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Trends in the disease burden of congenital heart disease in China over the past three decades
PAN Feixia,XU Weize,LI Jiabin,HUANG Ziyan,SHU Qiang
J Zhejiang Univ (Med Sci), 2022, 51(3): 267-277.   https://doi.org/10.3724/zdxbyxb-2022-0072
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Objective: To investigate the disease burden of congenital heart disease (CHD) in China from 1990 to 2019. Methods: Using the data from Global Burden of Disease (GBD) study 2019, the incidence, age-standardized incidence rates, the mortality, age-standardized mortality rates, disability-adjusted life year (DALY) and age-standardized DALY rates of CHD were calculated. Time trend analysis of disease burden-related indicators was analyzed by Joinpoint regression model. Age-period-cohort model was used to describe age, period, and birth cohort effects in CHD mortality population. The relationship between age-standardized incidence, mortality, DALY rates of congenital heart disease and human development index (HDI) were analyzed by Pearson correlation. Results: From 1990 to 2019, the mean annual percentage change (AAPC) in age-standardized incidence rate, mortality rate and DALY rate of CHD in China were –0.1%(95%CI: –0.7%-0.4%)、–3.5%(95%CI: –3.7%-–3.2%) and -3.5%(95%CI: –3.7%-–3.2%), respectively. CHD usually occurred in the first year of life. The mean incidence rate at birth was 2497.9/100 000, and the mean incidence rate under 1?year of age was 2626.6/100 000. During the period of 1995—2000, the incidence rate in newborn and <1?year children showed an exponential upward trend, then it remained a steady downward trend. However, there was an exponential increase in <1?year children during 2010—2013 and 2014—2015, followed by an exponential decrease to the lowest value in the last three decades. The mortality of CHD tended to decrease with age, with mortality of 101.67/100 000 for children under 5?years of age and a decrease after 5?years of age. However, there was a transient increase in mortality in age group 55-<60. From 1995 to 2019, the relative risk of death of patients with CHD showed a downward trend. Compared with 1995—1999, the rate ratio of death decreased by 24% in 2015—2019. Such downward trend was also observed in the birth cohort after 1945. Compared with the 1945—1949 birth cohort, the rate ratio of death for patients with CHD decreased by 75% in the 2015—2019 birth cohort. When HDI<0.58 (before 1999), the age-standardized incidence of CHD was positively correlated with HDI ( r=0.74, P<0.05). When HDI≥0.58 (after 1999), the age-standardized incidence of CHD was negatively correlated with HDI (r=–0.76, P<0.01). The age-standardized mortality and DALY rates were negatively correlated with HDI (r=–0.95 and –0.93, both P<0.01).Conclusions: During 1990 to 1999, the incidence of CHD increases and is positively correlated with the social development. During 1999 to 2019, the incidence of CHD decreases and is negatively correlated with the social development. The disease burden of CHD decreases and is negatively correlated with the social development. Some progress has been made in the field of prevention and control of CHD, but the disease burden remains high among younger population in China.

Clinical characteristics and related gene mutations of infants with short-chain acyl-CoA dehydrogenase deficiency by neonatal screening in Beijing
GONG Lifei,YANG Nan,ZHAO Jinqi,YANG Haihe,TANG Yue,LI Lulu,KONG Yuanyuan
J Zhejiang Univ (Med Sci), 2022, 51(3): 278-283.   https://doi.org/10.3724/zdxbyxb-2022-0214
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Objective: To investigate the clinical characteristics of infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) and related gene mutations in Beijing. Methods: The acylcarnitine levels in the blood samples of 100?603 neonates in Beijing during August 2014 and March 2022 were measured by tandem mass spectrometry (MS/MS). The suspected SCADD neonates were rechecked by MS/MS, urine gas chromatography-mass spectrometry (GC/MS) and next-generation sequencing (NGS) for diagnosis. The clinical, biochemical and gene mutation characteristics of infants with SCADD were analyzed; the growth and intellectual development of these patients were observed regularly. Results: Among 100 603 live births, the elevated C4 concentration or elevated C4/C3 ratio were detected in the initial screening from 196 neonates, and 131 were recalled. Five cases of SCADD were diagnosed with an incidence rate of 4.97/100?000 (1/20?121). There was no significant abnormality in clinical manifestations, however, the blood butyrylcarnitine (C4) level and the ratio of C4 to propionylcarnitine (C3) were raised in all diagnosed cases. Urinary organic acids were analyzed in 4 cases, all of whom had increased ethyl malonate acid levels. Seven mutations were detected in the ACADS gene, all of which were known missense mutations. One patient had homozygous mutation, and the others showed compound heterozygous mutations. No clinical symptoms were observed, and the physical and intellectual development was normal in all patients at a median age of 33 (4-40) months during follow-up. Conclusions: The incidence rate of SCADD was 1/20?121 in Beijing. Neonates with early diagnosis and without clinical symptoms usually have good prognosis.

