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Vol 16, No 2
Vol 16, No 2 April 2020 ISSN 1708-8569
Review articles
Original articles
Clinical images
Review articles:
Forkhead box M1 transcription factor: a novel target for pulmonary arterial hypertension therapy
  Li Gu, Han-Min Liu
Background: Forkhead box M1 (FoxM1), a member of forkhead family, plays a key role in carcinogenesis, progression, invasion, metastasis and drug resistance. Based on the similarities between cancer and pulmonary arterial hypertension, studies on the roles and mechanisms of FoxM1 in pulmonary arterial hypertension have been increasing. This article aims to review recent advances in the mechanisms of signal transduction associated with FoxM1 in pulmonary arterial hypertension.
Data sources: Articles were retrieved from PubMed and MEDLINE published after 1990, including¡ªbut not limited to¡ªFoxM1 and pulmonary arterial hypertension.
Results: FoxM1 is overexpressed in pulmonary artery smooth muscle cells in both pulmonary arterial hypertension patients and animal models, and promotes pulmonary artery smooth muscle cell proliferation and inhibits cell apoptosis via regulating cell cycle progression. Multiple signaling molecules and pathways, including hypoxia-inducible factors, transforming growth factor-¦Â/Smad, SET domain-containing 3/vascular endothelial growth factor, survivin, cell cycle regulatory genes and DNA damage response network, are reported to cross talk with FoxM1 in pulmonary arterial hypertension. Proteasome inhibitors are effective in the prevention and treatment of pulmonary arterial hypertension by inhibiting the expression and transcriptional activity of FoxM1.
Conclusions: FoxM1 has a crucial role in the pathogenesis of pulmonary arterial hypertension and may represent a novel therapeutic target. But more details of interaction between FoxM1 and other signaling pathways need to be clarified in the future.
  [Abstract] [Full Text] [PDF]  
A review of isolated muscular ventricular septal defect
  Toshiharu Miyake
Background: Color Doppler echocardiography greatly facilitates the diagnosis of isolated muscular ventricular septal defect with a small shunt.
Data sources: Original research articles were collected from database, including PubMed and Google scholar. Relevant articles about muscular ventricular septal defect were included.
Results: The frequency of isolated muscular ventricular septal defect is 5.7% in preterm infants and 1.1-5.3% in term infants. Spontaneous closure in muscular ventricular septal defect occurs with higher frequency and earlier than in perimembranous ventricular septal defect. Approximately 80-90% of isolated muscular ventricular septal defect closes spontaneously by 12 months of age. Midventricular muscular ventricular septal defect is spontaneously closed earlier in the short term, but no site difference is found in the long term. The spontaneous closure mechanism is regarded as aposition of the muscle tissue or fibrous tissue formation in the right ventricular side, but in rare cases involves aneurysm formation of the fibrous tissue. Regarding spontaneous closure of isolated muscular ventricular septal defect diagnosed for the fetus, further studies are needed. Chromosomal microarray analysis of fetuses with isolated muscular ventricular septal defect has revealed that it is not a severe risk factor of chromosomal abnormalities.
Conclusions: This paper presents a review of the history of the diagnosis and frequency of ventricular septal defect, with discussion of its natural history from the fetal period to after birth in patients with isolated muscular ventricular septal defect.
  [Abstract] [Full Text] [PDF]  
Diagnosis and treatment of herpangina: Chinese expert consensus
  Hui Yu, Xing-Wang Li, Quan-Bo Liu, Hui-Ling Deng, Gang Liu, Rong-Meng Jiang, Ji-Kui Deng, Ying-Zi Ye, Jian-Hua Hao, Ying-Hu Chen, Guang-Min Nong, Zhao-Bo Shen, Chang-Shan Liu, Ying-Xue Zou, Jin-Zhun Wu, Xing-Dong Wu, Bi-Quan Chen, Ru-Ping Luo, Ai-Wei Lin, Yan Chen, Xiao-Dong Liu
Background: Herpangina is a common infectious disease in childhood caused by an enterovirus. This consensus is aiming to standardize and improve herpangina prevention and clinical diagnosis.
Methods: The Subspecialty Group of Infectious Diseases, the Society of Pediatric, Chinese Medical Association and Nation Medical Quality Control Center for Infectious Diseases gathered 20 experts to develop the consensus, who are specialized in diagnosis and treatment of herpangina.
