GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3

The antimicrobial peptides (AMP) produced by intestinal epithelial cells (IEC) play crucial roles in the regulation of intestinal homeostasis by controlling microbiota. Gut microbiota has been shown to promote IEC expression of RegIIIγ and certain defensins. However, the mechanisms involved are still not completely understood. In this report, we found that IEC expression levels of RegIIIγ and β-defensins 1, 3, and 4 were lower in G protein-coupled receptor (GPR)43^−/− mice compared to that of wild-type (WT) mice. Oral feeding with short-chain fatty acids (SCFA) promoted IEC production of RegIIIγ and defensins in mice. Furthermore, SCFA induced RegIIIγ and β-defensins in intestinal epithelial enteroids generated from WT but not GPR43^−/− mice. Mechanistically, SCFA activated mTOR and STAT3 in IEC, and knockdown of mTOR and STAT3 impaired SCFA induction of AMP production. Our studies thus demonstrated that microbiota metabolites SCFA promoted IEC RegIIIγ and β-defensins in a GPR43-dependent manner. The data thereby provide a novel pathway by which microbiota regulates IEC expression of AMP and intestinal homeostasis.     

Smad nuclear interacting protein 1 (SNIP1) inhibits intestinal inflammation through regulation of epithelial barrier function

Smad nuclear interacting protein 1 (SNIP1) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms involved are still largely unknown. Our results demonstrated that SNIP1 was markedly decreased in intestinal epithelial cells (IEC) from IBD patients compared with healthy controls. Impaired expression of SNIP1 caused a significant decrease of transepithelial electrical resistance but an increase of fluorescein isothiocyanate-dextran flux in Caco-2 monolayers, whereas overexpression of SNIP1 reversed such effects. Overexpression of SNIP1 also inhibited the activity of NF-κB p65 and proinflammatory cytokine production (e.g., TNF-α, IL-1β, and IL-8) by IEC. Importantly, supplementation of exogenous SNIP1 significantly ameliorated intestinal mucosal inflammation in experimental colitis, characterized by less-severe intestinal epithelial barrier damage and decreased proinflammatory cytokine production. Our data thus demonstrated a novel mechanism whereby SNIP1 regulates intestinal inflammation through modulating intestinal epithelial barrier function. Targeting SNIP1 may provide a therapeutic approach for the treatment of IBD.     

Dynamic changes in maternal decidual leukocyte populations from first to second trimester gestation

IntroductionDecidual leukocytes are critical to the development of the fetomaternal interface, regulating tolerance to the semi-allogeneic fetus and vascular transformation of the uterine spiral arteries. Despite the continuation of these processes beyond the first trimester of pregnancy, the second trimester has largely been unstudied, with investigation focusing on early gestation and term tissues. We sought to characterize changes in decidual leukocyte populations from first to second trimester.MethodsMulticolor flow cytometry was performed on isolated decidual leukocytes from elective terminations of pregnancy between 6 and 20 weeks of gestation for study of first (6–12 weeks) and second trimesters (13–20 weeks). Specific subpopulations were identified by comparison to isotype and fluorescent-minus-one (FMO) controls.ResultsDecidual natural killer cells (CD56⁺CD16⁻CD3⁻) did not change in number, although a population of dNK with decreased CD56 brightness was observed in second trimester decidua. CD14⁺HLA-DR⁺ macrophage numbers declined from first to second trimester (p = 0.031), yet a CD163⁺CD206⁺ subset designating alternatively activated M2-like macrophages increased during the same period (p = 0.015). Intermediate CD205⁺ dendritic cells demonstrated significant decline (p = 0.022), but immature CD209⁺ and mature CD83⁺ dendritic cells did not differ between trimesters. Total CD3⁺ and CD3⁺CD4⁺ T lymphocytes increased (p = 0.0079, p = 0.0028); CD3⁺CD8⁺ T cells trended towards increase but did not differ significantly.ConclusionSeveral changes in leukocyte subsets are observed in the second trimester that promote a tolerogenic and angiogenic decidual microenvironment through mid-gestation.     

Socioeconomic status and changing inequalities in colorectal cancer? A review of the associations with risk,treatment and outcome

BackgroundUpcoming mass screening for colorectal cancer (CRC) makes a review of recent literature on the association with socioeconomic status (SES) relevant, because of marked and contradictory associations with risk, treatment and outcome.MethodsThe Pubmed database using the MeSH terms ‘Neoplasms’ or ‘Colorectal Neoplasms’ and ‘Socioeconomic Factors’ for articles added between 1995 and 1st October 2009 led to 62 articles.ResultsLow SES groups exhibited a higher incidence compared with high SES groups in the US and Canada (range risk ratio (RR) 1.0–1.5), but mostly lower in Europe (RR 0.3–0.9). Treatment, survival and mortality all showed less favourable results for people with a lower socioeconomic status: Patients with a low SES received less often (neo)adjuvant therapy (RR ranging from 0.4 to 0.99), had worse survival rates (hazard ratio (HR) 1.3–1.8) and exhibited generally the highest mortality rates up to 1.6 for colon cancer in Europe and up to 3.1 for rectal cancer.ConclusionsA quite consistent trend was observed favouring individuals with a high SES compared to those with a low SES that still remains in terms of treatment, survival and thus also mortality. We did not find evidence that the low/high SES gradients for treatment chosen and outcome are decreasing. To meet increasing inequalities in mortality from CRC in Europe for people with a low SES and to make mass screening successful, a high participation rate needs to be realised of low SES people in the soon starting screening program.     

Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?

Leber hereditary optic neuropathy (LHON) is a major cause of inherited blindness in young males. Approximately 1 in 7 individuals with LHON harbor a mixture of mutated and wild‐type (normal) mtDNA (heteroplasmy), and the risks of developing blindness in heteroplasmic LHON individuals are not well characterized. MtDNA is inherited exclusively down the maternal line, and although the risks of a relative within a homoplasmic LHON pedigree are relatively well established, the risks of transmission in heteroplasmic LHON pedigrees have not been studied in detail. We analyzed 17 independent pedigrees that harbor the most prevalent LHON mutation: G11778A. The pedigrees were influenced by incomplete ascertainment bias, which was reduced by omitting the affected probands from the analysis. We made the following observations: (1) The frequency of blindness in males was related to the mutation load in that individual’s blood. (2) Mothers with ≤80% mutant mtDNA in blood were less likely to have clinically affected sons than mothers with 100% mutant mtDNA in their blood. (3) Within individual lineages, changes in mutation load from one generation to the next were largely determined by random genetic drift in these pedigrees. This study provides insights into the mutation load, or threshold, necessary for expression of the optic neuropathy, the relationship between mutation load in the mother and the risk of blindness in her children, and the complex inheritance of heteroplasmic mtDNA defects. © 2001 Wiley‐Liss, Inc.     

Exposure to violence and associated health-risk behaviors among adolescent girls.

OBJECTIVE: To examine the relationship between exposure to violence and health-risk behaviors. DESIGN: Cross-sectional survey. SETTING: University-based outpatient family planning clinic. PATIENTS: Sexually active adolescent girls younger than 18 years (N = 517) who presented for contraceptive care. MAIN OUTCOME MEASURES: Prevalence of witnessing or experiencing violence and the associations with health-risk behaviors, including high-risk sexual behaviors, substance use, and self-injury. RESULTS: Compared with adolescents who had not been exposed to violence, those who had only witnessed violence were 2 to 3 times more likely to report using tobacco and marijuana, drinking alcohol or using drugs before sex, and having intercourse with a partner who had multiple partners. Those who had experienced, but not witnessed violence were at increased risk of these same behaviors and were 2 to 4 times more likely than those who had neither witnessed nor experienced violence to report early initiation of intercourse, intercourse with strangers, multiple partners, or partners with multiple partners, tobacco, alcohol and drug use, or to have positive test results for a sexually transmitted disease. Individuals who had both witnessed and experienced violence demonstrated the greatest risk of adverse health behaviors. These adolescents demonstrated 3 to 6 times greater risk of suicidal ideation (odds ratio [OR], 3.1; 95% confidence interval [CI], 2.2-4.0) or suicide attempts (OR, 4.5; 95% CI, 2.2-9.4), self-injury (OR, 5.8; 95% CI, 2.6-12.9), and use of drugs before intercourse (OR, 6.2; 95% CI, 3.0-12.9) than those who had neither witnessed nor experienced violence. CONCLUSIONS: Adolescents exposed to violence are at increased risk of multiple adverse health behaviors. Programs designed to improve health outcomes should target this high-risk group.     

Rapid receptor-clustering assay to detect uropathogenic and diarrheal Escherichia coli isolates bearing adhesins of the Dr family

Infections caused by Escherichia coli isolates expressing adhesins of the Dr family are associated with diarrhea and urinary tract infections, and these E. coli strains recognize the complement regulatory protein decay-accelerating factor (DAF) as their receptor. Clustering of the DAF receptor at the sites of bacterial adherence to epithelial cells is proposed as an alternative to PCR assay for rapid detection of Dr-positive E. coli.     

Predicting Mobility Limitations in Patients With Total Knee Arthroplasty in the Inpatient Setting

ObjectiveTo develop a prediction model for postoperative day 3 mobility limitations in patients undergoing total knee arthroplasty (TKA).DesignProspective cohort study.SettingInpatients in a tertiary care hospital.ParticipantsA sample of patients (N=2300) who underwent primary TKA in 2016-2017.InterventionsNot applicable.Main Outcome MeasureCandidate predictors included demographic variables and preoperative clinical and psychosocial measures. The outcome of interest was mobility limitations on post-TKA day 3, and this was determined a priori by an ordinal mobility outcome hierarchy based on the type of the gait aids prescribed and the level of physiotherapist assistance provided. To develop the model, we fitted a multivariable proportional odds regression model with bootstrap internal validation. We used a model approximation approach to create a simplified model that approximated predictions from the full model with 95% accuracy.ResultsOn post-TKA day 3, 11% of patients required both walkers and therapist assistance to ambulate safely. Our prediction model had a concordance index of 0.72 (95% confidence interval, 0.68-0.75) when evaluating these patients. In the simplified model, predictors of greater mobility limitations included older age, greater walking aid support required preoperatively, less preoperative knee flexion range of movement, low-volume surgeon, contralateral knee pain, higher body mass index, non-Chinese race, and greater self-reported walking limitations preoperatively.ConclusionWe have developed a prediction model to identify patients who are at risk for mobility limitations in the inpatient setting. When used preoperatively as part of a shared-decision making process, it can potentially influence rehabilitation strategies and facilitate discharge planning.