Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis

Collagen type II-induced arthritis (CIA) in Dark Agouti rats, a model of rheumatoid arthritis (RA), reproduces sexual dimorphism in the incidence and severity of the human disease. Th17 cells are central in the induction/propagation of autoimmune inflammation in CIA and RA. To assess mechanisms underlying this dimorphism in CIA rats, in lymph nodes draining inflamed joints and adjacent tissues (dLNs) from CIA rats of both sexes Th17/CD25+Foxp3+CD4+ T-regulatory cell (Treg) ratio, Th17 cell redifferentiation in functionally distinct subsets and Treg transdifferentiation into IL-17-producing cells (exTregs) were examined. In female rats (developing more severe CIA than their male counterparts) the higher frequency of all Th17 cells (reflecting partly their greater proliferation), followed by the higher frequency of highly pathogenic IFN-γ/GM-CSF-co-producing cells, but lower frequency of less pathogenic/immunoregulatory IL-10-producing cells among them was found. Additionally, compared with male rats, in female rats the lower frequency of Tregs was observed. Moreover, Tregs from female rats exhibited diminished proliferative and suppressive capacity (judging by PD-1 expression) and enhanced conversion into IL-17-producing cells. Given that TGF-β concentration was comparable in collagen-type II-stimulated dLN cell cultures from female and male rats, the shift in Th17/Treg ratio followed by augmented Th17 cell redifferentiation into IFN-γ/GM-CSF-co-producing cells and Treg transdifferentiation into IL-17-producing cells in female rats was associated with increased concentration of IL-6 in female rat dLN cell cultures, and the higher frequency of IL-1β- and IL-23-producing cells among their dLN cells. The lower frequency of IL-10-producing B cells, presumably B regulatory cells (Bregs) could also contribute to the shift in Th17/Treg ratio in female rat compared with male rat dLNs. Consistently, the lower expression of IL-35 (the cytokine promoting Treg expansion directly and indirectly, by favoring Breg expansion and conversion into IL-10/IL-35-producing cells) in female rat dLN cells was detected. Thus, the study identified putative cellular and molecular substrates of the sexual dimorphism in the immunopathogenesis and clinical outcome of CIA and suggested mechanisms to be targeted in females to improve control of Th17 response, and consequently clinical outcome of CIA, and possibly RA.     

拉唑B防治大鼠胃溃疡的实验研究

目的评价新型质子泵抑制剂拉唑B对大鼠胃溃疡模型的防治效果,并初步探讨其机制。方法在构建大鼠消炎痛、幽门结扎、水应激型溃疡模型之前,及构建慢性醋酸型溃疡模型(醋酸注射)之后灌胃不同剂量的拉唑B、雷贝拉唑(阳性对照)和0.5%甲基纤维素钠(空白对照),比较各组实验用大鼠的溃疡指数、溃疡抑制率或溃疡面积/体积的差异。实验用大鼠乙醚麻醉下行幽门结扎术,术时经十二指肠分别给予不同剂量的拉唑B、雷贝拉唑和0.5%甲基纤维素钠(对照)。处死动物后制备胃标本,收集胃液并测量体积,用0.1molNaOH滴定法测定胃液中HCl含量,测定胃蛋白酶活性。结果予不同剂量的拉唑B预处理后,消炎痛、幽门结扎、水应激各建模组大鼠胃溃疡指数/面积明显减少,且具有较好的剂量-效应关系,与雷贝拉唑相当,但与空白对照组差异明显(P<0.05或P<0.01)。拉唑B对消炎痛、幽门结扎、水应激型大鼠胃溃疡模型抑制半数有效量(ED50)依次为14.1、16.0和18.8μmol/kg。慢性醋酸型大鼠溃疡模型给予拉唑B后,溃疡面积明显减少,作用与雷贝拉唑相似。大鼠给予拉唑B后,胃酸分泌量明显减少(P<0.01),且有较好的剂量-效应关系;胃液量也明显减少(P<0.05或P<0.01);虽然单位体积胃蛋白酶活性未见变化,但由于胃液量减少,胃蛋白酶总活性明显降低(P<0.05或P<0.01);雷贝拉唑也有相似作用。结论拉唑B能有效防治消炎痛、幽门结扎、水应激等导致的大鼠胃溃疡,主要机制与其能够抑制胃酸分泌与胃蛋白酶活性有关。     

Spectrum-effect relationships between UPLC fingerprints and bioactivities of crude secondary roots of Aconitum carmichaelii Debeaux (Fuzi) and its three processed products on mitochondrial growth coupled with canonical correlation analysis

