Crohn’s disease as the intestinal manifestation of pan-lymphatic dysfunction:An exploratory proposal based on basic and clinical data

Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biological and small-molecule drugs have advanced the treatment of CD;however,a considerable proportion of patients are non-responsive to all known drugs.To achieve a breakthrough in this field,innovations that could guide the further development of effective therapies are of utmost urgency.In this review,we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases,and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data.The supporting evidence is fully summarized,including the existence of lymphatic system dysfunction,recognition of the inside-out model,disorders of immune cells,changes in cell plasticity,partial overlap of the underlying mechanisms,and common gut-derived fatty and bile acid metabolism.Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases,especially CD,as this model is good at presenting and mimicking lymphatic dysfunction.More importantly,the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

Challenging anticoagulation therapy for multiple primary malignant tumors combined with thrombosis:A case report and review of literature

BACKGROUND Venous thromboembolism significantly contributes to patient deterioration and mortality.Management of its etiology and anticoagulation treatment is intricate,necessitating a comprehensive consideration of various factors,including the bleeding risk,dosage,specific anticoagulant medications,and duration of therapy.Herein,a case of lower extremity thrombosis with multiple primary malignant tumors and high risk of bleeding was reviewed to summarize the shortcomings of treatment and prudent anticoagulation experience.CASE SUMMARY An 83-year-old female patient was admitted to the hospital due to a 2-wk history of left lower extremity edema that had worsened over 2 d.Considering her medical history and relevant post-admission investigations,it was determined that the development of left lower extremity venous thrombosis and pulmonary embolism in this case could be attributed to a combination of factors,including multiple primary malignant tumors,iliac venous compression syndrome,previous novel coronavirus infection,and inadequate treatment for prior thrombotic events.However,the selection of appropriate anticoagulant medications,determination of optimal drug dosages,and establishment of an appropriate duration of anticoagulation therapy were important because of concurrent thrombocytopenia,decreased quantitative fibrinogen levels,and renal insufficiency.CONCLUSION Anticoagulant prophylaxis should be promptly initiated in cases of high-risk thrombosis.Individualized anticoagulation therapy is required for complex thrombosis.

Exogenous insulin autoimmune syndrome:A case report and review of literature

BACKGROUND Insulin autoimmune syndrome(IAS)is a severe manifestation of spontaneous hypoglycemia.It is characterized by elevated levels of immune-reactive insulin and highly potent insulin autoantibodies(IAAs),which are induced by endogenous insulin circulating in the bloodstream.It is distinguished by recurring instances of spontaneous hypoglycemia,the presence of IAA within the body,a substantial elevation in serum insulin levels,and an absence of prior exogenous insulin administration.Nevertheless,recent studies show that both conventional insulin and its analogs can induce IAS episodes,giving rise to the notion of nonclassical IAS.Therefore,more attention should be paid to these diseases.CASE SUMMARY In this case report,we present a rare case of non-classical IAS in an 83-year-old male patient who present with symptoms of a psychiatric disorder.Upon symptom onset,the patient exhibited Whipple's triad(including hypoglycemia,blood glucose level less than 2.8 mmol/L during onset,and rapid relief of hypoglycemic symptoms after glucose administration).Concurrently,his serum insulin level was significantly elevated,which contradicted his C-peptide levels.After a comprehensive examination,the patient was diagnosed with exogenous insulin autoimmune syndrome.Considering that the patient had type 2 diabetes mellitus and a history of exogenous insulin use before disease onset,it was presumed that non classical IAS was induced by this condition.The PubMed database was used to search for previous cases of IAS and non-classical IAS to analyze their characteristics and treatment approaches.CONCLUSION The occurrence of non-classical IAS is associated with exogenous insulin or its analogs,as well as with sulfhydryl drugs.Symptoms can be effectively alleviated through the discontinuation of relevant medications,administration of hormones or immunosuppressants,plasma exchange,and lifestyle adjustments.

