Disruption of the murine Glp2r impairs Paneth cell function and increases susceptibility to small bowel enteritis

Exogenous glucagon-like peptide-2 receptor (GLP-2R) activation elicits proliferative and cytoprotective responses in the gastrointestinal mucosa and ameliorates experimental small and large bowel gut injury. Nevertheless, the essential physiological role(s) of the endogenous GLP-2R remain poorly understood. We studied the importance of the GLP-2R for gut growth, epithelial cell lineage allocation, the response to mucosal injury, and host-bacterial interactions in Glp2r(-/-) and littermate control Glp2r(+/+) mice. Glp2r(-/-) mice exhibit normal somatic growth and preserved small and large bowel responses to IGF-I and keratinocyte growth factor. However, Glp2r(-/-) mice failed to up-regulate intestinal epithelial c-fos expression in response to acute GLP-2 administration and do not exhibit changes in small bowel conductance or small or large bowel growth after administration of GLP-2R agonists. The crypt and villus compartment and the numbers and localization of Paneth, enteroendocrine, and goblet cells were comparable in Glp2r(+/+) vs. Glp2r(-/-) mice. Although the severity and extent of colonic mucosal injury in response to 3% oral dextran sulfate was similar across Glp2r genotypes, Glp2r(-/-) mice exhibited significantly increased morbidity and mortality and increased bacterial translocation after induction of enteritis with indomethacin and enhanced mucosal injury in response to irinotecan. Moreover, bacterial colonization of the small bowel was significantly increased, expression of Paneth cell antimicrobial gene products was reduced, and mucosal bactericidal activity was impaired in Glp2r(-/-) mice. Although the Glp2r is dispensable for gut development and the response to colonic injury, Glp2r(-/-) mice exhibit enhanced sensitivity to small bowel injury, and abnormal host-bacterial interactions in the small bowel.     

Intestinotrophic glucagon-like peptide-2 (GLP-2) activates intestinal gene expression and growth factor-dependent pathways independent of the vasoactive intestinal peptide gene in mice

The enteroendocrine and enteric nervous systems convey signals through an overlapping network of regulatory peptides that act either as circulating hormones or as localized neurotransmitters within the gastrointestinal tract. Because recent studies invoke an important role for vasoactive intestinal peptide (VIP) as a downstream mediator of glucagon-like peptide-2 (GLP-2) action in the gut, we examined the importance of the VIP-GLP-2 interaction through analysis of Vip(-/-) mice. Unexpectedly, we detected abnormal villous architecture, expansion of the crypt compartment, increased crypt cell proliferation, enhanced Igf1 and Kgf gene expression, and reduced expression of Paneth cell products in the Vip(-/-) small bowel. These abnormalities were not reproduced by antagonizing VIP action in wild-type mice, and VIP administration did not reverse the intestinal phenotype of Vip(-/-) mice. Exogenous administration of GLP-2 induced the expression of ErbB ligands and immediate-early genes to similar levels in Vip(+/+) vs. Vip(-/-) mice. Moreover, GLP-2 significantly increased crypt cell proliferation and small bowel growth to comparable levels in Vip(+/+) vs. Vip(-/-) mice. Unexpectedly, exogenous GLP-2 administration had no therapeutic effect in mice with dextran sulfate-induced colitis; the severity of colonic injury and weight loss was modestly reduced in female but not male Vip(-/-) mice. Taken together, these findings extend our understanding of the complex intestinal phenotype arising from loss of the Vip gene. Furthermore, although VIP action may be important for the antiinflammatory actions of GLP-2, the Vip gene is not required for induction of a gene expression program linked to small bowel growth after enhancement of GLP-2 receptor signaling.     

Intraaortic balloon pump: incidence and predictors of complications in the Florence registry

Background:

The intraaortic balloon pump (IABP) is the most commonly used mechanical circulatory support for patients with acute coronary syndromes and cardiogenic shock. Nevertheless, IABP‐related complications are still frequent and associated with a poor prognosis.

Hypothesis:

To prospectively assess the incidence and predictors of complications in patients treated with IABP.

Methods:

A total of 481 patients treated with IABP were prospectively enrolled in our registry (the Florence Registry). At multivariable logistic regression analysis the following variables were independent predictors for complications (when adjusted for age >75 years, eGFR and time length of IABP support): use of inotropes (OR 2.450, P < 0.017), nadir platelet count (1000/µL step; OR 0.990, P < 0.001), admission lactate (OR 1.175, P = 0.003). Nadir platelet count showed a negative correlation with length of time of IABP implantation (r?0.31; P < 0.001). A nadir platelet count cutoff value of less than 120,000 was identified using a receiver operating characteristic (ROC) curve for the development of complications (area under the curve [AUC] 0.70; P < 0.001).

Results:

Complications were observed in the 13.1%, among whom 33 of 63 showed major bleeding. The incidence of complications was higher in patients aged >75 years (P = 0.015) and in those who had an IABP implanted for more than 24 hours (P = 0.001). Patients with complications showed an in Intensive Cardiac Care Unit (ICCU) mortality higher than patients who did not (44.4% vs 17.2%, P < 0.001).

Conclusions:

In consecutive patients treated with IABP support, the degree of hemodynamic impairment and the decrease in platelet count were independent predictors of complications, whose development was associated with higher in‐ICCU mortality. © 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.

     

Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia

We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10(-16)). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development.     

ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease

Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is characterized by neuronal cytoplasmic inclusions containing TDP-43. Apolipoprotein E4 (apoE4), derived from the apoE ?4 allele, enhances brain atrophy in FTLD through unknown mechanisms. Here, we studied two siblings with C9ORF72-linked familial FTLD-MND, an apoE ?4 homozygote and an apoE ?3 homozygote. The apoE ?4 homozygote had more cognitive-behavioral symptoms, fronto-insulo-temporal atrophy, and apoE fragments and aggregates in the anterior cingulate cortex. ApoE formed complexes with TDP-43 that were more abundant in the apoE ?4 homozygote. Although differences seen in a sibling pair could arise due to chance, these findings raise the possibility that apoE4 exacerbates brain pathology in FTLD through formation of neurotoxic apoE fragments and interactions with TDP-43.     

Socioeconomic and psychosocial predictors of dental healthcare use among Brazilian preschool children

Background

Disparities in utilization of oral healthcare services have been attributed to socioeconomic and individual behavioral factors. Parents’ socioeconomic status, demographics, schooling, and perceptions of oral health may influence their children’s use of dental services. This cross-sectional study assessed the relationships between socioeconomic and psychosocial factors and the utilization of dental health services by children aged 1–5 years.

Methods

Data were collected through clinical exams and a structured questionnaire administered during the National Day of Children’s Vaccination. A Poisson regression model was used to estimate prevalence ratios and 95% confidence intervals.

Results

Data were collected from a total of 478 children. Only 112 (23.68%) were found to have visited a dentist; 67.77% of those had seen the dentist for preventive care. Most (63.11%) used public rather than private services. The use of dental services varied according to parental socioeconomic status; children from low socioeconomic backgrounds and those whose parents rated their oral health as “poor” used dental services less frequently. The reason for visiting the dentist also varied with socioeconomic status, in that children of parents with poor socioeconomic status and who reported their child’s oral health as “fair/poor” were less likely to have visited the dentist for preventive care.

Conclusion

This study demonstrated that psychosocial and socioeconomic factors are important predictors of the utilization of dental care services.