The pathogenesis of Kawasaki disease / 中国小儿急救医学

Kawasaki disease is an acute systemic vascular inflammatory syndrome, which is the main cause of acquired heart disease in children.It is most likely to cause serious complications such as coronary artery dilation, coronary artery aneurysm, and acute myocardial infarction.At present, there is no accurate conclusion about the etiology and pathogenic mechanism of Kawasaki disease.We performed this review to realize the etiology of Kawasaki disease regarding infectious pathogens, environmental factors, immune disorders and genetic tendencies.Meanwhile, this study will focus on the abnormal activation of the immune system, the up-regulated expression of inflammatory cytokines, the increased activity of metal matrix proteinases (MMPs), and vascular endothelial injury/vascular endothelial dysfunction to review the pathogenic mechanism of Kawasaki disease.

Corrigendum: Ivabradine Treatment Reduces Cardiomyocyte Apoptosis in a Murine Model of Chronic Viral Myocarditis.

[This corrects the article DOI: 10.3389/fphar.2018.00182.].

The mediation mechanism of coronary artery lesions in both male and female patients with Kawasaki disease / 中华流行病学杂志

Objective@#To explore the mediation mechanism of coronary artery lesion among both male and female Kawasaki disease (KD) children.@*Methods@#Children with KD that hospitalized in the Wenzhou Medical University affiliated Yuying Children’s Hospital from January 2009 to December 2014, were included in this study. Differences on demographical characteristics, clinical manifestations, laboratory indicators, regimen and time of treatment, results from pre/post echocardiography and treatment between male and female patients, were compared. The independent effect of gender on the risk of coronary artery lesions (CAL) was evaluated, and the mediating effect of BMI, visiting time and KD type on the association between gender and CAL were also studied.@*Results@#The average BMI level of male patients was higher than that of female patients. The difference was statistically significant (P<0.001). The prevalence of overweight among male patients (20.9%) was higher than female (14.1%). The difference was statistically significant (P=0.011). Data from the multivariate logistic regression analysis confirmed that the incidence of CAL in male patients was higher than that in female patients (aOR=1.50, 95%CI: 1.06-2.12) but the CAL was mainly different before on the immunoglobulin therapy. Results from the mediation analysis showed that BMI was an important mediator in the association between gender and CAL, with the indirect effect as 1.05 (95%CI: 1.01- 1.10) and the proportion mediated as 13.0%.@*Conclusions@#Male patients presented higher incidence of CAL but was mainly reflected in the difference of CAL before the treatment. BMI was probably an important mediator related to the association between gender and CAL.

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4+ T cell differentiation.

Many studies have found that abnormalities in the proportion and differentiation of CD4+ T cells (Th cells) are closely related to the pathogenesis of viral myocarditis (VMC). Our previous research indicates that the cholinergic anti-inflammatory pathway (CAP) attenuates the inflammatory response of VMC and downregulates the expression of cytokines in Th1 and Th17 cells. This suggests that the cholinergic anti-inflammatory pathway likely attenuates the inflammatory response in VMC by altering Th cell differentiation. The aim of this study is to investigate the effect of CAP on CD4+ T cell differentiation in VMC mice. CD4+ T cells in the spleen of VMC mice were obtained and cultured in the presence of nicotine or methyllycaconitine (MLA). Cells were harvested and analyzed for the percentage of each Th cell subset by flow cytometry and transcription factor release by Western blot. Then, we detected the effect of CAP on the differentiation of Th cells in vivo. Nicotine or MLA was used to activate and block CAP, respectively, in acute virus-induced myocarditis. Nicotine treatment increased the proportion of Th2 and Treg cells, decreased the proportion of Th1 and Th17 cells in the spleen, reduced the level of proinflammatory cytokines, and attenuated the severity of myocardium lesions and cellular infiltration in viral myocarditis. MLA administration had the opposite effect. Our result demonstrated that CAP effectively protects the myocardium from virus infection, which may be attributable to the regulation of Th cell differentiation.

Ivabradine Treatment Reduces Cardiomyocyte Apoptosis in a Murine Model of Chronic Viral Myocarditis.

