Positive effects were observed with CII at the lowest dosage tested, and the presence of serum antibodies to CII at baseline may predict response to therapy. No side effects were associated with this novel therapeutic agent. Further controlled studies are required to assess the efficacy of this treatment approach.

Giardia lamblia is a leading protozoan cause of diarrheal disease worldwide. It colonizes the lumen and epithelial surface of the small intestine, but does not invade the mucosa. Acute infection causes only minimal mucosal inflammation. Effective immune defenses exist, yet their identity and mechanisms remain incompletely understood. Interleukin (IL)-17A has emerged as an important cytokine involved in inflammation and antimicrobial defense against bacterial pathogens at mucosal surfaces. In this study, we demonstrate that IL-17A has a crucial function in host defense against Giardia infection. Using murine infection models with Giardia muris and G. lamblia, we observed marked and selective induction of intestinal IL-17A with peak expression after two weeks. Th17 cells in the lamina propria and innate immune cells in the epithelial compartment of the small intestine were responsible for the IL-17A response. Experiments in gene-targeted mice revealed that the cytokine, and its cognate receptor IL-17RA, were required for eradication of the parasite. The actions of the cytokine were mediated by hematopoietic cells, and were required for the transport of IgA into the intestinal lumen, since IL-17A deficiency led to marked reduction of fecal IgA levels, as well as for increased intestinal expression of several other potential effectors, including β-defensin 1 and resistin-like molecule β. In contrast, intestinal hypermotility, another major antigiardial defense mechanism, was not impacted by IL-17A loss. Taken together, these findings demonstrate that IL-17A and IL-17 receptor signaling are essential for intestinal defense against the important lumen-dwelling intestinal parasite Giardia.

Entamoeba histolytica cysteine proteinases (EhCPs) play a key role in disrupting the colonic epithelial barrier and the innate host immune response during invasion of E. histolytica, the protozoan cause of human amebiasis. EhCPs are encoded by 50 genes, of which ehcp4 (ehcp-a4) is the most up-regulated during invasion and colonization in a mouse cecal model of amebiasis. Up-regulation of ehcp4 in vivo correlated with our finding that co-culture of E. histolytica trophozoites with mucin-producing T84 cells increased ehcp4 expression up to 6-fold. We have expressed recombinant EhCP4, which was autocatalytically activated at acidic pH but had highest proteolytic activity at neutral pH. In contrast to the other amebic cysteine proteinases characterized so far, which have a preference for arginine in the P2 position, EhCP4 displayed a unique preference for valine and isoleucine at P2. This preference was confirmed by homology modeling, which revealed a shallow, hydrophobic S2 pocket. Endogenous EhCP4 localized to cytoplasmic vesicles, the nuclear region, and perinuclear endoplasmic reticulum (ER). Following co-culture with colonic cells, EhCP4 appeared in acidic vesicles and was released extracellularly. A specific vinyl sulfone inhibitor, WRR605, synthesized based on the substrate specificity of EhCP4, inhibited the recombinant enzyme in vitro and significantly reduced parasite burden and inflammation in the mouse cecal model. The unique expression pattern, localization, and biochemical properties of EhCP4 could be exploited as a potential target for drug design.

Objective Ruptured aortic aneurysm is a condition with a high rate of mortality that requires prompt surgical intervention. It has been noted that in some conditions requiring such prompt intervention, in-hospital mortality is increased in patients admitted on the weekends as compared to patients admitted on weekdays. We sought to determine if this was indeed the case for both ruptured thoracic and abdominal aortic aneurysm and elucidate the possible reasons. Methods Using the Nationwide Inpatient Sample (NIS), a publicly available database of inpatient care, we analyzed the incidence of mortality among 7200 patients admitted on the weekends compared to weekdays for ruptured aortic aneurysm. Among these patients 19% had thoracic aortic aneurysm and 81% had abdominal aortic aneurysm and were analyzed for differences in mortality during the hospitalization. We adjusted for demographics, comorbid conditions, hospital characteristics, rates of surgical intervention, timing of surgical intervention and use of additional therapeutic measures. Results Patients admitted on the weekend for both ruptured thoracic and abdominal aortic aneurysm had a statistically significant increase in mortality as compared to those admitted on the weekdays, Odds ratio (OR) = 2.55, 95% confidence interval (CI) 1.77–3.68, p=0.03 for thoracic and OR =1.32, 95% CI 1.13–1.55, p=0.0004 for abdominal aortic aneurysm. Among those with thoracic aortic aneurysm, a surgical intervention was performed on day of admission in 62.1% of weekday admissions vs. 34.9% weekend admissions, p<.0001. This difference was much smaller among those with an aortic aneurysm, 79.6% had a surgical intervention on day of admission when admitted on a weekday vs. 77.2% on weekend, p<.0001. Conclusions Weekend admission for ruptured aortic aneurysm is associated with an increased mortality when compared to those admitted on the weekend and this is likely due to several factors including a delay in prompt surgical intervention.

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