Innate immune and inflammatory responses have been implicated in myocardial ischemia/reperfusion (I/R) injury. However, the mechanisms by which innate immunity and inflammatory response are involved in myocardial I/R have not been elucidated completely. Recent studies highlight the role of Toll-like receptors (TLRs) in the induction of innate immune and inflammatory responses. Growing evidence has demonstrated that TLRs play a critical role in myocardial I/R injury. Specifically, deficiency of TLR4 protects the myocardium from ischemic injury, whereas modulation of TLR2 induces cardioprotection against ischemic insult. Importantly, cardioprotection induced by modulation of TLRs involves activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, suggesting that there is a crosstalk between TLRs and PI3K/Akt signaling pathways. In addition, TLRs also associate with other coreceptors, such as macrophage scavenger receptors in the recognition of their ligands. TLRs are also involved in the induction of angiogenesis, modulation of stem cell function, and expression of microRNA, which are currently important topic areas in myocardial I/R. Understanding how TLRs contribute to myocardial I/R injury could provide basic scientific knowledge for the development of new therapeutic approaches for the treatment and management of patients with heart attack.

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The potential health impact of ambient ozone and PM2.5 concentrations modulated by climate change over the United States is investigated using combined atmospheric and health modeling. Regional air quality modeling for 2001 and 2050 was conducted using CMAQ Modeling System with meteorology from the GISS Global Climate Model, downscaled regionally using MM5, keeping boundary conditions of air pollutants, emission sources, population, activity levels, and pollution controls constant. BenMap was employed to estimate the air pollution health outcomes at the county, state, and national level for 2050 caused by the effect of meteorology on future ozone and PM2.5 concentrations. The changes in calculated annual mean PM 2.5 concentrations show a relatively modest change with positive and negative responses (increasing PM2.5 levels across the northeastern U.S.) although average ozone levels slightly decrease across the northern sections of the U.S., and increase across the southern tier. Results suggest that climate change driven air quality-related health effects will be adversely affected in more than 2/3 of the continental U.S. Changes in health effects induced by PM2.5 dominate compared to those caused by ozone. PM 2.5-induced premature mortality is about 15 times higher than that due to ozone. Nationally the analysis suggests approximately 4000 additional annual premature deaths due to climate change impacts on PM2.5 vs 300 due to climate change-induced ozone changes. However, the impacts vary spatially. Increased premature mortality due to elevated ozone concentrations will be offset by lower mortality from reductions in PM2.5 in 11 states. Uncertainties related to different emissions projections used to simulate future climate, and the uncertainties forecasting the meteorology, are large although there are potentially important unaddressed uncertainties (e.g., downscaling, speciation, interaction, exposure, and concentration-response function of the human health studies).

Mucocutaneous fungal infections are typically found in patients who have no known immune defects. We describe a family in which four women who were affected by either recurrent vulvovaginal candidiasis or onychomycosis had the early-stop-codon mutation Tyr238X in the β-glucan receptor dectin-1. The mutated form of dectin-1 was poorly expressed, did not mediate β-glucan binding, and led to defective production of cytokines (interleukin-17, tumor necrosis factor, and interleukin-6) after stimulation with β-glucan or Candida albicans. In contrast, fungal phagocytosis and fungal killing were normal in the patients, explaining why dectin-1 deficiency was not associated with invasive fungal infections and highlighting the specific role of dectin-1 in human mucosal antifungal defense.

Background: Erythropoietin (EPO) and carbamylated erythropoietin (CEPO) can protect tissue from injury; however, CEPO has its protective effect in the absence of erythropoietic stimulation. The mechanism whereby CEPO protects heart from acute ischemia/reperfusion (I/R) injury remains unknown. Methods: BALB/c mice were subjected to myocardial ischemia for 45 min followed by reperfusion for 4 h, and they received a single dose of CEPO intraperitoneal at the onset of reperfusion. Myocardial infarct size and cardiac function were assessed. The association of erythropoietin receptor with β common receptor (βcR) was examined. The level of Akt phosphorylation in the myocardium was assayed as well as a series of downstream target genes of PI3K/Akt,including p-GATA-4, GATA-4, MHC, and troponin I. Results: CEPO administration immediately before reperfusion decreased infarction by 40% and increased ejection fraction (27%) and fractional shortening (22%), compared with untreated ischemic hearts (P < .05 each). CEPO promoted association of the EPO receptor and βcR. Furthermore, CEPO administration increased the levels of phospho-Akt in the myocardium by 59% (P < .05). A PI3K inhibitor, wortmannin, blocked the beneficial effect of CEPO on infarct size and cardiac function and attenuated the CEPO-induced Akt phosphorylation. CEPO also increased the expression of p-GATA-4, GATA-4, myosin heavy chain, and troponin I. Conclusion: A single dose of CEPO at the onset of reperfusion attenuated acute myocardial I/R injury in the mouse. CEPO-induced cardioprotection appears to be mediated through a PI3K/Akt-dependent mechanism.