Triceps skinfold thickness trajectories and the risk of all-cause mortality:A prospective cohort study

BACKGROUND The measurement of triceps skinfold(TSF)thickness serves as a noninvasive metric for evaluating subcutaneous fat distribution.Despite its clinical utility,the TSF thickness trajectories and their correlation with overall mortality have not been thoroughly investigated.AIM To explore TSF thickness trajectories of Chinese adults and to examine their associations with all-cause mortality.METHODS This study encompassed a cohort of 14747 adults sourced from the China Health and Nutrition Survey.Latent class trajectory modeling was employed to identify distinct trajectories of TSF thickness.Subjects were classified into subgroups reflective of their respective TSF thickness trajectory.We utilized multivariate Cox regression analyses and mediation examinations to explore the link between TSF thickness trajectory and overall mortality,including contributory factors.RESULTS Upon adjustment for multiple confounding factors,we discerned that males in the‘Class 2:Thin-stable’and‘Class 3:Thin-moderate’TSF thickness trajectories exhibited a markedly reduced risk of mortality from all causes in comparison to the‘Class 1:Extremely thin’subgroup.In the mediation analyses,the Geriatric Nutritional Risk Index was found to be a partial intermediary in the relationship between TSF thickness trajectories and mortality.For females,a lower TSF thickness pattern was significantly predictive of elevated all-cause mortality risk exclusively within the non-elderly cohort.CONCLUSION In males and non-elderly females,lower TSF thickness trajectories are significantly predictive of heightened mortality risk,independent of single-point TSF thickness,body mass index,and waist circumference.

Dipeptidyl peptidase-4 inhibitors and the risk of infection: A systematic review and meta-analysis of cardiovascular outcome trials

BACKGROUND Since adverse events during treatment affect adherence and subsequent glycemic control,understanding the safety profile of oral anti-diabetic drugs is imperative for type 2 diabetes mellitus(T2DM)therapy.AIM To evaluate the risk of infection in patients with T2DM treated with dipeptidyl-peptidase 4(DPP-4)inhibitors.METHODS Electronic databases were searched.The selection criteria included randomized controlled trials focused on cardiovascular outcomes.In these studies,the effects of DPP-4 inhibitors were directly compared to those of either other active anti-diabetic treatments or placebo.Six trials involving 53616 patients were deemed eligible.We calculated aggregate relative risks employing both random-effects and fixed-effects approaches,contingent upon the context.RESULTS The application of DPP-4 inhibitors showed no significant link to the overall infection risk[0.98(0.95,1.02)]or the risk of serious infections[0.96(0.85,1.08)],additionally,no significant associations were found with opportunistic infections[0.69(0.46,1.04)],site-specific infections[respiratory infection 0.99(0.96,1.03),urinary tract infections 1.02(0.95,1.10),abdominal and gastrointestinal infections 1.02(0.83,1.25),skin structure and soft tissue infections 0.81(0.60,1.09),bone infections 0.96(0.68,1.36),and bloodstream infections 0.97(0.80,1.18)].CONCLUSION This meta-analysis of data from cardiovascular outcome trials revealed no heightened infection risk in patients undergoing DPP-4 inhibitor therapy compared to control cohorts.

Antagonizing adipose tissue-derived exosome miR-103-hepatocyte phosphatase and tensin homolog pathway alleviates autophagy in non-alcoholic steatohepatitis:A trans-cellular crosstalk

BACKGROUND Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis(NASH).However,the underlining mechanism is still unclear,where adipose tissue(AT)derived exosomes may actively participate.MicroRNAs(miRNAs)are commonly secreted from exosomes for cell communication.Though the regulation of miR-103 on insulin sensitivity has been reported,the specific role of AT-derived exosomes miR-103 in NASH is still vague and further investigation may provide novel therapeutic choices.AIM To determine the specific role of AT-derived exosomes miR-103 in developing NASH through various methods.METHODS The expression levels of miR-103 in the AT-derived exosomes and livers were detected and compared between NASH mice and control.The effect of miR-103 on NASH progression was also explored by antagonizing miR-103,including steatosis and inflammation degree changes.The interaction between miR-103 and the autophagy-related gene phosphatase and tensin homolog(PTEN)was confirmed by dual-luciferase reporter assay.The role of the interaction between miR-103 and PTEN on autophagy was verified in NASH-like cells.Finally,the effects of miR-103 from adipose-derived exosomes on NASH and autophagy were analyzed through animal experiments.RESULTS The expression of miR-103 was increased in NASH mice,compared to the control,and inhibition of miR-103 could alleviate NASH.The results of the dual-luciferase reporter assay showed miR-103 could interact with PTEN.MiR-103-anta decreased p-AMPKa,p-mammalian target of rapamycin(mTOR),and p62 but increased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in NASH mice.Similar results were also observed in NASH-like cells,and further experiments showed PTEN silencing inhibited the effect of miR-103-anta.AT derivedexosome miR-103 aggravated NASH and increased the expressions of p-AMPKa,p-mTOR,and p62 but decreased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in mice.CONCLUSION AT derived-exosome increased the levels of miR-103 in the liver,and miR-103 aggravated NASH.Mechanically,miR-103 could interact with PTEN and inhibit autophagy.

