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Helminth Therapy in a Murine Model of Chemically Induced ColitisHunter, Meaghan M. 06 1900 (has links)
<p> Helminth parasite infection induces a strong immune response in the host aimed at destroying the parasite and reducing any associated inflammation. In humans and rodents, this response is dominated by the Th2 cytokines and involves the activation of mast cells, B cells and eosinophils, as well as increased production of lgE. There is evidence from both murine and human studies that the helminth-induced anti-inflammatory response is also capable of protecting the host from co-existing autoimmune disease, including asthma, allergies and colitis. My hypothesis is that infection with the parasitic helminth H. diminuta can treat and/or prevent the symptoms of Th1-dominated inflammation. This anti-colitic effect is dependent on IL-10 and involves the recruitment of the alternatively activated macrophages.</p> <p> Using the dinitrobenzene sulfonic acid (DNBS) model of colitis, I examined the ability of the rat tapeworm, Hymenolepis diminuta, to reduce inflammation in a non-permissive mouse host. H. diminuta was chosen as the ideal candidate for treating intestinal disease because it is non-invasive, does not have hooks or teeth which can damage the host, and can be easily maintained in the laboratory and controlled during experimental infection. Mice that received DNBS alone developed colitis within 72 hours. Mice that had been previously infected with five H. diminuta larvae were significantly protected from the colitis, as measured by reduced clinical disease and histological damage scores as well as reduced levels of myeloperoxidase (MPO) from colonic tissue samples. It was also determined that the anticolitic effect was dependent on a viable parasite infection. Infection with H. diminuta induced an increase in colonic IL-10 mRNA and IL-10 secretion by stimulated splenocytes - when IL-10 was blocked by administration of an anti-IL-10 antibody, the anticolitic effect of H. diminuta infection was reduced. H. diminuta infection also induced increased expression of the alternatively activated macrophage (AAM) markers arginase 1 and FIZZ1. Treatment with in vitro-derived AAMs reduced the symptoms of DNBS-colitis.</p> <p> The effect of H. diminuta infection on oxazolone colitis, a chemically induced colitis characterized by increases in IL-4 and IL-13, was also examined. Infection with H. diminuta induced a significant increase in inflammation and inhibited recovery from oxazolone-colitis. Increases in IL-5 and eosinophils were also observed. Further examination revealed that increased IL-5, induced by administration of an adenovirus carrying the IL-5 gene, had a deleterious impact on the oxazolone colitis, exacerbating inflammation and increasing eosinophilia.</p> <p> While the idea of helminth therapy may be unappealing, there is increasing interest in the use of helminth parasites for the treatment of inflammatory disease. There is some concern, however, that the Th2 response induced by H. diminuta infection could exacerbate some disorders involving increases in the Th2 cytokines. Thus, while this therapy may be beneficial for most, careful characterization of the immunological basis of any pre-existing disorders would be necessary in order to avoid any harmful side-effects.</p> / Thesis / Doctor of Philosophy (PhD)
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Surgical Stress Promotes the Development of Cancer Metastases by a Coagulation-Dependent Mechanism in a Murine ModelSeth, Rashmi 07 September 2011 (has links)
Surgery precipitates a hypercoagulable state and has been shown to increase the development of cancer metastases in animal models, however mechanism(s) responsible for this are largely unknown. We hypothesize that the prometastatic effect of surgery may be secondary to postoperative hypercoagulable state. Surgical stress was induced in mice by partial hepatectomy or nephrectomy, preceded by intravenous injection of CT26-LacZ or B16F10-LacZ cells to establish pulmonary metastases with or without perioperative anticoagulation and their lung tumor cell emboli (TCE) were quantified. Fibrinogen and platelets were fluorescently labeled prior to surgical stress to evaluate TCE-associated fibrin and platelet clots. Surgery significantly increased metastases while anticoagulation with five different agents attenuated this effect. Fibrin and platelet clots were associated with TCE significantly more frequently in surgically stressed mice. Surgery promotes the formation of fibrin and platelet clots around TCE and this appears to be the mechanism for the increase in metastases seen following surgery.
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Surgical Stress Promotes the Development of Cancer Metastases by a Coagulation-Dependent Mechanism in a Murine ModelSeth, Rashmi 07 September 2011 (has links)
Surgery precipitates a hypercoagulable state and has been shown to increase the development of cancer metastases in animal models, however mechanism(s) responsible for this are largely unknown. We hypothesize that the prometastatic effect of surgery may be secondary to postoperative hypercoagulable state. Surgical stress was induced in mice by partial hepatectomy or nephrectomy, preceded by intravenous injection of CT26-LacZ or B16F10-LacZ cells to establish pulmonary metastases with or without perioperative anticoagulation and their lung tumor cell emboli (TCE) were quantified. Fibrinogen and platelets were fluorescently labeled prior to surgical stress to evaluate TCE-associated fibrin and platelet clots. Surgery significantly increased metastases while anticoagulation with five different agents attenuated this effect. Fibrin and platelet clots were associated with TCE significantly more frequently in surgically stressed mice. Surgery promotes the formation of fibrin and platelet clots around TCE and this appears to be the mechanism for the increase in metastases seen following surgery.
