Umberto Eco, Narratives of Conspiracy and the Anti-Semite Among Us

http://www.quest-cdecjournal.it/discussion.php?id=3

Characteristics of transposable element exonization within human and mouse

Insertion of transposed elements within mammalian genes is thought to be an important contributor to mammalian evolution and speciation. Insertion of transposed elements into introns can lead to their activation as alternatively spliced cassette exons, an event called exonization. Elucidation of the evolutionary constraints that have shaped fixation of transposed elements within human and mouse protein coding genes and subsequent exonization is important for understanding of how the exonization process has affected transcriptome and proteome complexities. Here we show that exonization of transposed elements is biased towards the beginning of the coding sequence in both human and mouse genes. Analysis of single nucleotide polymorphisms (SNPs) revealed that exonization of transposed elements can be population-specific, implying that exonizations may enhance divergence and lead to speciation. SNP density analysis revealed differences between Alu and other transposed elements. Finally, we identified cases of primate-specific Alu elements that depend on RNA editing for their exonization. These results shed light on TE fixation and the exonization process within human and mouse genes.Comment: 11 pages, 4 figure

Toward Precision Phenotyping of Multiple Sclerosis

The classification of multiple sclerosis (MS) has been established by Lublin in 1996 and revised in 2013. The revision includes clinically isolated syndrome, relapsing-remitting, primary progressive and secondary progressive MS, and has added activity (i.e., formation of white matter lesions or clinical relapses) as a qualifier. This allows for the distinction between active and nonactive progression, which has been shown to be of clinical importance. We propose that a logical extension of this classification is the incorporation of additional key pathological processes, such as chronic perilesional inflammation, neuroaxonal degeneration, and remyelination. This will distinguish MS phenotypes that may present as clinically identical but are driven by different combinations of pathological processes. A more precise description of MS phenotypes will improve prognostication and personalized care as well as clinical trial design. Thus, our proposal provides an expanded framework for conceptualizing MS and for guiding development of biomarkers for monitoring activity along the main pathological axes in MS.</p

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD

Short-term disability progression in two multiethnic multiple sclerosis centers in the treatment era

Background: Short-term disease progression is well documented in clinical trials, but there are limited published data on disease course in real-life practice. Methods: Patient-derived Multiple Sclerosis Severity Score (PMSSS), a disease severity rank score, was computed at each visit for consecutive MS patients attending two large, ethnically diverse MS centers in New York metropolitan area. Disability was assessed via Patient-Determined Disease Steps (PDDS). Clinicians recorded disease subtype and relapse status at each visit, but did not rate disability. PMSSS change from the first to the last visit was calculated for the cohort as a whole and for subgroups of interest. Multivariable regression models were constructed for predicting final PMSSS based on readily available predictor variables collected at the initial visit and relapse history during follow up. Results: A total of 1740 consecutive patients from New York University ( n =  1079) and Barnabas ( n =  661) MS Care Centers were included. During follow up (mean 2.4 ± 0.82   years, range 1–4   years), mean PDDS score increased from 1.9 ± 2.2 to 2.3 ± 2.2 ( p <  0.0001), while PMSSS remained roughly unchanged (initial PMSSS = 3.71 ± 2.73, last PMSSS = 3.81 ± 2.76, paired t test, p =  0.28). The only major predictor of final PMSSS was the initial PMSSS. Demographic variables (age, sex, race) or relapse status did not predict final severity score. Conclusions: Baseline disability in two MS clinics was much lower than in the reference population from which PMSSS was derived. We observed no discernable slowing of disability accumulation during the short-term follow up in our cohort compared with the reference cohort. Overwhelmingly the most important predictor of final disease severity rank score was the initial disease severity rank score

