Clostridium difficile infection in Polish pediatric outpatients with inflammatory bowel disease

The prevalence of Clostridium difficile infection (CDI) in pediatric patients with inflammatory bowel disease (IBD) is still not sufficiently recognized. We assessed the prevalence of CDI and recurrences in outpatients with IBD. In addition, the influence of IBD therapy on CDI and antimicrobial susceptibility of the potentially causative C. difficile strains was assessed. This was a prospective, single-center, observational study. All specimens were obtained between January 2005 and January 2007 from the IBD outpatient service and screened for C. difficile and its toxins. C. difficile isolates were genotyped by PCR ribotyping. Diagnosis of Crohn’s disease (CD) and ulcerative colitis (UC) was based on Porto criteria. Severity of disease was assessed using the Hyams scale (for Crohn’s disease) and the Truelove–Witts scale (for ulcerative colitis). One hundred and forty-three fecal samples from 58 pediatric IBD patients (21 with Crohn’s disease and 37 with ulcerative colitis) were screened. The risk of C. difficile infection was 60% and was independent of disease type (CD or UC) (χ2 = 2.5821, df = 3, p = 0.4606). About 17% of pediatric IBD patients experienced a recurrence of CDI. All C. difficile strains were susceptible to metronidazole, vancomycin and rifampin. A high prevalence of C. difficile infection and recurrences in pediatric outpatients with IBD was observed, independent of disease type. There was no significant correlation between C. difficile infection and IBD therapy. PCR ribotyping revealed C. difficile re-infection and relapses during episodes of IBD in pediatric outpatients

Toxin-Specific Antibodies for the Treatment of Clostridium difficile: Current Status and Future Perspectives †

Therapeutic agents targeting bacterial virulence factors are gaining interest as non-antibiotic alternatives for the treatment of infectious diseases. Clostridium difficile is a Gram-positive pathogen that produces two primary virulence factors, enterotoxins A and B (TcdA and TcdB), which are responsible for Clostridium difficile-associated disease (CDAD) and are targets for CDAD therapy. Antibodies specific for TcdA and TcdB have been shown to effectively treat CDAD and prevent disease relapse in animal models and in humans. This review summarizes the various toxin-specific antibody formats and strategies under development, and discusses future directions for CDAD immunotherapy, including the use of engineered antibody fragments with robust biophysical properties for systemic and oral delivery

Structure–activity study of N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a bitopic ligand that acts as a negative allosteric modulator of the dopamine D2 receptor

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharma- cology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R

Coxiella burnetii, the Agent of Q Fever, Replicates within Trophoblasts and Induces a Unique Transcriptional Response

Q fever is a zoonosis caused by Coxiella burnetii, an obligate intracellular bacterium typically found in myeloid cells. The infection is a source of severe obstetrical complications in humans and cattle and can undergo chronic evolution in a minority of pregnant women. Because C. burnetii is found in the placentas of aborted fetuses, we investigated the possibility that it could infect trophoblasts. Here, we show that C. burnetii infected and replicated in BeWo trophoblasts within phagolysosomes. Using pangenomic microarrays, we found that C. burnetii induced a specific transcriptomic program. This program was associated with the modulation of inflammatory responses that were shared with inflammatory agonists, such as TNF, and more specific responses involving genes related to pregnancy development, including EGR-1 and NDGR1. In addition, C. burnetii stimulated gene networks organized around the IL-6 and IL-13 pathways, which both modulate STAT3. Taken together, these results revealed that trophoblasts represent a protective niche for C. burnetii. The activation program induced by C. burnetii in trophoblasts may allow bacterial replication but seems unable to interfere with the development of normal pregnancy. Such pathophysiologocal processes should require the activation of immune placental cells associated with trophoblasts

Preparing the Next Generation of Public Land Managers: A Collaborative Approach to Summer Internships

In the late 1990s, the growing disconnect among agency managers, academics, and students had become apparent. Managers and educators grew concerned about the supply of experienced replacements, the lack of focused efforts to introduce new graduates into the federal workforce, and the decreased transfer of institutional knowledge within an agency and between an agency and academic institutions. Tehabi, filled this void with an internship program focusing on the technical aspects of management and the coping strategies needed to “survive” and even “thrive” in an agency culture. The program emphasizes collaboration among students, managers and educators and provides an experience with the larger organizational and environmental context of land management as well as day-to-day activities

A Pilot Feasibility Randomized Controlled Trial on the Ontario Brain Injury Association Peer Support Program

Background: The long-term consequences of traumatic brain injury can create major barriers to community integration. Peer support represents a sustainable model of support across this transition. The objective of the current study was to determine the feasibility of conducting a randomized controlled trial on the Ontario Brain Injury Association Peer Support Program and the preliminary effectiveness of the program on community integration, mood, health-related quality of life, and self-efficacy; Methods: A pilot feasibility randomized controlled trial with an embedded qualitative component was conducted. Mentees with moderate-to-severe traumatic brain injury (n = 13) were randomized to a weekly intervention or waitlist control group. Interviews were conducted with a subset of mentees and peer mentors (n = 10). Integration of the quantitative and qualitative data was completed using a joint display approach; Results: No statistically significant results were found for community integration, mood, or self-efficacy; however, changes in these outcomes were accompanied by moderate-to-large effect sizes. Within health-related quality of life, the mean pain score of the intervention group was significantly lower than that of the control group at the two-month timepoint but not at completion. Interviews revealed proximal improvements in knowledge, skills, and goals, and identified two domains related to trial acceptability: (1) environmental context and resources, and (2) reinforcement; Conclusions: Given the conceivable importance of proximal improvements in domains such as knowledge, skills, and/or goals for the attainment of more distal outcomes, modifications to the existing Peer Support Program may be warranted. The introduction of program recommendations which promote discussion around particular domains may help facilitate long-term improvements in health outcomes