Direct association between pharyngeal viral secretion and host cytokine response in severe pandemic influenza

<p>Abstract</p> <p>Background</p> <p>Severe disease caused by 2009 pandemic influenza A/H1N1virus is characterized by the presence of hypercytokinemia. The origin of the exacerbated cytokine response is unclear. As observed previously, uncontrolled influenza virus replication could strongly influence cytokine production. The objective of the present study was to evaluate the relationship between host cytokine responses and viral levels in pandemic influenza critically ill patients.</p> <p>Methods</p> <p>Twenty three patients admitted to the ICU with primary viral pneumonia were included in this study. A quantitative PCR based method targeting the M1 influenza gene was developed to quantify pharyngeal viral load. In addition, by using a multiplex based assay, we systematically evaluated host cytokine responses to the viral infection at admission to the ICU. Correlation studies between cytokine levels and viral load were done by calculating the Spearman correlation coefficient.</p> <p>Results</p> <p>Fifteen patients needed of intubation and ventilation, while eight did not need of mechanical ventilation during ICU hospitalization. Viral load in pharyngeal swabs was 300 fold higher in the group of patients with the worst respiratory condition at admission to the ICU. Pharyngeal viral load directly correlated with plasma levels of the pro-inflammatory cytokines IL-6, IL-12p70, IFN-γ, the chemotactic factors MIP-1β, GM-CSF, the angiogenic mediator VEGF and also of the immuno-modulatory cytokine IL-1ra (p < 0.05). Correlation studies demonstrated also the existence of a significant positive association between the levels of these mediators, evidencing that they are simultaneously regulated in response to the virus.</p> <p>Conclusions</p> <p>Severe respiratory disease caused by the 2009 pandemic influenza virus is characterized by the existence of a direct association between viral replication and host cytokine response, revealing a potential pathogenic link with the severe disease caused by other influenza subtypes such as H5N1.</p

Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro

BACKGROUND: Digalloyl-resveratrol (di-GA) is a synthetic compound aimed to combine the biological effects of the plant polyhydroxy phenols gallic acid and resveratrol, which are both radical scavengers and cyclooxygenase inhibitors exhibiting anticancer activity. Their broad spectrum of activities may probably be due to adjacent free hydroxyl groups. METHODS: Protein activation and expression were analysed by western blotting, deoxyribonucleoside triphosphate levels by HPLC, ribonucleotide reductase activity by 14 C-cytidine incorporation into nascent DNA and cell-cycle distribution by FACS. Apoptosis was measured by Hoechst 33258/propidium iodide double staining of nuclear chromatin and the formation of gaps into the lymphendothelial barrier in a three-dimensional co-culture model consisting of MCF-7 tumour cell spheroids and human lymphendothelial monolayers. RESULTS: In HL-60 leukaemia cells, di-GA activated caspase 3 and dose-dependently induced apoptosis. It further inhibited cell-cycle progression in the G1 phase by four different mechanisms: rapid downregulation of cyclin D1, induction of Chk2 with simultaneous downregulation of Cdc25A, induction of the Cdk-inhibitor p21(Cip/Waf) and inhibition of ribonucleotide reductase activity resulting in reduced dCTP and dTTP levels. Furthermore, di-GA inhibited the generation of lymphendothelial gaps by cancer cell spheroid-secreted lipoxygenase metabolites. Lymphendothelial gaps, adjacent to tumour bulks, can be considered as gates facilitating metastatic spread. CONCLUSION: These data show that di-GA exhibits three distinct anticancer activities: induction of apoptosis, cell-cycle arrest and disruption of cancer cell-induced lymphendothelial disintegration. British Journal of Cancer (2010) 102, 1361-1370. doi:10.1038/sj.bjc.6605656 www.bjcancer.com (C) 2010 Cancer Research U

Cardiopulmonary and inflammatory biomarkers in heartworm disease

Abstract In heartworm disease, several biomarkers of cardiopulmonary injury and inflammatory activity have been studied during the recent years. D-dimer is a fibrin degradation product present after a clot is degraded, which has been reported to provide support for the diagnosis of pulmonary thromboembolism in heartworm disease. Furthermore, concentrations increment with increased disease severity and during the adulticide treatment. This increase in concentration has proved to be valuable. Cardiac biomarkers troponin I, myoglobin and NT-proBNP demonstrated presence of myocardial injury and heart failure, especially in chronic infections, which in some cases, slightly improve after the adulticide treatment. An acute phase response in dogs with Dirofilaria immitis, characterized by variations of acute phase proteins (APP), has been reported, indicating inflammatory processes that could contribute to disease progression. Among them, C-reactive protein (CRP) increases according to the severity of the disease; and a strong correlation between pulmonary hypertension and CRP has been observed. In cats, little work has been done to ascertain the utility of these biomarkers in feline heartworm; the only published study in D. immitis–seropositive cats reported significantly higher concentrations in positive APP serum amyloid A, haptoglobin and ceruloplasmin

Quantifying the Sensitivity of Microearthquake Slip Inversions to Station Distribution Using a Dense Nodal Array

ABSTRACT To investigate the sensitivity of slip inversions to station distribution and choice of empirical Green’s function (EGF), we examine three microearthquakes that occurred within the high-density LArge-n Seismic Survey in Oklahoma (LASSO) nodal seismic array. The LASSO array’s dense distribution of 1825 geophones provides an exceptional level of spatial and azimuthal coverage, allowing for more accurate inversions of slip than are possible with typical station distributions. The highly accurate slip inversions, in turn, allow for the exploration of the sensitivity of slip inversions to station distribution and parameter choices. We examine the effects of these choices using three well-recorded strike-slip microearthquakes (ML 1.7, 2.3, and 2.7) using an EGF method. From this analysis and the systematic testing of varied network arrangements, we find that station distributions that have uniform coverage of azimuth and distance can retrieve the overall pattern of slip, but the estimated amplitude of slip can vary by 30% for high-slip regions due to small variations in station location. In addition, we find that the distance range that accurately resolves the overall pattern of slip is the one that contains the takeoff angles of 45°–65°. Concerning azimuthal coverage, a network with &amp;gt;270° performs similarly to having complete coverage. The choice of EGF can shift the location of resolved areas of slip and their amplitude, depending on its similarity in location and radiation pattern to the target earthquake.</jats:p