Ethnopharmacological relevance: The crude secondary roots of Aconitum carmichaelii Debeaux (Fuzi), together with its processed products, including Yanfuzi, Heishunpian and Paofupian, are commonly applied in clinic using for thousands of years, such as collapse, syncope, rheumatic fever, painful joints and various tumors.Aim of the study: To explore the different effects of Fuzi and its processed products on energy metabolism, with mitochondria as the model with the aim of guiding the clinical use of Fuzi and its products. fingerprints of Fuzi, Yanfuzi, Heishunpian and Paofupian were established by Ultra-high Performance Liquid Chromatography (UPLC) and effects of Fuzi and its processed products on rat’s liver׳s mitochondrial metabolism were studied by microcalorimetry. Spectrum-effect relationships between UPLC fingerprints and energy metabolism of mitochondria were investigated using canonical correlation analysis (CCA).Results: Because of their inherent differences in chemical compositions, the main activities of energy metabolism of mitochondria were different among Fuzi and its processed products. The potential bioactivity sequence of the tested products was Fuzi>Heishunpian>Paofupian>Yanfuzi. Results of CCA showed that compounds mesaconitine, benzoylaconitine, and benzoylhypacoitine might be the principal active components.Conclusion: Altogether, this work provides a general model of combination of UPLC and microcalorimetry to study the spectrum-effect relationships of Fuzi and its processed products which can offer some references for detecting principal components of traditional Chinese medicine on bioactivity to mitochondrial growth.     

Deep learning methods for automatic evaluation of delayed enhancement-MRI. The results of the EMIDEC challenge

A key factor for assessing the state of the heart after myocardial infarction (MI) is to measure whether the myocardium segment is viable after reperfusion or revascularization therapy. Delayed enhancement-MRI or DE-MRI, which is performed 10 min after injection of the contrast agent, provides high contrast between viable and nonviable myocardium and is therefore a method of choice to evaluate the extent of MI. To automatically assess myocardial status, the results of the EMIDEC challenge that focused on this task are presented in this paper. The challenge’s main objectives were twofold. First, to evaluate if deep learning methods can distinguish between non-infarct and pathological exams, i.e. exams with or without hyperenhanced area. Second, to automatically calculate the extent of myocardial infarction. The publicly available database consists of 150 exams divided into 50 cases without any hyperenhanced area after injection of a contrast agent and 100 cases with myocardial infarction (and then with a hyperenhanced area on DE-MRI), whatever their inclusion in the cardiac emergency department. Along with MRI, clinical characteristics are also provided. The obtained results issued from several works show that the automatic classification of an exam is a reachable task (the best method providing an accuracy of 0.92), and the automatic segmentation of the myocardium is possible. However, the segmentation of the diseased area needs to be improved, mainly due to the small size of these areas and the lack of contrast with the surrounding structures.     

Retrolisthesis and lumbar disc herniation: a postoperative assessment of patient function

Background contextThe presence of retrolisthesis has been associated with the degenerative changes of the lumbar spine. However, retrolisthesis in patients with L5–S1 disc herniation has not been shown to have a significant relationship with worse baseline pain or function. Whether it can affect the outcomes after discectomy, is yet to be established.PurposeThe purpose of this study was to determine the relationship between retrolisthesis (alone or in combination with other degenerative conditions) and postoperative low back pain, physical function, and quality of life. This study was intended to be a follow-up to a previous investigation that looked at the preoperative assessment of patient function in those with retrolisthesis and lumbar disc herniation.Study designCross-sectional study.Patient samplePatients enrolled in SPORT (Spine Patient Outcomes Research Trial) who had undergone L5–S1 discectomy and had a complete magnetic resonance imaging scan available for review (n=125). Individuals with anterolisthesis were excluded.Outcome measuresTime-weighted averages over 4 years for the Short Form (SF)-36 bodily pain scale, SF-36 physical function scale, Oswestry Disability Index (ODI), and Sciatica Bothersomeness Index (SBI).MethodsRetrolisthesis was defined as a posterior subluxation of 8% or more. Disc degeneration was defined as any loss of disc signal on T2 imaging. Modic changes were graded 1 to 3 and collectively classified as vertebral end plate degenerative changes. The presence of facet arthropathy and ligamentum flavum hypertrophy was classified jointly as posterior degenerative changes. Longitudinal regression models were used to compare the time-weighted outcomes over 4 years.ResultsPatients with retrolisthesis did significantly worse with regard to bodily pain and physical function over 4 years. However, there were no significant differences in terms of ODI or SBI. Similarly, retrolisthesis was not a significant factor in the operative time, blood loss, lengths of stay, complications, rate of additional spine surgeries, or recurrent disc herniations. Disc degeneration, modic changes, and posterior degenerative changes did not affect the outcomes.ConclusionsAlthough retrolisthesis in patients with L5–S1 disc herniation did not affect the baseline pain or function, postoperative outcomes appeared to be somewhat worse. It is possible that the contribution of pain or dysfunction related to retrolisthesis became more evident after removal of the disc herniation.     

拉唑B防治大鼠胃溃疡的实验研究

目的评价新型质子泵抑制剂拉唑B对大鼠胃溃疡模型的防治效果,并初步探讨其机制。方法在构建大鼠消炎痛、幽门结扎、水应激型溃疡模型之前,及构建慢性醋酸型溃疡模型（醋酸注射）之后灌胃不同剂量的拉唑B、雷贝拉唑（阳性对照）和0.5%甲基纤维素钠（空白对照）,比较各组实验用大鼠的溃疡指数、溃疡抑制率或溃疡面积/体积的差异。实验用大鼠乙醚麻醉下行幽门结扎术,术时经十二指肠分别给予不同剂量的拉唑B、雷贝拉唑和0.5%甲基纤维素钠（对照）。处死动物后制备胃标本,收集胃液并测量体积,用0.1molNaOH滴定法测定胃液中HCl含量,测定胃蛋白酶活性。结果予不同剂量的拉唑B预处理后,消炎痛、幽门结扎、水应激各建模组大鼠胃溃疡指数/面积明显减少,且具有较好的剂量-效应关系,与雷贝拉唑相当,但与空白对照组差异明显（P〈0.05或P〈0.01）。拉唑B对消炎痛、幽门结扎、水应激型大鼠胃溃疡模型抑制半数有效量（ED50）依次为14.1、16.0和18.8μmol/kg。慢性醋酸型大鼠溃疡模型给予拉唑B后,溃疡面积明显减少,作用与雷贝拉唑相似。大鼠给予拉唑B后,胃酸分泌量明显减少（P〈0.01）,且有较好的剂量-效应关系;胃液量也明显减少（P〈0.05或P〈0.01）;虽然单位体积胃蛋白酶活性未见变化,但由于胃液量减少,胃蛋白酶总活性明显降低（P〈0.05或P〈0.01）;雷贝拉唑也有相似作用。结论拉唑B能有效防治消炎痛、幽门结扎、水应激等导致的大鼠胃溃疡,主要机制与其能够抑制胃酸分泌与胃蛋白酶活性有关。     

Peroxiredoxin 6 knockout aggravates cecal ligation and puncture-induced acute lung injury

BackgroundThe aim of present study was to investigate the effects and mechanisms of peroxiredoxin (Prdx) 6 on cecal ligation and puncture (CLP) induced acute lung injury (ALI) in mice.MethodsThe cecal of male Prdx 6 knockout and wildtype C57BL/6J mice were ligated and perforated. Stool was extruded to ensure wound patency. Two hours, 4 h, 8 h and 16 h after stimulation, the morphology, wet/dry ratio, protein concentration in bronchial alveolar lavage fluid (BALF) were measured to evaluate lung injury. Myeloperoxidase (MPO) activity, hydrogen peroxide (H₂O₂), malondialdehyde (MDA), total superoxide dismutase (SOD), xanthine oxidase (XOD), CuZn-SOD, total anti-oxidative capability (TAOC), glutathione peroxidase (GSH-PX), catalase (CAT) in lungs were measured by assay kits. The mRNA expression of lung tumor necrosis factor (TNF-α), interleukin (IL)-1β, and matrix metalloproteinases (MMP) 2 and 9 were tested by real-time RT-PCR. The nuclear factor (NF)-κB activity was measured by TransAM kit.ResultsCLP-induced ALI was characterized by inflammation in morphology, increased wet/dry ratio, elevated protein concentration in BALF and higher level of MPO activity. The levels of H₂O₂, MDA, and XOD were significantly increased and SOD, CuZn-SOD, GSH-PX, CAT, and T-AOC were significantly decreased in lungs after CLP. The activity of NF-κB was significantly increased and subsequently, the mRNA expression of TNF-α, IL-1β and MMP2 and MMP9 were significantly increased after CLP. Those above injury parameters were more severe in Prdx 6 knockout mice than those in wildtype mice.ConclusionsPrdx 6 knockout aggravated the CLP induced lung injury by augmenting oxidative stress, inflammation and matrix degradation partially through NF-κB pathway.     

