Multimodal MRI assessment for first episode psychosis: A major change in the thalamus and an efficient stratification of a subgroup

Multi‐institutional brain imaging studies have emerged to resolve conflicting results among individual studies. However, adjusting multiple variables at the technical and cohort levels is challenging. Therefore, it is important to explore approaches that provide meaningful results from relatively small samples at institutional levels. We studied 87 first episode psychosis (FEP) patients and 62 healthy subjects by combining supervised integrated factor analysis (SIFA) with a novel pipeline for automated structure‐based analysis, an efficient and comprehensive method for dimensional data reduction that our group recently established. We integrated multiple MRI features (volume, DTI indices, resting state fMRI—rsfMRI) in the whole brain of each participant in an unbiased manner. The automated structure‐based analysis showed widespread DTI abnormalities in FEP and rs‐fMRI differences between FEP and healthy subjects mostly centered in thalamus. The combination of multiple modalities with SIFA was more efficient than the use of single modalities to stratify a subgroup of FEP (individuals with schizophrenia or schizoaffective disorder) that had more robust deficits from the overall FEP group. The information from multiple MRI modalities and analytical methods highlighted the thalamus as significantly abnormal in FEP. This study serves as a proof‐of‐concept for the potential of this methodology to reveal disease underpins and to stratify populations into more homogeneous sub‐groups.     

A Demonstration of the Generalizability of Twin-based Research on Antisocial Behavior

Researchers typically analyze samples of twin pairs in order to decompose trait variance into genetic and environmental components. This methodological technique, referred to as twin-based research, rests on several assumptions that must be satisfied in order to produce unbiased results. While research has analyzed the tenability of certain assumptions such as equal environments, less attention has been given to whether results gleaned from samples of twins generalize to the broader population of non-twins. The current study analyzed data drawn from the National Longitudinal Study of Adolescent Health and findings suggested twins do not systematically differ from the general population of non-twins on many measures of behavior and development. Furthermore, the effects of specific covariates on measures of antisocial behavior did not appear to differ across twin status. In sum, evidence concerning the etiology of antisocial behavior (e.g., heritability estimates) gleaned from twin-based research is likely to generalize to the non-twin population.     

Slam Haplotype 2 Promotes NKT But Suppresses Vγ4+ T-Cell Activation in Coxsackievirus B3 Infection Leading to Increased Liver Damage But Reduced Myocarditis

