ZBP-89 regulates expression of tryptophan hydroxylase I and mucosal defense against Salmonella typhimurium in mice.

BACKGROUND & AIMS: ZBP-89 (also ZNF148 or Zfp148) is a butyrate-inducible zinc finger transcription factor that binds to GC-rich DNA elements. Deletion of the N-terminal domain is sufficient to increase mucosal susceptibility to chemical injury and inflammation. We investigated whether conditional deletion of ZBP-89 from the intestinal and colonic epithelium of mice increases their susceptibility to pathogens such as Salmonella typhimurium. METHODS: We generated mice with a conditional null allele of Zfp148 (ZBP-89(FL/FL)) using homologous recombination to flank Zfp148 with LoxP sites (ZBP-89(FL/FL)), and then bred the resulting mice with those that express VillinCre. We used microarray analysis to compare gene expression patterns in colonic mucosa between ZBP-89(ΔInt) and C57BL/6 wild-type mice (controls). Mice were gavaged with 2 isogenic strains of S. typhimurium after administration of streptomycin. RESULTS: Microarray analysis revealed that the colonic mucosa of ZBP-89(ΔInt) mice had reduced levels of tryptophan hydroxylase 1 (Tph1) messenger RNA, encoding the rate-limiting enzyme in enterochromaffin cell serotonin (5-hydroxytryptamine [5HT]) biosynthesis. DNA affinity precipitation demonstrated direct binding of ZBP-89 to the mouse Tph1 promoter, which was required for its basal and butyrate-inducible expression. ZBP-89(ΔInt) mice did not increase mucosal levels of 5HT in response to S. typhimurium infection, and succumbed to the infection 2 days before control mice. The ΔhilA isogenic mutant of S. typhimurium lacks this butyrate-regulated locus and stimulated, rather than suppressed, expression of Tph1 approximately 50-fold in control, but not ZBP-89(ΔInt), mice, correlating with fecal levels of butyrate. CONCLUSIONS: ZBP-89 is required for butyrate-induced expression of the Tph1 gene and subsequent production of 5HT in response to bacterial infection in mice. Reductions in epithelial ZBP-89 increase susceptibility to colitis and sepsis after infection with S. typhimurium, partly because of reduced induction of 5HT production in response to butyrate and decreased secretion of antimicrobial peptides.

The effect of load carriage on the gait of girls with adolescent idiopathic scoliosis and normal controls.

Adolescent idiopathic scoliosis (AIS) and load-bearing both appear to place similar demands on gait, but no data regarding the combined effects of load-bearing gait in subjects with AIS could be found. The gait patterns of 22 normal adolescent girls and 28 girls with mild AIS (Cobb angle<25 degrees ) were recorded at backpack loads of 0, 7.5, 10, 12.5 and 15% body weight. Temporal-distance and joint kinematic, moment and power parameters were analyzed by repeated measures ANOVA. Findings showed that backpack carriage places an increased demand on the musculature of the lower limb and results in a gait characterized by reduced pelvic motion and greater hip flexion-extension. AIS has a generally similar effect on gait kinematics as backpack carriage, with AIS subjects having significantly longer double support durations, shorter single support durations and lower knee joint power generation and absorption than normal subjects. No interaction between backpack load and AIS was found however, although investigation of parameters indicating a critical response to load showed that this typically occurred at lower backpack loads (7.5% body weight) in the AIS group. Overall, both AIS and load-bearing place increased demands on gait, but carriage of a loaded backpack does not appear to cause any greater demand on subjects with AIS than normal controls.

The effect of backpack load on the gait of normal adolescent girls.

Concerns regarding the effects of load carriage have led to recommendations that backpacks be limited to 10?-?15% of body weight, based on significant changes in physical performance. However, gait responses to backpack loads are not entirely consistent and there is a particular lack of data regarding load-bearing gait in adolescent females. Gait patterns of 22 normal adolescent girls were recorded at backpack loads of 0, 7.5, 10.0, 12.5 and 15.0% body weight. Temporal-distance, ground reaction force and joint kinematic, moment and power parameters were analysed by repeated measures ANOVA with factors of backpack load and side (left or right). Walking speed and cadence decreased significantly with increasing backpack load, while double support time increased. Kinematic changes were most marked at the proximal joints, with a decreased pelvic motion but a significant increase in the hip sagittal plane motion. Increased moments and power at the hip, knee and ankle showed increasing demand with backpack load. Parameters showed different responses to increasing load, and those that suggested a critical load indicated this to be approximately 10% body weight. While this may be due to a change in gait due to increased demand, further work is required to verify this and also to examine the cumulative effects of backpack load on the musculoskeletal system, which may be more appropriate in determining recommended load limits.