Potential protein-phenotype correlation in three lipopolysaccharide-responsive beige-like anchor protein-deficient patients.

BACKGROUND: Patients with lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency have a variety of clinical symptoms, but there is no apparent genotype-phenotype correlation, and patients carrying the same mutations may have different phenotypes. Therefore, it is not easy for doctors to make a decision regarding hematopoietic stem cell transplantation (HSCT) for LRBA-deficient patients. We hypothesized that there may be a protein-phenotype correlation to indicate HSCT for LRBA-deficient patients. AIM: To report on three Chinese LRBA-deficient patients and determine the correlation between residual protein expression and disease phenotypes. METHODS: Clinical data of three Chinese LRBA-deficient patients were collected, and protein levels were detected by Western blot analysis. In addition, LRBA mutation information of another 83 previously reported patients was summarized. RESULTS: All the major clinical findings indicated enteropathy, but patients 1 and 3 presented with more severe symptoms than patient 2. Endoscopy and histology indicated nonspecific colitis for patients 1 and 3 but Crohn's disease-like colitis for patient 2. Compound heterozygous mutations in LRBA were found in patient 1, and homozygous mutations in LRBA were found in patient 2 and patient 3. Only patient 2 responded well to traditional immunosuppressive treatment. Residual expression of the LRBA protein in patients 1 and 3 was very low, but in patient 2, a more than 0.5-fold in expression of the LRBA protein was found compared to that in the control. After HSCT, patient 1 had increased LRBA protein expression. We summarized the genetic information of 86 patients, and the mutations in patients 1 and 3 were novel mutations. CONCLUSION: We described three Chinese LRBA-deficient patients, two of whom carried novel mutations. These patients had no genotype-phenotype correlations, but their residual LRBA protein expression might be associated with disease outcome and could be an indicator for HSCT.

Special clinical characteristics and outcomes in Chinese pediatric patients with early-onset Crohn's disease.

OBJECTIVE: To study the clinical and nutritional characteristics of early-onset Crohn's disease (EO-CD) in China. METHODS: Patients were defined as having EO-CD (age at diagnosis <10 y) or late-onset Crohn's disease (LO-CD; age at diagnosis of 10-17 y). Their characteristics, clinical, and nutritional data were collected at baseline and at each follow-up visit. Statistical analyses were used to compare differences in both groups. RESULTS: From July 1993 to February 2017, of the 137 children enrolled, 68 (49.6%) had EO-CD and 69 (50.4%) had LO-CD. More patients with EO-CD than those with LO-CD presented with diarrhea, hematochezia, growth delay, anemia and skin disease, and had higher pediatric Crohn's disease activity index scores at diagnosis (all P < 0.05). Fewer patients with EO-CD achieved their first remission (42.6% vs 76.8%, P < 0.0001) during follow-up. Patients with EO-CD required a longer treatment time to reach remission (P = 0.0049) and had a higher mortality rate (P = 0.0133), as well as lower height and weight percentiles (P = 0.0200 and 0.0288, respectively), hemoglobin (P = 0.0185) and albumin levels (P = 0.0002), zinc (P = 0.0024) and iron (P = 0.0110) concentrations in blood at diagnosis. CONCLUSION: The EO-CD group had worse clinical outcomes and nutritional status than the LO-CD group.

Bidirectional Mediating Role of Loneliness in the Association Between Shyness and Generalized Pathological Internet Use in Chinese University Students: A Longitudinal Cross-Lagged Analysis.

This 1-year longitudinal study examined the bidirectional mediating role of loneliness in the association between shyness and generalized pathological Internet use (GPIU) in a sample of 291 Chinese university students (143 men, mean age = 19.07 years). A fully cross-lagged panel design was used in which shyness, loneliness, and GPIU were assessed at 3 time points separated by 6-month intervals (named T1, T2, and T3). The results indicated that relationships among shyness, loneliness, and GPIU were dynamic and bidirectional. Specifically, T1 shyness positively predicted increased T2 loneliness, T2 shyness positively predicted increased T3 loneliness, and T2 loneliness positively predicted increased T3 shyness. Additionally, T1 GPIU positively predicted increased T2 loneliness, T2 GPIU positively predicted increased T3 loneliness, and T2 loneliness positively predicted increased T3 GPIU. Loneliness was found to play a bidirectional mediating role in the association between shyness and GPIU. Specifically, T1 shyness and T3 GPIU were mediated through increased loneliness at T2, and T1 GPIU and T3 shyness were mediated through increased loneliness at T2. Furthermore, relationships among shyness, loneliness, and GPIU were the same across the 2 groups, with the strength of relationships being stronger for men.

A20 inhibits lipopolysaccharide-induced inflammation in enterocytes.

AIM: To examine the role of A20 in the regulation of intestinal epithelial cells (IECs) inflammation. METHODS: Using gene transfection, both stable overexpression and knockdown A20-expressed HT-29 cell lines were established. Accordingly, the cells were divided into the following groups: The control group, the A20 overexpression group, the A20 knockdown group and the respective controls. A20 was stimulated with lipopolysaccharide (LPS) in a dose- and time-dependent manner and was detected using western blotting and real-time polymerase chain reaction (PCR) analyses. Immunofluorescence and western blotting analyses were performed to investigate the role of A20 in the regulation of nuclear factor (NF)-κB activation and translocation into the nucleus. ELISA and real-time PCR were performed to examine A20 in regulating the release of the following inflammatory cytokines: Tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 and IL-8. RESULTS: The expression of A20 in IECs was inducible. When intestinal epithelial cells were subjected to the stimulation of LPS, the expression of A20 was increased, and the expression of A20 was induced in a dose- and time-dependent manner. The expression of A20 was very low in HT-29 cells without LPS stimulation but rapidly increased and was maintained at a high level 2-4 h after stimulation with LPS. These levels gradually declined with a change in time-course, and the expression of A20 increased with increasing LPS stimulation. Western blotting and immunofluorescence revealed that overexpression of A20 can inhibit NF-κB activation and its translocation to the nucleus. The overexpression of A20 can reduce the levels of proinflammatory cytokines involved in the pathophysiology of inflammatory bowel disease. There was no significant difference in the expression of IL-8 mRNA in the control group, A20 overexpression group or A20 knockdown group without LPS stimulation (P > 0.05); however, while after 2 h, 4 h and 8 h stimulation with LPS, the expression of IL-8 in the A20 overexpression group was lower than the control group and the A20 knockdown group (P < 0.05 or P < 0.01). The expression of TNF-α was different at different time points after 8 h of LPS stimulation (F = 31.33, DF = 5, P < 0.001), and the expression of TNF-α increased as the LPS stimulation time increased. Upon LPS stimulation, lower levels of TNF-α were detected in the A20 overexpression cell lines (P < 0.05). There were no significant differences in the induction of IL-6 and IL-1ß among the control group, A20 overexpression group and A20 knockdown group (P > 0.05). CONCLUSION: A20 plays an important role in limiting inflammation by inhibiting LPS-induced NF-κB responses in the gut luminal. A20 may be a potential therapeutic tool for inflammatory diseases.