ABSTRACT
Objective: To investigate the pathogenic mechanism and clinical characteristics of the novel splicing variant of ATP-binding cassette subfamily B member 4 (ABCB4) and provide a basis for subsequent genetic diagnosis. Methods: The clinical data of a 5-year-old child with cholestatic liver disease admitted to the Beijing Children's Hospital of Capital Medical University was retrospectively analyzed. The pathogenic variations were detected by whole exome sequencing and verified by Sanger sequencing, and bioinformatics was used to predict the pathogenicity of the mutation sites. Possible pathogenic variations were verified in vitro by Minigene assay. The clinical outcome was followed after discharge from hospital. Results: The 5-year-old boy had developed cholestasis at the age of 11 months. His physical examination showed obvious enlargement of the liver and spleen. Cholestatic cirrhosis was diagnosed by liver function tests, abdominal ultrasonography, liver biopsy and pathology. The results of genetic analysis showed that the patient was a complex heterozygote of the ABCB4 gene, with a pathogenic mutation c.2860G>A and a novel mutation c.2065-8T>G, derived from the mother and father respectively. The conservative prediction of the c.2065-8T>G site showed that this region was highly conserved and may affect splicing. Minigene assay results confirmed that the c.2065-8T>G mutation resulted in a 7 bp retention of intron 16 in the mature mRNA. In the absence of nonsense-mediated mRNA decay, the amino acid frameshift forms a truncated protein, which is represented by p.Glu689ValfsTer19. The patient was diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3) and treated with ursodeoxycholic acid (UDCA). His clinical symptoms improved during 18 months of follow-up. Conclusions: The c.2065-8T>G variant is confirmed to affect the splicing process and exhibits complex heterozygosity with c.2860G>A, which is identified as the cause of the disease. PFIC3 children with this variant showed cholestatic liver disease as the main manifestation with a slow progression and was sensitive to treatment with UDCA.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B , Cholestasis, Intrahepatic , Mutation , Phenotype , Humans , Male , Cholestasis, Intrahepatic/genetics , Cholestasis, Intrahepatic/diagnosis , Child, Preschool , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/deficiency , Exome Sequencing , Genotype , Heterozygote , Retrospective Studies , Ursodeoxycholic Acid/therapeutic use , Liver/pathologyABSTRACT
Objective: To explore the infection rate and clinical characteristics of toxigenic Clostridium difficile in children with inflammatory bowel disease (IBD). Methods: From July 2015 to October 2016, the fecal samples and clinical data of 30 IBD children admitted to Department of Gastroenterology, Beijing Children's Hospital, Capital Medical University, as well as the specimens and data of 30 healthy children were collected in the meantime. The toxin gene of Clostridium difficile was detected and clinical characteristics of children with positive toxin gene were analyzed retrospectively. χ(2) test was used to compare the variables between groups. Results: Among the 30 IBD patients, 15 were in ulcerative colitis (UC) group and 15 in Crohn's disease (CD) group. In the IBD group, 6 (3 in UC and 3 in CD group) had positive result of toxigenic Clostridium difficile (20%), among whom 5 were toxin Clostridium difficile A (tcdA) +toxin Clostridium difficile B (tcdB) -, and 1 was tcdA+tcdB+. In the healthy group, only one had positive result of toxigenic Clostridium difficile (3%), which was tcdA+tcdB-. Binary toxin gene was negative in both groups. The infection rate of toxigenic Clostridium difficile in IBD group was significantly higher than that in healthy control group (χ(2)=4.043, P=0.044). In UC group, no Clostridium difficile toxin gene was detected during the remission period (0/1), one case was positive for toxin gene (1/11) during mild active period, and 2 cases were (2/3) during moderately active period. There were significant differences in the infection rate of toxigenic Clostridium difficile between patients in different active period (χ(2)=4.000, P=0.046). The main manifestations of the 6 cases were diarrhea, abdominal pain and bloody stool, and the relapsed case was characterized by sudden aggravation. TcdA was detected in all toxin gene positive samples, and 1 case combined with tcdB had more serious bloody mucopurulent stool. Five cases had colonoscopy, but there was no obvious characteristics of toxigenic Clostridium difficile colitis such as yellow white plaques or pseudomembranous spot. Three cases had antibiotic exposure history. All 6 cases were sensitive to metronidazole treatment, and stable without relapse during the 3-month follow-up. Conclusions: The infection rate of toxigenic Clostridium difficile in children with IBD is higher than that in healthy children. The patients with both tcdA and tcdB could have more serious clinical symptoms, although there may not be specific pathological changes of toxigenic Clostridium difficile colitis. The recognition of toxigenic Clostridium difficile infection in IBD children should be strengthened in clinical work.
