Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation

Crohn’s disease is a chronic, idiopathic condition characterized by intestinal inflammation and debilitating gastrointestinal symptomatology. Previous studies of inflammatory bowel disease (IBD), primarily in colitis, have shown reduced inflammation after electrical or pharmacological activation of the vagus nerve, but the scope and kinetics of this effect are incompletely understood. To investigate this, we studied the effect of electrical vagus nerve stimulation (VNS) in a rat model of indomethacin-induced small intestinal inflammation. 1 min of VNS significantly reduced small bowel total inflammatory lesion area [(mean ± SEM) sham: 124 ± 14 mm2, VNS: 62 ± 14 mm2, p = 0.002], intestinal peroxidation and chlorination rates, and intestinal and systemic pro-inflammatory cytokine levels as compared with sham-treated animals after 24 h following indomethacin administration. It was not known whether this observed reduction of inflammation after VNS in intestinal inflammation was mediated by direct innervation of the gut or if the signals are relayed through the spleen. To investigate this, we studied the VNS effect on the small bowel lesions of splenectomized rats and splenic nerve stimulation (SNS) in intact rats. We observed that VNS reduced small bowel inflammation also in splenectomized rats but SNS alone failed to significantly reduce small bowel lesion area. Interestingly, VNS significantly reduced small bowel lesion area for 48 h when indomethacin administration was delayed. Thus, 1 min of electrical activation of the vagus nerve reduced indomethacin-induced intestinal lesion area by a spleen-independent mechanism. The surprisingly long-lasting and spleen-independent effect of VNS on the intestinal response to indomethacin challenge has important implications on our understanding of neural control of intestinal inflammation and its potential translation to improved therapies for IBD.

CARNet: Cascade attentive RefineNet for multi-lesion segmentation of diabetic retinopathy images

Diabetic retinopathy is the leading cause of blindness in working population. Lesion segmentation from fundus images helps ophthalmologists accurately diagnose and grade of diabetic retinopathy. However, the task of lesion segmentation is full of challenges due to the complex structure, the various sizes and the interclass similarity with other fundus tissues. To address the issue, this paper proposes a cascade attentive RefineNet (CARNet) for automatic and accurate multi-lesion segmentation of diabetic retinopathy. It can make full use of the fine local details and coarse global information from the fundus image. CARNet is composed of global image encoder, local image encoder and attention refinement decoder. We take the whole image and the patch image as the dual input, and feed them to ResNet50 and ResNet101, respectively, for downsampling to extract lesion features. The high-level refinement decoder uses dual attention mechanism to integrate the same-level features in the two encoders with the output of the low-level attention refinement module for multiscale information fusion, which focus the model on the lesion area to generate accurate predictions. We evaluated the segmentation performance of the proposed CARNet on the IDRiD, E-ophtha and DDR data sets. Extensive comparison experiments and ablation studies on various data sets demonstrate the proposed framework outperforms the state-of-the-art approaches and has better accuracy and robustness. It not only overcomes the interference of similar tissues and noises to achieve accurate multi-lesion segmentation, but also preserves the contour details and shape features of small lesions without overloading GPU memory usage.

Ginsenoside Rb2 Alleviated Atherosclerosis by Inhibiting M1 Macrophages Polarization Induced by MicroRNA-216a

