COGNITION, REPETITIVE THOUGHT, AND SYSTEMIC INFLAMMATION IN THE MIDLIFE IN THE UNITED STATES STUDY

Segerstrom et al. (2017) found that more repetitive thought (RT) was related to lower interleukin-6 (IL-6), in older adults at average IQ. This study aimed to replicate and extend this finding in midlife adults, with a daily measure of RT, and additional inflammatory biomarkers. 153 participants were drawn from the Midlife in the United States (MIDUS) Refresher project; ages 25-70 (M = 45.07, SD = 10.96), 50.3% female, and 83% Caucasian. Cognition was assessed via the Brief Test of Adult Cognition by Telephone, biological data via fasted blood draw, and RT data were collected as part of the National Study of Daily Experiences daily diary. Total RT (amount one engages in RT) and RT valence (positive vs. negative thought content) were analyzed. As IQ increased, more positive RT was associated with lover levels of IL-6 and CRP after adjusting for age, BMI, and statin use (β = -.161, p = .029; β = -.240, p = .002). Results did not replicate Segerstrom et al. (2017) but suggested that crystallized intelligence and RT total reflect a cognitive system different than that of fluid intelligence, executive functioning, and RT valence. Future studies should continue to investigate effects of RT on health outcomes

Translational evidence for two distinct patterns of neuroaxonal injury in sepsis: a longitudinal, prospective translational study

Background Brain homeostasis deteriorates in sepsis, giving rise to a mostly reversible sepsis-associated encephalopathy (SAE). Some survivors experience chronic cognitive dysfunction thought to be caused by permanent brain injury. In this study, we investigated neuroaxonal pathology in sepsis. Methods We conducted a longitudinal, prospective translational study involving (1) experimental sepsis in an animal model; (2) postmortem studies of brain from patients with sepsis; and (3) a prospective, longitudinal human sepsis cohort study at university laboratory and intensive care units (ICUs). Thirteen ICU patients with septic shock, five ICU patients who died as a result of sepsis, fourteen fluid-resuscitated Wistar rats with fecal peritonitis, eleven sham-operated rats, and three human and four rat control subjects were included. Immunohistologic and protein biomarker analysis were performed on rat brain tissue at baseline and 24, 48, and 72 h after sepsis induction and in sham-treated rats. Immunohistochemistry was performed on human brain tissue from sepsis nonsurvivors and in control patients without sepsis. The clinical diagnostics of SAE comprised longitudinal clinical data collection and magnetic resonance imaging (MRI) and electroencephalographic assessments. Statistical analyses were performed using SAS software (version 9.4; SAS Institute, Inc., Cary, NC, USA). Because of non-Gaussian distribution, the nonparametric Wilcoxon test general linear models and the Spearman correlation coefficient were used. Results In postmortem rat and human brain samples, neurofilament phosphoform, β-amyloid precursor protein, β-tubulin, and H&E stains distinguished scattered ischemic lesions from diffuse neuroaxonal injury in septic animals, which were absent in controls. These two patterns of neuroaxonal damage were consistently found in septic but not control human postmortem brains. In experimental sepsis, the time from sepsis onset correlated with tissue neurofilament levels (R = 0.53, p = 0.045) but not glial fibrillary acidic protein. Of 13 patients with sepsis who had clinical features of SAE, MRI detected diffuse axonal injury in 9 and ischemia in 3 patients. Conclusions Ischemic and diffuse neuroaxonal injury to the brain in experimental sepsis, human postmortem brains, and in vivo MRI suggest these two distinct lesion types to be relevant. Future studies should be focused on body fluid biomarkers to detect and monitor brain injury in sepsis. The relationship of neurofilament levels with time from sepsis onset may be of prognostic value

A fully human anti-IL-7Rα antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer for which treatment options often result in incomplete therapeutic efficacy and long-term side-effects. Interleukin 7 (IL-7) and its receptor IL-7Rα promote T-ALL development and mutational activation of IL-7Rα associates with very high risk in relapsed disease. Using combinatorial phage-display libraries and antibody reformatting, we generated a fully human IgG1 monoclonal antibody (named B12) against both wild-type and mutant human IL-7Rα, predicted to form a stable complex with IL-7Rα at a different site from IL-7. B12 impairs IL-7/IL-7R-mediated signaling, sensitizes T-ALL cells to treatment with dexamethasone and can induce cell death per se. The antibody also promotes antibody-dependent natural killer-mediated leukemia cytotoxicity in vitro and delays T-cell leukemia development in vivo, reducing tumor burden and promoting mouse survival. B12 is rapidly internalized and traffics to the lysosome, rendering it an attractive vehicle for targeted intracellular delivery of cytotoxic cargo. Consequently, we engineered a B12-MMAE antibody-drug conjugate and provide proof-of-concept evidence that it has increased leukemia cell killing abilities as compared with the naked antibody. Our studies serve as a stepping stone for the development of novel targeted therapies in T-ALL and other diseases where IL-7Rα has a pathological role

Liver segmentation in MRI: a fully automatic method based on stochastic partitions

