Efficient pulse sequence for multisection dual-repetition time MR image acquisition

A magnetic resonance imaging pulse sequence was developed in which multisection spin-echo image data are simultaneously acquired for two repetition time (TR) intervals (TR1 and TR2) in one imaging sequence. In a conventional multisection image at a single TR, the number of sections is limited to TR/TS, where TS is the readout time. With this new sequence, the number of sections that can be imaged at both TRs in one acquisition is equal to (TR1 + TR2)/(TS1 + TS2), where TS1 and TS2 may be different for the two TRs. Imaging time is equal to that for a single image at a TR of TR1 + TR2. Clinical images were obtained with the new sequence from 15 patients and compared with images acquired at the same TR/TE by means of standard multisection single-TR methods. Relative image quality was assessed by three radiologists in 37 comparisons. In general, the dual-TR results at the long TR were judged equivalent to those from a single-TR image. Dual-TR results at the short TR had a modest reduction in contrast, but in none of 15 cases were any pathologic features missed.     

On-chip phenotypic analysis of inflammatory monocytes in atherogenesis and myocardial infarction

Monocyte recruitment to inflamed arterial endothelium initiates plaque formation and drives progression of atherosclerosis. Three distinct monocyte subsets are detected in circulation (CD14⁺⁺CD16⁻, CD14⁺⁺CD16⁺, and CD14⁺CD16⁺⁺), and each may play distinct roles during atherogenesis and myocardial infarction. We studied a range of subjects that included otherwise healthy patients with elevated serum triglyceride levels to patients presenting with acute myocardial infarction. Our objective was to correlate an individual’s risk with the activation state of each monocyte subset as a function of changes in adhesion receptor expression using flow cytometric quantitation of integrins and l-selectin membrane expression. A microfluidic-based laboratory-on-a-chip was developed to quantify the adhesion efficiency of monocytes sheared in whole blood on vascular cell adhesion molecule-1, while characterizing adhesion receptor expression and topography on captured monocytes. CD14⁺⁺CD16⁺ monocytes adhered with sevenfold higher efficiency than other subsets, and in patients with myocardial infarction the capture efficiency of this subset was double that for healthy subjects. In patients with hypertriglyceridemia, this increase in monocyte adhesion was attributable to CD14⁺⁺CD16⁺ uptake of triglyceride-rich lipoproteins and subsequent signaling via a Phospholipase C–dependent mechanism to increase CD11c expression, very late antigen–4 function, and integrin coclustering within focal adhesive sites on vascular cell adhesion molecule-1. In summary, we introduce a unique laboratory-on-a-chip method for quantifying the activation state of monocyte subsets. These experiments reveal that CD11c/CD18 is an inducible integrin whose expression correlates with a monocyte inflammatory state in subjects at risk for atherogenesis and in patients with myocardial infarction.     

A Translational Rodent Assay of Affective Biases in Depression and Antidepressant Therapy

The subjective measures used to study mood disorders in humans cannot be replicated in animals; however, the increasing application of objective neuropsychological methods provides opportunities to develop translational animal tasks. Here we describe a novel behavioral approach, which has enabled us to investigate similar affective biases in rodents. In our affective bias test (ABT), rats encounter two independent positive experiences—the association between food reward and specific digging substrate—during discrimination learning sessions. These are performed on separate days under either neutral conditions or during a pharmacological or affective state manipulation. Affective bias is then quantified using a preference test where both previously rewarded substrates are presented together and the rat''s choices recorded. The absolute value of the experience is kept consistent and all other factors are counterbalanced so that any bias at recall can be attributed to treatment. Replicating previous findings from studies in healthy volunteers, we observe significant positive affective biases following acute treatment with typical (fluoxetine, citalopram, reboxetine, venlafaxine, clomipramine) and atypical antidepressants (agomelatine, mirtazapine), and significant negative affective biases following treatment with drugs associated with inducing negative affective states in humans (FG7142, rimonabant, 13-cis retinoic acid). We also observed that acute psychosocial stress and environmental enrichment induce significant negative and positive affective biases, respectively, and provide evidence that these affective biases involve memory consolidation. The positive and negative affective biases induced in our test also mirror the antidepressant and pro-depressant effects of these drugs in patients suggesting our test has both translational and predictive validity. Our results suggest that cognitive affective biases could contribute to drug- or stress-induced mood changes in people and support the hypothesis that a cognitive neuropsychological mechanism contributes to antidepressant drug efficacy.     