Introduction: Atherosclerosis is a chronic disease characterized by the inflammatory process and lipid depositions. We previously reported that microRNA-216a (miR-216a) can accelerate the progression of atherosclerosis by promoting the polarization of M1 pro-inflammatory phenotype. Ginsenoside Rb2 (Rb2), the major pharmacologically active compound extracted from ginseng, has a high affinity to miR-216a. In this study, we aimed to investigate whether Rb2 can counteract the effect of miR-216a in macrophages to ameliorate atherosclerosis.Methods: The apolipoprotein E deficiency (ApoE−/−) mice model was chronically infected with miR-216a adenovirus via the tail vein and then intraperitoneally injected with Rb2. The plaque lesion area and stability of thoracic aorta were examined. The human myeloid leukemia mononuclear cells (THP-1) or human peripheral blood mononuclear cells (PBMCs) were cultured in vitro, transfected with miR-216a mimics, and treated with Rb2 to explore the mechanisms of Rb2 on the polarization of M1 macrophages, inflammatory process, and lipid accumulation.Results: In the atherosclerotic ApoE−/− mice model, miR-216a greatly increased en face aortic lesion area of the thoracic aorta, lipid accumulation, and M1 macrophages infiltration in plaques, whereas these effects of miR-216a on atherosclerosis burden were significantly alleviated by Rb2 treatment. In the in vitro THP-1 model, the flow cytometry experiment showed that Rb2 treatment inhibited miR-216a–mediated polarization of M1 macrophages characterized by the surface marker CD86 expression but had no effects on M2 polarization characterized by the surface marker CD206 expression. Mechanistically, Rb2 suppressed the miR-216a–mediated inflammatory response through the Smad3/nuclear factor kappa B inhibitor alpha pathway. Moreover, Rb2 reduced the lipid uptake and promoted cholesterol efflux by counteracting the effects of miR-216a in the THP-1–derived foam cells and in the PBMC-derived foam cells under the oxidized low-density lipoproteins.Conclusion: Our findings indicated that Rb2 might be a potential therapeutic molecule for atherosclerosis by attenuating the atherosclerosis plaque lesion, lipid accumulation, and M1 macrophages polarization by targeting miR-216a. Given that accumulation of foam cells in the intima takes place chronically, the role of Rb2 in atherosclerosis progression needs further investigation.

Diffusion tensor imaging in unclear intramedullary tumor-suspected lesions allows separating tumors from inflammation

Design Prospective diagnostic study. Objectives Primary imaging-based diagnosis of spinal cord tumor-suspected lesions is often challenging. The identification of the definite entity is crucial for dedicated treatment and therefore reduction of morbidity. The aim of this trial was to investigate specific quantitative signal patterns to differentiate unclear intramedullary tumor-suspected lesions based on diffusion tensor imaging (DTI). Setting Medical Center - University of Freiburg, Germany. Methods Forty patients with an unclear tumor-suspected lesion of the spinal cord prospectively underwent DTI. Primary diagnosis was determined by histological or clinical work-up or remained indeterminate with follow-up. DTI metrics (FA/ADC) were evaluated at the central lesion area, lesion margin, edema, and normal spinal cord and compared between different diagnostic groups (ependymomas, other spinal cord tumors, inflammations). Results Mean DTI metrics for all spinal cord tumors (n = 18) showed significantly reduced FA and increased ADC values compared to inflammatory lesions (n = 8) at the lesion margin (p < 0.001, p = 0.001) and reduced FA at the central lesion area (p < 0.001). There were no significant differences comparing the neoplastic subgroups of ependymomas (n = 10) and other spinal cord tumors (n = 8), but remaining differences for both compared to the inflammation subgroup. We found significant higher ADC (p = 0.040) and a trend to decreased FA (p = 0.081) for ependymomas compared to inflammations at the edema. Conclusion Even if distinct differentiation of ependymomas from other spinal cord neoplasms was not possible based on quantitative DTI metrics, FA and ADC were feasible to separate inflammatory lesions. This may avoid unnecessary surgery in patients with unclear intramedullary tumor-suspected lesions.

Fine Mapping of the Mouse Ath28 Locus Yields Three Atherosclerosis Modifying Sub-Regions