Results: The main pathogenic serotypes of herpangina include Coxsackievirus-A, Enterovirus-A and Echovirus. Its diagnosis can be rendered on the basis of history of epidemiology, typical symptoms, characteristic pharyngeal damage and virological tests. The treatment is mainly symptomatic, and incorporates topical oral spray with antiviral drugs. The course of herpangina generally lasts 4-6 days with a good prognosis.
Conclusion: The consensus could provide advices and references for the diagnosis, treatment and management of herpangina in children.
  [Abstract] [Full Text] [PDF]  
Bifidobacterium and Lactobacillus for preventing necrotizing
  Xue Jiao, Meng-Di Fu, Ya-Yun Wang, Jiang Xue, Yuan Zhang
Background: The therapeutic effect of Bifidobacterium and Lactobacillus on necrotizing enterocolitis (NEC) in very-low-birth-weight preterm infants was controversial, and we aimed to explore the exact impact of the two probiotics.
Methods: The PubMed, EMBASE, Web of Science and Cochrane Library were systematically searched for studies published from January 1, 2010 to February 28, 2019. Results were combined with fixed-effect model or random-effect model with specific conditions. Sensitivity analysis was conducted by the trim-and-fill method, and the Begger¡¯s and Egger¡¯s test were used to measure publication bias.
Results: The meta-analysis included 16 original articles with 4632 very-low-birth-weight preterm infants. With respect to the intervention of Bifidobacterium, we estimated non-significant decrease in the morbidity of NEC with a risk ratio (RR) of 0.75 [95% confidence internal (CI) 0.56-1.01, P = 0.06]. Regarding the effect of Lactobacillus, there was no evidence of significant lower risk in the incidence of NEC (RR = 0.67, 95% CI 0.39-1.17, P = 0.16). The use of mixture of probiotics (Bifidobacterium and Lactobacillus) reduced the risk of NEC in the probiotics group (RR = 0.45, 95% CI 0.25-0.80, P = 0.007).
Conclusion: The mixture of Bifidobacterium and Lactobacillus could prevent the morbidity of NEC in very-low-birth-weight preterm infants. But Bifidobacterium or Lactobacillus alone did not show this effect.
  [Abstract] [Full Text] [PDF]  
Maternal exposure to antibiotics increases the risk of infant eczema before one year of life: a meta-analysis of observational studies
  Fa-Qing Huang, Chang-Yu Lu, Shi-Ping Wu, Shao-Zhi Gong, Yan Zhao
Background: There are some conflicting evidences showing that maternal exposure to antibiotics may increase the risk of infant eczema. The present study aims to estimate the effect of prenatal antibiotics administration on infant eczema.
Methods: According to the established inclusion criteria, eligible observational studies were collected by comprehensive database search. The qualities of the included studies were assessed using the Newcastle-Ottawa Scale. Effect sizes that were adjusted by multivariable models were extracted and combined. Publication bias was evaluated by visual inspection of funnel plot.
Results: A total of seven observational studies were included. The qualities of the included studies were at moderate or high level. Prenatal antibiotics use was positively associated with eczema before one year of age [odds ratio (OR) = 1.93, 95% confidence interval (CI) 1.35-2.76]. In addition, antibiotics exposure in utero was likely to be related to eczema after one year of age (OR 1.21, 95% CI 0.98-1.49). The exposure to antibiotics during third trimester was not associated with infant eczema (OR 0.97, 95% CI 0.86-1.09).
Conclusions: Maternal exposure to antibiotics is associated with eczema by one-year age and may have a prolonged effect on eczema after 1-year age. The influence of timing of antibiotics exposure during pregnancy needs more studies to clarify.
  [Abstract] [Full Text] [PDF]  
Original articles:
Re-induction with modified CLAG regimen in relapsed or refractory acute myeloid leukemia in children bridging to allogeneic hematopoietic stem cell transplantation
  Na Zhang, Jing-Bo Shao, Hong Li, Jing-Wei Yang, Kai Chen, Jia-Shi Zhu, Hui Jiang
Background: The prognosis for relapsed or refractory acute myeloid leukemia (RR-AML) in children is poor, and the preferred salvage chemotherapy is unclear. One regimen is cladribine, cytarabine, and granulocyte-colony stimulating factor (CLAG), but little is known about its efficacy and safety in children with RR-AML.