There are few fully automated methods for liver segmentation in magnetic resonance images (MRI) despite the benefits of this type of acquisition in comparison to other radiology techniques such as computed tomography (CT). Motivated by medical requirements, liver segmentation in MRI has been carried out. For this purpose, we present a new method for liver segmentation based on the watershed transform and stochastic partitions. The classical watershed over-segmentation is reduced using a marker-controlled algorithm. To improve accuracy of selected contours, the gradient of the original image is successfully enhanced by applying a new variant of stochastic watershed. Moreover, a final classifier is performed in order to obtain the final liver mask. Optimal parameters of the method are tuned using a training dataset and then they are applied to the rest of studies (17 datasets). The obtained results (a Jaccard coefficient of 0.91 +/- 0.02) in comparison to other methods demonstrate that the new variant of stochastic watershed is a robust tool for automatic segmentation of the liver in MRI. (C) 2014 Elsevier Ireland Ltd. All rights reserved.This work has been supported by the MITYC under the project NaRALap (ref. TSI-020100-2009-189), partially by the CDTI under the project ONCOTIC (IDI-20101153), by Ministerio de Educacion y Ciencia Spain, Project Game Teen (TIN2010-20187) projects Consolider-C (SEJ2006-14301/PSIC), "CIBER of Physiopathology of Obesity and Nutrition, an initiative of ISCIII" and Excellence Research Program PROMETEO (Generalitat Valenciana. Conselleria de Educacion, 2008-157). We would like to express our gratitude to the Hospital Clinica Benidorm, for providing the MR datasets and to the radiologist team of Inscanner for the manual segmentation of the MR images.López-Mir, F.; Naranjo Ornedo, V.; Angulo, J.; Alcañiz Raya, ML.; Luna, L. (2014). Liver segmentation in MRI: a fully automatic method based on stochastic partitions. Computer Methods and Programs in Biomedicine. 114(1):11-28. https://doi.org/10.1016/j.cmpb.2013.12.022S1128114

ADAMTSL3 as a candidate gene for schizophrenia: Gene sequencing and ultra-high density association analysis by imputation

We previously reported an association with a putative functional variant in the ADAMTSL3 gene, just below genome-wide significance in a genome-wide association study of schizophrenia. As variants impacting the function of ADAMTSL3 (a disintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3) could illuminate a novel disease mechanism and a potentially specific target, we have used complementary approaches to further evaluate the association. We imputed genotypes and performed high density association analysis using data from the HapMap and 1000 genomes projects. To review all variants that could potentially cause the association, and to identify additional possible pathogenic rare variants, we sequenced ADAMTSL3 in 92 schizophrenics. A total of 71 ADAMTSL3 variants were identified by sequencing, many were also seen in the 1000 genomes data, but 26 were novel. None of the variants identified by re-sequencing was in strong linkage disequilibrium (LD) with the associated markers. Imputation analysis refined association between ADAMTSL3 and schizophrenia, and highlighted additional common variants with similar levels of association. We evaluated the functional consequences of all variants identified by sequencing, or showing direct or imputed association. The strongest evidence for function remained with the originally associated variant, rs950169, suggesting that this variant may be causal of the association. Rare variants were also identified with possible functional impact. Our study confirms ADAMTSL3 as a candidate for further investigation in schizophrenia, using the variants identified here. The utility of imputation analysis is demonstrated, and we recommend wider use of this method to re-evaluate the existing canon of suggestive schizophrenia associations

Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease

The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of 111In-labeled neutrophils at these sites and clearance of 32P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway

The prognostic value of neurofilament levels in patients with sepsis-associated encephalopathy - A prospective, pilot observational study

Sepsis-associated encephalopathy (SAE) contributes to mortality and neurocognitive impairment of sepsis patients. Neurofilament (Nf) light (NfL) and heavy (NfH) chain levels as biomarkers for neuroaxonal injury were not evaluated in cerebrospinal fluid (CSF) and plasma of patients with sepsis-associated encephalopathy (SAE) before. We conducted a prospective, pilot observational study including 20 patients with septic shock and five patients without sepsis serving as controls. The assessment of SAE comprised a neuropsychiatric examination, electroencephalography (EEG), magnetic resonance imaging (MRI) and delirium screening methods including the confusion assessment method for the ICU (CAM-ICU) and the intensive care delirium screening checklist (ICDSC). CSF Nf measurements in sepsis patients and longitudinal plasma Nf measurements in all participants were performed on days 1, 3 and 7 after study inclusion. Plasma NfL levels increased in sepsis patients over time (p = 0.0063) and remained stable in patients without sepsis. Plasma NfL values were significantly higher in patients with SAE (p = 0.011), significantly correlated with the severity of SAE represented by ICDSC values (R = 0.534, p = 0.022) and correlated with a poorer functional outcome after 100 days (R = -0.535, p = 0.0003). High levels of CSF Nf were measured in SAE patients. CSF NfL levels were higher in non-survivors (p = 0.012) compared with survivors and correlated with days until death (R = -0.932, p<0.0001) and functional outcome after 100 days (R = -0.749, p<0.0001). The present study showed for the first time that Nf levels provide complementary prognostic information in SAE patients indicating a higher chance of death and poorer functional/cognitive outcome in survivors

Correction: The prognostic value of neurofilament levels in patients with sepsis-associated encephalopathy - A prospective, pilot observational study

[This corrects the article DOI: 10.1371/journal.pone.0211184.]