Screening and follow-up results of neonate medium-chain acyl-CoA dehydrogenase deficiency in Zibo, Shandong province
DONG Liping,JI Chanchan,XU Jia,CUI Yanguo
J Zhejiang Univ (Med Sci), 2022, 51(3): 284-289.   https://doi.org/10.3724/zdxbyxb-2022-0114
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Objective: To analyze the incidence, phenotype, genotype and prognosis of neonatal medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in Zibo city of Shandong province. Methods: A total of 241 297 neonates were screened for MCADD in Zibo city of Shandong province from November 2013 to January 2022. Non-derivatized tandem mass spectrometry was used to detect blood free carnitine and acylcarnitine profiles in neonatal screening. Neonates with octanoylcarnitine (C8)≥0.25?μmol/L, or combined with C8/decanoylcarnitine (C10)≥1.5 were recalled, and second-generation high-throughput sequencing was performed for genetic diagnosis. Results: Among 241?297 neonates, 6 cases of MCADD were screened, including 2 boys and 4 girls, with an incidence of 1/40 216. Two mutation sites of ACADM gene were identified in all MCADD infants, and 12 mutation with 8 types were detected in total. The hot spot mutations were c.449_452del (p.T150Rfs*4) and c.387+1delG, and exon 11 c.1076C>T (p.A359V) was a newly detected mutation. No phenotype-genotype correlation was found. One case died on day 4 after birth; 5 cases were followed up for 2 to 60?months, none of them received special diet treatment. The growth and intellectual development of the surviving cases were normal, and no abnormality was found in routine biochemical indicators.Conclusions: The incidence of MCADD in Zibo city seems to be higher than that in other areas in China. The ACADM gene mutations c.449_452del (p.T150Rfs*4) and c.387+1delG are common, and a new mutation c.1076C>T (p.A359V) has been detected. No phenotype-genotype correlation has been found. Early diagonsis and treatment are effective measures to reduce poor prognosis.