Methods: We enrolled RR-AML patients aged 0-18 years who received modified CLAG regimen for re-induction between July 1, 2015 and April 1, 2018, or conventional induction between August 1, 2011 and April 1, 2018. Patients were followed up to March 31, 2019. Patients underwent allogeneic stem cell transplantation (allo-SCT) or chemotherapy after the induction of complete remission (CR). The CR rate, survival, and side effects were analyzed.
Results: The CR rate for induction was 66.7% after one cycle and 75.0% after two cycles of the CLAG regimen in 12 children. The nine children who received conventional chemotherapy had a CR rate of 22.2% after one cycle and 33.3% after two cycles (P = 0.087 vs. CLAG). The 3-year event-free survival (EFS) of the CLAG group and the conventional treatment group were 44.4 ¡À 15.7% and 22.2 ¡À 13.8% (P = 0.112). The 3-year overall survival of the two groups were 59.5 ¡À 16.2% and 22.2% ¡À 13.8% (P = 0.057). The 3-year EFS for allo-SCT and chemotherapy after CLAG regimen was 66.7 ¡À 19.2% and 25.0 ¡À 21.7% (P = 0.015). A single case of chemotherapy-related death was recorded.
Conclusion: Our data suggest a promising CR rate using CLAG salvage treatment in childhood RR-AML. Allo-SCT after CR may improve the long-term outcome in these patients.
  [Abstract] [Full Text] [PDF]  
Efficacy and safety of tacrolimus and low-dose prednisone in Chinese children with steroid-resistant nephrotic syndrome
  Hai-Xia Chen, Qia Cheng, Fang Li, Qing-Nan He, Yan Cao, Zhu-Wen Yi, Xiao-Chuan Wu
Background: Tacrolimus, a calcineurin inhibitor, is recommended by the recent guidelines from the Kidney Disease Improving Global Outcomes Group as the first-line treatment for steroid-resistant nephrotic syndrome (SRNS), but its clinical application in China is still limited. We investigated the efficacy and safety of tacrolimus combined with low-dose corticosteroids in a population of Chinese children with SRNS.
Methods: In this prospective non-randomized, non-controlled study, Chinese children with SRNS who failed the previous full-dose prednisone treatment were given tacrolimus (0.1 mg/kg/day) and low-dose prednisone (0.25-0.50 mg/kg/day). We compared the overall remission rate (ORR) and adverse events in the follow-up period with this therapeutic regimen.
Results: A total of 76 children were enrolled into the study with an average follow-up period of 18 ¡À 6 months (maximum 36 months). ORR achieved by the first, third, and sixth months was 94.7%, 94.7%, and 96.0%, respectively. All patients who attained an initial tacrolimus trough concentration (FK506C 0 ) > 6 ng/mL (60.3%) achieved remission. The relative risk of relapse at FK506C 0 < 3 ng/mL compared to 3-6 ng/mL, 6-9 ng/mL, and 9-12 ng/mL was 2.3, 3.2, and 16.9, respectively. During the follow-up period, adverse effects that had been previously reported were rare.
Conclusions: Combination of tacrolimus and low-dose prednisone was safe and effective for the treatment of children with SRNS, with high remission rates observed as early as the fi rst month. Relapses were infrequent, but tended to increase significantly with decreases in FK506C0.
  [Abstract] [Full Text] [PDF]  
Intestinal microbiome analysis demonstrates azithromycin
  Elpiniki Nikolaou, Elena Kamilari, Dragana Savkov, Artemy Sergeev, Irina Zakharova, Paris Vogazianos, Marios Tomazou, Athos Antoniades, Christos Shammas
Background: Next-generation sequencing has revolutionized our perspective on the gut microbiome composition, revealing the true extent of the adverse effects of antibiotics. The impact of antibiotic treatment on gut microbiota must be considered and researched to provide grounds for establishing new treatment strategies that are less devastating on commensal bacteria. This study investigates the impact on gut microbiome when a commonly used antibiotic, azithromycin is administered, as well as uncovers the benefits induced when it is used in combination with lactulose, a prebiotic known to enhance the proliferation of commensal microbes.
Methods: 16S rRNA gene sequencing analysis of stool samples obtained from 87 children treated with azithromycin in combination with or without lactulose have been determined. Children¡¯s gut microbial profile was established at the pre- and post-treatment stage.
