Multiparametric magnetic resonance imaging of normal and degenerative lumbar intervertebral discs

Magnetic resonance imaging (MRI) has been shown to improve the diagnosis and management of patients with intervertebral disc (IVD) related disorders. Multiparametric MRI offers the possibility of noninvasively assessing multiple aspects of pathophysiological processes that exist simultaneously, thereby further assisting in patient treatment management. The purpose of this study is to determine the correlation between relaxation parameters (T1ρ and T2), diffusion properties including fractional anisotropy (FA) and mean diffusivity (MD) measured by diffusion tensor imaging (DTI) and various clinical findings in human IVD. Our results suggest that each parameter may attribute different sensitivity to tissue properties.postprin

Ultrashort time-to-echo MRI of the cartilagenous endplate and relationship to degenerative disc disease and schmorl's nodes

Session - The Short of ItINTRODUCTION: The vertebral endplate is composed of an inner bony and outer cartilaginous endplates (CEP). The CEP supplies the intervertebral disc (IVD) with nutrients and metabolites, and is instrumental for metabolism, exchange of waste products and biomechanics of the disc 1. Lumbar disc degeneration on MRI is a risk factor for the development of low back pain 2. It has been previously hypothesized that changes in disc mechanics may be initiated by damage to the endplate 3, 4. Similarly, CEP defects may be involved in the formation of Schmorl’s nodes (SNs) (i.e. invagination of IVD material into the adjacent endplates) 5, which associated with severity of lumbar disc degeneration 6. The ultrashort time-to-echo (UTE) MRI is an imaging technique that enables improved visualization of tissues with short T2 relaxation that appear dark in signal on conventional T2-weighted (T2W) imaging. By employing this technique in the lumbar spine, we believe that the CEP, which appears hypointense in T2W MRI, may be observed as continuous high-signal and may thus be differentiated from the bony endplate. Although cadaveric studies have addressed the feasibility of UTE in assessing the CEP 7, studies addressing such technology in live human subjects …published_or_final_versionThe 19th Annual Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine (ISMRM 2011), Montreal, QC., 7-13 May 2011. In Proceedings of the 19th ISMRM, 2011, v. 19, p. 57

Ultrashort time-to-echo MRI of the cartilagenous endplate & relationship to degenerative disc disease & Schmorl’s nodes

Session - The Short of It: no. 570Early diagnosis of CEP defects by UTE technique may provide useful information for understanding the pathogenesis of each of DDD and Schmorl¡¦s nodes (SN). The objective of this study was to assess CEP integrity in normal IVD levels, levels with degenerated IVDs and levels with SNs. Based on the UTE images, CEP defects were defined as discontinuity of high signal over 4 consecutive slices. Results showed that CEP defects were found to have a 4.5 fold increased likelihood of having DDD. No association between CEP defects and SNs was established. The effects of age and CEP defects were found to be level dependent. (abstract by publisher)postprin

Assessment of the neurocentral synchondrosis in pediatric spines and the "developmental" etiology of Schmorl's nodes

Special Poster: no. SP13INTRODUCTION: Schmorl's nodes of the thoraco-lumbar region have been associated with the presence and severity of disc degeneration in adults. The etiology of Schmorl's nodes remains precarious; however a unique multilevel phenotype of 'kissing' nodes seems to suggest a developmental origin. The neurocentral synchondrosis (NCS) are cartilaginous growth plates near the neural arch ossification centres in a growing vertebrae that may play a direct role in the development of endplate abnormalities, such as Schmorl's nodes. This study assessed the NCS in ...postprin

Limited effects of m6A modification on mRNA partitioning into stress granules

The presence of the m6A modification in mammalian mRNAs is proposed to promote mRNA recruitment to stress granules through the interaction with YTHDF proteins. We test this possibility by examining the accumulation of mRNAs in stress granules in both WT and ∆METTL3 mES cells, which are deficient in m6A modification. A critical observation is that all m6A modified mRNAs partition similarly into stress granules in both wild-type and m6A-deficient cells by single-molecule FISH. Moreover, multiple linear regression analysis indicates m6A modification explains only 6% of the variance in stress granule localization when controlled for length. Finally, the artificial tethering of 25 YTHDF proteins on reporter mRNAs leads to only a modest increase in mRNA partitioning to stress granules. Since most mammalian mRNAs have 4 or fewer m6A sites, and those sites are not fully modified, this argues m6A modifications are unlikely to play a significant role in recruiting mRNAs to stress granules. Taken together, these observations argue that m6A modifications play a minimal, if any, role in mRNA partitioning into stress granules. &nbsp;</p