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Surgical Stress Promotes the Development of Cancer Metastases by a Coagulation-Dependent Mechanism in a Murine ModelSeth, Rashmi 07 September 2011 (has links)
Surgery precipitates a hypercoagulable state and has been shown to increase the development of cancer metastases in animal models, however mechanism(s) responsible for this are largely unknown. We hypothesize that the prometastatic effect of surgery may be secondary to postoperative hypercoagulable state. Surgical stress was induced in mice by partial hepatectomy or nephrectomy, preceded by intravenous injection of CT26-LacZ or B16F10-LacZ cells to establish pulmonary metastases with or without perioperative anticoagulation and their lung tumor cell emboli (TCE) were quantified. Fibrinogen and platelets were fluorescently labeled prior to surgical stress to evaluate TCE-associated fibrin and platelet clots. Surgery significantly increased metastases while anticoagulation with five different agents attenuated this effect. Fibrin and platelet clots were associated with TCE significantly more frequently in surgically stressed mice. Surgery promotes the formation of fibrin and platelet clots around TCE and this appears to be the mechanism for the increase in metastases seen following surgery.
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Evaluating the healing potential of PTH on femoral shaft fractures in B6, C3, and AJ miceFoster, Pete 08 April 2016 (has links)
Parathyroid hormone is a vital mediator of bone metabolism and studies have shown that exogenous treatment can enhance the fracture repair process in murine models. Bone remodeling is a complex process that necessitates multiple molecular and cellular interactions that are affected by genetic variations. These differences contribute to both histological and whole organ level differences of fracture healing. This study was performed to determine the effect of genetic variability of fracture healing in mice treated with parathyroid hormone during two time windows. The first window was the first 14-day period post fracture associated with chondrogensis and the second was the day 15 to day 28 post fracture, which is associated with osteogenesis. Three inbred strains of mice A/J (AJ), C57BL/6J (B6), and C3H/HeJ (C3) that have material and structural differences in bone quality were given Femoral shaft fractures and healing was evaluated at different time points post fracture using quantitative real-time polymerase chain reaction (qRT-PCR) and qualitative radiographic analysis. Chondrogenic genes Sox9, ColIIa, aggrecan, and ColXa and osteogenic genes ostrix, osteocalcin, BSP, and DMP1 were examined. The temporal analysis of mRNA expression revealed that PTH treatment given in the first 14 days post fracture enhanced osteogenic and chondrogenic expression in B6 mice, but hindered expression in AJ mice. Treatment with PTH from post fracture day 14 to day 28 greatly affected the osteogenic expression of B6 mice, but had little affect on other animals. Radiographic analysis showed that each strain presents callus formation at approximately day 7 and reaches maximum size at day 21 post fracture. Additionally B6 mice appear with the largest callus and AJ the smallest. Taken together, these results are consistent with past studies in showing that different strains of mice express a unique temporal and mRNA expression pattern of chondrogenic and osteogenic differentiation. Furthermore, these variations affect the biomechanical properties of the fracture callus during bone remodeling.
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Functional analysis of type 2 diabetes associated transcriptsRichards, Hannah B. January 2014 (has links)
Genome wide association studies (GWAS) have transformed the study of the heritability of complex diseases such as type 2 diabetes (T2D), with the current tally of established risk loci close to ninety. Each of these loci has the potential to offer novel insights into the biology of this disease, and opportunities for clinical exploitation. However, the complexity of T2D has often frustrated efforts to achieve these functional and translational advances. This thesis aims to delve into the functional characterisation of two known susceptibility loci, KLF14 and ADCY5, and describe findings relevant to disease pathology. KLF14 and ADCY5 are two loci associated with T2D predisposition working through disparate mechanisms. Variants at the maternally imprinted KLF14 locus are associated with measures of insulin resistance and expression data has implicated KLF14 as a master regulator of genes in adipose tissue. In contrast, variation at the ADCY5 locus is associated with impaired beta cell function, high fasting glucose, and low birth weight suggesting ADCY5 is having an effect on insulin secretion. In this thesis, ENU mouse models of these two genes are investigated functionally to elucidate more about the pathology of common human variation at these loci. A mouse model was derived with an ENU point mutation at Adcy5 Y1064C. Phenotyping of this model revealed improved oral glucose tolerance, and secretion studies from isolated islet cells demonstrated impaired glucagon secretion from mice homozygous for the Y1064C mutation in the presence of adrenaline. These results suggest that Adcy5 is involved in glucagon regulation in the alpha cell. The Adcy5 Y1064C confers a protective effect against hyperglycaemia in mouse indicating that the T2D risk allele at the ADCY5 locus in humans may have the opposite direction of effect. A mouse model containing the ENU point mutation Klf14 R238L predicted to be disruptive to KLF14 protein function showed no significant difference in body weight, measures of insulin resistance, or blood cholesterol. However, expression of several genes associated in trans with variation near KLF14 in humans was changed in adipose tissue and skeletal muscle when the R238L mutation was inherited maternally compared to mice which had inherited the mutation paternally or carried two wild type alleles. This result suggests a mechanism by which Klf14 is regulating genes across metabolic tissues.
