Title: Detection of aberrant hippocampal mossy fiber connections: Ex vivo mesoscale diffusion MRI and microtractography with histological validation in a patient with uncontrolled temporal lobe epilepsy
Authors: Vasudeva K, Vodovotz Y, Azhar N, Barclay D, Janjic JM, Pollock JA.
Title: In vivo and systems biology studies implicate IL-18 as a central mediator in chronic pain.
Summary: Inflammation is associated with peripheral neuropathy, however the interplay among cytokines, chemokines, and neurons is still unclear. We hypothesized that this neuroinflammatory interaction can be defined by computational modeling based on the dynamics of protein expression in the sciatic nerve of rats subjected to chronic constriction injury. Using Dynamic Bayesian Network inference, we identified interleukin (IL)-18 as a central node associated with neuropathic pain in this animal model. Immunofluorescence supported a role for inflammasome activation and induction of IL-18 at the site of injury. Combined in vivo and in silico approaches may thus highlight novel targets in peripheral neuropathy.
Authors: Brown D, Namas RA, Almahmoud K, Zaaqoq A, Sarkar J, Barclay DA, Yin J, Ghuma A, Abboud A, Constantine G, Nieman G, Zamora R, Chang SC, Billiar TR, Vodovotz Y.
Title: Trauma in silico: Individual-specific mathematical models and virtual clinical populations
Summary: Trauma-induced critical illness is driven by acute inflammation, and elevated systemic interleukin-6 (IL-6) after trauma is a biomarker of adverse outcomes. We constructed a multicompartment, ordinary differential equation model that represents a virtual trauma patient. Individual-specific variants of this model reproduced both systemic inflammation and outcomes of 33 blunt trauma survivors, from which a cohort of 10,000 virtual trauma patients was generated. Model-predicted length of stay in the intensive care unit, degree of multiple organ dysfunction, and IL-6 area under the curve as a function of injury severity were in concordance with the results from a validation cohort of 147 blunt trauma patients. In a subcohort of 98 trauma patients, those with high-IL-6 single-nucleotide polymorphisms (SNPs) exhibited higher plasma IL-6 levels than those with low IL-6 SNPs, matching model predictions. Although IL-6 could drive mortality in individual virtual patients, simulated outcomes in the overall cohort were independent of the propensity to produce IL-6, a prediction verified in the 98-patient subcohort. In silico randomized clinical trials suggested a small survival benefit of IL-6 inhibition, little benefit of IL-1Î² inhibition, and worse survival after tumor necrosis factor-Î± inhibition. This study demonstrates the limitations of extrapolating from reductionist mechanisms to outcomes in individuals and populations and demonstrates the use of mechanistic simulation in complex diseases.