Within-Host Dynamics of Multi-Species Infections: Facilitation, Competition and Virulence

Host individuals are often infected with more than one parasite species (parasites defined broadly, to include viruses and bacteria). Yet, research in infection biology is dominated by studies on single-parasite infections. A focus on single-parasite infections is justified if the interactions among parasites are additive, however increasing evidence points to non-additive interactions being the norm. Here we review this evidence and theoretically explore the implications of non-additive interactions between co-infecting parasites. We use classic Lotka-Volterra two-species competition equations to investigate the within-host dynamical consequences of various mixes of competition and facilitation between a pair of co-infecting species. We then consider the implications of these dynamics for the virulence (damage to host) of co-infections and consequent evolution of parasite strategies of exploitation. We find that whereas one-way facilitation poses some increased virulence risk, reciprocal facilitation presents a qualitatively distinct destabilization of within-host dynamics and the greatest risk of severe disease

The Prometastatic Microenvironment of the Liver

The liver is a major metastasis-susceptible site and majority of patients with hepatic metastasis die from the disease in the absence of efficient treatments. The intrahepatic circulation and microvascular arrest of cancer cells trigger a local inflammatory reaction leading to cancer cell apoptosis and cytotoxicity via oxidative stress mediators (mainly nitric oxide and hydrogen peroxide) and hepatic natural killer cells. However, certain cancer cells that resist or even deactivate these anti-tumoral defense mechanisms still can adhere to endothelial cells of the hepatic microvasculature through proinflammatory cytokine-mediated mechanisms. During their temporary residence, some of these cancer cells ignore growth-inhibitory factors while respond to proliferation-stimulating factors released from tumor-activated hepatocytes and sinusoidal cells. This leads to avascular micrometastasis generation in periportal areas of hepatic lobules. Hepatocytes and myofibroblasts derived from portal tracts and activated hepatic stellate cells are next recruited into some of these avascular micrometastases. These create a private microenvironment that supports their development through the specific release of both proangiogenic factors and cancer cell invasion- and proliferation-stimulating factors. Moreover, both soluble factors from tumor-activated hepatocytes and myofibroblasts also contribute to the regulation of metastatic cancer cell genes. Therefore, the liver offers a prometastatic microenvironment to circulating cancer cells that supports metastasis development. The ability to resist anti-tumor hepatic defense and to take advantage of hepatic cell-derived factors are key phenotypic properties of liver-metastasizing cancer cells. Knowledge on hepatic metastasis regulation by microenvironment opens multiple opportunities for metastasis inhibition at both subclinical and advanced stages. In addition, together with metastasis-related gene profiles revealing the existence of liver metastasis potential in primary tumors, new biomarkers on the prometastatic microenvironment of the liver may be helpful for the individual assessment of hepatic metastasis risk in cancer patients

Canine cancer immunotherapy studies: linking mouse and human

Despite recent major clinical breakthroughs in human cancer immunotherapy including the use of checkpoint inhibitors and engineered T cells, important challenges remain, including determining the sub-populations of patients who will respond and who will experience at times significant toxicities. Although advances in cancer immunotherapy depend on preclinical testing, the majority of in-vivo testing currently relies on genetically identical inbred mouse models which, while offering critical insights regarding efficacy and mechanism of action, also vastly underrepresent the heterogeneity and complex interplay of human immune cells and cancers. Additionally, laboratory mice uncommonly develop spontaneous tumors, are housed under specific-pathogen free conditions which markedly impacts immune development, and incompletely model key aspects of the tumor/immune microenvironment. The canine model represents a powerful tool in cancer immunotherapy research as an important link between murine models and human clinical studies. Dogs represent an attractive outbred combination of companion animals that experience spontaneous cancer development in the setting of an intact immune system. This allows for study of complex immune interactions during the course of treatment while also directly addressing long-term efficacy and toxicity of cancer immunotherapies. However, immune dissection requires access to robust and validated immune assays and reagents as well as appropriate numbers for statistical evaluation. Canine studies will need further optimization of these important mechanistic tools for this model to fulfill its promise as a model for immunotherapy. This review aims to discuss the canine model in the context of existing preclinical cancer immunotherapy models to evaluate both its advantages and limitations, as well as highlighting its growth as a powerful tool in the burgeoning field of both human and veterinary immunotherapy

Antibacterial effect of calcium hydroxide combined with chlorhexidine on Enterococcus faecalis: a systematic review and meta-analysis

