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Approach to loss of response to advanced therapies in inflammatory bowel disease

World Journal of Gastroenterology 2024年第22期30卷 2902-2919页

作者： Nikil Vootukuru Abhinav Vasudevan Department of Gastroenterology and Hepatology Eastern HealthVictoriaBox Hill 3128Australia eastern health clinical school Monash UniversityVictoriaBox Hill 3128Australia

BACKGROUND Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease.Clinicians now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many patients.However,issues of primary non-response(PNR)and secondary loss of response(SLOR)to non-tumour necrosis factor inhibitor(TNFi)therapies remains a common problem.Specific issues include the choice of optimization of therapy,identifying when dose optimization will recapture response,establishing optimal dose for escalation and when to switch therapy.AIM To explores the issues of PNR and SLOR to non-TNFi therapies.METHODS This review explores the current evidence and literature to elucidate management options in cases of PNR/SLOR.It will also explore potential predictors for response following SLOR/PNR to therapies including the role of therapeutic drug monitoring(TDM).RESULTS In the setting of PNR and loss of response to alpha-beta7-integrin inhibitors and interleukin(IL)-12 and IL-23 inhibitors dose optimization is a reasonable option to capture response.For Janus kinase inhibitors dose optimization can be utilized to recapture response with loss of response.CONCLUSION The role of TDM in the setting of advanced non-TNFi therapies to identify patients who require dose optimization and as a predictor for clinical remission is not yet established and this remains an area that should be addressed in the future.

关键词： Inflammatory bowel disease Ulcerative colitis Crohn Biologics Interleukin-12 and interleukin-23 inhibitors Alpha-beta7-integrin inhibitors Janus kinase inhibitors Sphingosine-1-phosphate receptor modulators

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Nutritional and lipid profile status of children with spinal muscular atrophy in China: A retrospective case-control study

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中华医学杂志(英文版) 2024年第10期137卷 1243-1245页

作者： Feng Yijie Wei Jia Yao Mei Jin Jianing Cui Yiqin Long Qi Chen Fei Hong Yi Zhou Dongming Hu Jingjing Chen Xiao Gao Feng Yuan Changzheng Mao Shanshan Department of Neurology Children’s Hospital Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang China Department of Infection Children’s Hospital Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang China Department of Nutrition Children’s Hospital Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang China Children’s Hospital Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang China school of Public health Zhejiang University School of Medicine Hangzhou Zhejiang China Children’s Hospital School of Public Health Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang China

5q spinal muscular atrophy (5qSMA) is an autosomal recessive neuromuscular disorder caused by the lack of the survival motor neuron (SMN) protein encoded by the SMN1 gene, located at 5q11.2-q13.3.[1] The incidence is 1/10,000-1/6000 live births, and the mutation carrier rate in China is 1/42.[1] Spinal muscular atrophy (SMA) is mainly divided into four subtypes: SMA type I, II, III, and IV, based on the motor milestones ever achieved. Types I-III occur in children,[1] which often result in progressive muscular atrophy and weakness as well as multi-system dysfunction, including nutritional and metabolic issues.[2] Children with SMA may have hidden nutritional and lipid imbalances, despite normal body appearance and anthropometric measurements, making it difficult to detect early and intervene. Fewer studies have elucidated both the nutritional status and lipid metabolism in SMA patients,[2] especially in Asia, which may have some of the highest numbers of SMA patients in the world. To inform the development of targeted nutritional management strategies, this study aimed to investigate the nutritional status and serum lipid profile characteristics in children with SMA, based on a hospital-based case-control study in China. This study was approved by the Ethics Committee of Children's Hospital of Zhejiang University school of Medicine (No. 2019-IRB-171). Written informed consent was obtained from all the patients and their legal guardians.

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NLRP3 activation in macrophages promotes acute intestinal injury in neonatal necrotizing enterocolitis

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World Journal of Pediatrics 2024年第2期20卷 153-164页

作者： Bo Shi Cheng-Jie Lyu Zhen-Kai Le Hao-Sen Ji Yi Xiao Yuan-Yuan Zhang Shou-Jiang Huang Lin-Jun Yu Qiang Shu Jin-Fa Tou Deng-Ming Lai Department of Neonatal Surgery Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China Department of Pulmonology Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China Department of Thoracic and Cardiovascular Surgery Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China