F-18 Fluorodeoxyglucose non-avid hepatosplenic T cell lymphoma: a diagnostic pitfall

published_or_final_versionSpringer Open Choice, 21 Feb 201

Innate immunity defines the capacity of antiviral T cells to limit persistent infection

Effective immunity requires the coordinated activation of innate and adaptive immune responses. Natural killer (NK) cells are central innate immune effectors, but can also affect the generation of acquired immune responses to viruses and malignancies. How NK cells influence the efficacy of adaptive immunity, however, is poorly understood. Here, we show that NK cells negatively regulate the duration and effectiveness of virus-specific CD4+ and CD8+ T cell responses by limiting exposure of T cells to infected antigen-presenting cells. This impacts the quality of T cell responses and the ability to limit viral persistence. Our studies provide unexpected insights into novel interplays between innate and adaptive immune effectors, and define the critical requirements for efficient control of viral persistence

A Daphnane Diterpenoid Isolated from Wikstroemia polyantha Induces an Inflammatory Response and Modulates miRNA Activity

MicroRNAs (miRNAs) are endogenously expressed single-stranded ∼21–23 nucleotide RNAs that inhibit gene expression post-transcriptionally by binding imperfectly to elements usually within the 3′untranslated region (3′UTR) of mRNAs. Small interfering RNAs (siRNAs) mediate site-specific cleavage by binding with perfect complementarity to RNA. Here, a cell-based miRNA reporter system was developed to screen for compounds from marine and plant extracts that inhibit miRNA or siRNA activity. The daphnane diterpenoid genkwanine M (GENK) isolated from the plant Wikstroemia polyantha induces an early inflammatory response and can moderately inhibit miR-122 activity in the liver Huh-7 cell line. GENK does not alter miR-122 levels nor does it directly inhibit siRNA activity in an in vitro cleavage assay. Finally, we demonstrate that GENK can inhibit HCV infection in Huh-7 cells. In summary, the development of the cell-based miRNA sensor system should prove useful in identifying compounds that affect miRNA/siRNA activity

Periconceptional multiple-micronutrient supplementation and placental function in rural Gambian women: a double-blind, randomized, placebo-controlled trial

BACKGROUND: Maternal micronutrient deficiencies are commonly associated with clinical indicators of placental dysfunction. OBJECTIVE: We tested the hypothesis that periconceptional multiple-micronutrient supplementation (MMS) affects placental function. DESIGN: We conducted a double-blind, randomized, placebo-controlled trial of MMS in 17- to 45-y-old Gambian women who were menstruating regularly and within the previous 3 mo. Eligible subjects were pre-randomly assigned to supplementation with the UNICEF/WHO/United Nations University multiple micronutrient preparation (UNIMMAP) or placebo on recruitment and until they reached their first antenatal check-up or for 1 y if they failed to conceive. Primary outcome measures were midgestational indexes of utero-placental vascular-endothelial function [ratio of plasminogen-activator inhibitor (PAI) 1 to PAI-2 and mean uterine-artery resistance index (UtARI)] and placental active transport capacity at delivery [fetal to maternal measles antibody (MMA) ratio]. RESULTS: We recruited 1156 women who yielded 415 pregnancies, of which 376 met all of the inclusion criteria. With adjustment for gestational age at sampling, there were no differences in PAI-1 to PAI-2 or MMA ratios between trial arms, but there was a 0.02-unit reduction in UtARI between 18 and 32 wk of gestation (95% CI: -0.03, -0.00; P = 0.040) in women taking UNIMMAP. CONCLUSIONS: Placental vascular function was modifiable by periconceptional micronutrient supplementation. However, the effect was small and supplementation did not further affect other variables of placental function. This trial was registered at www.controlled-trials.com as ISRCTN 13687662

Identification of constrained sequence elements across 239 primate genomes

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals