Regulation of cytokine production during phagocytosis of apoptotic cells

Loss of self-tolerance and expansion of auto-reactive lymphocytes are the basis for autoimmunity. Apoptosis and the rapid clearance of apoptotic cells by phagocytes usually occur as coordinated processes that ensure regulated cellularity and stress response with non-pathological outcomes. Defects in clearance of apoptotic ceils would contribute to the generation of self-reactive lymphocytes, which drive autoimmune disorders such as rheumatoid arthritis （RA） and systemic lupus erythematosus （SLE）. The IL-12 family of cytokines （IL-12, IL-23, and IL-27） and IL-10 are produced by phagocytic macrophages and play critical roles in the regulation of antigen-presenting cells （APCs） and effector lymphocytes during an immune response to pathogens. Inappropriate expression of these cytokines and their dysregulated activities have been strongly implicated in the pathogenesis of several autoimmune diseases. The production of pro- and anti-inflammatory cytokines by phagocytic APCs is delicately regulated during the ingestion of apoptotic cells as part of an intrinsic mechanism to prevent inflammatory autoimmune reactions. How apoptotic cell-derived signals regulate cytokine production is poorly understood. A recent study by our group demonstrated that phagocytosis of apoptotic cells by activated macrophages results in strong inhibition of IL-12 p35 gene expression by activating a novel transcription repressor, which we named GC-binding protein （GC-BP）, through tyrosine dephosphorylation. We are also beginning to understand the molecular mechanisms underlying apoptotic cell-triggered production of IL-10 by phagocytes. These studies will help to elucidate some novel immune regulatory mechanisms and explore the regulation of immune responses to autoantigens with potentials to discover new therapeutic targets for the treatment of autoimmune disorders.

Overview and comparison of guidelines for management of pancreatic cystic neoplasms

Pancreatic cysts are identified at an increasing frequency.Although mucinous cystic neoplasms represent a pre-malignant condition,the majority of these lesions do not progress to cancer.Over the last 10 years several societies have established guidelines for the diagnosis,initial evaluation and surveillance of these lesions.Here we provide an overview of five commonly used guidelines:2015 American Gastroenterological Association,2017 International Association of Pancreatology,American College of Gastroenterology 2018,European Study Group and American College of Radiology.We describe the similarities and differences between the methods used to formulate these guidelines,the population they target and their approaches towards initial evaluation and surveillance of cystic lesions.

Assessment of bone turnover and bone quality in type 2 diabetic bone disease： current concepts and future directions

Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due to altered bone properties in diabetes. Circulating biochemical markers of bone turnover have been found to be decreased in type 2 diabetes （T2D） and may be predictive of fractures independently of bone mineral density （BMD）. Serum sclerostin levels have been found to be increased in T2D and appear to be predictive of fracture risk independent of BMD. Bone imaging technologies, including trabecular bone score （TBS） and quantitative CT testing have revealed differences in diabetic bone as compared to non-diabetic individuals. Specifically, high resolution peripheral quantitative CT （HRpQCT） imaging has demonstrated increased cortical porosity in diabetic postmenopausal women. Other factors such as bone marrow fat saturation and advanced glycation endproduct （AGE） accumulation might also relate to bone cell function and fracture risk in diabetes. These data have increased our understanding of how T2D adversely impacts both bone metabolism and fracture risk.

Case report of acute-on-chronic liver failure secondary to diffuse large B-cell lymphoma

Acute liver failure is a rare presentation of hematologic malignancy. Acute on chronic liver failure(ACLF) is a newly recognized clinical entity that describes acute hepatic decompensation in persons with preexisting liver disease. Diffuse large B-cell lymphoma(DLBCL) is an aggressive non-Hodgkin's lymphoma(NHL) with increasing incidence in older males, females and blacks. However, it has not yet been reported, to present with acute liver failure in patients with preexisting chronic liver disease due to human immunodeficiency virus(HIV)/hepatitis C virus(HCV) co-infection. We describe a case of ACLF as the presenting manifestation of DLBCL in an elderly black man with HIV/HCV coinfection and prior Hodgkin's disease in remission for three years. The rapidly fatal outcome of this disease is highlighted as is the distinction of ACLF from decompensated cirrhosis. Due to the increased prevalence of HIV/HCV co-infection in the African American 1945 to 1965 birth cohort and the fact that both are risk factors for chronic liver disease and NHL we postulate that the incidence of NHL presenting as ACLF may increase.

Recommendations to quantify villous atrophy in video capsule endoscopy images of celiac disease patients

AIM To quantify the presence of villous atrophy in endoscopic images for improved automation.METHODS There are two main categories of quantitative descriptors helpful to detect villous atrophy:(1) Statistical and(2) Syntactic. Statistical descriptors measure the small intestinal substrate in endoscope-acquired images based on mathematical methods. Texture is the most commonly used statistical descriptor to quantify villous atrophy. Syntactic descriptors comprise a syntax, or set of rules, for analyzing and parsing the substrate into a set of objects with boundaries. The syntax is designed to identify and distinguish three-dimensional structures based on their shape.RESULTS The variance texture statistical descriptor is useful to describe the average variability in image gray level representing villous atrophy, but does not determine the range in variability and the spatial relationships between regions. Improved textural descriptors will incorporate these factors, so that areas with variability gradients and regions that are orientation dependent can be distinguished. The protrusion syntactic descriptor is useful to detect three-dimensional architectural components, but is limited to identifying objects of a certain shape. Improvement in this descriptor will require incorporating flexibility to the prototypical template, so that protrusions of any shape can be detected, measured, and distinguished.CONCLUSION Improved quantitative descriptors of villous atrophy are being developed, which will be useful in detecting subtle, varying patterns of villous atrophy in the small intestinal mucosa of suspected and known celiac disease patients.

Implementation of a polling protocol for predicting celiac disease in videocapsule analysis

AIM: To investigate the presence of small intestinal villous atrophy in celiac disease patients from quantitative analysis of videocapsule image sequences.METHODS: Nine celiac patient data with biopsy-proven villous atrophy and seven control patient data lacking villous atrophy were used for analysis. Celiacs had biopsy-proven disease with scores of Marsh Ⅱ-Ⅲ C except in the case of one hemophiliac patient. At four small intestinal levels (duodenal bulb, distal duodenum, jejunum, and ileum), video clips of length 200 frames (100 s) were analyzed. Twenty-four measurements were used for image characterization. These measurements were determined by quantitatively processing the videocapsule images via techniques for texture analysis, motility estimation, volumetric reconstruction using shape-from-shading principles, and image transformation. Each automated measurement method, or automaton, was polled as to whether or not villous atrophy was present in the small intestine, indicating celiac disease. Each automaton's vote was determined based upon an optimized parameter threshold level, with the threshold levels being determined from prior data. A prediction of villous atrophy was made if it received the majority of votes (≥ 13), while no prediction was made for tie votes (12-12). Thus each set of images was classified as being from either a celiac disease patient or from a control patient. RESULTS: Separated by intestinal level, the overall sensitivity of automata polling for predicting villous atrophy and hence celiac disease was 83.9%, while the specificity was 92.9%, and the overall accuracy of automata-based polling was 88.1%. The method of image transformation yielded the highest sensitivity at 93.8%, while the method of texture analysis using subbands had the highest specificity at 76.0%. Similar results of prediction were observed at all four small intestinal locations, but there were more tie votes at location 4 (ileum). Incorrect prediction which reduced sensitivity occurred for two celiac patients with Marsh type Ⅱ pattern, which is characterized by crypt hyperplasia, but normal villous architecture. Pooled from all levels, there was a mean of 14.31 ± 3.28 automaton votes for celiac vs 9.67 ± 3.31 automaton votes for control when celiac patient data was analyzed (P<0.001). Pooled from all levels, there was a mean of 9.71 ± 2.8128 automaton votes for celiac vs 14.32 ± 2.7931 automaton votes for control when control patient data was analyzed (P<0.001). CONCLUSION: Automata-based polling may be useful to indicate presence of mucosal atrophy, indicative of celiac disease, across the entire small bowel, though this must be confirmed in a larger patient set. Since the method is quantitative and automated, it can potentially eliminate observer bias and enable the detectionof subtle abnormality in patients lacking a clear diagnosis. Our paradigm was found to be more efficacious at proximal small intestinal locations, which may suggest a greater presence and severity of villous atrophy at proximal as compared with distal locations.

Effect of Dachaihu decoction on non-alcoholic fatty liver disease model rats induced by a high-fat high-sugar diet

Objective:To establish an animal model consistent with the occurrence and development of non-alcoholic fatty liver disease(NAFLD)with which to assess the effects of a classical traditional Chinese medicine formula known as Dachaihu Decoction(DD)on NAFLD.Methods:Sixty rats were randomized into four groups:control,model,pioglitazone hydrochloride(PH)and DD in equal.NAFLD was produced via administration of a high-fat high-sugar diet for 16 weeks in all but the control group.From the 13th week,a solution of PH or DD prepared with water was delivered via intragastric administration to the PH and DD groups;the remaining two groups received an equivalent volume of distilled water.Twelve hours from the last administration,we selected eight rats from each group in random.After anesthetization,the abdominal aorta blood and liver tissues were collected.The morphological changes were observed and the levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),total cholesterol(TC),triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),highdensity lipoprotein cholesterol(HDL-C),fasting plasma glucose(FBG),transforming growth factor-β1(TGF-β1),tumor necrosis factor-α(TNF-α),toll-like receptor-4(TLR4),and nuclear factor-kappa B(NF-κB)were tested.Results:Compared with the control group,the levels of serum ALT,AST,TC,TG,LDL-C and FBG,and TGF-β1,TNF-α,TLR4,NF-κB in the model group all showed significant increases(P<.01).Compared with the model group,these same indicators in the PH and DD groups all showed remarkable decreases(P<.05).Conclusion:The efficacy of DD in NAFLD rats was shown to be effectively equivalent to that of PH,with demonstrated effects of DD that included reductions in hepatic steatosis and serum and hepatic lipid levels,and lowered blood glucose levels.We deduce that DD has an inhibitory effect on NAFLD induced by a high-fat high-sugar diet in rats.

Bone lesions in recurrent glucagonoma: A case report and review of literature

Glucagonomas are rare neuroendocrine tumors that arise from cells of the pancreatic islets. Most of them are malignant and usually present as metastatic disease. Sites most commonly involved in metastases are the liver and regional lymph nodes. Bone metastases are rare events and only a few cases have been reported in the literature. We present the case of a 53-year-old male with a medical history of recurrent non-functioning glucagonoma. He presented 17 years after the initial diagnosis with new blastic bone lesions involving the T1 vertebra and the sacrum. Diagnostic steps and medical management in metastatic glucagonoma are also reviewed.

Seroprevalence of celiac disease among United Arab Emirates healthy adult nationals: A gender disparity

AIM: To determine celiac disease (CD) prevalence and associated manifestations or risk factors in healthy adult Emiratis.

Effect of verapamil on nitric oxide synthase in a portal veinligated rat model: Role of prostaglandin

AIM： To investigate the effects of verapamil on nitric oxide （NO） synthesis in a portal vein-ligated rat model. METHODS： Systemic and splanchnic hemodynamics were measured by radiolabeled microspheres in portal hypertensive rats after acute administration of verapamil （2 mg/kg） on chronic treatment with N^W-nitro-L-arginine （NNA）（80 mg/kg） and/or indomethacin （2 mg/kg） . RESULTS： Verapamil （2 mg/kg） caused a marked fall in both arterial pressure and cardiac output accompanied by an insignificant change in the portal pressure and no change in portal venous inflow. This result suggested that verapamil did not cause a reduction in portal vascular resistance of portal hypertensive rats, which was similar between N^w- nitro-Loarginine-treated and indomethacin-treated groups. CONCLUSION： In portal hypertensive rats pretreated with NNA and/or indomethacin, acute verapamil administration can not reduce the portal pressure, suggesting that NO and prostaglandin play an important role in the pathogenesis of splanchnic arterial vasodilation in portal hypertension.

Treatment of early stage(T1) esophageal adenocarcinoma:Personalizing the best therapy choice

Esophagectomy is considered the primary form of management for esophageal adenocarcinoma(EAC);however,the surgery is associated with high rates of morbidity and mortality.For patients with early-stage EAC,endoscopic resection(ER)presents a potential curative treatment option that is less invasive and carries fewer risks procedure related risks,but it is associated with higher rates of cancer recurrence following the procedure.For some patients,age and comorbidities may prevent them from having esophagectomy as a treatment option,while other patients may be operative candidates but do not wish to undergo esophagectomy for a variety of reasons related to their values and preferences.Furthermore,while anxiety of cancer recurrence following ER may significantly diminish a patient’s quality of life(QOL),so might the morbidity surrounding esophagectomy.In addition to considering health status,patient preferences,and impacts on QOL,physicians and patients must also consider what treatments would be both beneficial and available to the patient,considering esophagectomy methods-minimally invasive vs open-or the use of chemoradiotherapy in addition to ER.Our article reviews and summarizes available treatment options for patients with early EAC and their potential effects on the health and wellbeing of patients based on the current data.We conclude with a request for more research of available options for early EAC patients,the conditions that determine when each option should be employed,and their effects not only on patient health but also QOL.

LDLR^(-/-)小鼠中脂代谢相关基因的表达

目的分析LDLR基因敲除小鼠体内脂代谢相关基因ApoB100、PPARα、LXRα以及ABCA1与野生型相比表达水平的差异情况。方法应用多重PCR的方法对LDLR-/-小鼠基因型进行鉴定;接着分别对LDLR-/-小鼠和野生型小鼠脂代谢相关基因的mRNA相对丰度以及蛋白表达水平进行qRT-PCR、ELISA分析。结果与野生型相比,LDLR-/-小鼠中ApoB100、PPARα的mRNA及蛋白表达均上调(P<0.05);ABCA1的表达水平下降(P<0.01),蛋白水平上的下降幅度更为明显;而LXRα不管在mRNA或蛋白水平上均检测不到差异表达。结论 LDLR基因功能的缺失对不同的脂类代谢相关基因的表达产生不同的影响。本研究有助于人们进一步了解家族性高胆固醇血症的发病机制,同时也为药物设计中靶位点的选择提供参考价值。

利用RNA干扰技术抑制小鼠羟甲基戊二酸单酰辅酶A还原酶基因的表达

目的为了探寻一种更有效的家族性高胆固醇血症(FH)基因治疗新途径,通过慢病毒介导RNA干扰的方法在H22细胞系及C57BL/6J纯系小鼠中抑制内源性羟甲基戊二酸单酰辅酶A还原酶(HMG-CoAR)基因表达进行研究。方法从HMG-CoAR基因序列中选择三段作为靶序列(T1、T2和T3),并构建重组慢病毒RNAi载体;经体外包装后,分别感染H22细胞系及注射小鼠。通过qRT-PCR检测HMG-CoAR mRNA丰度;利用WesternBlot、ELISA方法分析HMG-CoAR的表达水平。结果与空载体对照相比,三个实验组中稳定转染细胞的HMG-CoAR表达水平显著降低(P<0.05),同时感染5天后小鼠的肝脏HMG-CoAR mRNA水平、蛋白含量以及血浆中HMG-CoAR表达均显著降低(P<0.05),其中T3位点的抑制效率最高,是空质粒对照的1/3。另外,对三个载体的持续性抑制能力分析显示,在处理后的至少50天内,三个实验组小鼠中HMG-CoAR表达量均有效地被抑制,其中T1靶点的抑制效果最为稳定,而T3靶点的波动最大,但抑制效率一直最高。结论三个重组慢病毒RNAi载体均可显著抑制内源性HMG-CoAR表达,可为下一步试图通过下调HMG-CoAR表达的方式,降低FH患者体内胆固醇水平的FH基因治疗奠定基础。

Venous thromboembolism in inflammatory bowel disease

Patients with inflammatory bowel disease(IBD)are at an increased risk for venous thromboembolism(VTE).VTE events carry significant morbidity and mortality,and have been associated with worse outcomes in patients with IBD.Studies have suggested that the hypercoagulable nature of the disease stems from a complex interplay of systems that include the coagulation cascade,natural coagulation inhibitors,fibrinolytic system,endothelium,immune system,and platelets.Additionally,clinical factors that increase the likelihood of a VTE event among IBD patients include older age(though some studies suggest younger patients have a higher relative risk of VTE,the incidence in this population is much lower as compared to the older IBD patient population),pregnancy,active disease,more extensive disease,hospitalization,the use of certain medications such as corticosteroids or tofacitinb,and IBD-related surgeries.Despite the increased risk of VTE among IBD patients and the safety of pharmacologic prophylaxis,adherence rates among hospitalized IBD patients appear to be low.Furthermore,recent data suggests that there is a population of high risk IBD patients who may benefit from post-discharge prophylaxis.This review will provide an overview of patient specific factors that affect VTE risk,elucidate reasons for lack of VTE prophylaxis among hospitalized IBD patients,and focus on recent data describing those at highest risk for recurrent VTE post-hospital discharge.

Acid and non-acid reflux in patients refractory to proton pump inhibitor therapy:Is gastroparesis a factor?

AIM:To determine whether an increased number and duration of non-acid reflux events as measured using the multichannel intraluminal impedance pH(MII-pH)is linked to gastroparesis(GP).METHODS:A case control study was conducted in which 42 patients undergoing clinical evaluation for continued symptoms of gastroesophageal reflux disease(both typical and atypical symptoms)despite acid suppression therapy.MII-pH technology was used over 24 h to detect reflux episodes and record patients’symptoms.Parameters evaluated in patients with documented GP and controls without GP by scintigraphy included total,upright,and supine number of acid and non-acid reflux episodes(pH<4 and pH>4,respectively),the duration of acid and non-acid reflux in a 24-h period,and the number of reflux episodes lasting longer than 5 min.RESULTS:No statistical difference was seen between the patients with GP and controls with respect to the total number or duration of acid reflux events,total number and duration of non-acid reflux events or the duration of longest reflux episodes.The number of nonacid reflux episodes with a pH>7 was higher in subjects with GP than in controls.In addition,acid reflux episodes were more prolonged(lasting longer than 5min)in the GP patients than in controls;however,these values did not reach statistical significance.Thirty-five patients had recorded symptoms during the 24 h study and of the 35 subjects,only 9%(n=3)had a positive symptom association probability(SAP)for acid/non-acid reflux and 91%had a negative SAP.CONCLUSION:The evaluation of patients with a documented history of GP did not show an association between GP and more frequent episodes of non-acid reflux based on MII-pH testing.

Microbial manipulation as primary therapy for Crohn's disease

While antimicrobials are clinically effective in preventing post-operative recurrence,the role for antibiotics in primary therapy for Crohn's disease(CD) remains unclear.The recent multicenter phase 2 trial by Prantera et al received wide attention because it demonstrated an increase in the week 12 remission rate in patients with moderately active CD treated with rifaximin and renewed interest in microbial manipulation as primary therapy for CD.In this commentary,we discuss aspects of durability,immune cell polarization,and safety of microbial manipulation as primary therapy for CD.