Screening for newborn fatty acid oxidation disorders in Chongqing and the follow-up of confirmed children
CHEN Min,YIN Yifan,LIU Hao,PENG Yong,YE Liang,LUO Qian,MIAO Jingkun
J Zhejiang Univ (Med Sci), 2022, 51(3): 290-297.   https://doi.org/10.3724/zdxbyxb-2022-0218
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Objective: To investigate the incidence, clinical characteristics, gene mutations and prognosis of fatty acid oxidation disorders (FAOD) in newborns in Chongqing. Methods: Blood samples were collected from 35 374 newborns for screening of FAOD in the Neonatal Screening Center of Women and Children’s Hospital of Chongqing Medical University from July 2020 to February 2022. The acylcarnitine spectrum was detected by tandem mass spectrometry, the positive children in primary screening were recalled within 2 weeks, and the diagnosis of FAOD was confirmed by urine organic acid measurement, blood biochemistry testing and genetic analysis. The confirmed children were given early intervention, treatment and followed-up. Results: Among 35 374 newborns, there were 267 positive children in primary screening, with a positive rate of 0.75%. Five children with FAOD were diagnosed by gene detection, with an incidence rate of 1/7075. Among them, there were 3 cases of primary carnitine deficiency (PCD, 1/11 791), 1 case of short-chain acyl-CoA dehydrogenase deficiency (SCADD, 1/35 374) and 1 case of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, 1/35 374). The c.1400C>G and c.338G>A were the common mutations ofSLC22A5 gene in 3 children with PCD, while c.621G>T was a novel mutation. There were no clinical manifestations during the follow-up period in 2 children with supplementation of L-carnitine. Another child with PCD did not follow the doctor’s advice of L-carnitine treatment, and had acute attack at the age of 6?months. The child recovered after treatment, and developed normally during the follow-up. The detectedACADS gene mutations were c.417G>C and c.1054G>A in child with SCADD, who showed normal intelligence and physical development without any clinical symptoms. The mutations ofACADVL gene were c.1349G>A and c.1843C>T in child with VLCADD, who showed acute attack in the neonatal period and recovered after treatment; the child was fed with milk powder rich in medium-chain fatty acids and had normal development during the follow-up.Conclusions: The incidence of FAOD in Chongqing area is relatively high. PCD is the most common type, and the clinical phenotype of VLCADD is serious. After early diagnosis through neonatal screening, standardized treatment and management is followed, most of FAOD children can have good prognosis.

Clinical characteristics and genotype analysis of five infants with cblX type of methylmalonic acidemia
WANG Fei,LIANG Lili,LING Shiying,YU Yue,CHEN Ting,XU Feng,GONG Zhuwen,HAN Lianshu
J Zhejiang Univ (Med Sci), 2022, 51(3): 298-305.   https://doi.org/10.3724/zdxbyxb-2022-0194
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Objective: To investigate the clinical and genetic characteristics of infants with cobalamin (cbl) X type of methylmalonic acidemia (MMA). Methods: The clinical data of 5 infants with cblX type of MMA diagnosed in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and Shanghai Children’s Hospital from the year 2016 to 2020 were collected. The levels of blood acylcarnitines were detected by tandem mass spectrometry, the levels of urinary organic acids were detected by gas-chromatography mass spectrometry, the pathogenic genes were detected by whole exon gene sequencing, and the effect of new pathogenic mutations on three-dimensional protein structure was predicted by bioinformatics analysis. Results: Five infants with cblX type were diagnosed, including 4 males and 1 female, and the onset age was 0–6?months. The main clinical manifestations of 4 males were intractable epilepsy, mental and motor retardation, metabolic abnormalities presented mild increase of blood homocysteine level. Among them, 3 cases were accompanied by slight increase of urinary methylmalonic acid, and 1 case was accompanied by increase of blood propionylcarnitine (C3) and C3/acetylcarnitine (C2). Gene detection found that 2 cases carried a same hemizygous mutation c.344C>T (p.A115V) ofHCFC1 gene, which was the most reported mutation, and the other 2 cases carried novel pathogenic mutations, c.92G>A (p.R31Q) and c.166G>C (p.V56L). These 3 gene mutations located in the Kelch domain of HCFC1 protein. One female infant carried a benign mutation of c.3731G>T (p.R1244L). Her clinical symptoms were mild, and only the urinary methylmalonic acid was slightly increased.Conclusions: The clinical manifestations of children with cblX type of MMA are intractable epilepsy, mental and motor retardation, and other serious neurological symptoms. Their metabolic abnormalities present the increase of blood homocysteine with methylmalonic acid (urinary methylmalonic acid or/and blood C3, C3/C2). The clinical and biochemical phenotypes are separated, so the diagnosis should be in combination with the results of gene testing.

