Inflammatory bowel disease in pediatric and adolescent patients:A biomolecular and histopathological review

Crohn’s disease(CD)and ulcerative colitis(UC)are the two main forms of inflammatory bowel disease(IBD)with both overlapping and distinct clinical,pathological and biomolecular features.It has been suggested that pediatric IBD is a distinct disease entity,with probably different disease subtypes.The aim of this study is to review and summarize the evolution of the current concept of pediatric IBD.The results of this review reinforce the idea that pediatric CD and UC may be further classified in various clinicopathologic entities.For clinicians and pathologists convenience,practical algorithms for the distinction of the various subphenotypes of pediatric IBD are also provided.

Klotho in cardiovascular disease:Current and future perspectives

Protein Klotho,beyond its role as a regulator of the phosphatemia,is also involved in the maintaining of the cardiovascular health,being associated its alterations with the development of cardiovascular damage and increased morbi-mortality. For all this,nowadays Klotho is the subject of a thorough research which is focused on uncover its intimate mechanisms of action,and in analyzing the utility of its modulation as a potential strategy with clinical applicability. Molecular mechanisms of Klotho are not well understood but an emerging research area links Klotho deficiency with vascular pathology. Changes in this protein have been associated with cardiovascular-related complications like inflammation,vascular calcification,and endothelial dysfunction. All this is particularly relevant if considering the recent discovery of Klotho expression in vascular tissue.

Inflammatory pathways of importance for management of inflammatory bowel disease

Inflammatory bowel disease(IBD)is a group of chronic disorders of the gastrointestinal tract comprising Crohn’s disease(CD)and ulcerative colitis(UC).Their etiologies are unknown,but they are characterised by an imbalanced production of pro-inflammatory mediators,e.g.,tumor necrosis factor(TNF)-α,as well as increased recruitment of leukocytes to the site of inflammation.Advantages in understanding the role of the inflammatory pathways in IBD and an inadequate response to conventional therapy in a large portion of patients,has over the last two decades lead to new therapies which includes the TNF inhibitors(TNFi),designed to target and neutralise the effect of TNF-α.TNFi have shown to be efficient in treating moderate to severe CD and UC.However,convenient alternative therapeutics targeting other immune pathways are needed for patients with IBD refractory to conventional therapy including TNFi.Indeed,several therapeutics are currently under development,and have shown success in clinical trials.These include antibodies targeting and neutralising interleukin-12/23,small pharmacologic Janus kinase inhibitors designed to block intracellular signaling of several pro-inflammatory cytokines,antibodies targeting integrins,and small anti-adhesion molecules that block adhesion between leukocytes and the intestinal vascular endothelium,reducing their infiltration into the inflamed mucosa.In this review we have elucidated the major signaling pathways of clinical importance for IBD therapy and highlighted the new promising therapies available.As stated in this paper several new treatment options are under development for the treatment of CD and UC,however,no drug fits all patients.Hence,optimisations of treatment regimens are warranted for the benefit of the patients either through biomarker establishment or other rationales to maximise the effect of the broad range of mode-of-actions of the present and future drugs in IBD.

Zebrafish as a disease model for studying human hepatocellular carcinoma

Liver cancer is one of the world's most common cancers and the second leading cause of cancer deaths. Hepatocellular carcinoma(HCC), a primary hepatic cancer, accounts for 90%-95% of liver cancer cases. The pathogenesis of HCC consists of a stepwise process of liver damage that extends over decades, due to hepatitis, fatty liver, fibrosis, and cirrhosis before developing fully into HCC. Multiple risk factors are highly correlated with HCC, including infection with the hepatitis B or C viruses, alcohol abuse, aflatoxin exposure, and metabolic diseases. Over the last decade, genetic alterations, which include the regulation of multiple oncogenes or tumor suppressor genes and the activation of tumorigenesis-related pathways, have also been identified as important factors in HCC. Recently, zebrafish have become an important living vertebrate model organism, especially for translational medical research. In studies focusing on the biology of cancer, carcinogen induced tumors in zebrafish were found to have many similarities to human tumors. Several zebrafish models have therefore been developed to provide insight into the pathogenesis of liver cancer and the related drug discovery and toxicology, and to enable the evaluation of novel smallmolecule inhibitors. This review will focus on illustrativeexamples involving the application of zebrafish models to the study of human liver disease and HCC, through transgenesis, genome editing technology, xenografts,drug discovery, and drug-induced toxic liver injury.