Background Macrophages are involved in various immune inflammatory disease conditions.This study aimed to investigate the role and mechanism of macrophages in regulating acute intestinal injury in neonatal necrotizing enterocolitis(NEC).Methods CD68,nucleotide-binding oligomerization domain,leucine-rich repeat,and pyrin domain-containing 3(NLRP3),cysteine aspartate-specific protease-1(caspase-1),and interleukin-1β(IL-1β)in paraffin sections of intestinal tissues from NEC and control patients were detected with immunohistochemistry,immunofluorescence,and western blot.Hypertonic pet milk,hypoxia and cold stimulation were used to establish a mouse(wild type and Nlrp3^(-/-))model of NEC.The mouse macrophage(RAW 264.7)and rat intestinal epithelial cell-6 lines were also cultured followed by various treatments.Macrophages,intestinal epithelial cell injuries,and IL-1β release were determined.Results Compared to the gut“healthy”patients,the intestinal lamina propria of NEC patients had high macrophage infiltration and high NLRP3,caspase-1,and IL-1β levels.Furthermore,in vivo,the survival rate of Nlrp3^(-/-)NEC mice was dramatically improved,the proportion of intestinal macrophages was reduced,and intestinal injury was decreased compared to those of wild-type NEC mice.NLRP3,caspase-1,and IL-1β derived from macrophages or supernatant from cocultures of macrophages and intestinal epithelial cells also caused intestinal epithelial cell injuries.Conclusions Macrophage activation may be essential for NEC development.NLRP3/caspase-1/IL-1β cellular signals derived from macrophages may be the underlying mechanism of NEC development,and all these may be therapeutic targets for developing treatments for NEC.

关键词： Caspase-1 Interleukin-1β Macrophage Necrotizing enterocolitis NLRP3

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Coinfection of SARS-CoV-2 Omicron variant and other respiratory pathogens in children

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World Journal of Pediatrics 2024年第1期20卷 92-96页

作者： Wei Li Bing-Han Wang Bao-Hai Chen Yi Sun Lin Li Wen-Qing Xiang Ahmed Faisal Ali Lin-Xuan Su Hai-Yan Mao Hong-Qiang Shen Qiang Shu Department of clinical Laboratory Children's HospitalNational Clinical Research Center for Child HealthZhejiang University School of MedicineHangzhouChina school of Public health Zhejiang University School of MedicineHangzhouChina Department of Information Center Children's HospitalZhejiang University School of MedicineHangzhouChina Zhejiang Provincial Center for Disease Control and Prevention HangzhouChina Department of Thoracic&Cardiovascular Surgery Children's HospitalNational Clinical Research Center for Child HealthZhejiang University School of MedicineHangzhouChina

Since the outbreak of coronavirus disease 2019(COVID-19),the entire world has been affected by the epidemic[1,2].On November 9,2021,a variant of the novel coronavirus B.1.1.529 was detected for the first time from case samples in South Africa.The Omicron strain spread and mutated significantly fast.This variant has the characteristics of escape immunity,which can induce relatively extreme disease and reduce the neutralization of antibodies in vaccinators,and is more likely to be reinfected[3,4].The clinical presentation of severe acute respiratory syndrome coronavirus 2(SARSCoV-2)in children has mild symptoms and a lower risk of hospitalization and death.

关键词： respiratory immunity acute

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Role of mitochondrial dysfunction in kidney disease: Insights from the cGAS-STING signaling pathway

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中华医学杂志(英文版) 2024年第9期137卷 1044-1053页

作者： Li Lu Liu Fei Feng Chunyue Chen Zhenjie Zhang Nan Mao Jianhua Department of Nephrology Children’s Hospital Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang China Department of Pediatric Intensive Care Unit Children’s Hospital Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang China

Over the past decade, mitochondrial dysfunction has been investigated as a key contributor to acute and chronic kidney disease. However, the precise molecular mechanisms linking mitochondrial damage to kidney disease remain elusive. The recent insights into the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthetase (cGAS)-stimulator of interferon gene (STING) signaling pathway have revealed its involvement in many renal diseases. One of these findings is that mitochondrial DNA (mtDNA) induces inflammatory responses via the cGAS-STING pathway. Herein, we provide an overview of the mechanisms underlying mtDNA release following mitochondrial damage, focusing specifically on the association between mtDNA release-activated cGAS-STING signaling and the development of kidney diseases. Furthermore, we summarize the latest findings of cGAS-STING signaling pathway in cell, with a particular emphasis on its downstream signaling related to kidney diseases. This review intends to enhance our understanding of the intricate relationship among the cGAS-STING pathway, kidney diseases, and mitochondrial dysfunction.