Gene mutations in children with permanent congenital hypothyroidism in Yunnan, China
GONG Yanling,ZHANG Yinhong,LIU Fan,ZHU Baosheng,ZHOU Xiaoyan,CHAN Ying,LI Suyun,LI Li
J Zhejiang Univ (Med Sci), 2022, 51(3): 306-313.   https://doi.org/10.3724/zdxbyxb-2022-0199
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Objective: To investigate molecular and clinical characteristics of children with permanent congenital hypothyroidism (CH) in Yunnan, China. Methods: The clinical data of 40 children with CH diagnosed and treated in the First People’s Hospital of Yunnan Province during January 2016 and January 2019 were retrospectively analyzed. All children were followed up to 3?years old, and Gesell intelligent score was evaluated at age of 1, 2 and 3?years, respectively. Developmental status and prognosis were evaluated. Next-generation sequencing (NGS) was used to screen all exons and exon-intron boundary sequences of the 27 known CH associated genes, and the relationship between genotypes and clinical phenotypes was analyzed. Results: Among the 40 children, the thyroid related pathogenic gene mutations were detected in 23 cases with a rate of 57.5%, and a total of 32 mutations of 8 genes were detected. Mutations in DUOX2, TPO and TSHR genes were the most common ones with mutation frequencies of 65.9%(29/44), 11.4%(5/44) and 9.1%(4/44), respectively. DUOX2 gene mutations were detected in 17 children with CH, and a total of 17 mutation types were detected. p.K530* was the most common mutation in DUOX2 gene, accounting for 20.7%(6/29). There was no significant difference in physical development and intelligence assessment between children with DUOX2 heterozygous mutation and compound heterozygous mutations. None of patients could terminate medication at 3?years of the follow-up and all of them were provisionally assessed as permanent CH. The physical and mental development assessment of children with other gene mutations were also in the normal range. Conclusion: The detection rate of DUOX2, TPO and TSHR pathogenic mutations are high among children with permanent CH in Yunnan area, and no correlation is observed between gene mutation types and prognosis in children with CH.

Clinical features and outcomes of 31 children with congenital hypothyroidism missed by neonatal screening
XIE Ting,TAN Minyi,JIANG Xiang,FENG Yuyu,CHEN Qianyu,MEI Huifen,CAI Yanying,ZOU Hongmei,HUANG Yonglan
J Zhejiang Univ (Med Sci), 2022, 51(3): 314-320.   https://doi.org/10.3724/zdxbyxb-2022-0213
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Objective: To investigate the clinical features and outcomes of children with congenital hypothyroidism (CH) missed by neonatal screening. Methods: The clinical and laboratory date of 31 children with CH missed by neonatal screening from February 2015 to February 2022 in Guangzhou Women and Children’s Medical Center were retrospectively analyzed. Whole-exome high-throughput sequencing analysis was performed in 17 patients. Results: Among the 31 patients, 19 cases (61.3%) were preterm, 12 cases (38.7%) were term neonates. The median value of gestation age was 36 (26-40) weeks, birth weight was 2.35 (0.75-3.70)?kg, diagnosed age was 20?d (7?d-4?years), dry blood spot thyrotropin was 4.18 (0.34-8.97)?mU/L. Nine cases (29.0%) were same-sex twins and 4 cases (12.9%) had a family history of hypothyroidism. The initial clinical symptoms were growth retardation in 11 cases (35.5%), prolonged jaundice in 7 cases (22.6%), short stature, abdominal distension, fetal edema and goiter in 1 case (3.2%), respectively. Genetic analysis of the 17 children showed that DUOX2 gene mutations were detected in 10 cases (6 cases with biallelic mutations and 4 cases with monoallelic mutations), of whom 3 had a family history of hypothyroidism. A total of 22 patients were reevaluated at the age of 2-3?years, of whom 17 cases (77.3%) were transient CH and 5 cases (22.7%) were permanent CH. Among the 10 cases with DUOX2 gene mutations, 6 cases were transient CH, 1 case was permanent CH, and 3 cases (< 3 years old) were still under treatment with L-thyroxine.Conclusions: False negative results on neonatal screening for CH often occurs in preterm birth, low birth weight, same-sex twins, family history of hypothyroidism, and DUOX2 defects are the common molecular pathogenesis, most of whom are transient CH. Thyroid function should be evaluated in time for children with unexplained slow growth and delayed jaundice regression.