This study was designed to explore the effects of ivabradine on cardiomyocyte apoptosis in a murine model of chronic viral myocarditis (CVMC). Mice were inoculated intraperitoneally with Coxsackievirus B3 at days 1, 14, and 28, respectively. On day 42, the mice were gavaged with ivabradine for 30 days until the 72nd day. The heart of infected mice was dilated and a large number of interstitial fibroblasts infiltrated into the myocardium on day 42. Compared with the untreated CVMC mice, mice treated with ivabradine showed a significant reduction in heart rate and less impairment of left ventricular function on day 72. The positive apoptosis of myocardial cells in the untreated CVMC group was significantly higher than that of the normal group and was significantly reduced after treatment with ivabradine. The expression levels of Bax and Caspase-3 in the untreated CVMC group were significantly higher than those of the normal group and were apparently reduced in the ivabradine-treated group versus the untreated CVMC group. Bcl-2 showed a high expression in the normal group and low expression in the untreated CVMC group, but its expression level in the ivabradine-treated group were higher than that of the untreated CVMC group. These results indicate that ivabradine could attenuate the expression of Caspase-3 by downregulation of Bax and upregulation of Bcl-2 to prevent the deterioration of cardiac function resulting from ventricular myocyte loss by cardiomyocyte apoptosis.

Early prediction of the risk of coronary artery lesions in K awasaki disease by oxidized low-density lipoproteins / 中华风湿病学杂志

Objective To study the expression of plasma oxidized low-density lipoprotein (oxLDL) in children with acute phase Kawasaki disease (KD), and investigate its value for early prediction of coronary artery lesions in KD. Methods Totally 80 children with KD were collected. Children were divided into four groups by the results of echocardiogram of coronary artery in different periods: CAL1 group (children with coronary artery lesions (CAL+) both in acute and sub-acute phase, 8 cases), CAL2 group (children with CAL+in acute phase but recovery normal (CAL-) in sub-acute phase, 10 cases), NCAL1 group (children with CAL-in acute phase but occur CAL+ in sub-acute phase, 10 cases) and NCAL2 group (children with CAL- both in acute and sub-acute phase, 52 cases). The serum samples (before the use of intravenous immunoglobulin) were collected in acute phase. Twenty healthy controls and twenty fever controls were enrolled into the study, and their serum samples were collected. OxLDL was measured by enzyme linked immunosorbent assay (ELISA). They were compared using ANOVA, pairwise comparison LSD-t test. And ROC curve analysis was used to determine the threshold. Results Compared with the control groups,plasma oxLDL levels were higher in children with KD, both CA+and CAL-[(15.0±3.3) mU/L, (12.3±3.5) mU/L vs (9.2±2.2) mU/L, (8.0±2.3) mU/L, F=20.435, P<0.05]. Plasma oxLDL levels were increased more significantly in children with CAL+ than children with CAL- in KD [(15.0 ±3.3) mU/L vs (12.3 ±3.5) mU/L, t=2.28, P=0.002]. There was significant difference in the concentration of oxLDL between the groups of Kawasaki disease (F=5.068, P=0.003). Plasma oxLDL levels were significantly higher in the NCAL1 group than those in the NCAL2 group [(14.5 ±3.8) mU/L vs (11.9±3.3) mU/L, t=2.29, P=0.02], but there were no statistically significant difference between the NCAL1 group and CAL1 or CAL2 group [(14.5±3.8) mU/L vs (15.9±3.9) mU/L, (14.5±3.8) mU/L vs (14.2±2.7) mU/L, t=0.73, 0.20;P=0.41, 0.84]. ROCs analysis indicated that oxLDL≥13.83 mU/L, could be the threshold for the prediction of coronary artery lesions with the sensitivity of 0.607 and a specificity of 0.75. Conclusion OxLDL plays an important role in coronary artery lesions in KD. The coronary endothelial dysfunction is earlier than coronary dilatation, and oxLDL is expected to become a reliable early predictor of coronary artery lesions in KD.

Expression of MMP-2 and NF-κB in myocardium of mice with viral myo-carditis / 中国病理生理杂志

[ ABSTRACT] AIM: To observe the effects of TNF-α/nuclear factor-κB( NF-κB) /matrix metalloproteinase-2 (MMP-2) pathway on the expression of MMP-2 in the mice with viral myocarditis.METHODS: Six-week-old inbred male mice were randomly assigned to control and myocarditis group.The mice in myocarditis group and control group were intra-peritoneally inoculated with 0.1 mL 10-5.69 TCID50 /mL coxsackievirus B3 and vehicle (PBS), respectively.Ten mice were sacrificed at the 4th and 10th days after injection.The blood and heart specimens were harvested.The serum content of TNF-αwas measured by ELISA.The myocardial levels of MMP-2, NF-κB p65 and IκBαwere determined by Western blot.RESULTS: Compared with control group, the protein expression of MMP-2 and NF-κB p65 in the myocardium and the serum content of TNF-αwere significantly increased in myocarditis group (P <0.05).The protein expression of IκBαwas lower in myocarditis group than that in control group (P <0.05).CONCLUSION: TNF-α, NF-κB p65 and MMP-2 were higher in the mice with acute viral myocarditis.The increased expression of them might be involved in the pathogene-sis of viral myocarditis.

