The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS.

The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays a critical role in antiviral immunity and autoimmunity. The activity and stability of cGAS are fine-tuned by post-translational modifications. Here, we show that ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) catalyzes the mono-ISGylation and induces the oligomerization of cGAS, thereby promoting antiviral immunity and autoimmunity. Knockdown or knockout of ARIH1 significantly inhibits herpes simplex virus 1 (HSV-1)- or cytoplasmic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Consistently, tamoxifen-treated ER-Cre;Arih1fl/fl mice and Lyz2-Cre; Arih1fl/fl mice are hypersensitive to HSV-1 infection compared with the controls. In addition, deletion of ARIH1 in myeloid cells alleviates the autoimmune phenotypes and completely rescues the autoimmune lethality caused by TREX1 deficiency. Mechanistically, HSV-1- or cytosolic DNA-induced oligomerization and activation of cGAS are potentiated by ISGylation at its K187 residue, which is catalyzed by ARIH1. Our findings thus reveal an important role of ARIH1 in innate antiviral and autoimmune responses and provide insight into the post-translational regulation of cGAS.

IL-36γ and IL-36Ra Reciprocally Regulate Colon Inflammation and Tumorigenesis by Modulating the Cell-Matrix Adhesion Network and Wnt Signaling.

Inflammatory bowel disease and colorectal cancer are associated with dysregulation of cytokine networks. However, it is challenging to target cytokines for effective intervention because of the overlapping functions and unpredictable interactions of cytokines in such diverse networks. Here, it is shown that IL-36γ and IL-36Ra, an agonist and an antagonist for IL-36R signaling respectively, reciprocally regulate the experimental colitis and the colon cancer development in mice. Knockout or neutralization of IL-36γ alleviates dextran sulfate sodium (DSS)-induced colitis and inhibits colon cancer development, whereas knockout of IL-36Ra exacerbates DSS-induced colitis and promotes colonic tumorigenesis in multiple colon cancer models in mice. Mechanistically, IL-36γ upregulates extracellular matrix and cell-matrix adhesion molecules and facilitates Wnt signaling, which is mitigated by IL-36Ra or IL-36γ neutralizing antibody. Consistently, IL-36γ levels are positively correlated with extracellular matrix levels and ß-catenin levels in human colorectal tumor biopsies. These findings suggest the critical role of IL-36γ and IL-36Ra in gut inflammation and tumorigenesis and indicate that targeting the IL-36γ/IL-36Ra signal balance provides potential therapeutic strategy for inflammatory bowel disease and gastrointestinal cancers.

IL-36γ and IL-36Ra Reciprocally Regulate NSCLC Progression by Modulating GSH Homeostasis and Oxidative Stress-Induced Cell Death.

The balance between antioxidants and reactive oxygen species (ROS) critically regulates tumor initiation and progression. However, whether and how the tumor-favoring redox status is controlled by cytokine networks remain poorly defined. Here, it is shown that IL-36γ and IL-36Ra reciprocally regulate the progression of non-small cell lung cancer (NSCLC) by modulating glutathione metabolism and ROS resolution. Knockout, inhibition, or neutralization of IL-36γ significantly inhibits NSCLC progression and prolongs survival of the KrasLSL-G12D/+ Tp53fl/fl and KrasLSL-G12D/+ Lkb1fl/fl mice after tumor induction, whereas knockout of IL-36Ra exacerbates tumorigenesis in these NSCLC mouse models and accelerates death of mice. Mechanistically, IL-36γ directly upregulates an array of genes involved in glutathione homeostasis to reduce ROS and prevent oxidative stress-induced cell death, which is mitigated by IL-36Ra or IL-36γ neutralizing antibody. Consistently, IL-36γ staining is positively and negatively correlated with glutathione biosynthesis and ROS in human NSCLC tumor biopsies, respectively. These findings highlight essential roles of cytokine networks in redox for tumorigenesis and provide potential therapeutic strategy for NSCLC.