Cut-off values of neonatal lysosomal storage disease-related enzymes detected by tandem mass spectrometry
LI Gaijie,TIAN Liping,GUO Yuanfang,LI Yulin,SUN Meng,ZOU Hui
J Zhejiang Univ (Med Sci), 2022, 51(3): 321-325.   https://doi.org/10.3724/zdxbyxb-2022-0095
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Objective: To establish cut-off values of lysosomal storage disease (LSD)-related enzymes by tandem mass spectrometry. Methods: A total of 26 689 newborns and 7 clinically confirmed LSD children underwent screening for LSDs (glycogen storage disease typeⅡ, Fabry disease, mucopolysaccharidosis type Ⅰ, Krabbe disease, Niemann-Pick disease A/B and Gaucher disease). The activities of LSD-related enzymes were detected by tandem mass spectrometry. The 20% of the median enzyme activity of each batch of acid β-glucocerebrosidase, acid sphingomyelinase, β-galactocerebroside, α-L-iduronidase and acid α-glucosidase, and the 30% of the median enzyme activity of α-galactosidase were taken as cut-off values of corresponding enzymes. The genetic diagnosis was performed in neonates whose enzyme activity was lower than 70% of the cut-off value. Results: The enzyme activities of 7 clinically confirmed cases were all lower than the cut-off values. Among 26 689 newborns, 142 cases (0.53%) were suspected positive for LSDs, including 25 cases of β-galactocerebroside deficiency, 1 case of α-L-iduronidase deficiency, 19 cases of α-galactosidase deficiency, and 97 cases of acid α-glucosidase deficiency. Eight infants were genetically diagnosed with LSDs, including 3 cases of glycogen storage disease type Ⅱ, 3 cases of Krabbe disease, and 2 cases of Fabry disease, with a positive predictive value of about 5.6%. Cut-off values ??of the 6 LSD enzyme activities all showed a downward trend from March to August, and an upward trend from September to December. There was a statistically significant difference in LSD enzyme activity among different months (P<0.05).Conclusion: The established cut-off values of LSD-related enzyme activities detected by tandem mass spectrometry can be used for screening LSDs in neonates, and the enzyme activity would be affected by temperature and humidity.

Risk of maternal exposure to mixed air pollutants during pregnancy for congenital heart diseases in offspring
QU Yanji,ZHOU Xinli,LIU Xiaoqing,WANG Ximeng,YANG Boyi,CHEN Gongbo,GUO Yuming,NIE Zhiqiang,OU Yanqiu,GAO Xiangmin,WU Yong,DONG Guanghui,ZHUANG Jian,CHEN Jimei
J Zhejiang Univ (Med Sci), 2022, 51(3): 326-333.   https://doi.org/10.3724/zdxbyxb-2022-0073
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Objective: To explore the risk of maternal exposure to mixed air pollutants of particulate matter 1 (PM1), particulate matter 2.5 (PM2.5), particulate matter 10 (PM10) and NO2 for congenital heart disease (CHD) in offspring, and to estimate the ranked weights of the above pollutants. Methods: 6038 CHD patients and 5227 healthy controls from 40 medical institutions in 21 cities in Guangdong Registry of Congenital Heart Disease (GRCHD) from 2007 to 2016 were included. Logistic regression model was used to estimate the effect of maternal exposure to a single air pollutant on the occurrence of CHD in offspring. Spearman correlation coefficient was used to analyze the correlation between various pollutants, and Quantile g-computation was used to evaluate the joint effects of mixed exposure of air pollutants on CHD and the weights of various pollutants. Results: The exposure levels of PM1, PM2.5, PM10 and NO2 in the CHD group were significantly higher than those in the control group (all P<0.01). The correlation coefficients among PM1, PM2.5, PM10 and NO2 were greater than 0.80. PM1, PM2.5, PM10 and NO2 exposure were associated with a significantly increased risk of CHD in offspring. Mixed exposure of these closely correlated pollutants presented much stronger effect on CHD than exposure of any single pollutants. There was a monotonic increasing relationship between mixed exposure and CHD risk. For each quantile increase in mixed exposure, the risk of CHD increased by 47% (OR=1.47, 95%CI: 1.34–1.61). Mixed exposure had greater effect on CHD in the early pregnancy compared with middle and late pregnancy, but the greatest effect was the exposure in the whole pregnancy. The weight of PM10 is the highest in the mixed exposure (81.3%). Conclusions: Maternal exposure to the mixture of air pollutants during pregnancy increases the risk of CHD in offspring, and the effect is much stronger than that of single exposure of various pollutants. PM10 has the largest weights and the strongest effect in the mixed exposure.