Distance management of inflammatory bowel disease:Systematic review and meta-analysis

AIM:To review the effectiveness of distance management methods in the management of adult inflammatory bowel disease(IBD)patients.METHODS:A systematic review and meta-analysis of randomized controlled trials comparing distance management and standard clinic follow-up in the management of adult IBD patients.Distance management intervention was defined as any remote management method in which there is a patient self-management component whereby the patient interacts remotely via a self-guided management program,electronic interface,or self-directs open access to clinic follow up.The search strategy included electronic databases(Medline,PubMed,CINAHL,The Cochrane Central Register of Controlled Trials,EMBASE,KTPlus,Web of Science,and SCOPUS),conference proceedings,and internet search for web publications.The primary outcome was the mean difference in quality of life,and the secondary outcomes included mean difference in relapse rate,clinic visit rate,and hospital admission rate.Study selection,data extraction,and risk of bias assessment were completed by two independent reviewers.RESULTS:The search strategy identified a total of4061 articles,but only 6 randomized controlled trials met the inclusion and exclusion criteria for the systematic review and meta-analysis.Three trials involved telemanagement,and three trials involved directed patient self-management and open access clinics.The total sample size was 1463 patients.There was a trend towards improved quality of life in distance management patients with an end IBDQ quality of life score being 7.28(95%CI:-3.25-17.81)points higher than standard clinic follow-up.There was a significant decrease in the clinic visit rate among distance management patients mean difference-1.08(95%CI:-1.60--0.55),but no significant change in relapse rate or hospital admission rate.CONCLUSION:Distance management of IBD significantly decreases clinic visit utilization,but does not significantly affect relapse rates or hospital admission rates.

Heartburn and regurgitation have different impacts on life quality of patients with gastroesophageal reflux disease

AIM:To investigate the impact of heartburn and regurgitation on the quality of life among patients with gastroesophageal reflux disease(GERD).METHODS:Data from patients with GERD,who were diagnosed according to the Montreal definition,were collected between January 2009 and July 2010.The enrolled patients were assigned to a heartburn or a regurgitation group,and further assigned to an erosive esophagitis(EE)or a non-erosive reflux disease(NERD)subgroup,depending on the predominant symptoms and endoscopic findings,respectively.The general demographic data,the scores of the modified Chinese version of the GERDQ and the Short-form 36(SF-36)questionnaire scores of these groups of patients were compared.RESULTS:About 108 patients were classified in the heartburn group and 124 in the regurgitation group.The basic characteristics of the two groups were similar,except for male predominance in the regurgitation group.Patients in the heartburn group had more sleep interruptions(22.3%daily vs 4.8%daily,P=0.021),more eating or drinking problems(27.8%daily vs 9.7%daily,P=0.008),more work interferences(11.2%daily vs none,P=0.011),and lower SF-36 scores(57.68 vs64.69,P=0.042),than patients in the regurgitation group did.Individuals with NERD in the regurgitation group had more impaired daily activities than those with EE did.CONCLUSION:GERD patients with heartburn or regurgitation predominant had similar demographics,but those with heartburn predominant had more severely impaired daily activities and lower general health scores.The NERD cases had more severely impaired daily activity and lower scores than the EE ones did.

Atrial fibrillation and gastroesophageal reflux disease:From the cardiologist perspective

We have read with interest the paper by Roman C.and colleagues discussing the relationship between gastroesophageal reflux disease and atrial fibrillation.The review is presenting the available evidence for the common pathogenic mechanisms.However,from a cardiologist perspective,some available data were not highlighted in the review,cardiovascular involvement in gastroesophageal reflux is less assessed.Hypertension,obesity or diabetes mellitus are substrate for left atrial remodeling that initiate and sustained atrial fibrillation development.One of the pathophysiologic mechanisms in atrial fibrillation is the presence of a trigger.Gastroesophageal reflux could be only a trigger for this arrhythmia.We believe that atrial fibrillation should be considered as possible extraesophageal syndrome in the gastroesophageal reflux classification.

