Mathematical models and simulations have become an important tool in understanding the key causal relationships in normal and pathophysiological human processes. We have developed a comprehensive model of integrative human physiology called HumMod consisting of about 5000 variables describing cardiovascular, renal, respiratory, endocrine, neural and metabolic physiology. HumMod simulates the time-dependent evolution of body systems in physiological and pathological conditions. HumMod is comprised of a series of files describing the physiological variables, the mathematical relationships between them and the display characteristics of the simulations. HumMod.exe uses numerical methods for solving algebraic and differential equations, and generates screen updates and controls the simulation.
The physiological equations, variables, parameters and quantitative relationships as well as all other model details are described in XML text files. Model structure is based upon documented physiological responses from the peer-reviewed literature. Users can view time-dependent solutions and interactively alter parameters to investigate physiological responses. Pathophysiological states can be mimicked through the use of radiobuttons and sliderbars that allow alterations in basal physiological responses, such as cardiac contractility, renal artery stenosis, or altered hormone levels.
HumMod allows the user to provide clinical treatments, including pharmacological agents, placing the patient on a ventilator, administering IV fluids, or performing a blood transfusion. HumMod allows the user to adjust many characteristics of the patient's physical environment, such as temperature, humidity, and barometric pressure. Additionally users can determine physiological responses in a more in-depth basis, particularly expanding physiological parameters that are not directly measurable.
HumMod contains a highly detailed representation of physiological and pathophysiological mechanisms and provides a rich environment for understanding human physiology. HumMod can be downloaded at http://hummod.org.
Trauma injuries are the leading cause of mortality in individuals under 50 years of age in the United States, with obese patients exhibiting increased inflammation and multi-organ failure. The goal of work is to understand the mechanisms where by orthopedic trauma in the setting of obesity leads to higher incidences of acute lung injury (ALI) and acute kidney injury (AKI), the earliest and most frequently occurring components of multiple organ failure that leads to mortality.
Post-trauma hyperglycemia has been recently recognized as a risk factor that exacerbates complications, organ dysfunction, and mortality. The early hyperglycemia within the first day after trauma is a more reliable predictor of poor outcomes and mortality as compared to later increases in plasma glucose. However, intensive control of the post-trauma glucose leads to controversial results. This is because the mechanisms for early hyperglycemia following trauma and its impacts on immune responses are unclear, resulting a lack of treatments that can effectively target causal factors for early hyperglycemia with minimal side effects.
Insulin treatment is currently used for glucose control but simultaneously increases incidence of hypoglycemic episodes that can adversely affect outcomes after trauma. Importantly, insulin treatments can be more challenging in obese trauma patients, as the dosages of insulin and the responses of early glucose following insulin administration are difficult to predict and control due to the frequent presence of insulin resistance. The work within the laboratory has addressed three important questions: (1) Is the early post-trauma hyperglycemia increased in obesity and what are the mechanisms? (2) Does the early post-trauma hyperglycemia increase incidence of ALI? (3) Does the early post-trauma hyperglycemia increase incidence of AKI through which mechanisms?
We have developed a model of orthopedic trauma in the obese Zucker rat (OZ, an animal model of obesity and insulin resistance). The rodent experiments enable us to determine the pathological process of ALI and AKI, and use specific treatments to better understand the mechanisms for post-trauma hyperglycemia and its impacts on the innate immune responses. Our published study shows an increased ALI and AKI in OZ as compared to lean Zucker rats (LZ) following severe trauma. the ALI in OZ is associated with exacerbated neutrophil retention in the lung and neutrophil-derived oxidative stress, which increases pulmonary capillary filtration coefficient (Kf) and edema. The AKI is due to a ~50% decrease in glomerular filtration rate within 24 hours following the orthopedic trauma. Future studies will focus on the mechanisms responsible for the decrease in renal function following orthopedice trauma.
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