Identification of a Regulatory Single Nucleotide Polymorphism in the Adiponectin (APM1) Gene Associated with Type 2 Diabetes in Han Nationality

Objective To identify the genetic defects of the the adiponectin （APM1） gene that contribute to the development of type 2 diabetes （T2DM） and determine the functional single nucleotide polymorphisms （SNPs） in the APMI gene associated with T2DM in Han nationality. Methods The APMI gene 5＇-UTR was screened by direct sequencing to identify common polymorphisms. Identified SNPs were genotyped in 585 nondiabetic controls, 278 subjects with impaired glucose intolerance （IGT） and 212 patients with T2DM. The functions of SNPs in the regulatory region were assessed by reporter gene assay. Possible association between SNPs and plasma APMI levels or metabolic parameters was statistically asses,sed. Results Three SNPs were identified in the APMI gene 5＇-UTR. A case-control study revealed that SNP -11377 G/C had significant differences in allele frequencies between T2DM patients and nondiabetic controls （G 0.314/C 0.686 vs. G 0.265/C 0.735, P=0.03）. Haplotype analysis of three SNPs in the APM1 gene showed that no significant association of haplotypes with T2DM. IGT was detected in the present study. Reporter gene assay showed that SNP did not influence the transcription efficiency in the 3T3-LI cell line. Conclusion SNP - 11377 G/C in the proximal promoter region of the APM 1 gene contributes to the development of T2DM in Han nationality but may not be a functional SNP in the APM1 gene.

Association of Gghrelin Polymorphisms with Metabolic Syndrome in Han Nationality Chinese

Objective To investigate the association of ghrelin gene polymorphisms with metabolic syndrome in Han Nationality Chinese. Methods A total of 240 patients with metabolic syndrome and 427 adults aged above forty years were recruited. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analysis. Results The allelic frequency of the Leu72Met polymorphism was 17.3% in the patient group and 11.9% in the control group （x^2=7.36, P=0.007）. Metabolic syndrome was more prevalent among carriers of the Met72 variant （43.8 vs 33.1%, age- and sex-adjusted odds ratio=1.57, P=0.01）. No Arg51Gln variants were found in our study subjects. Conclusion Rather than being associated with its individual components, Leu72Met polymorphism is associated with metabolic syndrome in the Han Nationality Chinese. Arg51Gln polymorphism is rare in the Han Nationality Chinese.

Nursing a patient with latent autoimmune diabetes in adults with insulin-related lipodystrophy,allergy,and exogenous insulin autoimmune syndrome:A case report

BACKGROUND Latent autoimmune diabetes in adults(LADA)is a special type of type 1 diabetes mellitus.During the early stages,patients with LADA are treated with oral antidiabetics.However,insulin treatment is still required as islet function gradually declines.Once patients have developed insulin allergy,clinical treatment and nursing care become very challenging.CASE SUMMARY Here,we report a case of LADA with insulin-related lipodystrophy,allergy,and exogenous insulin autoimmune syndrome during insulin treatment,thus making it very difficult to effectively control glucose levels with insulin.We attempted subcutaneous injection and an insulin pump to desensitize the patient’s response to insulin,and finally assisted the doctor to select the appropriate insulin treatment for the patient.We describe the management of this patient from a nursing viewpoint.CONCLUSION We summarize the nursing experience of a case with complex insulin allergy requiring desensitization treatment.Our approach is very practical and can be applied to similar patients needing insulin desensitization.