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Surgical Stress Promotes the Development of Cancer Metastases by a Coagulation-Dependent Mechanism in a Murine ModelSeth, Rashmi January 2011 (has links)
Surgery precipitates a hypercoagulable state and has been shown to increase the development of cancer metastases in animal models, however mechanism(s) responsible for this are largely unknown. We hypothesize that the prometastatic effect of surgery may be secondary to postoperative hypercoagulable state. Surgical stress was induced in mice by partial hepatectomy or nephrectomy, preceded by intravenous injection of CT26-LacZ or B16F10-LacZ cells to establish pulmonary metastases with or without perioperative anticoagulation and their lung tumor cell emboli (TCE) were quantified. Fibrinogen and platelets were fluorescently labeled prior to surgical stress to evaluate TCE-associated fibrin and platelet clots. Surgery significantly increased metastases while anticoagulation with five different agents attenuated this effect. Fibrin and platelet clots were associated with TCE significantly more frequently in surgically stressed mice. Surgery promotes the formation of fibrin and platelet clots around TCE and this appears to be the mechanism for the increase in metastases seen following surgery.
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Biofilm producing Staphylococcus epidermidis (RP62A strain) inhibits osseous integration without osteolysis and histopathology in a murine septic implant model / マウスインプラント感染モデルにおいてバイオフィルムを産生する表皮ブドウ球菌・RP62A株は骨溶解を生じず骨結合を阻害するTomizawa, Takuya 23 March 2020 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22331号 / 医博第4572号 / 新制||医||1041(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中川 一路, 教授 長尾 美紀, 教授 秋山 芳展 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Elucidating the Immunoactivity of a Goat Serum PeptideParker, Todd Avery 11 May 2002 (has links)
The purpose of these studies was to determine if an immunomodulator was present in caprine serum. Controlled studies demonstrated that CSF-I, material fractionated from caprine serum possessed an immunomodulatory compound. Caprine serum was further fractionated into it?s peptidic components and a small contaminant of immunoglobulin G and albumin (Caprine serum fraction - immunomodulator 2, or CSF-I2). This was refined to a three peptidic isolate collectively identified as tri-peptidic immunostimulant or TPI. CSF-I2 does not possess antibacterial capabilities (as typically characteristic of a cationic peptide or defensin), does not contain a level of endotoxin sufficient to promote a pyrogenic response, and its functional ability to improve animal survival after an infectious challenge does not reside with molecular weight components greater than 10 kilodaltons, effectively excluding the immunoglobins, albumin, cytokines, and collectins. CSF-I2 was able to significantly reduce the mortality observed in chickens (from 80% to 13%) infected with Pasteurella multocida (Willeford et al., 2000), in mice (from 83% to 13.3%) infected with Salmonella typhimurium, and in canines (from 50% to 9.8%) diagnosed with parvovirus. CSF-I2 may well prove to provide prophylactic and therapeutic health benefits to humans. CSF-I2 may effectively combat pathogenesis when used as either an adjunct with conventional therapy (e.g., antibiotics) or when provided as the primary medicant.
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The Skeletal Phenotype Of The Kk/Ay Murine Model Of Type 2 DiabetesChowdhury, Nusaiba Nahola 08 1900 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Type-2-diabetes (T2D) is a progressive metabolic disease characterized by insulin resistance and β-cell dysfunction leading to persistent hyperglycemia. It is a multisystem disease that causes deterioration of multiple organ systems and obesity. Of interest, T2D affects the urinary system and is the leading cause of kidney disease. Both T2D and chronic kidney negatively impacts the skeletal system and increases fracture incidence in patients. Therefore, it is important to establish an animal model that captures the complex multiorgan effects that is common in T2D. In this study, we characterized the metabolic phenotype of the KK/Ay mouse model, a polygenic mutation model of T2D. We concluded that KK/Ay mice closely mimic T2D and are hyperglycemic, hyperinsulinemic and insulin resistant. KK/Ay mice have also had worsened kidney function as supported by elevated levels of blood urea nitrogen, phosphorous, creatinine, and calcium in plasma exhibiting the kidney’s inefficiency in clearing waste from the body. Even though we were able to confirm a metabolic phenotype for T2D and diabetic nephropathy, the skeletal effects of the disease were minimal and major differences in bone physiology were driven by sex differences. This study offered valuable insight into preliminary endpoints for the KK/Ay mouse mode that will decide the direction for future use of this model. We plan to use older mice in future studies to allow a longer time for skeletal effects to more prominently manifest.
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