Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / "August 2002." Typescript. Vita. Includes bibliographical references (leaves 95-109).

Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 95-109). Also available on the Internet.

Typical Hemolytic Uremic Syndrome (HUS) presents as a complication of infection with Shiga-toxin producing E. coli (STEC). While there are many animal models for infection, few show true signs of HUS. Additionally, these models differ greatly from the clinical presentation that affects small children and elderly populations. Immunohistochemical assays of tissues from a known HUS model may provide insight into molecular changes associated with the condition, particularly as it pertains to clotting factors. In this study, tissue factor (TF) was investigated in the kidneys of non-human primates previously injected with Shiga-Toxin 2 (STX2). The animals’ condition was indicative of HUS through three main clinical signs: thrombocytopenia, hemolytic anemia and decreased kidney function. Tissue factor antigen in the kidneys varies between animals that exhibited HUS when compared to those that had recovered or treated with anti-STX2 antibody. Overall, tissue factor is strongly detected in the renal tubules of those afflicted with HUS; tissue factor was not strongly expressed in the glomerular epithelial space, as it was in recovered, clinically healthy animals. This suggests a change throughout the time course of disease and recovery. Investigating tissue factor’s role, if any, in the pathology of the disease could lead to new therapeutics. Although many types of treatments have been suggested and tried, the primary clinical procedure is to administer fluids and allow symptoms to subside. With increasing knowledge about HUS through studies like these, we can hope to gain insight into potent therapeutics and therefore, save lives associated with typical HUS.

Uremic pruritus remains one of the most frustrating and potentially disabling symptoms in patients with endstage renal disease. It affects up to 90% of patients on dialysis. Several hypotheses have been postulated for the possible underlying etiology, but none is conclusive. Aside from kidney transplantation, which is the only definitive treatment, therapeutic approaches have largely been empirical, and no firm evidence-based treatments are available. The main goal of therapy remains to minimize the severity of pruritus and improve the quality of life especially among those who are not transplantation candidates or are waiting for surgery.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online as viewed 8/06/2009 through Digital Dissertations.

This thesis is concerned with applying engineering principles to the use of polymeric nanoporous adsorbents for use in blood purification to obtain original knowledge. Styrene divinylbenzene copolymer nanoporous adsorbents offer a potential means to remove middle molecular (MM) sized molecules when in direct contact with blood. (Continues...).

Μελετήθηκε η επίδραση ουραιμικού ορού στο σύστημα των μεταλλοπρωτεϊνασών MMP-2 και MMP-9 και των αναστολέων τους TIMP-1 και TIMP-2 καθώς και σε βασικές βιολογικές δράσεις των ενδοθηλιακών κυττάρων σε καλλιέργειες HUVEC. Ο ορός συλλέχθηκε από ασθενείς που υποβάλλονταν σε συνεδρίες αιμοκάθαρσης (πριν και μετά τις συνεδρίες). Διαπιστώθηκε πως ο ουραιμικός ορός μειώνει την ικανότητα πολλαπλασιασμού, μετανάστευσης και επούλωσης τρύματος, ενώ επάγει την απόπτωση. Επιπλέον, ο ουραιμικός ορός επάγει τις μεταλλοπρωτεϊνάσες MMP-2 και MMP-9, καταστέλλει τους αναστολείς τους TIMP-1 και TIMP-2 και μειώνει την παραγωγή κολλαγόνου τύπου IV και ελαστίνης. / -

Sub-acute/chronic inflammatory diseases are often associated with altered inflammatory response, leading to increased host vulnerability to secondary inflammatory challenges. In the first study, by employing streptozotocin (STZ)-induced diabetes in mice, we further investigate mechanisms leading to enhanced polymorphonuclear leukocytes (PMN) response under hyperglycemia. We show that existence of a proinflammatory state associated with broad increases of macrophages in various organs plays a dominant role in promoting PMN response in diabetic mice. Studies of PMN infiltration during zymosan-induced peritonitis reveal that hyperglycemia enhances PMN recruitment through increasing F4/80+ macrophages in the peritoneal cavity. Insulin reversal of hyperglycemia reduces peritoneal macrophage numbers and ameliorates PMN infiltration. Significantly increased macrophages are also observed in the liver, kidneys, and intestines under hyperglycemia, and are attributable to exacerbated nephropathy and colitis when respective inflammatory conditions are induced. We also find that significant monocytosis of inflammatory F4/80+Gr-1+ monocytes from the spleen and macrophage proliferation in situ synergistically contribute to the increased macrophage population under hyperglycemia. In conclusion, our results demonstrate that STZ-induced hyperglycemic/diabetic mice develop a systemic proinflammatory state mediated by broad infiltration of macrophages. In the second study, we focus on the identification of the carrier that binds to and delivers Shiga toxin 2(Stx2) to the target organ causing hemolytic uremic syndrome (HUS). By employing a murine HUS model through co-injection of LPS-Stx2, we show that, adoptive transfer of CD11b+ leukocytes, but not CD11b- leukocytes, RBC, platelets or plasma, isolated from mice with HUS induces HUS in healthy recipients. Interestingly, we find that LPS priming of mice significantly promotes CD11b+ leukocytes binding to Stx2. Compared to CD11b+ leukocytes from mice without LPS priming, CD11b+ leukocytes isolated from mice after LPS priming demonstrate higher frequencies of toxin binding and augmented potency to induce HUS. In sum, our results demonstrate peripheral CD11b+ myeloid leukocytes act as effective Stx2 carriers that deliver toxin to kidneys causing HUS and that LPS-induced inflammation enhances the carrier capacity and aggravates HUS.

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