Reversal of IgM deficiency following a gluten-free diet in seronegative celiac disease

Selective Ig M deficiency(s IGMD)is very rare;it may be associated with celiac disease(CD).We present the case of an 18-year-old man with s IGMD masking seronegative CD.Symptoms included abdominal pain,diarrhea and weight loss.Laboratory tests showed reduced Ig M,DQ2-HLA and negative anti-transglutaminase.Villous atrophy and diffuse immature lymphocytes were observed at histology.Tissue transglutaminase m RNA mucosal levels showed a 6-fold increase.The patient was treated with a gluten-free diet(GFD)and six months later the symptoms had disappeared,the villous architecture was restored and mucosal tissue transglutaminase m RNA was comparable to that of healthy subjects.After 1 year of GFD,a complete restoration of normal Ig M values was observed and duodenal biopsy showed a reduction of immature lymphocytes and normal appearance of mature immune cells.

Mycobacterium avium subspecies paratuberculosis in the etiology of Crohn's disease, cause or epiphenomenon?

The origin of inflammatory bowel disease is unknown. Attempts have been made to isolate a microorganism that could explain the onset of inflammation, but no pathological agent has ever been identified. Johne's disease is a granulomatous chronic enteritis of cattle and sheep caused by Mycobacterium avium subspecies paratuberculosis(MAP) and shows some analogies with Crohn's disease(CD). Several studies have tried to clarify if MAP has a role in the etiology of CD. The present article provides an overview of the evidence in favor and against the "MAP-hypothesis", analyzing the methods commonly adopted to detect MAP and the role of antimycobacterial therapy in patients with inflammatory bowel disease. Studies were identified through the electronic database, MEDLINE, and were selected based on their relevance to the objective of the review. The presence of MAP was investigated using multiple diagnostic methods for MAP detection and in different tissue samples from patients affected by CD or ulcerative colitis and in healthy controls. On the basis of their studies, several authors support a close relationship between MAP and CD. Although increasing evidence of MAP detection in CD patients is unquestionable, a clear etiological link still needs to be proven.

A Study on the Correlation Between Cerebral Small Vascular Disease and Constitution Types of Traditional Chinese Medicine

Objective:To study the correlation between cerebral small vascular disease and constitution types of Traditional Chinese Medicine(TCM).Methods:The severity of lacunar infarction and leukoaraiosis were graded in 230 patients with cerebral small vascular disease,and they were divided into TCM constitution types.The survey of TCM constitution types was carried out by using standardized TCM constitution scale,and order multivariate Logistic regression was used to analyze the correlation between TCM constitution types with severity of lacunar infarction and leukoaraiosis.Results:Yang-deficiency(阳虚)constitution,blood-stasis constitution and phlegm-dampness constitution were the most common TCM constitution types in patients with lacunar infarction,accounting for 33.7%,12.5%,11.5%respectively.Yang-deficiency constitution,blood-stasis constitution and Yin-deficiency(阴虚)constitution were the most common TCM constitution types in patients with leukoaraiosis,accounting for 28.8%,18.5%,13.7%respectively.There were significant differences in lacunar infarction of Yang-deficiency constitution and blood stasis constitution(P<0.05),and there were significant differences in leukoaraiosis of phlegmdampness constitution and blood-stasis constitution(P<0.05).Single factor analysis showed that the main risk factors of lacunar infarction were age,smoking,alcohol consumption,Yang-deficiency constitution and blood-stasis constitution,and the main risk factors of leukoaraiosis were age,smoking,hypertensive disease,phlegm-dampness constitution and blood-stasis constitution.The ordered multivariate Logistic regression analysis found that the severity of lacunar infarction was closely related to age,and the severity of leukoplosis was closely related to age,smoking and hypertension disease.Conclusion:TCM constitution types of lacunar infarction in patients with small cerebral vascular disease is mainly Yang-deficiency constitution and blood-stasis constitution,and the risk factors include age,smoking,alcohol consumption,Yang-deficiency constitution and blood-stasis constitution.Age is closely related with lacunar infarction.TCM constitution types with leukoaraiosis are mainly phlegm-dampness constitution and blood-stasis constitution,and the risk factors are age,smoking,hypertension disease,phlegm-dampness constitution and blood-stasis constitution.Age,smoking and hypertension disease are closely related with leukoaraiosis.

