Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy

Natalizumab is an approved medication for highly active multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) may occur as a severe side effect of this drug. Here, we describe pathological and radiological characteristics of immune reconstitution inflammatory syndrome (IRIS), which occurs in natalizumab-associated PML after the cessation of therapy, and we differentiate it from ongoing PML. Brain biopsy tissue and MRI scans from five MS patients with natalizumab-associated PML were analyzed and their histology compared with non-MS PML. Histology showed an extensive CD8-dominated T cell infiltrate and numerous macrophages within lesions, and in nondemyelinated white and grey matter, in four out of five cases. Few or no virally infected cells were found. This was indicative of IRIS as known from HIV patients with PML. Outstandingly high numbers of plasma cells were present as compared to non-MS PML and typical MS lesions. MRI was compatible with IRIS, revealing enlarging lesions with a band-like or speckled contrast enhancement either at the lesion edge or within lesions. Only the fifth patient showed typical PML pathology, with low inflammation and high numbers of virally infected cells. This patient showed a similar interval between drug withdrawal and biopsy (3.5 months) to the rest of the cohort (range 2.5–4 months). MRI could not differentiate between PML-associated IRIS and ongoing PML. We describe in detail the histopathology of IRIS in natalizumab-associated PML. PML–IRIS, ongoing PML infection, and MS exacerbation may be impossible to discern clinically alone. MRI may provide some clues for distinguishing different pathologies that can be differentiated histologically. In our individual cases, biopsy helped to clarify diagnoses in natalizumab-associated PML

Functional Energetics of CD4+-Cellular Immunity in Monoclonal Antibody-Associated Progressive Multifocal Leukoencephalopathy in Autoimmune Disorders

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system- (CNS-) infection that typically occurs in a subset of immunocompromised individuals. An increasing incidence of PML has recently been reported in patients receiving monoclonal antibody (mAb) therapy for the treatment of autoimmune diseases, particularly those treated with natalizumab, efalizumab and rituximab. Intracellular CD4(+)-ATP-concentration (iATP) functionally reflects cellular immunocompetence and inversely correlates with risk of infections during immunosuppressive therapy. We investigated whether iATP may assist in individualized risk stratification for opportunistic infections during mAb-treatment. METHODOLOGY/PRINCIPAL FINDINGS: iATP in PHA-stimulated, immunoselected CD4(+)-cells was analyzed using an FDA-approved assay. iATP of mAb-associated PML (natalizumab (n = 8), rituximab (n = 2), efalizumab (n = 1)), or other cases of opportunistic CNS-infections (HIV-associated PML (n = 2), spontaneous PML, PML in a psoriasis patient under fumaric acids, natalizumab-associated herpes simplex encephalitis (n = 1 each)) was reduced by 59% (194.5±29 ng/ml, mean±SEM) in comparison to healthy controls (HC, 479.9±19.8 ng/ml, p<0.0001). iATP in 14 of these 16 patients was at or below 3(rd) percentile of healthy controls, similar to HIV-patients (n = 18). In contrast, CD4(+)-cell numbers were reduced in only 7 of 15 patients, for whom cell counts were available. iATP correlated with mitochondrial transmembrane potential (ΔΨ(m)) (iATP/ΔΨ(m)-correlation:tau = 0.49, p = 0.03). Whereas mean iATP of cross-sectionally analysed natalizumab-treated patients was unaltered (448.7±12 ng/ml, n = 150), iATP was moderately decreased (316.2±26.1 ng/ml, p = 0.04) in patients (n = 7) who had been treated already during the pivotal phase III trials and had received natalizumab for more than 6 years. 2/92 (2%) patients with less than 24 months natalizumab treatment revealed very low iATP at or below the 3(rd) percentile of HC, whereas 10/58 (17%) of the patients treated for more than 24 months had such low iATP-concentrations. CONCLUSION: Our results suggest that bioenergetic parameters such as iATP may assist in risk stratification under mAb-immunotherapy of autoimmune disorders

Cogena, a novel tool for co-expressed gene-set enrichment analysis, applied to drug repositioning and drug mode of action discovery

This work was supported by the portfolio of translational research of the National Institutes for Health Research Cardiovascular Biomedical Research Unit at Barts, the UK Medical Research Council (JID-2015-0339), Major Research Plan of The National Natural Science Foundation of China [grant number U1435222], Plan for Innovative Graduate Student at NUDT [grant number B140202], Plan for interdisciplinary joint PhD students at NUDT and China Scholarship Council [to ZJ]

A Centrifuge Model Test of the Ground Motion Response in a Moderately Stiff Soil

The ground motion response in a moderately stiff soil in seismic events has been traditionally studied based on the actual field records which, however, have yet to offer consistent results regarding the amplification effect of the ground motion. In the present study, a centrifuge model of the moderately stiff soil field is designed to study the amplification effect of the ground motion in response to seismic loads. Four El Centro waves of different strengths are used as the input wave at the base under a gravitational field of 75 g. Ground motion data at different depths are collected via a number of sensors to study the acceleration peak, time history, and response spectrum of the ground motion. The measured amplitude and energy of seismic waves are found to gradually increase from the bottom to the surface during the propagation of seismic waves, and the peak acceleration at the surface is significantly magnified. The response spectrum analysis shows that the acceleration response spectrum gradually moves to the high-frequency direction from the base to the surface and the value of the response spectrum decreases with the increase of the depth in the present study

Stimuli involved in dental anxiety: What are patients afraid of? A descriptive study

Background: Dental anxiety is a psychological response inducing aversion following a dental ill-defined stimulus, non-imminent and perceived as potentially dangerous. It is better to intervene during childhood than to resolve in adulthood when dental anxiety is more settled. Aim: The purpose of this study is to determine the nature of dental anxiety-provoking stimuli in young patients. Design: A questionnaire was submitted to 566 children between 3 to 18 years in health institutions and schools in Brussels, Belgium. The items were divided into 3 groups: environment (ENV), local anaesthesia (LA), and intervention (INT) and summarized through averaging per group. Descriptive analysis and non-parametric testing were combined with logistic regression after discretization, above mild, for the group averages. Results: About 7.2% of the respondents expressed high to severe dental anxiety. Several items presented a clear bimodal distribution dividing the population in fearless and fearing patients, for example, sight and feel of the syringe, sight and taste of blood and extraction. Others presented with a gradually lower incidence with increasing fear level. Fear for the environment was generally low. Gender and ethnic origin contribute significantly to the prediction of fear caused by LA. For fear caused by INT, first the place of questioning enters the models, thereafter follow: negative experience, frequency of dental visit, and gender (P <.05). Conclusions: While the dental environment is in general not causing fear, the invasive part of the anaesthesia and the invasive dental procedures are involved. Fear seems to be related to culture, previous experience, and gender.SCOPUS: ar.jinfo:eu-repo/semantics/publishe