Inter-subject registration-based one-shot segmentation with alternating union network for cardiac MRI images

Medical image segmentation based on deep-learning networks makes great progress in assisting disease diagnosis. However, currently, the training of most networks still requires a large amount of data with labels. In reality, labeling a considerable number of medical images is challenging and time-consuming. In order to tackle this challenge, a new one-shot segmentation framework for cardiac MRI images based on an inter-subject registration model called Alternating Union Network (AUN) is proposed in this study. The label of the source image is warped with deformation fields discovered from AUN to segment target images directly. Initially, the volumes are pre-processed by aligning affinely and adjusting the global intensity to simplify subsequent deformation registration. AUN consists of two kinds of subnetworks trained alternately to optimize segmentation gradually. The first kind of subnetwork takes a pair of volumes as inputs and registers them using global intensity similarity. The second kind of subnetwork, which takes the predicted labels generated from the previous subnetwork and the labels refined using the information of intrinsic anatomical structures of interest as inputs, is intensity-independent and focuses attention on registering structures of interest. Specifically, the input of AUN is a pair of a labeled image with the texture in regions of interest removed and a target image. Additionally, a new similarity measurement more appropriate for registering such image pair is defined as Local Squared Error (LSE). The proposed registration-based one-shot segmentation pays attention to the problem of the lack of labeled medical images. In AUN, only one labeled volume is required and a large number of unlabeled ones can be leveraged to improve segmentation performance, which has great advantages in clinical application. In addition, the intensity-independent subnetwork and LSE proposed in this study empower the framework to segment medical images with complicated intensity distribution.     

Characterizing the propagation pathway of neuropathological events of Alzheimer's disease using harmonic wavelet analysis

Empirical imaging biomarkers such as the level of the regional pathological burden are widely used to measure the risk of developing neurodegenerative diseases such as Alzheimer's disease (AD). However, ample evidence shows that the brain network (wirings of white matter fibers) plays a vital role in the progression of AD, where neuropathological burdens often propagate across the brain network in a prion-like manner. In this context, characterizing the spreading pathway of AD-related neuropathological events sheds new light on understanding the heterogeneity of pathophysiological mechanisms in AD. In this work, we propose a manifold-based harmonic network analysis approach to explore a novel imaging biomarker in the form of the AD propagation pattern, which eventually allows us to identify the AD-related spreading pathways of neuropathological events throughout the brain. The backbone of this new imaging biomarker is a set of region-adaptive harmonic wavelets that represent the common network topology across individuals. We conceptualize that the individual's brain network and its associated pathology pattern form a unique system, which vibrates as do all natural objects in the universe. Thus, we can computationally excite such a brain system using selected harmonic wavelets that match the system's resonance frequency, where the resulting oscillatory wave manifests the system-level propagation pattern of neuropathological events across the brain network. We evaluate the statistical power of our harmonic network analysis approach on large-scale neuroimaging data from ADNI. Compared with the other empirical biomarkers, our harmonic wavelets not only yield a new imaging biomarker to potentially predict the cognitive decline in the early stage but also offer a new window to capture the in-vivo spreading pathways of neuropathological burden with a rigorous mathematics insight.     

Ghrelin alleviates traumatic brain injury-induced acute lung injury through pyroptosis/NF-κB pathway

Acute lung injury (ALI) is one of the severe complications in patients with traumatic brain injury (TBI), contributing to the high mortality. Ghrelin has protective effects against various inflammatory diseases, but the effects of Ghrelin on TBI-induced ALI and its mechanisms remain unknown. In this study, Ghrelin administration was performed on the mice with TBI, then histological change in cortex and lung tissues, lung vascular permeability and macrophage number in bronchoalveolar lavage fluid (BALF) were examined, respectively. Simultaneously, the alterations of proinflammatory factors and pyroptosis-related proteins in lung tissues were detected. As a result, TBI-induced ALI was ameliorated after Ghrelin treatment, which was demonstrated by improved histology, reduced lung vascular permeability, and peripheral macrophage number. Furthermore, Ghrelin decreased the mRNA levels of proinflammatory factors (IL-1β, IL-6, TNF-α and IL-18), the protein levels of pyroptosis-related proteins (NLRP3, Caspase1-P20, HMGB1 and Gasdermin D), and the phosphorylation levels of NF-κB in lung tissues. These results showed that Ghrelin attenuating TBI-induced ALI might be via ameliorating inflammasome-induced pyroptosis by blocking NF-κB signal, which are important for the prevention and treatment of TBI-induced ALI.