Ischemic stroke is defined as a blockage or reduced flow of blood to select areas of brain tissue due to either plaque formation or buildup of blood clots in the small blood vessels. A characteristic of sickle cell anemic patients is the potential for them to experience a similar type of blockage due to the sticky nature of the sickled red blood cells as well as defective oxygen delivery to the brain. Because of this similarity, sickle cell anemia may represent a good animal research model for therapeutic intervention based on stroke models. In recent studies, Granulocyte-Colony Stimulating Factor (GCSF), has been shown to exhibit a robust range of neuroprotective properties against neurological disorders including ischemic stroke through preservation of the endoplasmic reticulum (ER) by modulating various ER stress pathways. Through cognitive deficit analysis in the form of behavioral and locomotor experiments in addition to in situ biomarker analysis by way of western blotting and immunohistochemistry, we found that G-CSF gene therapy exhibited neurogenic and neuroprotective effects in ischemic mouse models and could possibly serve as a good therapy for other diseases that share similar pathology to stroke. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2021. / FAU Electronic Theses and Dissertations Collection

Anaemia in chronic kidney disease (CKD) mostly results from a decrease in the production of erythropoietin (EPO) by the failing kidney. CKD progression requires treatment with erythropoiesis-stimulating agents and iron supplementation to ensure sufficient erythrocyte production. Best clinical practice guidelines should be adhered to in managing CKD to reduce morbidity and mortality related to anaemia associated cardiovascular disease. Likewise, guideline deviations create an increased strain on the resources of the treatment facility. It is uncertain to which extent these guidelines are followed by Nephrology Units in the public healthcare sector, or whether the documented international trends are prevalent locally due to the paucity of local data, and therefore further investigation is warranted. This study aimed to assess treatment trends in managing anaemia in CKD patients at the Steve Biko Academic Hospital (SBAH). Files of patients receiving treatment at the SBAH Nephrology Unit between 2 January 2018 - 31 August 2018 were reviewed. Only individuals with stage 5 CKD receiving either haemodialysis, or peritoneal dialysis were included, while those with less than three months’ treatment were excluded. Measured variables included demographical information, current EPO treatment and/or iron supplementation regimens versus serum haemoglobin/iron levels and quantity of administered blood products. Ninety-seven patients met the inclusion criteria. Haemodialysis accounted for 43% (n = 42), and peritoneal dialysis 57% (n = 55). Intergroup comparison between the number of results where both haemoglobin and iron were within the target range versus the number of results where both parameters fell outside the target range yielded a significant difference (p = 0.0031). Patients receiving peritoneal dialysis reached serum haemoglobin and iron levels closer to normal target values compared to those receiving haemodialysis. Managing anaemia in CKD is a complex process. More stringent iron control, especially for patients receiving haemodialysis, including the administration of long-acting EPO preparations once a month, is proposed. The latter will contribute to the improvement of clinical outcomes of patients with CKD. Keywords: Chronic kidney disease, anaemia, erythropoiesis stimulating agent, haemoglobin, iron / Dissertation (MSc (Pharmacology))--University of Pretoria, 2020. / Pharmacology / MSc (Pharmacology) / Unrestricted

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Recent studies have shown that postmenopausal follicle stimulating hormone (FSH) levels may be predictive of future cardiovascular disease risk. However, little is known about postmenopausal FSH levels, including the level of variation between women and factors associated with this variation. We assessed the relationship of multiple reproductive factors with FSH levels among 588 postmenopausal women in the Kuopio Ischemic Heart Disease Risk Factor Study. Participants were aged 53 to 73 years and not using hormone therapy at baseline (1998-2001). Reproductive factors were assessed at baseline, along with FSH levels. After adjustment for sex steroids, adiposity measures, plasma lipids, blood pressure, and behavioral factors, we observed that women with 3 or more births and an age at first birth of 25 or later had mean FSH levels that were significantly 7.6 IU/L lower than those of women with a 1 to 2 births and an age at first birth of 24 or less. Number of miscarriages was inversely correlated with FSH levels. Women reporting a 7 or more years of OC use and 4-6 or 7 or more years of HT use each had significantly higher mean FSH levels than women who had never used OCs or HT. In summary, multiple reproductive factors were associated with postmenopausal FSH levels, independent of estradiol, adiposity, and other factors. These findings warrant replication and further exploration of potential underlying mechanism.