Prediction value of regional oxygen saturation in intestine and kidney for acute kidney injury in children with congenital heart disease after surgery
LIU Liping,ZHANG Mingjie,CHEN Xi,WANG Liping,XU Zhuoming
J Zhejiang Univ (Med Sci), 2022, 51(3): 334-340.   https://doi.org/10.3724/zdxbyxb-2022-0069
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Objective: To study the prediction value of regional oxygen saturation (rSO2) in brain, intestine and kidney for acute kidney injury (AKI) in children with congenital heart disease after surgery. Methods: Fifty-seven children with congenital heart disease (CHD), whose weight >2.5?kg and age≤1 year were treated in Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine from January 2020 to December 2020. The rSO 2 of brain, intestine and kidney were monitored with near-infrared spectroscopy continuously for 48?h after surgery. The predictive values of cerebral, intestinal and renal rSO2 for occurrence and severity of postoperative AKI were analyzed. Results: Among 57 patients, postoperative AKI developed in 38 cases (66.7%), including 18 cases of AKI-1 (47.4%), 9 cases of AKI-2 (23.7%) and 11 cases of AKI-3 (28.9%). There was no significant difference in cerebral rSO2 between AKI group and non-AKI group (F=0.012, P>0.05), while the intestinal rSO2 and renal rSO2 in AKI group were significantly lower than those in non-AKI group (F=5.017 and 5.003, both P<0.05). There was no significant difference in brain rSO2 between children with or without AKI-2 and above (F=0.311, P>0.05), but the intestinal rSO2 and renal rSO2 in children with AKI-2 and above were lower than other children (F=6.431 and 14.139, both P<0.05). The area under ROC curve (AUC) of intestinal rSO2 3?h after surgery for predicting AKI was 0.823, and with intestinal rSO2 3?h after surgery <85%, the sensitivity and specificity were 66.7% and 89.5%, respectively. The AUC of renal rSO 2 for the diagnosis of AKI at 31?h after surgery was 0.918, and with intestinal rSO2 31?h after surgery <84%, the sensitivity and specificity were 72.2% and 84.2%, respectively. The AUC of intestinal rSO 23?h after surgery for the diagnosis of AKI-2 and above was 0.829, and with intestinal rSO2 3?h after surgery <84%, the sensitivity and specificity were 62.2% and 90.0%, respectively. The AUC of renal rSO 2 for the diagnosis of AKI-2 and above was 0.826 at 34?h postoperatively, and with intestinal rSO2 34?h after surgery <71%, the sensitivity and specificity were 91.9% and 55.0%, respectively. Conclusion: The monitoring of intestinal and renal rSO2 can predict the occurrence and severity of postoperative AKI in children with congenital heart disease after surgery.

