Douglas Brining

Pandemic Swine-Origin H1N1 Influenza A Virus Isolates Show Heterogeneous Virulence in Macaques

ABSTRACT The first influenza pandemic of the new millennium was caused by a newly emerged swine-origin influenza virus (SOIV) (H1N1). This new virus is characterized by a previously unknown constellation of gene segments derived from North American and Eurasian swine lineages and the absence of common markers predictive of human adaptation. Overall, human infections appeared to be mild, but an alarming number of young individuals presented with symptoms atypical for seasonal influenza. The new SOIV also showed a sustained human-to-human transmissibility and higher reproduction ratio than common seasonal viruses, altogether indicating a higher pathogenic potential for this newly emerged virus. To study the virulence of the SOIV, we used a recently established cynomolgus macaque model and compared parameters of clinical disease, virology, host responses, and pathology/histopathology with a current seasonal H1N1 virus. We here show that infection of macaques with two genetically similar but clinically distinct SOIV isolates from the early stage of the pandemic (A/Mexico/4108/2009 and A/Mexico/InDRE4487/2009) resulted in upper and lower respiratory tract infections and clinical disease ranging from mild to severe pneumonia that was clearly advanced over the mild infection caused by A/Kawasaki/UTK-4/2009, a current seasonal strain. Unexpectedly, we observed heterogeneity among the two SOIV isolates in virus replication, host transcriptional and cytokine responses, and disease progression, demonstrating a higher pathogenic potential for A/Mexico/InDRE4487/2009. Differences in virulence may explain more severe disease, as was seen with certain individuals infected with the emerged pandemic influenza virus. Thus, the nonhuman primate model closely mimics influenza in humans.

Host Response Dynamics Following Lethal Infection of Rhesus Macaques With Zaire ebolavirus

To gain further insight into the interdependent pathogenic processes in Ebola hemorrhagic fever (EHF), we have examined the dynamics of host responses in individual rhesus macaques infected with Zaire ebolavirus over the entire disease course. Examination of coagulation parameters revealed that decreased coagulation inhibitor activity triggered severe coagulopathy as indicated by prolonged coagulation times and decreased fibrinogen levels. This has been proposed as one of the significant mechanisms underlying disseminated intravascular coagulation in EHF patients. Furthermore, monitoring of expression levels for cytokines/chemokines suggested a mixed anti-inflammatory response syndrome (MARS), which indicates that a catastrophic uncontrolled immunological status contributes to the development of fatal hemorrhagic fever. These results highlight the pathological analogies between EHF and severe sepsis and not only contribute to our understanding of the pathogenic process, but will also help to establish novel postexposure treatment modalities.

An animal model for studying endoscopic ultrasound changes of early chronic pancreatitis with histologic correlation: A pilot study

BACKGROUND AND STUDY AIMS Due to the difficulty in obtaining pancreatic tissue for histology in humans, we developed an animal model for studying endoscopic ultrasound (EUS) changes of early chronic pancreatitis. This report on the animal model describes the serial changes of early chronic pancreatitis by EUS and correlates results with histology. MATERIALS AND METHODS Four 60 - 80-lb dogs were used in the study. Pancreatic EUS was performed to provide baseline images prior to any procedure. At laparotomy, a guide wire was passed into the pancreatic duct, and a 5-Fr pancreatic stent was introduced over the wire into the pancreatic duct. Animals were divided into two survival groups - 2 weeks and 4 weeks. In each group, EUS examination was performed under anesthesia to image the pancreas and then followed by euthanasia. Sequential pancreatic sections were taken from the head, body, and tail of the pancreas. EUS findings were correlated with histologic results with respect to degree of fibrosis, inflammation, and edema. RESULTS At baseline EUS, the pancreas appeared homogeneous with only a few echogenic septations and echogenic margins of the main pancreatic duct. At 2 and 4 weeks poststenting, EUS images showed the following changes: lobularity, hyper and hypoechoic foci, increased echogenic septations, visible pancreatic duct side branches, and irregular margins of the main pancreatic duct. CONCLUSIONS The dog model for chronic pancreatitis appears to be a promising method for studying sequential changes of chronic pancreatitis by EUS and correlating results with histology.