Microparticles derived from bone marrow mesenchymal stem cells pro-mote angiogenesis in rat myocardial infarction model / 中国病理生理杂志

AIM:Toobservetheeffectsofmicroparticlesderivedfrombonemarrowmesenchymalstemcells ( MSC-MPs) on angiogenesis and cardiac function in a rat myocardial infarction model .METHODS:MSCs were obtained from Sprague-Dawley rats.MSCs were treated under serum-free condition in hypoxia for 72 h, and the microparticles were isolated from the supernatants .The phenotypic profile of MSC-MPs was determined by bead-based flow cytometry and the morphology was observed under a transmission electron microscope .The rat myocardial infarction model was established . The cardiac function was evaluated by echocardiography after the intramyocardial injection of MSC -MPs.The myocardial in-farct size was observed by Masson staining .The blood vessel density in the peri-infarcted area was measured using immuno-histochemical staining for von Willebrand factor and α-smooth muscle actin.The expression of vascular endothelial growth factor ( VEGF) was analyzed by real-time PCR.RESULTS: Apoptotic MSCs released a large quantity of microparticles which were phenotypically similar to the parent MSCs and 100~1 000 nm in diameter.The cardiac functions of myocardial infarction rat model were improved at 7 d and 28 d after intramyocardial injection of MSC-MPs compared with control group . The myocardial infarct size was reduced and angiogenesis was promoted significantly in the infarcted heart injected with MSC-MPs 28 d after treatment .MSC-MPs treatment also increased the expression level of VEGF within 7 d.CONCLU-SION:MSC-MPs protect cardiac tissue from ischemic injury and improve cardiac function by promoting angiogenesis after myocardial infarction .

The protective role of hydrogen sulfide in a mouse model of viral myocarditis induced by Coxsachie-virus B3 / 中华微生物学和免疫学杂志

Objective To investigate the protective role of hydrogen sulfide and the expression of cystathionine gamma-lyase/hydrogen sulfide pathway in a mouse model of myocarditis induced by Coxsachie -virus B3(CVB3).Methods A total of 110 five-week-old BALB/c male mice were randomly divided into four groups:the control group, viral myocarditis group, sodium bisulfide (NaHS) group (50 μmol/kg) and DL-propargylglycine (PAG) group (40 mg/kg).The experimental model of viral myocarditis was induced by intraperitoneal injection of CVB 3.Then the four groups were respectively administered with PBS , PBS, NaHS and PAG from day 1 to day 10 after infection.Blood and heart specimens were harvested from 10 mice of each group on day 4 and day 10 for evaluation of myocardial edema .The pathological changes in heart tis-sues were observed through hematoxylin-eosin staining.Levels of H2 S, IL-6 and TNF-αwere measured by ELISA.The expressions of CSE and CVB 3 at mRNA level were determined by quantitative real time PCR ( qRT -PCR ) analysis and the expression of CSE at protein level was detected by Western blot .Results Compared with the control group , the levels of H2 S and the expressions of CSE at mRNA and protein levels were down-regulated in mice with CVB 3-induced myocarditis .With the treatment of NaHS , the levels of H 2 S in serum and tissue were both up-regulated , and the histopathological damage was alleviated .However , PAG as an irreversible CSE inhibitor inhibited the expressions of H 2 S and CSE and aggravated myocardial injury , inflammatory cells infiltration and interstitial edema .Moreover , the RT-PCR analysis also showed that the expression of CVB3 at mRNA level was inhibited by NaHS but enhanced by PAG .Conclusion The expres-sion of CSE/H2 S pathway is down-regulated in mice with CVB 3-induced viral myocarditis .PAG could pro-mote virus propagation and exacerbate the disease through inhibiting the production of endogenous H 2 S, while NaHS as a H2 S donor has a protective effect on infected myocardium by suppressing virus replication at an early stage .