关键词： Mitochondrial dysfunction Mitochondrial DNA cGAS-STING pathway Kidney diseases Chronic kidney disease

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Amyloid-beta and tau protein beyond Alzheimer's disease

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Neural Regeneration Research 2024年第6期19卷 1262-1276页

作者： Morteza Abyadeh Vivek Gupta Joao A.Paulo Arezoo Gohari Mahmoudabad Sina Shadfar Shahab Mirshahvaladi Veer Gupta Christine T.O.Nguyen David I.Finkelstein Yuyi You Paul A.Haynes Ghasem H.Salekdeh Stuart L.Graham Mehdi Mirzaei ProGene Technologies Pty Ltd. 2. Department of clinical Medicine Faculty of Medicine Health and Human Sciences Macquarie Medical School Macquarie University Department of Cell Biology Harvard Medical School school of Medicine Deakin University Department of Optometry and Vision Sciences School of Health Sciences Faculty of Medicine Dentistry and Health Sciences University of Melbourne The Florey Institute of Neuroscience and Mental health The University of Melbourne school of Natural Sciences Macquarie University

The aggregation of amyloid-beta peptide and tau protein dysregulation are implicated to play key roles in Alzheimer’s disease pathogenesis and are considered the main pathological hallmarks of this devastating disease. Physiologically, these two proteins are produced and expressed within the normal human body. However, under pathological conditions, abnormal expression, posttranslational modifications, conformational changes, and truncation can make these proteins prone to aggregation, triggering specific disease-related cascades. Recent studies have indicated associations between aberrant behavior of amyloid-beta and tau proteins and various neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as retinal neurodegenerative diseases like Glaucoma and age-related macular degeneration. Additionally, these proteins have been linked to cardiovascular disease, cancer, traumatic brain injury, and diabetes, which are all leading causes of morbidity and mortality. In this comprehensive review, we provide an overview of the connections between amyloid-beta and tau proteins and a spectrum of disorders.

关键词： amyloid-beta cancer cardiovascular diseases diabetes neurodegeneration Tau traumatic brain injury

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Development and validation of a novel non-invasive test for diagnosing nonalcoholic fatty liver disease in Chinese children

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World Journal of Pediatrics 2024年第4期20卷 413-421页

作者： Zhe-Wen Qin Qian-Nan Ren Hong-Xi Zhang Ya-Ru Liu Ke Huang Wei Wu Guan-Ping Dong Yan Ni Jun-Fen Fu Division of Endocrinology National Clinical Research Center for Child HealthNational Children’s Regional Medical CenterThe Children’s HospitalDepartment of EndocrinologyNational Clinical Research Center for Child HealthNational Children’s Regional Medical CenterThe Children’s HospitalZhejiang University School of MedicineHangzhou310052China

With the exploding prevalence of obesity,many children are at risk of developing nonalcoholic fatty liver disease.Using anthropometric and laboratory parameters,our study aimed to develop a model to quantitatively evaluate liver fat content(LFC)in children with obesity.Methods A well-characterized cohort of 181 children between 5 and 16 years of age were recruited to the study in the Endocrinology Department as the derivation cohort.The external validation cohort comprised 77 children.The assessment of liver fat content was performed using proton magnetic resonance spectroscopy.Anthropometry and laboratory metrics were measured in all subjects.B-ultrasound examination was carried out in the external validation cohort.The Kruskal-Wallis test,Spearman bivariate correlation analyses,univariable linear regressions and multivariable linear regression were used to build the optimal predictive model.Results The model was based on indicators including alanine aminotransferase,homeostasis model assessment of insulin resistance,triglycerides,waist circumference and Tanner stage.The adjusted R^(2)of the model was 0.589,which presented high sensitivity and specificity both in internal[sensitivity of 0.824,specificity of 0.900,area under curve(AUC)of 0.900 with a 95%confidence interval:0.783–1.000]and external validation(sensitivity of 0.918 and specificity of 0.821,AUC of 0.901 with a 95%confidence interval:0.818–0.984).Conclusions Our model based on five clinical indicators was simple,non-invasive,and inexpensive;it had high sensitivity and specificity in predicting LFC in children.Thus,it may be useful for identifying children with obesity who are at risk for developing nonalcoholic fatty liver disease.

关键词： Biochemical markers Children Magnetic resonance spectroscopy Nonalcoholic fatty liver disease Pediatric obesity

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Treatment of multisystem inflammatory syndrome in children

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World Journal of Pediatrics 2024年第4期20卷 325-339页

作者： Tong Tong Yi-Hua Jin Min Wang Fang-Qi Gong Department of Cardiology Children's HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthNo.3333 Binsheng RoadHangzhou 310052China