There are two major haplotypes of signal lymphocytic activation molecule (Slam) in inbred mouse strains, with the Slam haplotype 1 expressed in C57Bl/6 mice and the Slam haplotype 2 expressed in most other commonly used inbred strains, including 129 mice. Because signaling through Slam family receptors can affect innate immunity [natural killer T cell (NKT) and γ-δ T-cell receptor], and innate immunity can determine susceptibility to coxsackievirus B3 (CVB3) infection, the present study evaluated the response of C57Bl/6 and congenic B6.129c1 mice (expressing the 129-derived Slam locus) to CVB3. CVB3-infected C57Bl/6 male mice developed increased myocarditis but reduced hepatic injury compared with infected B6.129c1 mice. C57Bl/6 mice also had increased γδ⁺ and CD8⁺interferon-γ⁺ cells but decreased numbers of NKT (T-cell receptor β chain + mCD1d tetramer⁺) and CD4⁺FoxP3⁺ cells compared with B6.129c1 mice. C57Bl/6 mice were infected with CVB3 and treated with either α-galactosylceramide, an NKT cell-specific ligand, or vehicle (dimethyl sulfoxide/PBS). Mice treated with α-galactosylceramide showed significantly reduced myocarditis. Liver injuries, as determined by alanine aminotransferase levels in plasma, were increased significantly, confirming that NKT cells are protective for myocarditis but pathogenic in the liver.Myocarditis is an inflammation of the cardiac muscle that follows microbial infections.¹ Among viruses, enteroviruses including coxsackie B viruses are common etiologic agents.^2,3 Although infectious agents act as a trigger for myocarditis, there is considerable debate as to the actual mechanism(s) of myocardial injury. Viruses directly cause cellular dysfunction either through induced cell death, shut down of cell RNA and protein synthesis, or viral protease cleavage of contractile proteins.^4,5 In addition, cytokines such as IL-1β, IL-6, and tumor necrosis factor α, which are elicited from resident cells in the heart subsequent to infection, can suppress contractility, leading to cardiac dysfunction.⁶ Finally, host immune responses to infection may kill myocytes, leading to cardiac stress. Host response can be directed specifically toward virally infected cardiocytes or infection can trigger autoimmunity to cardiac antigens (autoimmunity), which destroys both infected and uninfected myocytes.⁷Host innate immune responses occur rapidly, subsequent to viral infections, and usually have broad specificity, unlike the classic adaptive immune response, which requires a week or more for development of a measurable response in the naive individual but is highly specific to the inducing pathogen. The innate immune response both helps to control microbe load before generation of the adaptive immune response and has a major impact on the phenotype and intensity of the adaptive response. Two types of T cells representing innate immunity are natural killer T cells (NKT) and T cells expressing the γ-δ T-cell receptor (γδ⁺). A study by Wu et al⁸ showed that in vivo administration of α-galactosylceramide, a ligand that specifically activates NKT cells, protects mice from coxsackievirus B3 (CVB3)-induced myocarditis. Prior studies have shown that signaling through Slam family receptors has a major impact on NKT cell development,^9–11 and that different Slam haplotypes can have distinct effects on NKT cell response and function.^9,12 There are two major Slam haplotypes, Slam haplotype 1 and Slam haplotype 2, that distinguish commonly used inbred mouse strains.^13,14 Slam haplotype 1 is present in C57Bl/6, and Slam haplotype 2 is present in most other commonly used mouse strains including 129S1/SvImJ and BALB/c mice. The congenic B6.129c1 mouse expresses the genetic region of chromosome 1 containing the 129-derived Slam haplotype 2 locus on the C57Bl/6 background and was used previously to show Slam haplotype control of liver NKT cell numbers and NKT cell cytokine production.¹² In addition, Slam haplotypes previously were shown to regulate macrophage tumor necrosis factor production in response to lipopolysaccharide.¹² Although less well studied, Slam family–receptor signaling also has been shown to affect γδ⁺ T-cell development. Studies using human peripheral blood mononuclear cells stimulated in vitro with antibody to CD3 and either IL-2, anti-CD150 (SLAM), or IL-15 showed that all three stimulation protocols resulted in γδ⁺ T-cell survival. However, co-culture with anti-CD3 and anti-CD150 resulted in selective proliferation of CD8⁺CD56⁺γδ⁺ T cells expressing the Vδ1 chain, and cells co-cultured with anti-CD3 and IL-15 resulted in preferential generation of CD8⁻CD56⁻γδ⁺ cells expressing the Vδ2 chain.¹⁵ Therefore, SLAM signaling can impact the generation of a subpopulation of the total γδ⁺ cell population in humans. Prior studies from the Huber laboratory have shown that a subpopulation of γδ⁺ cells is crucial to myocarditis susceptibility subsequent to CVB3 infection¹⁶ and that the relevant γδ⁺ cell expresses both CD8 and the Vγ4 chain.^16,17 This raised the question of whether Slam haplotypes modulated selected γδ⁺ cell subsets in the mouse, as it does in humans, and whether the Slam haplotype specifically could affect activation of the CD8⁺Vγ4⁺ T cell, which is known to be pathogenic in CVB3-induced myocarditis.CVB3 infection of mice results in multiple organ infection, including pancreas, liver, and heart with accompanying tissue injury in all tissues. There are well-established differences in disease susceptibility between BALB/c and C57Bl/6 mice, strains expressing the two distinct Slam haplotypes. C57Bl/6 mice are highly susceptible to type 2 autoimmune hepatitis and develop extensive hepatic inflammation, whereas BALB/c mice are resistant to this disease and show no inflammation.¹⁸ In contrast, BALB/c mice are more susceptible to myocarditis^19–22 compared with the more resistant C57Bl/6 strain. However, there are many genetic differences between BALB/c and C57Bl/6 mice, which may influence disease development or development and activation of specific innate effectors such as NKT and γδ T cells. The goal of the current study was to determine whether Slam haplotype affected NKT and Vγ4⁺ T-cell responses subsequent to CVB3 infection using C57Bl/6 congenic mice in which the Slam locus alone differed between the mouse strains, and whether haplotype-dependent NKT/Vγ4⁺ cell response had a distinct effect in different organs infected with the virus in the absence of the many other genetic differences between BALB/c and C57Bl/6 mice.     