Epidemiologic study of children admitted to hospital with Kawasaki disease in Wenzhou from 2001 to 2010 / 中华风湿病学杂志

Objective To evalute the incidence and epidemiologic characteristics of Kawasaki disease (KD) in Wenzhou,China.Methods We used a questionnaire survey and reviewed the medical records and reports of all patients with KD diagnosed during the 10 year periods from January,2001 to December,2010.Results We studied 827 inpatients diagnosed with KD during the 10-years period from 2001 to 2010.There were 613 cases (74.12％) with complete KD.The ratio of male to female ratio was 2.28∶1.Age at onset ranged from 37 days to 13 years old,and the peak age group was 1 year old.The disease occurred in all of the seasons,but the peak was from April to June.The incidence of cardiovascular damage in acute KD was 34.6％,and the most common sequela was coronary artery dilatation.There were16 patients with coronary aneurysm.Fifty-three patients did not respond to immunoglobulin (6.4％),and 12 patients (1.5％) developed recurrent KD.After treatment,114 cases (13.8％) developed neutropenia.There were no deaths during hospitalization.Conclusion Patients with KD has become more and more in Wenzhou.Cardiovascular damages were similar to those in Beijing and Guangzhou,but higher than that reported in Japan.

Effects of carvedilol on murine viral myocarditis / 中国病理生理杂志

AIM: To observe the effects of carvedilol on murine viral myocarditis model. METHODS: A total of 188 inbred male BALB/c mice of 4-6 weeks were divided into 4 groups: myocarditis group (group C, n=60), metoprolol treatment group (group M, n=60), carvedilol treatment group (group K, n=60), control group (group B, n=8). Myocardial histopathololgic changes were observed. The concentrations of cardiac troponin I (cTn-I) were detected by chemiluminescence immunoassay (CLIA). Western blotting was performed to analyze the contents of phosphorylated p38MAPK in myocardium. RESULTS: Metropolol and carvedilol lightened myocardial histopathololgic changes at acute stage, decreased cTn-I concentrations and myocardial phosphorylated p38MAPK value compared with myocarditis group. Treatment with carvedilol was more effective than treated with metropolol on those indexes. CONCLUSION: Carvedilol protects against viral myocarditis by inhibition of p38MAPK signal transduction pathway through blockade of β_1 and β_2 adrenergic receptors.

Changes of leptin,nitric oxide and interleukin-6 levels in children with Kawasaki disease / 中华风湿病学杂志

Objective To investigate the change of leptin,nitric oxide (NO) and interleukin-6 (IL- 6) levels in serum of children with Kawasaki disease (KD) and the possible relationship between leptin,NO and IL-6 levels,explore the role of leptin,NO and IL-6 in the pathogenesis of KD.Methods Fourty-five children with KD were studied.Twelve of them had coronary artery lesions and 33 had non-coronary artery lesions;thirty healthy children and 18 children with juvenile idiopathic arthritis or Henoch-Scholeion purpuru were enrolled as control subjects.Serum was collected from each patients during acute stage of KD and remission.Leptin,NO and IL-6 contents were detected by radioimmuno-assay and spectrophotometry and enzyme-linked immunoserbent assay.Meanwhile,C-reactive protein (CRP) were examined.Results ① The concentrations of serum leptin,NO,IL-6 and CRP in children with KD were significantly higher in the acute stage of KD than those at clinical remission and those of the normal control group (q=26.24,25.23; 21.38,31.30;35.37,33.68;16.32,15.66;P＜0.01,respectively).No significant differences in serum leptin, IL-6 and CRP were found between the clinical remission group and the normal control group (q=1.02,1.04, 0.61,P＞0.05,respectively);The concentrations of serum NO were significantly higher at clinical remission group than those of the normal control group (q=11.31,P＜0.01).② There was no significant difference in the concentrations of serum leptin,IL-6 and CRP at the acute stage of KD than those in patients with and without coronary artery lesions (q=1.17,1.92,1.60,P＞0.05).The concentrations of serum NO were significantly higher at the acute stage of KD with coronary artery lesions than those of KD without coronary artery lesions (q=6.91,P＜0.01).③ The concentrations of serum leptin in children with juvenile idiopathic arthritis or Henoch-Scholeion purpura were signifietantly higher than those of the normal control group (t=13.26,P＜ 0.01).No significant differences in serum leptin were found between children with juvenile idiopathic arthritis or Henoch-Seholeion purpura and children with KD (t=1.28,P＞0.05).④ Correlation was found between serum leptin values and levels of the following parameters (P＜0.01);NO (r=0.69),IL-6 (r=0.55),CRP (r=0.42).However,there were no associations between leptin and leukocytes (r=0.21,P＞0.05) or serum albumin level (r=-0.24,P＞0.05).Association was found between serum NO and IL-6 (r=0.45,P＜0.01)or CRP(r=0.49,P＜0.01).Conclusion These results suggest that leptin,NO and IL-6 may have a role in the immunoinflammatory process of KD,especially in the acute phase.Further in vivo and in vitro studies are needed to establish the roles of leptin,NO and IL-6 in the pathogenesis of KD.