This chapter focuses on recent advances in understanding of the mechanisms by which (1,3)lucans modulate innate immunity in mammals, and how modulation of innate immunity with glucan alters host response to disease. The ability of (1,3)----lucans to stimulate innate immunity has been known for more than four decades. However, recent advances in our knowledge in particular the discovery that Dectin is the primary (1,3)----lucan recognition protein have significantly increased our understanding of how (1,3)----lucans modulate innate immunity at the cellular and molecular level. These findings will be important in advancing our knowledge of the role that glucan plays as a pathogen associated molecular pattern and they may also be useful in the development of (1,3)----lucan based immunotherapeutics.

The fungus Candida albicans is the most common cause of mycotic infections in immunocompromised hosts. Little is known about the initial interactions between Candida and immune cell receptors, because a detailed characterization at the structural level is lacking. Antigen-presenting dendritic cells (DCs), strategically located at mucosal surfaces and in the skin, may play an important role in anti-Candida protective immunity. However, the contribution of the various Candida-associated molecular patterns and their counter-receptors to DC function remains unknown. Here, we demonstrate that two C-type lectins, DC-SIGN and the macrophage mannose receptor, specifically mediate C. albicans binding and internalization by human DCs. Moreover, by combining a range of C. albicans glycosylation mutants with receptor-specific blocking and cytokine production assays, we determined that N-linked mannan but not O-linked or phosphomannan is the fungal carbohydrate structure specifically recognized by both C-type lectins on human DCs and directly influences the production of the proinflammatory cytokine IL-6. Better insight in the carbohydrate recognition profile of C-type lectins will ultimately provide relevant information for the development of new drugs targeting specific fungal cell wall antigens.

Dectin-1 is the archetypal signaling, non-Toll-like pattern recognition receptor that plays a protective role in immune defense to Candida albicans as the major leukocyte receptor for β-glucans. Dectin-1-deficiency is associated with impaired recruitment of inflammatory leukocytes and inflammatory mediator production at the site of infection. In this study, we have used mice to define the mechanisms that regulate the dectin-1-mediated inflammatory responses. Myeloid cell activation by dectin-1 is controlled by inherent cellular programming, with distinct macrophage and dendritic cell populations responding differentially to the engagement of this receptor. The inflammatory response is further modulated by the progression of the phagocytosis, with "frustrated phagocytosis" resulting in dramatically augmented inflammatory responses. These studies demonstrate that dectin-1 in isolation is sufficient to drive a potent inflammatory response in a context-dependent manner. This has implications for the mechanism by which myeloid cells are activated during fungal infections and the processes involved in the therapeutic manipulation of the immune system via exogenous dectin-1 stimulation or blockade.

Microglia are the resident mononuclear phagocytic cells that are critical for innate and adaptive responses within the CNS. Like other immune cells, microglia recognize and are activated by various pathogen-associated molecular patterns. β-glucans are pathogen-associated molecular patterns present within fungal cell walls that are known to trigger protective responses in a number of immune cells. In an effort to better understand microglial responses to β-glucans and the underlying response pathways, we sought to determine whether Dectin-1, a major β-glucan receptor recently identified in leukocytes, plays a similar role in β-glucan-induced activation in microglia. In this study, we report that Dectin-1 is indeed expressed on the surface of murine primary microglia, and engagement of the receptor with particulate β-glucan resulted in an increase in tyrosine phosphorylation of spleen tyrosine kinase, a hallmark feature of the Dectin-1 signaling pathway. Moreover, phagocytosis of β-glucan particles and subsequent intracellular production of reactive oxygen species were also mediated by Dectin-1. However, unlike in macrophages and dendritic cells, β-glucan-mediated microglial activation did not result in significant production of cytokines or chemokines; thus, the interaction of microglial Dectin-1 with glucan elicits a unique response. Our results suggest that the Dectin-1 pathway may play an important role in antifungal immunity in the CNS.

The technical aspects of laparoscopic hepatic resection have evolved rapidly. The key to any approach is establishing a reliable method to prevent or control hemorrhage during parenchymal transection. Although combining a hand-assist technique with laparoscopy allows improved control of bleeding risk, this requires the addition of a hand-port incision. The development of novel devices that can be used to safely divide liver parenchyma laparoscopically may lessen the need for hand-assist. Here, we report a series of laparoscopic hepatic resections that were attempted without the use of hand-assistance (completely laparoscopic). Resections were performed using saline-cooled cautery (Tissue-Link Endohook) and/or hydrodissection (Erbe Helix Hydrojet). Fifteen laparoscopic hepatic resections were attempted by a single surgeon from 2002 to 2006. In each case, a nonanatomic, completely laparoscopic approach was attempted. Patients with lesions at the hepatic dome or those requiring lobectomy or hilar dissection were excluded. Fourteen of 15 cases (93%) were accomplished completely laparoscopically, while one patient required placement of a hand port. Resected tumors averaged 3.9 cm diameter. There were no bile leaks and no patient required transfusion. Average length of stay was 4.1 days (range 1-5). Complications included ileus (1) and atrial fibrillation (1). In six patients with malignancies, margins were negative and there have been no local or port recurrences. This report demonstrates the feasibility of completely laparoscopic hepatic resection using novel devices for parenchymal transaction. Hand-assist techniques remain useful as a salvage strategy or for larger resections.