A mouse strain intercross between Apoe−/− AKR/J and DBA/2J mice identified three replicated atherosclerosis quantitative trait loci (QTLs). Our objective was to fine map mouse atherosclerosis modifier genes within a genomic region known to affect lesion development in apoE-deficient (Apoe−/−) mice. We dissected the Ath28 QTL on the distal end of chromosome 2 by breeding a panel of congenic strains and measuring aortic root lesion area in 16-week-old male and female mice fed regular laboratory diets. The parental congenic strain contained ~9.65 Mb of AKR/J DNA from chromosome 2 on the DBA/2J genetic background, which had lesions 55% and 47% smaller than female and male DBA/2J mice, respectively (p < 0.001). Seven additional congenic lines identified three separate regions associated with the lesion area, named Ath28.1, Ath28.2, and Ath28.3, where the AKR/J alleles were atherosclerosis-protective for two regions and atherosclerosis-promoting for the other region. These results were replicated in both sexes, and in combined analysis after adjusting for sex. The congenic lines did not greatly impact total and HDL cholesterol levels or body weight. Bioinformatic analyses identified all coding and non-coding genes in the Ath28.1 sub-region, as well as strain sequence differences that may be impactful. Even within a <10 Mb region of the mouse genome, evidence supports the presence of at least three atherosclerosis modifier genes that differ between the AKR/J and DBA/2J mouse strains, supporting the polygenic nature of atherosclerosis susceptibility.

Comparative modelling of the destruction of a soft armour barrier using two- and threedimensional textile materials based on orthogonal fabrics

The article suggests an approach to virtual testing of textile materials for high-speed penetration. The comparison of two materials developed using different technologies – 3D orthogonal fabric and a package of plain weave fabric is carried out. For this purpose, such parameters of fabrics are selected so that the surface density is identical, the number of layers is the same, the linear density of the threads would be the same. The material of the threads is aramid fibre. In general, according to the assessment along the warp and weft, the lesion area for 3D orthogonal tissue is higher by up to 30 %. At the same time, 31.7 % more kinetic energy of the bullet was extinguished.

Ratiometric Mass Spectrometry Imaging for Stain-Free Delineation of Ischemic Tissue and Spatial Profiling of Ischemia-Related Molecular Signatures

Mass spectrometry imaging (MSI) serves as an emerging tool for spatial profiling of metabolic dysfunction in ischemic tissue. Prior to MSI data analysis, commonly used staining methods, e.g., triphenyltetrazole chloride (TTC) staining, need to be implemented on the adjacent tissue for delineating lesion area and evaluating infarction, resulting in extra consumption of the tissue sample as well as morphological mismatch. Here, we propose an in situ ratiometric MSI method for simultaneous demarcation of lesion border and spatial annotation of metabolic and enzymatic signatures in ischemic tissue on identical tissue sections. In this method, the ion abundance ratio of a reactant pair in the TCA cycle, e.g., fumarate to malate, is extracted pixel-by-pixel from an ambient MSI dataset of ischemic tissue and used as a surrogate indicator for metabolic activity of mitochondria to delineate lesion area as if the tissue has been chemically stained. This method is shown to be precise and robust in identifying lesions in brain tissues and tissue samples from different ischemic models including heart, liver, and kidney. Furthermore, the proposed method allows screening and predicting metabolic and enzymatic alterations which are related to mitochondrial dysfunction. Being capable of concurrent lesion identification, in situ metabolomics analysis, and screening of enzymatic alterations, the ratiometric MSI method bears great potential to explore ischemic damages at both metabolic and enzymatic levels in biological research.

Dioscorea deltoidei (Dioscoreaceae) leaf extract exerts anti-atherosclerotic effect in rats via down-regulation of phosphorylated JAK/STAT

Purpose: To investigate the effect of leaf extract of Dioscorea deltoidea (Dioscoreaceae) leaf (DDE) on atherosclerosis-induced aorta wall damage in a rat model, and the underlying mechanism of action.Methods: Rats were fed high-fat diet containing vitamin D2 for 16 weeks to induce atherosclerosis. Histopathological changes in the aorta were examined using hematoxylin and eosin (H & E) staining, while ELISA kits were used to measure cytokine levels.Results: Treatment with DDE significantly (p < 0.05) alleviated atherosclerosis-induced increase in mean lesion area in the rat aorta. The mean lesion area in atherosclerotic rats was decreased to 51.5, 21.2 and 2.3 mm2, on treatment with DDE at doses of 2.5, 5 and 10 mg/kg, respectively. Furthermore, DDE significantly suppressed atherosclerosis-induced elevation in IL-1β and IL-6 levels in the rat aorta (p < 0.05). The levels of MCP-1 and TNF-α decreased in the artherosclerotic rats on treatment with DDE. In DDE-treated rats, the atherosclerosis-induced increase in the levels of Ang II, AT1, AT2, p-STAT3, p-p65 and p-p38 were significantly decreased, relative to the model group (p < 0.05). However, DDE treatment did not alter the levels of total STAT3, p65 and p38 in the rat aorta tissues.Conclusion: These results indicate that DDE inhibits inflammatory response and atherosclerosisinduced damage to aorta wall. Moreover, RAAS expression, inflammatory cytokines and JAK/STAT signalling pathway were down-regulated in atherosclerotic rats on treatment with DDE. Thus, DDE may be a potential source of drug for the management of atherosclerosis.