多民族人群中卵圆孔未闭与缺血性卒中的发生风险

目的：拟评价北曼哈顿多民族的前瞻性队列中卵圆孔未闭（PFO）引起缺血性卒中的风险。背景：PFO被认为与缺血性卒中风险增加相关，证据主要来自病例对照研究。在普通人群中，实际的PFO相关性卒中风险仍不明确。方法：研究对象为来自北曼哈顿研究（NOMAS）中1100例年龄〉39岁（平均68．7±10．0岁）的无卒中受试者，利用造影剂注射经胸二维超声心动图检查评估基线时的PFO。同时记录房间隔动脉瘤（ASA）。受试者接受每年随访。在校正已知的卒中危险因素后，评价PFO／ASA相关的卒中风险。

Bone density, microarchitecture and stiffness in Caucasian and Caribbean Hispanic postmenopausal American women

Hispanic Americans of Caribbean origin are a fast-growing subset of the US population, but there are no studies on bone density, microstructure and biomechanical integrity in this minority group. In this study, we aimed to compare Caucasian and Caribbean Hispanic postmenopausal American women with respect to these characteristics. Thirty-three Caribbean Hispanics were age-matched to thirty-three Caucasian postmenopausal women. At the lumbar spine, the Hispanic women had significantly lower areal bone mineral density （aBMD）. At the radius by high-resolution peripheral quantitative computed tomography （HR-pQCT）, there were minimal differences between Hispanic and Caucasian women. At the tibia, Hispanic women had lower trabecular volumetric bone density and trabecular number, and higher trabecular separation. Individual trabecula segmentation （ITS） analyses indicated that at the tibia, Hispanic women not only had significantly lower bone volume fraction, but also had significantly lower rod bone volume fraction, plate trabecular number, rod trabecular number and lower plate-plate, plate-rod and rod-rod junction densities compared to Caucasian women. The differences in bone quantity and quality contributed to lower whole bone stiffness at the radius, and both whole bone and trabecular bone stiffness at the tibia in Hispanic women. In conclusion, Hispanic women had poorer bone mechanical and microarchitectural properties than Caucasian women, especially at the load-bearing distal tibia.

生物钟与男性健康

医生一般只有在谈及生育能力下降、胎儿出生缺陷风险增加以及女性激素水平随年龄增长而有所变化等问题时才会使用“生物钟”一词。然而，大量科学证据提示，男性可能也具有生物钟。为此，男性群体及其医生必须了解男性生物钟给性健康、生育健康以及糖尿病、心血管疾病、代谢综合征等重大疾病带来的潜在影响。

Traditional Chinese Medicine Synonymous Term Conversion:A Bidirectional Encoder Representations from Transformers-Based Model for Converting Synonymous Terms in Traditional Chinese Medicine

Background:The medical records of traditional Chinese medicine(TCM)contain numerous synonymous terms with different descriptions,which is not conducive to computer-aided data mining of TCM.However,there is a lack of models available to normalize synonymous TCM terms.Therefore,construction of a synonymous term conversion(STC)model for normalizing synonymous TCM terms is necessary.Methods:Based on the neural networks of bidirectional encoder representations from transformers(BERT),four types of TCM STC models were designed:Models based on BERT and text classification,text sequence generation,named entity recognition,and text matching.The superior STC model was selected on the basis of its performance in converting synonymous terms.Moreover,three misjudgment inspection methods for the conversion results of the STC model based on inconsistency were proposed to find incorrect term conversion:Neuron random deactivation,output comparison of multiple isomorphic models,and output comparison of multiple heterogeneous models(OCMH).Results:The classification-based STC model outperformed the other STC task models.It achieved F1 scores of 0.91,0.91,and 0.83 for performing symptoms,patterns,and treatments STC tasks,respectively.The OCMH method showed the best performance in misjudgment inspection,with wrong detection rates of 0.80,0.84,and 0.90 in the term conversion results for symptoms,patterns,and treatments,respectively.Conclusion:The TCM STC model based on classification achieved superior performance in converting synonymous terms for symptoms,patterns,and treatments.The misjudgment inspection method based on OCMH showed superior performance in identifying incorrect outputs.