Thesis (M.D.)--University of Pennsylvania, 1800. / "An inaugural dissertation, for the degree of Doctor of Medicine; submitted to the examination of the Rev. John Ewing, S.T.P. provost; the trustees & medical faculty, of the University of Pennsylvania, on the thirty-first of May 1800"--P. [3]. Signatures: [A]⁴ B-G⁴ (G4 blank). Not in Blake. Film 633 reel 88 is part of Research Publications Early American Medical Imprints collection (RP reel 88, no. 1758). DNLM

Simulation of fracture in ductile materials is a challenging problem, since it typically occurs at length scales that are orders of magnitude smaller than that of the structures in which the fracture is occurring and, hence, difficult to resolve . One approach is to avoid modelling the micro-mechanics of ductile fracture by describing the macroscopic effects of fracture using damage parameters. Damage in metals can be defined as a measure of discontinuous deformation of a body. Many numerical models include some measure of damage to predict when a material will fracture under certain conditions, however there is little consensus as to what measures and parameters will accurately predict the onset of fracture. Most notably, the effect of strain rate at the point of fracture is significant and must be taken into account. The literature indicates that in the quasistatic regime where inertial effects are negligible, an increase in strain rate increases the strain at fracture. However, the research conducted in this dissertation suggests the opposite is true. The aim of this research is to conduct further high strain rate ductile damage experiments so as to extend the available data set, and develop a pragmatic damage model to relate the plastic strain at fracture to material parameters such as triaxiality, lode angle and strain rate in a specimen, which is verified using experiments performed under various loading conditions and strain rates.

The triple antibiotic formulation, known as anti-MAP therapy, exhibits unique synergistic antimicrobial activity and should be effective for treatment of Crohn's disease (CD) associated with Mycobacterium avium subspecies paratuberculosis (MAP). The absence of MAP detection in some CD cases may be linked to poor diagnostics or lack of association with the disease. To understand the therapeutic response of some CD patients to anti-MAP therapy in absence of MAP detection, the immunomodulatory potency of anti-MAP therapy and its major ingredients, clarithromycin (CLA) and rifabutin (RIF), in THP-1, Caco-2, and Jurkat T-cells were investigated. Anti-MAP formulation at 2.0 µg/mL decreased MAP viability in macrophages by 18-fold over 72 h. Additionally, M1/M2 macrophage polarization ratio was reduced by 6.7-fold, and expression and protein levels of TNF-a and IL-6 were reduced by 2.9-fold, whereas IL-10 increased by 5.0-fold in these cells. Mechanistically, the effect of anti-MAP formulation on NF-kB activation was dose-dependent and decreased to 13.4% at 2.0 µg/mL. Anti-MAP therapy also reversed the pro-inflammatory response in lipopolysaccharide (LPS)-induced macrophages, which shows that the anti-inflammatory effect of the treatment is not just due to a decrease in MAP viability. Furthermore, this study shows that anti-MAP therapy exhibits anti-cytotoxic effects in Caco-2 monolayers infected with MAP or treated with dextran sodium sulfate (DSS). Anti-MAP therapy decreased T-cell proliferation by up to 4.8-fold following treatment with phytohemagglutinin (PHA) or MAP purified protein derivative (PPD). Overall, the data demonstrate that anti-MAP therapy plays a significant role in modulating and eliciting a protective immune response in macrophages, endothelial cells, and T lymphocytes, even in absence of infection. This may explain the therapeutic response of some CD patients to treatment, even in absence of MAP detection, infection, or total eradication. The study supports anti-MAP therapy as an alternate treatment option for CD, especially in absence of reliable MAP diagnostics.

published_or_final_version / Physics / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Physics / Doctoral / Doctor of Philosophy

published_or_final_version / Physics / Doctoral / Doctor of Philosophy

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