Celiac disease:Management of persistent symptoms in patients on a gluten-free diet

AIM:To investigate all patients referred to our center with non-responsive celiac disease (NRCD),to establish a cause for their continued symptoms.METHODS:We assessed all patients referred to our center with non-responsive celiac disease over an 18-mo period.These individuals were investigated to establish the eitiology of their continued symptoms.The patients were first seen in clinic where a thorough history and examination were performed with routine blood work including tissue transglutaminase antibody measurement.They were also referred to a specialist gastroenterology dietician to try to identift any lapses in the diet and sources of hidden gluten ingestion.A repeat small intestinal biopsy was also performed and compared to biopsies from the referring hospital where possible.Colonoscopy,lactulose hydrogen breath testing,pancreolauryl testing and computed tomography scan of the abdomen were undertaken if the symptoms persisted.Their clinical progress was followed over a minimum of 2 years.RESULTS:One hundred and twelve consecutive patients were referred with NRCD.Twelve were found not to have celiac disease (CD).Of the remaining 100 patients,45% were not adequately adhering to a strict gluten-free diet,with 24 (53%) found to be inadvertently ingesting gluten,and 21 (47%) admitting noncompliance.Microscopic colitis was diagnosed in 12% and small bowel bacterial overgrowth in 9%.Refractory CD was diagnosed in 9%.Three of these were diagnosed with intestinal lymphoma.After 2 years,78 patients remained well,eight had continuing symptoms,and four had died.CONCLUSION:In individuals with NRCD,a remediable cause can be found in 90%:with continued gluten ingestion as the leading cause.We propose an algorithm for investigation.

Treatment of rheumatic disease by Ch inese drugs fumigation and steaming

AIM:To observe therapeutic effect of fum igation and steaming with Chinese drugs in the rheumatic diseases.METHODS:Drugs removing rheumatic disease,warming channels and dispersing cold,activating blood circul ation were used for fumigation and steamin g treatment in 84cases with rheumati c diseases,once a day,20min each time ,10times as a treatment course.A-mong them,4cases received treatmen t for 2and 3course of treatment re-spectively.RESULTS:18cases were corrected completely,64were im-proved,2showed no improvement,and total effective rate was 98%.CONCLUSION:Through hot and therapeutic effect o f drugs,lesions can be managed directly in fumigation and s teaming treatment.

子宫静脉内平滑肌瘤1例并文献复习

子宫静脉内平滑肌瘤(IVL)是一种良性肿瘤,但可沿血管生长,表现出恶性生物学行为,临床上较为少见,严重者可累及多个器官,临床表现多样化。IVL发生率较低,且无特异性诊断方法,易发生漏诊、误诊情况。手术是本病首选的治疗方法,术前应充分评估患者情况、了解疾病受累情况、患者生育要求等,提供个性化手术方式。术后应定期随访,预防疾病复发。本文报道1例IVL患者的诊疗经过,总结IVL疾病特点,提高对IVL的认识。

An association between the location of white matter changes and the behavioral and psychological symptoms of dementia in Alzheimer's disease patients