Immunotoxicological profile of chloroform in female B6C3F1 mice when administered in drinking water

Chloroform can be formed as a disinfection by-product during water chlorination, one of the primary modalities for purifying municipal water supplies for human consumption. The aim of this study was to characterize the immunotoxic effects of chloroform in female B6C3F1 mice when exposure occurred via the drinking water. Consistent with human exposure, female B6C3F1 mice were exposed to chloroform-containing drinking water at 2.5, 10, 25, 100, and 250 ppm for 28 days. The examined endpoints included the effects of chloroform on body and organ weights, water consumption, hematology, innate immunity, humoral immunity, and cell-mediated immunity. The functions of natural killer, B-, and T-cells were not altered by chloroform in drinking water at the concentrations tested, except that an increase in splenocyte basal proliferation was observed at chloroform levels of 100 and 250 ppm. Following chloroform administration, there was a decreased number of circulating neutrophils in the blood in all treatment groups, but neutrophil function in lung homogenates, as evaluated using an assay for myeloperoxidase activity following lipopolysaccharide and N-Formyl-Met-Leu-Phe stimulation, was not compromised. Further, the results of host resistance to Listeria monocytogenes infection also suggested that neutrophil function was normal. At the highest treatment level of chloroform (250 ppm), erythrocyte number and hemoglobin levels were significantly decreased. Some significant changes were also observed for body weights, water consumption, and organ weights; however, most of these effects were only observed at the highest treatment level of chloroform (250 ppm). Taken together, the results demonstrate that while chloroform administered via the drinking water affects body weight and selected hematological parameters at high dose levels, overall immune responses, as measured in several tests for immune function, are not compromised.     

Temporal changes in cytokine gene expression profiles induced in mice by trimellitic anhydride

Prolonged (13 day) topical exposure of BALB/c strain mice to the chemical respiratory allergen trimellitic anhydride (TMA) induces a selective T helper (Th) 2 profile of cytokine secretion in cells isolated from the draining lymph node. The ability of chemical respiratory allergens to elicit preferential type 2 immune responses is a distinguishing characteristic and provides the theoretical basis for cytokine fingerprinting, a novel approach to hazard identification. This study aimed to further characterize the cytokine expression profile induced by TMA, and to investigate the kinetics of cytokine production at both the protein and mRNA level by comparison of acute (3 day) and chronic (13 day) exposure regimes. Acute exposure resulted in the expression of high levels of mRNA for both Th1- and Th2-type cytokines, including interleukins 4, 10, 15 (IL-4, IL-10, IL-15) and interferon gamma (IFN-gamma), and the inflammatory cytokine IL-6, as determined by ribonuclease protection assay (RPA). However, following chronic exposure marked down-regulation of message for IL-6 and IFN-gamma was observed along with concomitant up-regulation of IL-4 and IL-10 expression. These cytokine mRNA profiles were broadly paralleled at the protein level. There was also a marked increase with time of mRNA for the Th2 cytokine IL-9, a cytokine not associated previously with chemical allergy. These data show that as the immune response to TMA develops, the cytokine gene expression profile of allergen-activated lymph node cells evolves from a mixed Th1/Th2 phenotype to a more polarized Th2 profile.     

Alternative approaches to the identification and characterization of chemical allergens.

Chemical allergy can take a variety of forms, those of greatest importance in an occupational setting being skin sensitization resulting in allergic contact dermatitis and sensitization of the respiratory tract associated with asthma and other symptoms. In both cases there is a need for predictive test methods that allow the accurate identification of sensitizing chemicals. Well characterized methods are available for skin sensitization testing, and although to date no tests for respiratory sensitization have been formally validated, progress has been made in defining suitable animal models. In recent years there have been significant advances in our understanding of the cellular and molecular mechanisms through which allergic sensitization to chemicals is induced and regulated. Such progress provides us now with new opportunities to consider alternative approaches to sensitization testing, including the design of in vitro test methods. The greatest investment has been in exploring novel methods for the identification of contact sensitizers and it is upon this aspect of chemical allergy that this article is focused. Described here are some of the general requirements of in vitro test methods for skin sensitization, and progress that has been made in developing suitable approaches with particular emphasis on the utility of dendritic cell culture systems.     

Multidetector CT and histological features of benign mesenchymoma of the infratemporal space: a rare case report

Benign mesenchymoma is a soft tissue neoplasm composed of an admixture of two or more benign mesenchymal components in addition to fibrous tissue. A rare case of benign mesenchymoma of the infratemporal space in a 14-year-old boy is presented. In this case report we discuss the salient imaging and histopathological features of this rare entity.