Efficacy of one-stop endovascular intervention in treatment of left iliac vein compression syndrome complicated with deep venous thrombosis of lower limbs
JIANG Guangwei,DING Dianzhu,ZHANG Xiaoyu,NIU Shuai,LYU Bonan
J Zhejiang Univ (Med Sci), 2022, 51(3): 341-349.   https://doi.org/10.3724/zdxbyxb-2022-0121
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Objective: To evaluate the clinical effect and safety of one-stop endovascular intervention in treatment of left iliac vein compression syndrome (IVCS) complicated with deep venous thrombosis (DVT) of lower limbs. Methods: Clinical data of 26 patients with secondary DVT due to IVCS admitted in the Department of Vascular Surgery, Hebei General Hospital from January 2018 to December 2021 were retrospectively analyzed. All patients underwent one-stop endovascular intervention procedure, including ultrasound-guided deep venipuncture, Angiojet catheter aspiration, iliac vein balloon dilation, stent implantation and simultaneous filter retrieval. The operation time and catheter aspiration time were documented; the preoperative and postoperative left lower extremity deep vein venous patency, circumferences of bilateral limbs at 15?cm above the knee and 10?cm below the knee, and the levels of hemoglobin, creatinine, alanine aminotransferase (ALT), aspertate aminotransferase (AST), total bilirubin and indirect bilirubin were measured. The incidence of post-thrombotic syndrome (PTS) and iliac vein stent patency were recorded through follow-up. Results: The one-stop endovascular intervention was successfully performed in 26 patients, with the operation time of (171±35)?min and the thrombolysis time of (263±89)?s. After treatment, the left lower extremity deep vein venous patency, circumferences of bilateral limbs at 15?cm above the knee and 10?cm below the knee were decreased (all P<0.01); the hemoglobin level were decreased, the creatinine, ALT, AST, total bilirubin and indirect bilirubin levels were increased (allP<0.01). Patients were followed up for 1–12?months. Stent thrombosis occurred in 1 patient 7?months after procedure, and the symptoms were improved after conservative treatment; the stents were unobstructed in all patients, 1 patient had stent mural thrombosis, in whom the stent blood flow was not affected. No PTS was observed during the follow-up.Conclusions: The one-stop endovascular interventional treatment of IVCS complicated with DVT of left lower limb is safe and effective. Attention should be paid to the changes of liver and kidney function caused by catheter aspiration during the treatment, and corresponding intervention should be given in time to avoid the occurrence of related complications.

Influencing factors of pulp-dentin complex regeneration and related biological strategies
ZOU Jielin,MAO Jing,SHI Xin
J Zhejiang Univ (Med Sci), 2022, 51(3): 350-361.   https://doi.org/10.3724/zdxbyxb-2022-0046
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Regenerative endodontic therapy (RET) utilizing tissue engineering approach can promote the regeneration of pulp-dentin complex to restore pulp vascularization, neuralization, immune function and tubular dentin, therefore the regenerated pulp-dentin complex will have normal function. Multiple factors may significantly affect the efficacy of RET, including stem cells, biosignaling molecules and biomaterial scaffolds. Stem cells derived from dental tissues (such as dental pulp stem cells) exhibit certain advantages in RET. Combined application of multiple signaling molecules and activation of signal transduction pathways such as Wnt/β-catenin and BMP/Smad play pivotal roles in enhancing the potential of stem cell migration, proliferation, odontoblastic differentiation, and nerve and blood vessel regeneration. Biomaterials suitable for RET include naturally-derived materials and artificially synthetic materials. Artificially synthetic materials should imitate natural tissues for biomimetic modification in order to realize the temporal and spatial regulation of pulp-dentin complex regeneration. The realization of pulp-dentin complex regeneration depends on two strategies: stem cell transplantation and stem cell homing. Stem cell homing strategy does not require the isolation and culture of stem cells in vitro, so is better for clinical application. However, in order to achieve the true regeneration of pulp-dentin complex, problems related to improving the success rate of stem cell homing and promoting their proliferation and differentiation need to be solved. This article reviews the influencing factors of pulp-dentin complex regeneration and related biological strategies, and discusses the future research direction of RET, to provide reference for clinical translation and application of RET.