Objective:The frontal lobe may be involved in circuits associated with depression,apathy,aggression,and other psychiatric symptoms.Although white matter changes(WMC)are related to the severity of behavioral and psychological symptoms of dementia(BPSD)in patients with Alzheimer’s disease(AD),it is unclear which part of the WMC may play the most important role in BPSD.This study was designed to investigate the relationship between the location of WMC and the severity of BPSD in AD patients.Methods:Among patients diagnosed with Alzheimer’s disease between 2009 and2014,387 patients were retrospectively reviewed after those with pre‐existing organic brain syndrome,psychiatric diseases,or toxic‐metabolic encephalopathy were excluded.Patients’demographic and laboratory data,WMC measured with brain computed tomography and scored using the age‐related white matter changes(ARWMC)scale,and neuropsychological tests,including the cognitive abilities screening instrument(CASI),the Mini‐Mental State Examination(MMSE),the clinical dementia rating scale with sum‐box(CDR‐SB),and the neuropsychiatric inventory(NPI)were analyzed.Results:There was no significant difference in the NPI between patients with and without a history of stroke,hypertension,and diabetes.No significant difference in the NPI was identified between different sexes or different Apolipoprotein E(APOE)alleles.The NPI score was significantly correlated with the duration of education(r=–0.4515,P=0.0172),CASI(r=–0.2915,P<0.0001),MMSE(r=–0.8476,P<0.0001),and CDR‐SB(r=2.2839,P<0.0001).WMC in the right frontal lobe showed a significant difference in NPI in comparison to those without WMC(P=0.0255).After adjusting for age,duration of education,and CASI,WMC in the right frontal lobe remained significantly associated with the NPI score(β=3.8934,P=0.042).Conclusions:WMC involving the right frontal lobe may play an important role in the BPSD in AD patients during their dementia diagnosis.Further studies are necessary to confirm whether controlling the risk factors of WMC can slow the progression of BPSD.

基于N端脑利钠肽前体、D-二聚体及降钙素原和临床病例资料构建AECOPD预后模型

目的:探究重症慢性阻塞性肺疾病急性加重期(AECOPD)患者血清中N端脑利钠肽前体(NT-proBNP)、D-二聚体(D-D)、降钙素原(PCT)的水平以及三者联合评估患者出院1年内预后的预测价值。方法:回顾性分析2018年1月—2022年10月于我院接受住院治疗的AECOPD患者124例的临床资料,患者分为存活组(99例)和死亡组(25例)。多因素Logistic回归模型分析患者出院1年内死亡的独立危险因素。受试者工作特征(ROC)曲线分析三者联合检测评估患者出院1年内预后的预测价值。结果:多因素Logistic回归分析显示,上1年急性加重≥2次、改良版英国医学研究委员会呼吸问卷(mMRC)>2级、铜绿假单胞菌、无长期家庭氧疗(LTOT)、NT-proBNP>1.1g/L、D-D>2.4 mg/L、PCT>0.09g/L以及右心室增大,均为AECOPD患者出院后1年内死亡的独立危险因素(P<0.05)。三者联合预测时曲线下面积(AUC)为0.830(95%CI:0.801~0.859,P<0.001),灵敏度为95.15%,特异度为74.28%,表明联合预测价值较高。风险评分模型将患者分为低(≤77分)、中(>77分且≤89分)、高风险(>89分)3组人群。模型评价提示风险评分模型准确度高。结论:上1年急性加重≥2次、mMRC>2级、铜绿假单胞菌、无LTOT、NT-proBNP>1.1 g/L、D-D>2.4mg/L、PCT>0.09g/L以及右心室增大,均为AECOPD患者出院后1年内死亡的独立危险因素。NT-proBNP、D-D及PCT三者联合检测AECOPD患者出院后1年内预后情况具有的较高预测价值,为临床评估病情和判定预后提供参考。

A transcranial magnetic stimulation study on Alzheimer's diseae and behavioral variant frontotemporal dementia

Objective To investigate the changes in cortical excitability and inhibitory circuits of patients with Alzheimer’s disease(AD)or behavioral variant frontotemporal dementia(bv FTD)using transcranial magnetic stimulation(TMS).Methods Forty-four patients with AD,30 patients with bv FTD and 44 healthy controls were enrolled in the study.The epidemiological data