Background Multisystem inflammatory syndrome in children(MIS-C),a relatively uncommon but severe pediatric complication,is associated with coronavirus disease 2019(COVID-19).A variety of treatment approaches,including intravenous immunoglobulins(IVIGs),glucocorticoids(GCs)and biologic agents,such as anakinra and infliximab,have been described for the management of COVID-19-related MIS-C.Anticoagulant therapy is also important.However,a well-developed treatment system has not been established,and many issues remain controversial.Several recently published articles related to the treatment of MIS-C have been released.Hence,in this review,we identified relevant articles published recently and summarized the treatment of MIS-C more comprehensively and systematically.Data sources We reviewed the literature on the treatment of MIS-C through 20 September 2023.The PubMed/Medline,Web of Science,EMBASE,and Cochrane Library databases were searched with the combination of the terms"multisystem inflammatory syndrome","MIS-C","PIMS-TS","therapy","treatment","drug","IVIG","GCs","intravenous immunoglobulin","corticosteroids","biological agent",and"aspirin".Results The severity of MIS-C varies,and different treatment schemes should be used according to the specific condition.Ongoing research and data collection are vital to better understand the pathophysiology and optimal management of MIS-C.Conclusions MIS-Cis a disease involving multiple systems and has great heterogeneity.With the accumulation of additional experience,we have garnered fresh insights into its treatment strategies.However,there remains a critical need for greater standardization in treatment protocols,alongside the pressing necessity for more robust and meticulously conducted studies to deepen our understanding of these protocols.

关键词： Coronavirus disease 2019-Corticosteroids Intravenous immunoglobulin Multisystem inflammatory syndrome in children-Treatment

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Influencing Factors of healthy Aging Risk Assessed Using Biomarkers:A Life Course Perspective

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China CDC weekly 2024年第11期6卷 219-224,I0014-I0017页

作者： Cedric Zhang Bo Lua Yajie Gao Jinming Li Xingqi Cao Xinwei Lyu Yinuo Tu Shuyi Jin Zuyun Liu Center for clinical Big Data and Analytics of the Second Affiliated Hospital and Department of Big Data in Health Science School of Public Healththe Key Laboratory of Intelligent Preventive Medicine of Zhejiang ProvinceZhejiang University School of MedicineHangzhou CityZhejiang ProvinceChina Institute of Epidemiology and health Care University College LondonLondonUK College of Chemical and Biological Engineering Zhejiang UniversityHangzhou CityZhejiang ProvinceChina

Assessing individual risks of healthy aging using biomarkers and identifying associated factors have become important areas of research.In this study,we conducted a literature review of relevant publications between 2018 and 2023 in both Chinese and English databases.Previous studies have predominantly used single biomarkers,such as C-reactive protein,or focused on specific life course stages and factors such as socioeconomic status,mental health,educational levels,and unhealthy lifestyles.By summarizing the progress in this field,our study provides valuable insights and future directions for promoting healthy aging from a life course perspective.

关键词： such insight directions

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Differences in clinicopathological characteristics between lipohypertrophy and localized insulin-derived amyloidosis:A scoping review

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Chronic Diseases and Translational Medicine 2024年第1期10卷 22-30页

作者： Kanae Mukai Hiromasa Tanno Junko Sugama Toshihiko Yanagita Emi Kanno Department of clinical Nursing Faculty ofHealth SciencesInstitute of MedicalPharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan Department of Translational Science forNursing Tohoku University Graduate School ofMedicineSendaiJapan Research Center for Implementation NursingScience Initiative School of Health SciencesFujita Health UniversityToyoakeJapan Department of clinical Pharmacology Schoolof NursingUniversity of MiyazakiMiyazakiJapan

Insulin is used as a therapeutic agent in patients with diabetes,and cutaneous lipohypertrophy(LH)and localized insulin-derived amyloidosis(LIDA)are well-known adverse effects associated with insulin injections.The clinical implications,management,assessment methods,and pathological differentiation of LH and LIDA have been recently updated.This review was to update our knowledge of the pathological differentiation,effects of insulin absorption,hypoglycemic events,and recent assessment methods for LH and LIDA.A scoping review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for Scoping Reviews guidelines.Original studies and case reports in English were also included.PubMed and Scopus databases were searched for keywords to identify papers published up to January 2022.A total of 113 studies were identified through a database search,and 31 were eligible for inclusion in this scoping review.In the 31 studies included in this review,patients with type 2 diabetes had high frequencies of LH and LIDA.LH outcome parameters were assessed using pathological findings and imaging.LIDA is mainly determined by pathological methods,such as hematoxylin and eosin and Congo red staining.Several in vitro and in vivo LIDA models of LIDA have been developed.These results suggest that pathological analysis is required to identify LH and LIDA.It is important to consider LIDA,as it likely influences insulin adsorption and glycemic control.Although several studies have evaluated the LIDA process,little is known about the mechanisms underlying the development of adverse effects associated with insulin injections.

关键词： diabetes mellitus insulin injection lipohypertrophy localized insulin-derived amyloidosis

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