Objective: Enterococcus faecalis (E. faecalis) is the most frequently isolated strain in failed endodontic therapy cases since it is resistant to calcium hydroxide (CH). Whether a combination of CH and chlorhexidine (CHX) is more effective than CH alone against E. faecalis is a matter of controversy. Thus, the aim of this study was to conduct a systematic review and meta-analysis of the literature. Material and Methods: A comprehensive search in PubMed, EMbase, EBSCOhost, The Cochrane Library, SciELO, and BBO databases, Clinical trials registers, Open Grey, and conference proceedings from the earliest available date to February 1, 2013 was carried out and the relevant articles were identified by two independent reviewers. Backward and forward search was performed and then inclusion and exclusion criteria were applied. The included studies were divided into "comparisons" according to the depth of sampling and dressing period of each medicament. Meta-analysis was performed using Stata software 10.0. The level of significance was set at 0.05. Results: Eighty-five studies were retrieved from databases and backward/forward searches. Fortyfive studies were considered as relevant (5 in vivo, 18 in vitro, 18 ex vivo, and 4 review articles). Nine studies were included for meta-analysis. Inter-observer agreement (Cohen kappa) was 0.93. The included studies were divided into 21 comparisons for meta-analysis. Chi-square test showed the comparisons were heterogeneous (p<0.001). Random effect model demonstrated no significant difference between CH/CHX mixture and CH alone in their effect on E. faecalis (p=0.115). Conclusions: According to the evidence available now, mixing CH with CHX does not significantly increase the antimicrobial activity of CH against E. faecalis. It appears that mixing CH with CHX does not improve its ex vivo antibacterial property as an intracanal medicament against E. faecalis. Further in vivo studies are necessary to confirm and correlate the findings of this study with the clinical outcomes

Sealing Ability of Root-end Filling Materials.

BACKGROUND: The aim of this research was to compare the apical sealing ability of different root-end filling materials (SuperEBA(), ProRoot MTA(), thermoplasticized gutta-percha + AH-Plus(), thermoplasticized RealSeal()), by means of microbial indicators. MATERIALS AND METHODS: Thus, 50 human single-rooted teeth were employed, which were shaped until size 5 0, retro - prepared with ultrasonic tips and assigned to 4 groups, retro-filled with each material or controls. A platform was employed, which was split in two halves: upper chamber-where the microbial suspension containing the biological indicators was introduced (E. faecalis + S. aureus + P. aeruginosa + B. subtilis + C. albicans); and a lower chamber containing the culture medium brain, heart influsion, where 3 mm of the apical region of teeth were kept immersed. Lectures were made daily for 60 days, using the turbidity of the culture medium as indicative of microbial contamination. Statistical analyses were carried out at 5% level of significance. RESULTS: The results showed microbial leakage at least in some specimens in all of the groups. RealSeal() has more microbial leakage, statistically significant, compared to ProRoot() MTA and SuperEBA(). No significant differences were observed when compared ProRoot() MTA and SuperEBA(). The gutta-percha + AH Plus results showed no statistically significant differences when compared with the other groups. CONCLUSIONS: All the tested materials showed microbial leakage. Root-end fillings with Super-EBA or MTA had the lowest bacterial filtration and RealSeal shows highest bacterial filtration

A comparative scanning electron microscopy evaluation of smear layer removal with apple vinegar and sodium hypochlorite associated with EDTA

OBJECTIVE: The purpose of this study was to evaluate by scanning electron microscopy (SEM) the removal of smear layer from the middle and apical root thirds after use of different irrigating solutions. MATERIAL AND METHODS: Forty roots of permanent human teeth had their canals instrumented and were randomly assigned to 4 groups (n=10), according to the irrigating solution: apple vinegar (group A), apple vinegar finished with 17% ethylenediaminetetraacetic acid (EDTA) (group B), 1% sodium hypochlorite (NaOCl) finished with 17% EDTA (group C) and saline (group D - control). After chemomechanical preparation, the roots were cleaved longitudinally and their middle and apical thirds were examined by SEM at ×1,000 magnification. Two calibrated examiners (kappa=0.92) analyzed the SEM micrographs qualitatively attributing scores that indicated the efficacy of the solutions in removing the smear layer from the surface of the dentin tubules (1 - poor, 2 - good and 3 - excellent). Data from the control and experimental groups were analyzed by the Kruskal-Wallis and Dunn's test, while the Wilcoxon test was used to compare the middle and apical thirds of the canals within the same group (a=0.05). RESULTS: The middle third presented less amount of smear layer than the apical third, regardless of the irrigant. There was statistically significant difference (p=0.0402) among the groups in the middle third. In the apical third, the apple vinegar/EDTA group showed the greatest removal of smear layer (p=0.0373). CONCLUSION: Apple vinegar associated or not with EDTA was effective in removing smear layer when used as an endodontic irrigant