Improving IR Ergonomics Using a Flexible C-Arm System

PurposeTo evaluate the impact of a versatile flexible ceiling-mounted C-arm on active table and gantry repositioning during interventions and its effect on operator discomfort, system usability, and patient safety compared with a traditional ceiling-mounted system.Materials and MethodsThere were 100 IR procedures studied: 50 in a traditional IR system (standard group) and 50 with a novel multiaxis ceiling-mounted system (test group). FlexArm was capable of multiple gantry rotation points allowing increased access to the patient in addition to 236 cm of lateral x-ray detector travel. For each procedure, both the table and the gantry repositioning were measured. Patient safety, patient/equipment repositioning effort, and physical discomfort were evaluated through an operator survey.ResultsTable repositioning was reduced from 42 to 16 instances per procedure (P < .001) in the test group compared with the standard group. The operators perceived less table and gantry repositioning effort (P < .0001) and decreased risks of equipment collisions, displacement of vascular access, and dislodgment of tubes/lines with the test group (P < .0001). Operator discomfort was reduced for all body areas in the test group over the standard group (P < .0001).ConclusionsThe FlexArm system geometry enhances operator ergonomics, as there was a decrease need to move the table, leading to a perceived decrease in patient risk and decrease operator physical discomfort when compared to a traditional imaging system.     

Association of high-risk coronary atherosclerosis at CCTA with clinical and circulating biomarkers: Insight from CAPIRE study

BackgroundHigh-risk coronary atherosclerosis features evaluated coronary CT angiography (CCTA) were suggested to have a prognostic role. The present study aimed to evaluate the association of circulating biomarkers with high-risk plaque features assessed by CCTA.MethodsA consecutive cohort of subjects who underwent CCTA because of suspected CAD was screened for inclusion in the CAPIRE study. Based on risk factors (RF) burden patients were defined as having a low clinical risk (0–1 RF with the exclusion of patients with diabetes mellitus as single RF) or an high clinical risk (≥3 RFs). In all patients, measurement of inflammatory biomarkers and CCTA analysis focused on high-risk plaque features were performed. Univariate and multivariate logistic regression analysis were used to evaluate the relationship between clinical and biological variables with CCTA advanced plaque features.Results528 patients were enrolled in CAPIRE study. Older age and male sex appeared to be predictors of qualitative high-risk plaque features and associated with the presence of elevated total, non-calcified and low-attenuation plaque volume. Among circulating biomarkers only hs-CRP was found to be associated with qualitative high-risk plaque features (OR 2.02, p = 0.004 and 2.02, p = 0.012 for LAP and RI > 1.1, respectively) with borderline association with LAP-Vol (OR 1.52, p = 0.076); HbA1c and PTX-3 resulted to be significantly associated with quantitative high-risk plaque features (OR 1.71, p = 0.003 and 1.04, p = 0.002 for LAP-Vol, respectively).ConclusionsOur results support the association between inflammatory biomarkers (hs-CRP, PTX- 3), HbA1c and high-risk atherosclerotic features detected by CCTA. Male sex and older age are significant predictors of high-risk atherosclerosis.     

Rho guanine nucleotide exchange factor is an NFL mRNA destabilizing factor that forms cytoplasmic inclusions in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive disorder of unknown etiology characterized by the selective degeneration of motor neurons. Recent evidence supports the hypothesis that alterations in RNA metabolism in motor neurons can explain the development of protein inclusions, including neurofilamentous aggregates, observed in this pathology. In mice, p190RhoGEF, a guanine nucleotide exchange factor, is involved in neurofilament protein aggregation in an RNA-triggered transgenic model of motor neuron disease. Here, we observed that rho guanine nucleotide exchange factor (RGNEF), the human homologue of p190RhoGEF, binds low molecular weight neurofilament mRNA and affects its stability via 3′ untranslated region destabilization. We observed that the overexpression of RGNEF in a stable cell line significantly decreased the level of low molecular weight neurofilament protein. Furthermore, we observed RGNEF cytoplasmic inclusions in ALS spinal motor neurons that colocalized with ubiquitin, p62/sequestosome-1, and TAR (trans-active regulatory) DNA-binding protein 43 (TDP-43). Our results provide further evidence that RNA metabolism pathways are integral to ALS pathology. This is also the first described link between ALS and an RNA binding protein with aggregate formation that is also a central cell signaling pathway molecule.     

Virus species polemics: 14 senior virologists oppose a proposed change to the ICTV definition of virus species

The Executive Committee of the International Committee on Taxonomy of Viruses (ICTV) has recently decided to modify the current definition of virus species (Code of Virus Classification and Nomenclature Rule 3.21) and will soon ask the full ICTV membership (189 voting members) to ratify the proposed controversial change. In this discussion paper, 14 senior virologists, including six Life members of the ICTV, compare the present and proposed new definition and recommend that the existing definition of virus species should be retained. Since the pros and cons of the proposal posted on the ICTV website are not widely consulted, the arguments are summarized here in order to reach a wider audience.