Results: Azithromycin caused an increase in the relative abundance of opportunistic pathogens such as Streptococcus that was evident 60 days after treatment. While few days after treatment, children who also received lactulose started to show a higher relative abundance of saccharolytic bacteria such as Lactobacillus, Enterococcus, Anaerostipes, Blautia and Roseburia, providing a protective role against opportunistic pathogens. In addition, azithromycin-prebiotic combination was able to provide a phylogenetic profile more similar to the pre-treatment stage.
Conclusion: It is suggested that during azithromycin treatment, lactulose is able to reinstate the microbiome equilibrium much faster as it promotes saccharolytic microbes and provides a homeostatic effect that minimizes the opportunistic pathogen colonization.
  [Abstract] [Full Text] [PDF]  
Fever of unknown origin: a retrospective review of pediatric patients from an urban, tertiary care center in Washington, DC
  Ann Marie Szymanski, Hugo Clifford, Tova Ronis
Background: Fever of unknown origin (FUO) continues to challenge clinicians to determine an etiology and the need for treatment. This study explored the most common etiologies, characteristics, and average cost of hospitalization for FUO in a pediatric population at an urban, tertiary care hospital in Washington, DC.
Methods: Records from patients admitted to Children¡¯s National Health System between September 2008 and April 2014 with an admission ICD-9 code for fever (780.6) were reviewed. The charts of patients 2-18 years of age with no underlying diagnosis and a temperature greater than 38.3 oC for 7 days or more at time of hospitalization were included. Final diagnoses, features of admission, and total hospital charges were abstracted.
Results: 110 patients qualified for this study. The majority of patients (n = 42, 38.2%) were discharged without a diagnosis. This was followed closely by infection, accounting for 37.2% (n = 41) of patients. Rheumatologic disease was next (n = 16, 14.5%), followed by miscellaneous (n = 6, 5.4%) and oncologic diagnoses (n = 5, 4.5%). The average cost of hospitalization was 40,295 US dollars.
Conclusions: This study aligns with some of the most recent publications which report undiagnosed cases as the most common outcome in patients hospitalized with FUO. Understanding that, often no diagnosis is found may reassure patients, families, and clinicians. The cost associated with hospitalization for FUO may cause clinicians to reconsider inpatient admission for diagnostic work-up of fever, particularly given the evidence demonstrating that many patients are discharged without a diagnosis.
  [Abstract] [Full Text] [PDF]  
Clinical characteristics, molecular epidemiology and antimicrobial susceptibility of pertussis among children in southern China
  Jiao-Sheng Zhang, Hong-Mei Wang, Kai-Hu Yao, Ying Liu, Yan-Ling Lei, Ji-Kui Deng, Yong-Hong Yang
Background: Increasing numbers of pertussis cases have been reported in recent years. The reported cases from Shenzhen Children¡¯s Hospital were close to one tenth of all cases in China. The epidemiology of antigenic genotype and antibiotic resistance of circulating strains in children have been unknown in Shenzhen, southern China. The aim of this study was to describe the clinical features and explore the genotypes and antimicrobial susceptibility of circulating Bordetella pertussis among children in Shenzhen.
Methods: Data of hospitalized children with pertussis in Shenzhen Children¡¯s Hospital from August 2015 to April 2017 were collected. The genetic variability of isolates was investigated and Etest was performed for phenotypic susceptibility to erythromycin, azithromycin, clarithromycin, clindamycin, and trimethoprim/sulfamethoxazole.
Results: 469 children with pertussis confirmed by real-time quantitative polymerase chain reaction were hospitalized and strains were isolated from 105 patients. White blood cell count ¡Ý 20 ¡Á 109/L and lymphocyte proportion ¡Ý 60% were observed in 39.29% of infants younger than 3 months. The two predominant profiles of virulence-associated allelic genes were ptxA1/ptxC1/ptxP1/prn1 (48.6%) and ptxA1/ptxC2/ptxP3/prn2 (44.8%). Among the isolates, 48.6% (51/105) were found resistant to macrolides.
Conclusions: These findings indicate that leukocytosis is not a sensitive indicator of pertussis. Isolates with the gene profile ptxP3/prn2 were highly circulating in Shenzhen and less resistant to macrolides, different from patterns observed in other parts of China.