Ultrahigh-Field MR (7 T) Imaging of Brain Lesions in Neuromyelitis Optica

Background. Brain lesions are common in neuromyelitis optica spectrum disorder (NMOsd) and may resemble lesions of multiple sclerosis (MS). Objectives. To describe the imaging characteristics of supratentorial lesions in NMOsd on ultrahigh-field (7 T) MRI with special attention to vessel-lesion relationship. Methods. Ten NMOsd patients, all women and all seropositive for NMO IgG, with mean age of 51.3 ± 15.4 years and disease duration of 9.2 ± 6.4 years, were scanned at a 7 T whole-body human MR system with high-resolution 2D gradient echo sequence optimized to best visualize lesions and venous structures, T2- and T1-weighted imaging. Results. In 10 patients with NMOsd, a total of 92 lesions were observed (mean: 9.2 ± 8.8; range: 2–30), but only 8 lesions (9%) were traversed by a central venule. All lesions were <5 mm in diameter, and 83% were located in subcortical white matter. There were no lesions in the cortex or basal ganglia. Two patients exhibited diffuse periependymal abnormalities on FLAIR. Conclusions. Small, subcortical lesions without a central venule are the most consistent finding of NMOsd on 7 T MRI of the brain. Ultrahigh-field imaging may be useful for differentiating between NMOsd and MS

Sound Lateralization Test Distinguishes Unimpaired MS Patients from Healthy Controls

There is an urgent need to develop a practical and reliable clinical measure of disease progression in early and mild MS. We hypothesized that a test of sound lateralization, which is exquisitely sensitive to transmission delays in auditory brainstem, could be more useful for detecting processing speed deficits in mildly impaired MS subjects than standard cognitive tasks. Objective. To develop a practical test of sound lateralization for the clinic and to compare performance of MS subjects with variable disability and healthy subjects on Sound Lateralization Test (SLT) and two speed-of-processing tasks. Design. 42 healthy controls and 90 subjects with clinically definite MS, divided into no, mild, and moderate disability strata, were administered the Symbol Digit Modalities Test (SDMT), and 3-second Paced Auditory Serial Addition Test (PASAT). Results. All of the tests showed an overall difference in performance between controls and the three MS groups, but only the SLT measured a significant difference between controls and the no disability group. Conclusion. SLT is rapidly applied, technically simple, and superior to standard processing speed tests for discriminating between healthy controls and nondisabled MS subjects. SLT should be investigated as an outcome measure in early-phase trials and for monitoring early disease progression in the clinic

Longitudinal study of multiple sclerosis lesions using ultra-high field (7T) multiparametric MR imaging.

Pathophysiology of multiple sclerosis (MS) lesions is dynamic and changes over time. The purpose of this exploratory study was to determine the longitudinal changes in MS lesions over time on ultra-high field MR imaging. Nine patients with MS underwent high-resolution 3D-susceptibility weighted imaging (SWI) and 2D-gradient-echo-T2*-weighted imaging on 7T MRI at baseline and after ~2.4 years of follow-up. Morphologic imaging characteristics, signal intensity patterns and quantitative susceptibility mapping (QSM) values of lesions were recorded at both time points. Lesions were classified as "iron-laden" if they demonstrated hypointense signal on T2*-weighted images and/or SWI as well as hyperintense signal on QSM. Lesions were considered "non-iron-laden" if they were hyperintense on T2*/SWI and isointense or hyperintense on QSM. Total of 162 non-iron-laden and 29 iron-laden lesions were observed at baseline. No change in baseline lesion size during follow up was recorded in 92.7%; no change in lesion-vessel relationship in 86.5%; and no change in signal intensity pattern in 96.9% of lesions. Three lesions which were non-iron-laden at baseline, exhibited iron at follow-up. In two iron-laden lesions, redistribution of iron content was observed at follow-up. Two-thirds of these iron-laden lesions showed an increase in QSM at follow-up relative to baseline, and the remaining one-third exhibited decrease in QSM. Most of the newly formed lesions (11/13, 84.6%) at follow-up were iron-laden. 7T multiparametric MRI is a useful tool for tracking the evolution of MS lesions, especially with regard to changes in iron content