encapsulated with variable lobulation. Histologically, they were composed of bland plump epithelioid or ovoid to spindled mononuclear cells admixed with evenly distributed multinucleated osteoclast-type giant cells. Foci of stromal hemorrhage and hemosiderin were seen in all cases. The mitotic activity ranged from 2 to 14/10 high power fields (median: 10). Foci of necrosis and vascular invasion were seen in one case each. The mononuclear cells were immunoreactive with the AE1/AE3 keratin cocktail and less frequently/less diffusely for K7 and K19 but lacked expression of other lineage-associated markers. RNA-based next-generation sequencing revealed an HMGA2-NCOR2 fusion in all tumors. None of the keratin-negative conventional GCT-ST showed the HMGA2-NCOR2 fusion (0/7). Metaplastic bone (4/9) and SATB2 expression (3/4) were frequent in keratin-negative conventional GCT-ST but were lacking in keratin-positive HMGA2-NCOR2 fusion-positive tumors. The distinctive immunophenotype and genotype of these tumors strongly suggest that they represent a discrete entity, differing from conventional GCT-ST and other osteoclast-rich morphologic mimics. Their natural history appears favorable, although a study of additional cases and longer follow-up are warranted