Serum level of vitamin A in children with pneumonia aged less than 3 years / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the association of the serum level of vitamin A (VA) with the severity of pneumonia and recurrent respiratory infection (RRI) within one year after treatment in children with pneumonia, and to provide a basis for serum VA level used as an index for judgment of the condition of pneumonia and prediction of the risk of recurrent respiratory infection.</p><p><b>METHODS</b>A total of 88 children with pneumonia aged less than 3 years were enrolled as study subjects. Serum VA level was measured on admission, and the development of RRI was followed up by telephone within 1 year after discharge.</p><p><b>RESULTS</b>The children with pneumonia showed a reduction in the serum level of VA (0.8±0.3 μmol/L). The severe pneumonia group had a significantly lower serum level of VA than the mild pneumonia group (0.7±0.3 μmol/L vs 0.9±0.3 μmol/L; P<0.05), as well as a significantly higher detection rate of vitamin A deficiency (VAD) than the mild pneumonia group (63% vs 28%; P<0.05). The children were followed up for 1 year. The VAD-pneumonia group showed a significantly higher incidence of RRI than the normal VA-pneumonia group (49% vs 18%; P<0.05), while there were no significant differences in the incidence of RRI between the suspected subclinical vitamin A deficiency (SSVAD)-pneumonia group and the normal VA-pneumonia group, as well as between the VAD-pneumonia group and the SSVAD-pneumonia group (P>0.05).</p><p><b>CONCLUSIONS</b>Children with pneumonia often have a low level of VA, and the level of VA is associated with the severity of pneumonia and the development of RRI afterwards.</p>

Efficacy of regular or intermittent inhalation of corticosteroids in treatment of asthma and its effects on growth and development in children / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To observe the efficacy of regular or intermittent inhalation of salmeterol/fluticasone propionate (SM/FP) in the treatment of bronchial asthma and its effects on growth and development in children.</p><p><b>METHODS</b>A total of 112 children diagnosed with bronchial asthma between September 2012 and October 2013 were assigned to standardized treatment (standard group, n=56) and non-standardized treatment (intermittent group, n=56). Comparisons of clinical symptom scores and main pulmonary function indicators between the two groups were carried out before treatment and at 6 and 12 months after treatment. The growth velocity and changes in body mass index (BMI) were observed in the two groups.</p><p><b>RESULTS</b>At 6 and 12 months after the treatment, the standard group had significantly reduced clinical symptom scores and significantly increased pulmonary function indicators (percentage of predicted peak expiratory flow, PEF%; percentage of forced expiratory volume in 1 second, FEV1%) (P<0.05); the intermittent group had significantly reduced clinical symptom scores and significantly increased FEV1% (P<0.05), but PEF% was significantly increased only at 6 months after treatment (P<0.05). At 12 months after treatment, the standard group had significantly lower clinical symptom scores and significantly higher PEF% and FEV1% when compared with the intermittent group (P<0.05). The growth velocity and BMI showed no significant differences between the two groups at 6 and 12 months after treatment (P>0.05).</p><p><b>CONCLUSIONS</b>Compared with intermittent inhalation, long-term regular inhalation of SM/FP performs better in controlling clinical symptoms and enhancing pulmonary function in children with asthma. Inhalation of SM/FP for one year reveals no apparent effect on the growth and development of these children.</p>

Effect of clinical pathway management on pediatric pneumonia / 中华儿科杂志

<p><b>OBJECTIVE</b>To investigate effect of clinical pathway management on pediatric pneumonia.</p><p><b>METHOD</b>Data were colleted from children hospitalizated with bronchial pneumonia, bronchiolitis, mycoplasma pneumonia in Center of Respiratory Disorders in Children's Hospital of Chongqing Medical University from January 2011 to December 2012. According to implement of clinical pathway management, all patients were divided into pathway management group (n = 405) and non-pathway management group (n = 503). Length of stay, costs of hospitalization, clinical effect and use of antibiotics were compared in these two groups.</p><p><b>RESULT</b>In pathway management group, average length of stay of children with bronchial pneumonia and bronchiolitis was (6.1 ± 1.6) d and (6.2 ± 1.5) d respectively. While in non-pathway management group, length of stay was (7.2 ± 1.9) d and (7.3 ± 1.5) d (P = 0.000). There was no significant difference in length of stay between these two groups of children with mycoplasma pneumonia [ (6.9 ± 1.8) d vs.(7.7 ± 2.5) d] (P = 0.198). Costs of auxiliary tests in pathway management group was slightly higher than that in non-pathway management group. While other costs in pathway management group were significantly lower than those in non-pathway management group. Total costs of hospitalization of patients with these three diseases in pathway management group and non-pathway management group were ¥(4609 ± 1225) vs ¥ (5629 ± 1813) , ¥ (5006 ± 1250) vs. ¥ (5686 ± 1337), ¥ (4946 ± 1259) vs. ¥ (6488 ± 3032) respectively. There was a significant difference (P < 0.05). Percentages of antibiotics use in two groups were 70.9% vs.99.4%, 45.7% vs.93.4% and 96.2% vs.100.0%. Antibiotics related indicators such as mean number of day of use, ratio of combination and grade of antibiotics were significantly higher in pathway management group compared to non-pathway management group (P < 0.01). There was no significant difference in other indicators like clinical effect and unscheduled readmission in 30 days between two groups (P > 0.05).</p><p><b>CONCLUSION</b>Clinical pathway management can regulate medical behaviors through reduction of medical costs, avoidance of excessive laboratory tests and therapy, and regulation of antibiotic use.</p>