Peptides that regulate feeding behavior via the brain may also regulate energy storage and expenditure in the adipose tissue, a system collectively known as the "brain-fat axis". Neuropeptide Y (NPY) is orexigenic and promotes adipogenesis in both birds and mammals, although mechanisms in adipose tissue are unclear. The first objective was thus to evaluate effects of NPY on chick preadipocyte proliferation and differentiation. Preadipocytes were treated with NPY and gene expression and cellular proliferation were evaluated. Cells were also treated with NPY during differentiation and harvested during the later stages. With increased gene expression of proliferation markers in preadipocytes, and during differentiation increased expression of adipogenesis-associated factors, increased lipid accumulation, and increased activity of an adipogenic enzyme, glycerol-3-phosphate dehydrogenase, results suggest that NPY may enhance preadipocyte activity and adipogenesis and promotes lipid accumulation throughout chicken adipocyte differentiation. Another appetite-regulatory peptide, alpha-melanocyte stimulating hormone (α-MSH), is anorexigenic and mediates lipolysis in adipose tissue, but effects on fat in avians are unreported. The second objective was thus to determine the effects of exogenous α-MSH on adipose tissue physiology in broiler chicks. Chicks were intraperitoneally injected with α-MSH and adipose tissue and plasma collected. Cells isolated from abdominal fat of a different set of chicks were treated with α-MSH. Results suggest that α-MSH increases lipolysis and reduces adipogenesis in chick adipose tissue. Collectively, results of this research provide insights on how appetite-regulatory peptides like NPY and α-MSH affect adipose tissue physiology, thereby playing important roles in regulating whole-body energy balance. / Master of Science / Peptides that contribute to feeding behavior via the brain may also affect the way energy is stored and released in the adipose tissue. Neuropeptide Y (NPY) is a neurotransmitter that induces hunger, and promotes the growth of adipose tissue in both birds and mammals, although mechanisms in adipose tissue are unclear. The first objective was thus to evaluate effects of NPY on chick preadipocyte activity and the process by which preadipocyte cells differentiate into fully matures adipocytes, a process termed adipogenesis. Preadipocytes were treated with NPY and gene expression and cellular division were evaluated. Cells were also treated with NPY during differentiation and harvested during the later stages. With increased activity in preadipocytes, and during differentiation greater activity leading to increased fat accumulation, results suggest that NPY may enhance preadipocyte activity and adipogenesis and promotes fat accumulation throughout chicken adipocyte differentiation. Another appetite-regulatory peptide, alpha-melanocyte stimulating hormone (α-MSH), inhibits hunger and breaks down adipose tissue, but effects on fat in avians are unreported. The second objective was thus to determine the effects of α-MSH on adipose tissue physiology in chicks. Chicks were injected with α-MSH and cells isolated from abdominal fat of a different set of chicks were treated with α-MSH. Results suggest that α-MSH breaks down fat and reduces adipogenesis in chick adipose tissue. Collectively, results of this research provide insights on how NPY and α-MSH affect adipose tissue physiology, thereby playing important roles in regulating whole-body energy balance.

No / Prostaglandins are potent mediators of the inflam-matory response and are also involved in cancer development. In this study, we show that human melanocytes and FM55 melanoma cells express cyclooxygenase-1 and -2 (COX-1 and-2) and thus have the capability to produce prostaglandins. TheFM55 cells produced predominantly PGE2and PGF2a, whereas the HaCaT keratinocyte cell line produced mainly PGE2. The anti-inflammatory peptide, a-melanocyte stimulating hormone(a-MSH), reduced prostaglandin production in FM55 and HaCaT cells and reversed the effect of the pro-inflammatory cytokine TNF-a in the former. These results indicate that melanocytes produce prostaglandins and that a-MSH, by inhibiting this response, may play an important role in regulating inflammatory responses in the skin.

The oncofetal protein Migration Stimulating Factor (MSF) is a truncated isoform of human fibronectin which exhibits numerous bioactivities that are pertinent to cancer progression. The MSF protein (70kDa) has potent motogenic activity, with only femtomolar concentrations required to produce half-maximal. The proteolytic degradation of MSF generates the functionally equivalent 43kDa Gel-BD domain and 21kDa IGD peptide. The screening of conditioned medium (CM) for bioactivity revealed two sources of MSF-inhibitory (MSF-I) activity; the spontaneously immortalised human keratinocyte cell line (HaCaT) and endothelial cells (ENDO 742) specifically when exhibiting a cobblestone phenotype. The CM from the HaCaT keratinocyte line was fractionated by both molecular weight and ionic charge, followed by sequence analysis which identified the inhibitor as Neutrophil Gelatinase Associated Lipocalin (NGAL). Both recombinant and cell-produced NGAL neutralise the motogenic activity of MSF. This novel bioactivity for NGAL is not dependent on its iron transportation capability or direct binding to MSF. HaCaT cells also secrete MSF; the bioactivity of which is masked by the co-expression of NGAL. The relative expression levels of the pro- and anti-motogenic factors, MSF and NGAL, were assessed using an in vitro model for human skin carcinogenesis, the HaCaT –ras clones. The shift in tumorigenic potential from benign to metastatic was characterised by a decrease in NGAL and an increase in MSF expression, indicating their potential role in tumour progression. The protein responsible for the MSF inhibitory activity is cell- type specific; NGAL is not expressed by endothelial cells in vitro. MSF stimulates the generation of sprouting endothelial cells from a cobblestone monolayer and acts a survival factor for spontaneously sprouting cells within a 3D matrix. NGAL does not selectively the target sprouting phenotype of endothelial cells, but induces apoptosis in all endothelial cells. Fractionation of endothelial CM revealed that both sprouting and cobblestone cells express bioactive MSF and a MSF-I. Endothelial MSF-I was located in fractions of MW 70kDa, 40kDa and =25kDa; further investigation is required to identify the protein responsible.

Typescript (Photocopy) / Bibliography: leaves 170-198. / xx, 198 leaves, 1 leaf of col. plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1991

Thesis (Ph.D.). / Written for the Dept. of Mathematics and Statistics. Title from title page of PDF (viewed 2008/01/12). Includes bibliographical references.