Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances

Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism

Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells

Occupational and environmental exposures to airborne asbestos and silica are associated with the development of lung fibrosis in the forms of asbestosis and silicosis, respectively. However, both diseases display distinct pathological presentations, likely associated with differences in gene expression induced by different mineral structures, composition and bio-persistent properties. We hypothesized that effects of mineral exposure in the airway epithelium may dictate deviating molecular events that may explain the different pathologies of asbestosis vs. silicosis. Using robust gene expression-profiling in conjunction with in-depth pathway analysis, we assessed early (24 h) alterations in gene expression associated with crocidolite asbestos or cristobalite silica exposures in primary human bronchial epithelial cells (NHBE). Observations were confirmed in an immortal human bronchial epithelial cell line (BEAS-2B) by QRT-PCR and protein assays. Utilization of overall gene expression, unsupervised hierarchical cluster analysis and integrated pathway analysis revealed gene alterations that were common to both minerals or unique to either mineral. Our findings reveal that both minerals had potent effects on genes governing cell adhesion/migration, inflammation, and cellular stress, key features of fibrosis. Asbestos exposure was most specifically associated with aberrant cell proliferation and carcinogenesis, whereas silica exposure was highly associated with additional inflammatory responses, as well as pattern recognition, and fibrogenesis. These findings illustrate the use of gene-profiling as a means to determine early molecular events that may dictate pathological processes induced by exogenous cellular insults. In addition, it is a useful approach for predicting the pathogenicity of potentially harmful materials

Association between genotypes of rs34436714 of NLRP12 and serum tumor necrosis factor-alpha in inflammatory bowel disease: A case-control study

We aimed to investigate the impact of the single nucleotide polymorphisms of rs34436714 of the NOD-like receptor protein 12 gene on the production of tumor necrosis factor-alpha (TNFα) in patients with inflammatory bowel disease (IBD)In a matched case-control study 90 patients with IBD, 56 with Crohn disease (CD) and 34 with ulcerative colitis, were genotyped and compared to 98 healthy comparators matched for age and gender. Expression level of TNFα, interleukin (IL)-6, IL-12, and soluble triggering receptor expressed on myeloid cells were measured in patients' sera. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated for TNFα production.Serum TNFα was greater among carriers of GT/TT genotypes than GG genotypes of rs34436714. Stimulated TNFα production was also higher in carriers of GT/TT genotypes. The frequency of CD with fistulizing behavior and with CD involving the small intestine was greater among carriers of GT/TT genotypes than of the GG genotype. Distribution of the GG, GT, and TT genotypes of rs34436714 were in Hardy-Weinberg equilibrium in both groups. The genotype distribution was the same in both groups.Carriage of minor frequency alleles of rs34436714 was accompanied by greater circulating levels of TNFα and by greater capacity for stimulated TNFα production by PBMCs. These alleles had an impact on the phenotype of patients with CD. © 2019 Oxford University Press. All righs reserved

Antibiotic prophylaxis in TURP: a prospective analysis concerning antibiotic stewardship and a potential reduction of antibiotic use in TURP

PURPOSE: Antibiotic prophylaxis is standard procedure in transurethral resection of the prostate (TURP). We evaluated the necessity of antibiotic (AB) prophylaxis in TURP due to increasing microbial antibiotic resistance. METHODS: This is a prospective cohort study of 506 patients. Only patients with a pre-operative catheter/pyuria received AB-prophylaxis. Urine analysis (pre-operative, at discharge, and 3 week post-operative) was performed next to an analysis of the blood culture/irrigation fluid and of the resected prostatic tissue. Statistical analysis was performed using Fisher's exact test. RESULTS: 67/506 (13.2%) patients received prophylactic antibiotics. 56/67 (83.5%) patients had a pre-operative catheter and 11/67 (16.4%) had pre-operative pyuria in which a fluoroquinolone-resistance (FQ-R) rate of 69.2% in Escherichia coli (EC) was observed. Clinical infectious symptoms were present in 13/439 (2.9%) patients without antibiotic prophylaxis; 12/439 (2.7%) patients had uncomplicated fever ( 38.5°) observed. Uncomplicated fever developed in 7/67 (10.4%) patients who did receive AB-prophylaxis. FQ-R was observed in 60% of the positive urine cultures at discharge and in 53.8% 3 week post-operatively. CONCLUSIONS: Our data show a low infectious complication rate (2.9%) in patients without a pre-operative catheter or pyuria,undergoing TURP without AB-prophylaxis. These findings might question the current use of AB prophylaxis in TURP in patients without a pre-operative catheter or pyuria, in times of antibiotic stewardship due to the high rate of microbial-resistance in our population.status: publishe

Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort

BACKGROUND AND AIMS: This observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn's disease (CD) from a single centre during a median follow-up of 55 months (interquartile range (IQR) 27-83). METHODS: The primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of follow-up. The long-term effects of IFX on the course of CD as reflected by the rate of surgery and hospitalisations and need for corticosteroids were also analysed. RESULTS: 10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term treatment. In 68.3% of these, treatment with IFX was ongoing and in 31.7% IFX was stopped, with the patient being in remission. Seventy patients (12.8%) had to stop IFX due to side effects and 118 (21.6%) due to loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalisations and surgery decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group. CONCLUSIONS: In this large real-life cohort of patients with CD, long-term treatment with IFX was very efficacious to maintain improvement during a median follow-up of almost 5 years and changed disease outcome by decreasing the rate of hospitalisations and surgery

Mucosal Healing Predicts Long-term Outcome of Maintenance Therapy with Infliximab in Crohn's Disease

Background: Infliximab (IFX) treatment induces mucosal healing (MH) in patients with Crohn's disease (CD) but the impact of MH oil the long-term outcome of IFX treatment in CID is still debated. Methods: We studied MH during long-term treatment with IFX in 214 CID patients. A total of 193 patients (85.5%) responded to induction therapy and 31 patients (14.5%) were primary nonresponders. They underwent lower gastrointestinal (GI) endoscopy within a median of 0.7 months (interquartile range [IQR] 0.1-6.9) prior to first IFX and after a median of 6.7 months (IQR 1.4-24.6) after start of IFX and were further analyzed. The relationship between the outcome of IFX treatment long-term and MH was studied. Results: MH was observed in 67.8% of the 183 initial responders (n = 124), with 83 patients having complete healing (45.4%) and 41 having partial healing (22.4%). Scheduled IFX treatment from the start resulted in MH more frequently (76.9% MH rate) than episodic treatment (61.0% MH rate; P = 0.0222, odds ratio [OR] 2.14, 95% confidence interval [CI] 1.11-4.12). Concomitant treatment with corticosteroids (CS) had a negative impact on MH (37.9% in patients with CS versus 63.2% in patients without CS; P = 0.021, OR 0.36, 95% CI 0.16-0.80). MH was associated with a significantly lower need for major abdominal surgery (MAS) during long-term follow-up (14.1% of patients with MH needed MAS versus 38.4% of patients Without MH: P < 0.0001). Conclusions: MH induced by long-term maintenance IFX treatment is associated with an improved long-term outcome of the I disease especially with a lower need for major abdominal surgeries

Neutrophil gelatinase B-associated lipocalin-matrix metalloproteinase-9 (NGAL-MMP-9) complex as a surrogate serum marker for mucosal healing in ulcerative colitis

C