Palmitoylation in Crohn’s disease:Current status and future directions

S-palmitoylation is one of the most common post-translational modifications in nature;however,its importance has been overlooked for decades.Crohn’s disease(CD),a subtype of inflammatory bowel disease(IBD),is an autoimmune disease characterized by chronic inflammation involving the entire gastrointestinal tract.Bowel damage and subsequent disabilities caused by CD are a growing global health issue.Well-acknowledged risk factors for CD include genetic susceptibility,environmental factors,such as a westernized lifestyle,and altered gut microbiota.However,the pathophysiological mechanisms of this disorder are not yet comprehensively understood.With the rapidly increasing global prevalence of CD and the evident role of S-palmitoylation in CD,as recently reported,there is a need to investigate the relationship between CD and S-palmitoylation.In this review,we summarize the concept,detection,and function of S-palmitoylation as well as its potential effects on CD,and provide novel insights into the pathogenesis and treatment of CD.

Clinical Application of Gaofang(Medicated Paste)in Cardiovascular Disease

Gaofang(medicated paste),also known as gaoji in Chinese,is one of the eight dosage forms of traditional Chinese medicine.Originated in the Han and Tang dynasties,it is widely used in Shanghai,Jiangsu,Zhejiang,and Guangdong of China at present.It is generally believed that Gaofang can help reinforce deficiency,delay aging,and regulate the overall health status.Currently,Gaofang has been extensively used in the treatment of cardiovascular disease.Based on the relevant literature and clinical experience,this article reviews the general situation and the clinical application of Gaofang as well as the common Chinese medicines in Gaofang for cardiovascular diseases.

High-fat diet aggravates colitis via mesenteric adipose tissue derived exosome metastasis-associated lung adenocarcinoma transcript 1

BACKGROUND Obesity is associated with an increased risk of developing Crohn’s disease(CD),higher disease activity,and comparatively worse clinical outcomes.AIM To investigate the role of mesenteric adipose tissue-derived exosomes in the pathogenesis of CD aggravation in obese individuals.METHODS First,we induced colitis in mice initiated on high-fat and normal diets and compared the severity of colitis.We then extracted and identified exosomes from mesenteric adipose tissue and determined the levels of metastasis-associated lung adenocarcinoma transcript 1(MALAT1)in mesenteric adipose tissue-derived exosomes and the colon.Next,we demonstrated an interaction between MALAT1 and the miR-15a-5p/activating transcription factor 6(ATF6)axis.Finally,we explored the effects of mesenteric adipose tissue-derived exosomes extracted from mice fed a high-fat or normal diet on the severity of 2,4,6-trinitrobe-nzenesulfonic acid(TNBS)-induced colitis and ATF6-related endoplasmic reticulum stress pathways.RESULTS High-fat diet was found to aggravate TNBS-induced colitis in mice.The expression of MALAT1 in mesenteric adipose tissue-derived exosomes of high-fat diet-fed mice increased.The increased expression of MALAT1 in colon tissue exacerbated TNBS-induced colitis and activated the ATF6 endoplasmic reticulum stress pathway.This effect was partially reversed by the reduced expression of MALAT1 and overexpression of miR-15a-5p.CONCLUSION Mesenteric adipose tissue-derived exosome-encapsulated long noncoding RNAs MALAT1 targets the colon and aggravates TNBS-induced colitis in obese mice,which may potentially act on the miR-15a-5p/ATF6 axis and activate endoplasmic reticulum stress.

Approximate Customized Proximal Point Algorithms for Separable Convex Optimization

Proximal point algorithm(PPA)is a useful algorithm framework and has good convergence properties.Themain difficulty is that the subproblems usually only have iterative solutions.In this paper,we propose an inexact customized PPA framework for twoblock separable convex optimization problem with linear constraint.We design two types of inexact error criteria for the subproblems.The first one is absolutely summable error criterion,under which both subproblems can be solved inexactly.When one of the two subproblems is easily solved,we propose another novel error criterion which is easier to implement,namely relative error criterion.The relative error criterion only involves one parameter,which is more implementable.We establish the global convergence and sub-linear convergence rate in ergodic sense for the proposed algorithms.The numerical experiments on LASSO regression problems and total variation-based image denoising problem illustrate that our new algorithms outperform the corresponding exact algorithms.