Subject(s)
Bacterial Toxins , Clostridioides difficile , Clostridium Infections , Inflammatory Bowel Diseases , Bacterial Proteins , Bacterial Toxins/genetics , Child , Clostridioides difficile/genetics , Clostridioides difficile/pathogenicity , Clostridium Infections/drug therapy , Clostridium Infections/epidemiology , Enterotoxins/genetics , Feces , Humans , Inflammatory Bowel Diseases/microbiology , Retrospective StudiesABSTRACT
Recently, exposure to air pollutants has been associated with the development and progression of systemic lupus erythematosus (SLE). The current study aims to evaluate the effects of air pollutants on SLE hospital admissions in Bengbu, China. We performed distributed lag non-linear model combined with quasi-Poisson generalized linear regression to assess the impacts of air pollutants on SLE admissions from 2015 to 2017. Subgroup analyses by admission status (first admission or readmission) were also evaluated. A total of 546 hospital admissions during 2015-2017 were included. For single-day lag structures, the risk effects occurred from lag 2 to lag 9 for the 75th percentile particulate matter (PM)2.5, lag 3 to lag 9 for the 80th percentile PM2.5. For cumulative lag structures, the risk effects occurred from lag 0-5 to lag 0-14 for both 75th PM2.5 and 80th PM2.5, and no significant effect was observed for 90th PM2.5. In addition, the adverse effects on SLE first admissions occurred from lag 0 to lag 1 for NO2, lag 1 to lag 2 for SO2. The maximum effect of PM2.5 on SLE was 4.27 (95% confidence interval: 1.34-13.59) at lag 0-13 day, the minimum effect value was 1.12 (95% confidence interval: 1.03-1.23) at lag 9 day. These findings demonstrate that high PM2.5, NO2 and SO2 are associated with SLE hospital admissions. In addition, this study further revealed that exposure to high concentration of PM2.5 increased the risk of SLE relapse, while high levels of NO2 and SO2 increased the risk of SLE first admissions.
Subject(s)
Air Pollutants/toxicity , Air Pollution/adverse effects , Environmental Exposure/adverse effects , Lupus Erythematosus, Systemic/epidemiology , Adult , Air Pollutants/analysis , Air Pollution/analysis , China , Environmental Exposure/analysis , Female , Hospitalization/statistics & numerical data , Humans , Lupus Erythematosus, Systemic/etiology , Male , Particulate Matter/analysis , Particulate Matter/toxicity , Risk Factors , Time FactorsABSTRACT
Objective: To increase the recognition of pancreatic cystic fibrosis (PCF) in children and facilitate diagnosing and treatment of this rare entity. Method: This is a retrospective analysis of children who presented to Beijing Children's Hospital affiliated to Capital Medical University from January 2010 to December 2015. We describe their clinical features, laboratory testing and management. Result: Eleven children were diagnosed with PCF by genetic testing or sweat chloride test during these 5 years, including 4 boys and 7 girls. Their age ranged from 0.5-14.3 (mean 9.0±3.9) years. Family history was positive in 3 children. Significant clinical findings on presentation were: malnutrition 6, including 2 cases of mild, moderate and severe malnutrition each; diarrhea 4 (yellow mushy or watery stool with frequency ranging from 2-5 times a day), including 1 case of acute diarrhea and 3 of chronic diarrhea, 3 of them had steatorrhea; abdominal pain 3. All of them had pancreatic lesions shown by abdominal ultrasound. Blood tests showed 6 cases had elevated serum amylase and lipase. The main treatment was pancreatic replacement therapy and nutritional support. Conclusion: PCF is rare in children. Malnutrition, diarrhea and abdominal pain are the main clinical manifestations. Treatment is mostly pancreatic enzymes replacement and supportive care.