Research progress of live-cell RNA imaging techniques
SUN Pingping,ZOU Wei
J Zhejiang Univ (Med Sci), 2022, 51(3): 362-372.   https://doi.org/10.3724/zdxbyxb-2022-0017
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RNA molecules play diverse roles in many physiological and pathological processes as they interact with various nucleic acids and proteins. The various biological processes of RNA are highly dynamic. Tracking RNA dynamics in living cells is crucial for a better understanding of the spatiotemporal control of gene expression and the regulatory roles of RNA. Genetically encoded RNA-tagging systems include MS2/MCP, PP7/PCP, boxB/λN22 and CRISPR-Cas. The MS2/MCP system is the most widely applied, and it has the advantages of stable binding and high signal-to-noise ratio, while the realization of RNA imaging requires gene editing of the target RNA, which may change the characteristics of the target RNA. Recently developed CRISPR-dCas13 system does not require RNA modification, but the uncertainty in CRISPR RNA (crRNA) efficiency and low signal-to-noise ratio are its limitations. Fluorescent dye-based RNA-tagging systems include molecular beacons and fluorophore-binding aptamers. The molecular beacons have high specificity and high signal-to-noise ratio; Mango and Peppers outperform the other RNA-tagging system in signal-to-noise, but they also need gene editing. Live-cell RNA imaging allows us to visualize critical steps of RNA activities, including transcription, splicing, transport, translation (for message RNA only) and subcellular localization. It will contribute to studying biological processes such as cell differentiation and the transcriptional regulation mechanism when cells adapt to the external environment, and it improves our understanding of the pathogenic mechanism of various diseases caused by abnormal RNA behavior and helps to find potential therapeutic targets. This review provides an overview of current progress of live-cell RNA imaging techniques and highlights their major strengths and limitations.

Significance of initiating antiretroviral therapy in the early stage of HIV infection
SHAO Yueming,XUN Jingna,CHEN Jun,LU Hongzhou
J Zhejiang Univ (Med Sci), 2022, 51(3): 373-379.   https://doi.org/10.3724/zdxbyxb-2022-0052
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A growing number of guidelines now recommend that human immunodeficiency virus (HIV) infected patients should be given early antiretroviral therapy (ART), especially in acute HIV infection. ART during early infection can limit viral reservoirs and improve immune cell function. From a societal prospect, early-infected individuals who achieve a state of viral suppression through ART can reduce the chance of HIV transmission and reduce the acquired immunodeficiency syndrome (AIDS)-related disease burden. However, there are many problems in the early diagnosis and treatment of HIV infection, including personal and social factors, which hinder the implementation and development of early treatment. It is recommended that initiating ART in the early stage of HIV infection, combined with other treatment strategies, so as to achieve functional cure.

Research progress on vesicular trafficking in amyotrophic lateral sclerosis
YANG Chaosen,ZHANG Xiaoming
J Zhejiang Univ (Med Sci), 2022, 51(3): 380-387.   https://doi.org/10.3724/zdxbyxb-2022-0024
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Vesicular trafficking is a basic physiological process by which vesicles transport materials between cells and environment (intercellular transport) and between different cellular compartments (intracellular trafficking). In recent years, more and more evidences have suggested that vesicular trafficking dysfunction plays a key role in pathogenesis of neurodegenerative diseases. Abnormal vesicular trafficking promotes the propagation of misfolded proteins by mechanisms involving endocytosis, endosomal-lysosomal pathway, endosomal escape and exosome release, leading to further acceleration of disease progression. Amyotrophic lateral sclerosis (ALS), as a neurodegenerative disease, is characterized by the selective death of upper and lower motor neurons. A variety of causative genes for ALS have been implicated in vesicle trafficking dysfunction, such as C9ORF72, TARDBP and SOD1. Therefore, the aggregation and propagation of misfolded proteins may be prevented through regulation of vesicle trafficking-related proteins, thus delay the progression of ALS. A more in-depth understanding of vesicular trafficking in ALS will be helpful in revealing the mechanism and clinical treatment of ALS. This review focuses on molecular mechanisms of vesicular trafficking in ALS, to provide reference for exploring new therapeutic strategies.

15 articles