Anti-leishmanial activity of 29 daily sessions of intralesional-pentavalent antimony administration on Leishmania (Viannia)-infected BALB/c mice

Introduction: Intralesional-pentavalent antimonials (IL-SbV) are recommended for simple cutaneous leishmaniasis (CL). Few treatment sessions (1-5) and drug volumes (1-5 ml each), relative to lesion size (LS), are recommended. There is not a validated IL-SbV protocol using doses calculated as mg/kg body weight and administered over a large number of IL-sessions, with small injection volumes. Objective: The study aim was to determine the efficacy of different concentrations of IL-SbV administered in 29 daily sessions of 100 μL each, on CL infected mice. Methods: Leishmania (Viannia) panamensis and L. (V.) braziliensis-infected mice (N = 6) were treated with 150, 50, and 16.6 mgSbV/kg/day x 29 days. Percentage of lesion area reduction, aesthetic and final (no lesions, no parasites) efficacy and effective dose (ED)50 were determined. In vitro-SbV activity against parasites was evaluated for both species. Results: The ED50 values were 72.2 and 66.3 (at the end of treatment), 54.3 and 37.7 (15-days pt.), and 145.3 and 148.6 (60-days pt.) for each species, respectively. Differences were observed between Leishmania species at 15-days pt., but not later. At 60-day pt., IL-SbV-150 mg showed final cure rates of 66.6 % for L. (V.) panamensis and 33.3 % for L. (V.) braziliensis-infected mice. After 15 days pt., lesion reactivation was observed in some “aesthetically cured” mice. Glucantime was not active in in vitro assays. Conclusions: The IL-SbV use with a dose calculated as mg/kg body weight and administered over a large number of IL-sessions, with small injection volumes each day could be effective against L. (V.) panamensis and L. (V.) braziliensis-CL infection. An appropriate SbV-dose (higher than 150 mg/kg/day x less than 29 days) must be evaluated.

Quantitative Evaluation of the Relationship between Magnetic Resonance Elastic Value and Pathological Grade of Hepatocellular Carcinoma by Magnetic Resonance Elastography

Objectives: To try another non-invasive method to evaluate the relationship between Magnetic Resonance (MR) elastic value and pathological grade of Hepatocellular Carcinoma (HCC) using Magnetic Resonance Elastography (MRE). Methods: Forty-seven HCC patients underwent MR Imaging (MRI), elastography in the upper abdomen. The elastic value of the lesion area was measured, and that of the normal liver tissue was measured adjacent to the lesion area at the same level. The Mann-Whitney U test was used to compare the difference in elasticity between the lesion area and normal area, and the difference between the low and middle-high differentiation groups. The Receiver Operating Characteristic Curve (ROC) of the lesion area and normal area in the complete case group and different differentiation groups were used to determine the diagnostic cut-off value to distinguish the lesion area from the normal area in each group. Results: (1) There was a significant difference in elasticity between the normal area and HCC area (p<0.001). The diagnostic cut-off value was 4842 Pa. (2) There was a significant difference in elasticity between the low-and middle-high differentiation groups (p<0.001). The diagnostic cut-off value was 10456 Pa. (3) There was a statistically significant correlation between the elastic value on MRE and degree of pathological differentiation of HCC in the two groups (p<0.001). Conclusion: The elastic value of HCC measured using MRE can be used to evaluate the degree of pathological differentiation of HCC. MRE may be a non-invasive and reliable method for evaluating the pathological grade of HCC.