Subject(s)
Cystic Fibrosis/diagnosis , Genetic Testing , Pancreatic Diseases/diagnosis , Adolescent , Child , Child, Preschool , Cystic Fibrosis/complications , Diarrhea , Female , Humans , Infant , Lipase , Male , Pancreatic Diseases/complications , Retrospective Studies , UltrasonographyABSTRACT
Objective: To learn the colonization of Clostridium difficile in local healthy children and to investigate the colonization rate and toxin types of Clostridium difficile at different ages. Method: From September 2014 to January 2015 in a case observational study, healthy children's fecal specimens from the health care department of Beijing Children's Hospital were collected. The children were divided into four groups according to age: <1 year old(n=53), 1-<3 years old(n=50), 3-<6 years old(n=50) and 6-<14 years old(n=50) respectively. Polymerase chain reaction (PCR) was used to detect Clostridium difficile toxin genes including tcdA, tcdB, binary toxin CDT (cdtA and cdtB), and toxin regulatory genes including tcdC, tcdD and tcdE. And then the positive samples were sequenced. Measurement data were compared by using t test and rank sum test, while, enumeration data were compared using chi-square test. Result: Fifteen (7.4%) specimens were positive for Clostridium difficile toxin genes in 203 stool specimens. Of the 15 positive specimens, eight(53.3%) were tcdA(+) tcdB(-)(A(+) B(-)), four were A(+) B(+) , 3(20.0%) were A(-)B(+) , the binary toxin-positive specimens were not detected. TcdC, tcdD, tcdE positive specimens were 8, 6 and 11, respectively. Gene mutations were not found in positive samples by DNA sequencing. In the 15 positive samples, four (7.5%) specimens were in <1 year old group; four (8.0%) specimens were in 1-<3 years old group; one(2.0%) specimen was in 3-<6 years old group; and 6(12.0%) specimens were in 6-<14 years old group. The colonization rate had no significance in different age groups. Conclusion: The colonization rate of Clostridium difficile in healthy children was 7.4%. And toxigenic Clostridium difficile can be detected in all age groups.
Subject(s)
Clostridioides difficile , Feces/microbiology , Bacterial Proteins , Bacterial Toxins , Child , Child, Preschool , Clostridioides difficile/genetics , Enterotoxins , Humans , Polymerase Chain ReactionABSTRACT
Because recent studies have indicated that tissue plasminogen activator (tPA) aggravates neurodegenerative processes in many neural pathologies, we studied whether the endogenous tPA antagonist neuroserpin has a neuroprotective effect in an animal model of focal ischemic stroke. After induction of a focal ischemic stroke in the mouse by occlusion of the middle cerebral artery, we found that microglial cells accumulated in the marginal zone of the infarct are the most important source for both plasminogen activators, tPA and uPA. To investigate the effect of neuroserpin on the size and the histology of the infarct we produced transgenic mice overexpressing neuroserpin approximately sixfold in the nervous system. In the brain of these mice the total tPA activity in the uninjured tissue was strongly reduced. After induction of a focal ischemic stroke in the transgenic mice by a permanent occlusion of the middle cerebral artery (MCA), the infarcts were 30% smaller than in the wild-type mice. Immunohistochemical analyses and in situ hybridization revealed an attenuation of the microglial activation in the reactive zone. Concomitantly, the microglial production of tPA and uPA, as well as the PA-activity in the infarct region was markedly reduced. Thus, our results indicate that neuroserpin reduces microglial activation and, therefore, the PA activity and has a neuroprotective role after focal ischemic stroke.