以顽固性呕吐起病的视神经脊髓炎谱系疾病2例并文献复习

视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorder,NMOSD)是一种少见的免疫介导的中枢神经系统疾病。长节段脊髓炎(>3个椎体)、严重视神经炎和/或顽固性呕吐和呃逆极后区综合征(area postrema syndrome,APS)是该病的典型表现。其中有些病例以顽固性恶心、呕吐、呃逆为唯一的首发表现,早期易误诊、漏诊,造成诊疗延误。该文报道2例以顽固性恶心、呕吐、呃逆起病的视神经脊髓炎谱系疾病,以期为该类病例的及早正确诊治提供启示。

“因势利导”思想在疫病中的应用探讨

“因势利导”在中医学中有丰富的内涵。自《黄帝内经》始,“因势利导”思想一直指导并影响着临床治疗,并在疫病的防治实践中发挥着巨大作用。本文从病邪性质、位置之势而利导和传变之势而利导两方面,结合经典古籍和现代研究,探讨其在临床诊治中的应用。针对疫病来势凶猛、传变迅速、病机复杂的特点,因病位表里上下及病性寒热虚实的不同,注重“通”“透”之法,透邪外达,通至邪出,除尽疫邪;审机度势,平衡祛邪与扶正之法,顺人体之势扶正以先安未受邪之地,防邪深入。因势利导,以祛邪为要,注重扶正,往往事半功倍,以期为疫病的临床诊治提供参考。

中药复方芪明颗粒“眼肾同治”糖尿病视网膜病变和糖尿病肾病的网络药理学及分子对接研究

目的基于网络药理学及分子对接探究中药复方芪明颗粒发挥“眼肾同治”作用治疗糖尿病视网膜病变(DR)和糖尿病肾病(DN)的药理学机制。方法运用TCMSP和TCMID数据库检索筛选芪明颗粒的活性成分及成分靶点。通过GeneCards、TTD、Drug⁃Bank和OMIM数据库分别筛选DR和DN的靶点基因。汇总去重后与所获得的芪明颗粒成分靶点取交集,并导入STRING平台整合评估交集靶点的蛋白质间相互作用,最后借助Cytoscape 3.9.1软件构建“芪明颗粒⁃活性成分⁃作用靶点”网络和蛋白质互作网络。运用DAVID数据库对作用靶点进行基因本体(GO)分析和京都基因与基因组百科全书(KEGG)通路富集分析。最后利用AutoDock 1.5.7软件对核心作用靶点及主要药效成分进行分子对接。结果芪明颗粒治疗DR和DN的主要药效成分共8种,核心靶点共6个。GO富集涉及的条目包括生物过程1289个,细胞组成155个,分子功能263个。KEGG富集结果显示涉及的通路202个。分子对接结果显示主要药效成分与核心作用靶点具有很好的结合亲和力。结论芪明颗粒以其多成分、多靶点的优势,协同调控多种机制治疗DR和DN,其所突出的“眼肾同治”的治疗特色符合现代精准医疗所提倡的诊疗理念。本研究为今后开展芪明颗粒的药效研究及DR和DN的中医治疗研究阐明了路径。

高原低氧对认知功能的影响与相关防治进展

高原环境有低压、低氧等特点,这种特定的环境在引起人体急慢性高原病的同时,也会损伤人体的中枢神经系统,影响认知能力。这些损伤主要体现在记忆力、学习能力、知觉等方面。应激是造成损伤的原因之一,进入高原后的心理变化以及社会文化环境的改变会引起应激反应。此外,高原的低压低氧引起的氧化损伤、炎症反应、钙稳态失衡也会损伤神经系统,造成神经细胞凋亡。另一方面,表观遗传学在高原环境的适应及氧稳态相关基因的表达调控也逐渐受到关注,可能在高原居民的环境适应与遗传方面起到重要作用。面对高原损伤,阶梯式习服和吸氧是目前常见的应对措施,药物治疗以及心理干预也对高原病的防治起到了积极作用。随着相关技术的发展,新型的高原宜居方案也在逐步研发,为高原反应的防治带来了新的思路。本文综述了高原环境对认知功能的主要影响,高原反应应对方法现状,并介绍了最新的高原宜居方案研发进展,为高原环境认知功能障碍的防治和研究提供参考。