Transcriptional Profiling in Pathogenic and Non-Pathogenic SIV Infections Reveals Significant Distinctions in Kinetics and Tissue Compartmentalization

Simian immunodeficiency virus (SIV) infection leads to AIDS in experimentally infected macaques, whereas natural reservoir hosts exhibit limited disease and pathology. It is, however, unclear how natural hosts can sustain high viral loads, comparable to those observed in the pathogenic model, without developing severe disease. We performed transcriptional profiling on lymph node, blood, and colon samples from African green monkeys (natural host model) and Asian pigtailed macaques (pathogenic model) to directly compare gene expression patterns during acute pathogenic versus non-pathogenic SIV infection. The majority of gene expression changes that were unique to either model were detected in the lymph nodes at the time of peak viral load. Results suggest a shift toward cellular stress pathways and Th1 profiles during pathogenic infection, with strong and sustained type I and II interferon responses. In contrast, a strong type I interferon response was initially induced during non-pathogenic infection but resolved after peak viral load. The natural host also exhibited controlled Th1 profiles and better preservation of overall cell homeostasis. This study identified gene expression patterns that are specific to disease susceptibility, tissue compartmentalization, and infection duration. These patterns provide a unique view of how host responses differ depending upon lentiviral infection outcome

Effects of branching spatial structure and life history on the asymptotic growth rate of a population

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Theoretical Ecology 3 (2010): 137-152, doi:10.1007/s12080-009-0058-0.The dendritic structure of a river network creates directional dispersal and a hierarchical arrangement of habitats. These two features have important consequences for the ecological dynamics of species living within the network.We apply matrix population models to a stage-structured population in a network of habitat patches connected in a dendritic arrangement. By considering a range of life histories and dispersal patterns, both constant in time and seasonal, we illustrate how spatial structure, directional dispersal, survival, and reproduction interact to determine population growth rate and distribution. We investigate the sensitivity of the asymptotic growth rate to the demographic parameters of the model, the system size, and the connections between the patches. Although some general patterns emerge, we find that a species’ mode of reproduction and dispersal are quite important in its response to changes in its life history parameters or in the spatial structure. The framework we use here can be customized to incorporate a wide range of demographic and dispersal scenarios.Funding for this work came from the James S. McDonnell Foundation (EEG, HJL, WFF). MGN was supported by grants from the National Science Foundation (CMG-0530830, OCE-0326734, ATM-0428122)

R5-SHIV Induces Multiple Defects in T Cell Function during Early Infection of Rhesus Macaques Including Accumulation of T Reg Cells in Lymph Nodes

Background: HIV-1 is a pathogen that T cell responses fail to control. HIV-1gp120 is the surface viral envelope glycoprotein that interacts with CD4 T cells and mediates entry. HIV-1gp120 has been implicated in immune dysregulatory functions that may limit anti-HIV antigen-specific T cell responses. We hypothesized that in the context of early SHIV infection, immune dysregulation of antigen-specific T-effector cell and regulatory functions would be detectable and that these would be associated or correlated with measurable concentrations of HIV-1gp120 in lymphoid tissues. Methods: Rhesus macaques were intravaginally inoculated with a Clade C CCR5-tropic simian-human immunodeficiency virus, SHIV-1157ipd3N4. HIV-1gp120 levels, antigen-specificity, levels of apoptosis/anergy and frequency and function of Tregs were examined in lymph node and blood derived T cells at 5 and 12 weeks post inoculation. Results/Conclusions: We observed reduced responses to Gag in CD4 and gp120 in CD8 lymph node-derived T cells compared to the peripheral blood at 5 weeks post-inoculation. Reduced antigen-specific responses were associated with higher levels of PD-1 on lymph node-derived CD4 T cells as compared to peripheral blood and uninfected lymph node-derived CD4 T cells. Lymph nodes contained increased numbers of Tregs as compared to peripheral blood, which positively correlated with gp120 levels; T regulatory cell depletion restored CD8 T cell responses to Gag but not to gp120. HIV gp120 was also able to induce T regulatory cell chemotaxis in a dose-dependent, CCR5-mediated manner. These studies contribute to our broader understanding of the ways in which HIV-1 dysregulates T cell function and localization during early infection

Critical Loss of the Balance between Th17 and T Regulatory Cell Populations in Pathogenic SIV Infection

Chronic immune activation and progression to AIDS are observed after SIV infection in macaques but not in natural host primate species. To better understand this dichotomy, we compared acute pathogenic SIV infection in pigtailed macaques (PTs) to non-pathogenic infection in African green monkeys (AGMs). SIVagm-infected PTs, but not SIVagm-infected AGMs, rapidly developed systemic immune activation, marked and selective depletion of IL-17-secreting (Th17) cells, and loss of the balance between Th17 and T regulatory (Treg) cells in blood, lymphoid organs, and mucosal tissue. The loss of Th17 cells was found to be predictive of systemic and sustained T cell activation. Collectively, these data indicate that loss of the Th17 to Treg balance is related to SIV disease progression