Transcatheter closure of perimembrane ventricular septal defects with Amplartzer occluder device in children:A preliminary results of clinical application / 介入放射学杂志

Objective To evaluate the efficiency and preliminary results of transcatheter closure of perimembrane ventricular septal defects (PMVSD) using Amplartzer occluder device in children.Methods There were 5 children using transthoracic echocardiography(TTE) to confirm the PMVSD before the intervention. The diameters of the PMVSD were measured by angiography; Each of the children were treated with Amplartzer occluder device for transcatheter closure of PMVSD under TTE and fluoroscopy. The TTE and elec-trocardiograph(ECG)、chest X-ray were performed 24 hours,1 and 3、6 months after the procedure to evaluate the therapeutic effect. Results The mean diameter of the PMVSDs measured by angiography was 5.0?2.4 mm(Ranging from 2.5 to 8.3 mm). The mean diameter of the occluder selected was 7.4?3.2 mm(Ranging from 4 to 10 mm). The success rate was 100%, and no complication occurred during the procedure. No residual shunts were found by angiography immediately after the procedure in all cases. There were no malpositions of occluder and no residual shunts in the 5 cases by TTE after the procedure 24 hours , 1 and 3、 6 months. There were no cardiac arrhythmia found by ECG. It showed that both pulmonary vascularity were improved.Conclusions Transcatheter closure of perimembrane ventricular septal defects using Amplartzer occluder device is an efficient therapy for children with PMVSD. The operation is simple with a high success rate of placement and a good occlusion effect. Further studies of long term results are required.

Questionable and difficult points in malpractice disputes / 中华医院管理杂志

The implementation of the Malpractice Handling Regulations provides medical institutions with a new framework for guarding against and handling medical disputes. Compared with the Methods for Handling Malpractices, it has many merits. However, as a newly published set of laws and regulations, it will doubtlessly be tested and challenged in one way or another in actual practice. The authors attempt to present their viewpoints from the following perspectives. Firstly, the determination of the nature of a malpractice ought to be linked with the degree of involvement in it, and it is unwise to take cases of minor liabilities as malpractices. Secondly, the rules for identifying the degree of a malpractice in negotiated settlement fall short of being reasonable and are not easy to implement, thus adding to the difficulty of negotiated settlement. Thirdly, is the stipulation of compensation for malpractices only fair, sensible and legal? Is it conducive to the negotiated settlement of medical disputes? Fourthly, since the Malpractice Handling Regulations are lacking in attention to the problem of lengthy lingering in the hospital on the grounds of malpractices, the authors put forward the suggestion that administrative laws and regulations of health ought to provide necessary support in terms of health laws and regulations for the judicial settlement of such cases.

Effects of safflor injection on expression of cyclooxygenase-2 mRNA during lung ischemia/reperfusion injury in rabbits / 中国病理生理杂志

AIM: To investigate the effects of safflor injection(SI) on expression of cyclooxygenase-2 mRNA during lung ischemia/reperfusion injury(PIRI) in rabbits.METHODS: Rabbit lung model of ischemia/reperfusion injury was constructed in vivo.The rabbits were randomly divided into three groups: sham-operation group(group S),ischemia-reperfusion group(group I/R) and ischemia/reperfusion plus safflor injection group(group SI).The lung tissue sampled at the end of the experiment was assayed for wet/dry weight ratio(W/D),injured alveoli rate(IAR) and observed ultrastructure changes under electron microscope.The expressions of COX-1 and COX-2 were measured by immunohistochemistry(IHC).The expression of COX-1 mRNA and COX-2 mRNA were observed by in situ hybridization(ISH).RESULTS: The value of W/D and IAR was much higher in I/R group,but decreased in SI group.Electron microscope showed obvious ultrastructure injury brought by PIRI in I/R group,which was greatly attenuated in SI group.The IHC and ISH demonstrated that COX-2 and COX-2 expressions in pulmonary tissue of I/R group were significantly higher than those in S group(P