Surveillance for Respiratory Viruses in Children with Acute Lower Respiratory Infections in Chongqing between 2003 and 2007 / 实用儿科临床杂志

Objective To investigate the clinical spectrum of respiratory viruses in infants and young children with acute lower respiratory infection(ALRI) in Chongqing area from 2003-2007.And to assess the clinical diagnostic value of virus detection in nasopharyngeal secretions(NPS) and serum viral antibody detection for ALRI.Methods Cases of 2 529 specimens of NPS in hospitalized children with ALRI from Apr.2003 to Oct.2007 were taken for detecting 7 common respiratory virus antigens by immunofluorescence assay including respiratory syncytial virus (RSV),adenovirus(ADV),influenza A(IA),influenza B (IB),parainfluenza virus1-3 (PIV1,PIV2,PIV3).Fifty-five thousand eight hundred and eighty-seven samples were tested for ADV-IgM by ELISA.Among those,45 159 cases were further tested for RSV-IgM by ELISA.Results Respiratory virus pathogens were detected in 778 samples out of 2 529(30.76%) including RSV positive in 668 samples (85.86%),PIV3 positive in 75 samples (9.64%),IA positive in 22 samples (2.57%),ADV positive in 15 samples ( 1.93%),only 1 sample ( 0.13%) positive for both PIV1 and RSV. And the positive rate of RSV-IgM was 0.9%-15.2%,and the positive rate for ADV-IgM was about 0.6%-10.6%.RSV infection occured mainly in winter and spring.Conclusions Respiratory virus is the most common pathogen in children with ALRI during the survey period in Chongqing area,especially for RSV infection.The pattern of RSV circulation varied every year with seasonality.It is suggest that this year is peak one for RSV infection from the monthly positive results,especially in Feburary(50%) in 2007.But the infection rate of PIV3,IA,ADV and PIV1 are lower,particularly IB and PIV2 infection have not been seen for the last 5 years.It is fast and accurate to detect RSV antigen and suit to clinical diagnosis by using immunofluorescence assay than other antibody detection.

Effect of Budesonide Inhalation Suspension Treatment on Mild to Moderate Wheezing Diseases in Infants / 实用儿科临床杂志

Objective To explore the effect of atomization inhaled Budesonide on mild to moderate wheezing diseases in infants.Me-thods One hundred and twenty infants in the ward of center of respiratory were divided into 2 groups randomly during Jan. to Dec.2006.They suffered from bronchiolitis(56 cases)or wheezing bronchitis(11 cases) or asthzma of infants and young children(53 cases),aged 1 month to 3 years old.On the basis of the routine treatment, Budesonide inhalation suspension was administered on the therapeutic group, the dosage of Budesonide was 0.5 mg/time(1 month to 1 year old),1.0 mg/time(1 to 3 years old),2 times/d;Dexamethasone was given in the control group,the dosage of Dexamethasone was 5.0 mg/time(1 month to 1 year old),7.5 mg/time(1 to 3 years old),2 times/d. The persistence time of clinical symptoms,signs and staying in hospital were compared after the treatment, and the pulmonary function of two groups were also compared before and after treatment.Software of SPSS 12.0 was used to analyze data.Results There were significant differences in clinical symptoms (wheeze, cough), signs(wheezing rale) and time of staying in hospital between the treatment group and control group (t=3.98,5.44,4.61,2.96 Pa