  [Abstract] [Full Text] [PDF]  
The neuroprotective effect of mesenchymal stem cells is mediated through inhibition of apoptosis in hypoxic ischemic injury
  Fang Li, Kun Zhang, Hua Liu, Tan Yang, Dong-Jie Xiao, Yun-Shan Wang
Background: Neonatal hypoxia ischemia causes severe brain damage. Stem cell therapy is a promising method for treating neuronal diseases. Clinical translation of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) for the recovery of neurons after hypoxic ischemic encephalopathy (HIE) may represent an effective therapy.
Methods: Primary neurons were exposed to oxygen-glucose deprivation (OGD) and subsequently cocultured with UC-MSCs. Apoptosis was examined by Annexin V-FITC-PI. Genes related to apoptosis were detected using RT-PCR and western-blot analyses. Using an in vivo model, HIE was induced in postnatal day 7 mice, and UC-MSCs were transplanted via the intraventricular route. UC-MSC migration was investigated by immunofluorescence, and lesion volumes were measured by TTC staining. Apoptosis in injured brain cells was detected by the TUNEL assay. RT-PCR and ELISA were used to detect the expression of inflammatory factors in cells and animal tissues.
Results: Flow cytometry analysis revealed that apoptosis in injured neurons was inhibited by UC-MSCs. The RT-PCR and western blot results indicated that coculture inhibited the expression of proapoptotic genes and upregulated expression of antiapoptotic genes. In the animal model, transplanted UC-MSCs migrated toward the cerebral lesion site and decreased the lesion extent in HIE. TUNEL staining showed that the MSC group exhibited significantly reduced numbers of TUNEL-positive cells. RT-PCR and ELISA showed that UC-MSCs inhibited the upregulation of TNF-¦Á and IL-1¦Â in response to hypoxic ischemic injury.
Conclusion: These results indicate that UC-MSCs exert neuroprotective effects against hypoxic ischemic injury by inhibiting apoptosis, and the mechanism appears to be through alleviating the inflammatory response.
  [Abstract] [Full Text] [PDF]  
MiR-29b expression is altered in crescent formation of HSPN and accelerates Ang II-induced mesangial cell activation
  Shan Cheng, Chun-Hua Zhu, Ai-Hua Zhang, Song-Ming Huang
Background: MicroRNA-29b (miR-29b) has been suggested to possess pro-inflammatory activity, which can partially be explained by the repression of tumor necrosis factor alpha protein three antibody (TNFAIP3). Meanwhile, it also promotes thyroid cell proliferation via Smad signaling pathways. The present study aimed to elucidate the role of miR-29b in Henoch Schonlein purpura nephritis (HSPN) and its underlying molecular mechanism in angiotensin II (Ang II)-induced human glomerular mesangial cell (HGMC) activation.
Methods: We evaluated miR-29b expression in 35 HSPN renal tissues based on crescent formation, glomerular sclerosis, interstitial fibrosis, thrombosis formation and capillary loop necrosis. Meanwhile, HGMCs were cultured, treated with Ang II and then transfected with LV-hsa-miR-29b-1 to induce miR-29b overexpression or LV-hsa-miR-29b-3p-inhibition to inhibit miR-29b expression. Finally, we examined the effects of miR-29b on cell proliferation and release of inflammatory mediators.
Results: We observed that miR-29b expression was significantly higher in the crescent group than in the no crescent group. MiR-29b overexpression induced the release of intercellular adhesion molecule-1, interleukin-1¦Â (IL-1¦Â), IL-6, IL-8, the increase of CyclinA2, CyclinD1, and cell proliferation. It also could inhibit the expressions of TNFAIP3 and NF-kappa-B-repressing factor (NKRF). Correspondingly, miR-29b inhibition produced the opposite effects and increased the expression of TNFAIP3 and NKRF.
Conclusion: MiR-29b expression is altered in crescent formation of HSPN and accelerates Ang II-induced mesangial cell proliferation and release of inflammatory mediators.
  [Abstract] [Full Text] [PDF]  
Clinical images:
DOCK8 deficiency with mediastinal lymph node tuberculosis
  Lin-Qian Zhang, Xiao-Bing Li, Yun-Guang Bao
  [Abstract] [Full Text] [PDF]  
Adenovirus-associated hemophagocytic syndrome in a young child
  Fei-Zhou Zhang, Yu-Qing Cai, Lan-Fang Tang
  [Abstract] [Full Text] [PDF]  
World Journal of Pediatric Surgery
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