Image-Based 3-Dimensional Characterization of Laryngotracheal Stenosis in Children

Objectives Describe a technique for the description and classification of laryngotracheal stenosis in children using 3-dimensional reconstructions of the airway from computed tomography (CT) scans. Study Design Cross-sectional. Setting Academic tertiary care children’s hospital. Subjects and Methods Three-dimensional models of the subglottic airway lumen were created using CT scans from 54 children undergoing imaging for indications other than airway disease. The base lumen models were deformed in software to simulate subglottic airway segments with 0%, 25%, 50%, and 75% stenoses for each subject. Statistical analysis of the airway geometry was performed using metrics extracted from the lumen centerlines. The centerline analysis was used to develop a system for subglottic stenosis assessment and classification from patient-specific airway imaging. Results The scaled hydraulic diameter gradient metric derived from intersectional changes in the lumen can be used to accurately classify and quantitate subglottic stenosis in the airway based on CT scan imaging. Classification is most accurate in the clinically relevant 25% to 75% range of stenosis. Conclusions Laryngotracheal stenosis is a complex diagnosis requiring an understanding of the airway lumen configuration, anatomical distortions of the airway framework, and alterations of respiratory aerodynamics. Using image-based airway models, we have developed a metric that accurately captures subglottis patency. While not intended to replace endoscopic evaluation and existing staging systems for laryngotracheal stenosis, further development of these techniques will facilitate future studies of upper airway computational fluid dynamics and the clinical evaluation of airway disease

Image-Based 3-Dimensional Characterization of Laryngotracheal Stenosis in Children

Objectives Describe a technique for the description and classification of laryngotracheal stenosis in children using 3-dimensional reconstructions of the airway from computed tomography (CT) scans. Study Design Cross-sectional. Setting Academic tertiary care children’s hospital. Subjects and Methods Three-dimensional models of the subglottic airway lumen were created using CT scans from 54 children undergoing imaging for indications other than airway disease. The base lumen models were deformed in software to simulate subglottic airway segments with 0%, 25%, 50%, and 75% stenoses for each subject. Statistical analysis of the airway geometry was performed using metrics extracted from the lumen centerlines. The centerline analysis was used to develop a system for subglottic stenosis assessment and classification from patient-specific airway imaging. Results The scaled hydraulic diameter gradient metric derived from intersectional changes in the lumen can be used to accurately classify and quantitate subglottic stenosis in the airway based on CT scan imaging. Classification is most accurate in the clinically relevant 25% to 75% range of stenosis. Conclusions Laryngotracheal stenosis is a complex diagnosis requiring an understanding of the airway lumen configuration, anatomical distortions of the airway framework, and alterations of respiratory aerodynamics. Using image-based airway models, we have developed a metric that accurately captures subglottis patency. While not intended to replace endoscopic evaluation and existing staging systems for laryngotracheal stenosis, further development of these techniques will facilitate future studies of upper airway computational fluid dynamics and the clinical evaluation of airway disease

Contribution of age and gender to outcome of blunt splenic injury in adults: multicenter study of the eastern association for the surgery of trauma.

BACKGROUND: The purpose of this study was to examine the contribution of age and gender to outcome after treatment of blunt splenic injury in adults. METHODS: Through the Multi-Institutional Trials Committee of the Eastern Association for the Surgery of Trauma (EAST), 1488 adult patients from 27 trauma centers who suffered blunt splenic injury in 1997 were examined retrospectively. RESULTS: Fifteen percent of patients were 55 years of age or older. A similar proportion of patients \u3e or = 55 went directly to the operating room compared with patients \u3c 55 (41% vs. 38%) but the mortality for patients \u3e or = 55 was significantly greater than patients \u3c 55 (43% vs. 23%). Patients \u3e or = 55 failed nonoperative management (NOM) more frequently than patients \u3c 55 (19% vs. 10%) and had increased mortality for both successful NOM (8% vs. 4%, p \u3c 0.05) and failed NOM (29% vs. 12%, p = 0.054). There were no differences in immediate operative treatment, successful NOM, and failed NOM between men and women. However, women \u3e or = 55 failed NOM more frequently than women \u3c 55 (20% vs. 7%) and this was associated with increased mortality (36% vs. 5%) (both p \u3c 0.05). CONCLUSION: Patients \u3e or = 55 had a greater mortality for all forms of treatment of their blunt splenic injury and failed NOM more frequently than patients \u3c 55. Women \u3e or = 55 had significantly greater mortality and failure of NOM than women \u3c 55