A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Master of Pharmacy / Cervical Intraepithelial Neoplasia (CIN) or Human Papilloma Virus (HPV) is known as the precancerous stages of cervical cancer and may be treated with antineoplastic agents Current treatment includes intravenous administration of Gemcitabine and 5-Fluorouracil however, these drugs have an undesirable side effect profile. This may be overcome by local administration of chemotherapeutic drugs to the site of the cancer. The purpose of this study was to design a drug delivery system that can be locally administered to the site of the cervical cancer and possess thermosonic properties. Designs of three Thermosonic Injectable Organogels (TIO’s) were undertaken using ring opening polymerization (open ring reaction) to formulate three different gels to test the response ability of the gels against thermal and ultrasound exposure. The times taken for these gels to form were recorded at below 15 minutes. All three TIO’s responded differently to thermal and ultrasound stimuli. Physical changes in the gels were noted and further studies were undertaken to confirm their responsiveness towards the dual-stimuli. All three TIO’s showed a dense microstructure containing pores catering for the incorporation of drugs or drug-loaded carriers. Rheological studies showed that there was an increase in viscosity of the gels under increasing heat even though the response differed between TIO formulations. The gels were non-cytotoxic at distinct concentrations ranging between 6.1mg/ml-7.8mg/ml. Solid Lipid Nanospheres (SLN’s) were then designed which encapsulated the mode antineoplastic drug 5-Fluorouracil. The SLN’s were spherical in shape and had an acceptable poly dispersion index (PDI) which was below 0.7 after ultrasonication and filtration of prepared samples. The SLN’s were then incorporated by direct additition and dispersion into the TIO formulations before undertaking the open ring reaction to form Thermosonic Injectable Nano-Organogels (TINO’s). The TINO’s were analysed for its swelling and erosive properties. Results showed that the TINO’s posesses both swelling and erosive properties. Furthermore, the TINO’s underwent dissolution studies that involved thermal and thermal with ultrasound stimuli to test the drug release rate and the stimuli responsiveness of the TINO. Results of the SLN’s showed a very slow release rate whether exposed to a single (thermal) or both thermal and ultrasound stimuli, indicating that the addition of ultrasound stimuli did not alter the drug release from the SLN’s. However, the incorporation of the SLN’s into the TIO’s prolonged the release rate. Hence increasing the SLN concentration in the TIO’s reduced the response towards ultrasound stimuli. Therefore lower ratios of SLN:TIO provided superior responsiveness compared to higher concentrations of SLN:TIO. TIO 1 and TINO 2 released drug with thermal stimuli and higher drug release occurred with exposure to both thermal and ultrasound stimuli. These TINO’s in conjunction with ultrasound responsiveness may be used as a potential platform for the delivery of antineoplastics in treating cervical cancer. / MT2017

Melatonin is a strong antioxidant that has previously been observed to increase uteroplacental blood flow and increase postnatal calf growth when supplemented during gestation. The objective of the current study was to examine the effects of melatonin implants on uterine blood flow and subsequent offspring growth. Commercial beef heifers and cows were artificially inseminated and assigned to one of two treatment groups supplemented with (MEL) or without (CON) melatonin from days 180 to 240 of gestation. Total uterine artery blood flow was increased in MEL- versus CON-treated cattle. Fetal and birth weight were not different between treatments. However, at castration, body weight was increased in calves from MEL-treated dams compared with CON-treated dams. Further research on placental vascularization and the mechanism in which melatonin impacts angiogenic factors is necessary to understand the relationship between melatonin and compensatory growth that occurs in postnatal offspring.

A research report submitted to the Faculty of Health Sciences, University of the Witwaters-rand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Med-icine in Obstetrics and Gynaecology. Johannesburg 2019 / Background and objectives Cervical cancer can be prevented by screening and treatment of cervical cancer precursor lesions. Women with an abnormal Pap smear are referred to colposcopy for diagnosis and are then treated immediately in many South African colposcopy clinics. Hence accurate colposcopic diagnosis is important. The aim of this study was to determine the accuracy of diagnosing cervical intraepithelial neoplasia with either the Reid Colposcopic Index or the Swede score in HIV infected women. The components of the Reid colposcopic index are acetowhiteness, margins, vascular patterns and iodine staining. The Swede score has all the components of the Reid score with the addition of lesion size as a fifth compo-nent. Methods This was a secondary data analysis of the South African arm of the “HPV in Africa Research Partnership (HARP) study” comparing different screening tests in the prevention of cervical cancer in HIV infected women. Women were recruited from primary health care clinics and HIV treatment centres in Hillbrow, Johannesburg. All women had a Pap smear, Human papil-lomavirus testing, and visual inspection with lugol’s iodine and with acetic acid. All women with any positive screening test were referred to colposcopy. At colposcopy a four-quadrant biopsy and directed biopsies of any visible lesions were performed. The colposcopist rec-orded the colposcopy findings using the Swede score. For this study, the information from the Swede score was used to determine the Reid colposcopy index. Data was extracted from the HARP study database. Results A total of 624 women were eligible for the study in the South African arm, only 577 women were included for this study. The mean age was 34 years (SD±5.89). Antiretroviral therapy was used by 370 (64%) women. Abnormal Pap smears were found in 484 (88%) women, VIA was positive in 162 (28%), VILI was positive in 219 (37%) and HR HPV DNA was found in 374 (65%) women re-spectively. Histological findings showed that 263 (46%) of the women had no CIN, 185 (32%) had CIN 1, 76 (13%) had CIN 2 and 53 (9%) had CIN 3. The Swede score of 5 had a sensitivity of 72.9%, specificity of 71.9%, PPV of 42.7%and NPV of 90.2% respectively. A Reid score of 4 had a sensitivity of 72.9%, specificity of 69.4%, PPV of 40.7% and NPV of 89.9%. In comparison, the Area under the curve was higher for the Swede score compared to the Reid and this differ-ence was statistically significant. Conclusion This study shows that the Swede score when compared to the Reid score performs better in terms of accuracy for predicting CIN≥2 lesions. The addition of the lesion size has been shown to have an added advantage in the performance of the scoring. Both scores also demonstrated flexibility. There is a higher likelihood of HIV infected women to be referred for colposcopy as they have a higher incidence of cervical cancer precursor lesions. There was no difference in the performance of the Swede or Reid score by antecedent Pap smear and there was no difference in colposcopy findings on women with the presence of HR-HPV or no HR-HPV. / E.K. 2019

No description available.

Objective: Delay in diagnosis and treatment of endometrial cancer may be associated with disease progression and impact management and outcomes. Social and cultural barriers influence recognition of symptoms and self-advocacy in seeking and complying with care. Associations between social determinants of health (SDH) and disease presentation, treatment and outcomes has been shown in some healthcare systems. Our objective was to investigate these in Ontario’s universal access system. Methods: Endometrial cancer patients in Ontario diagnosed 2009-2017 were identified, and clinical, social and demographic information extracted from administrative databases. SDH were quantified using previously validated marginalization quintiles (material deprivation, residential instability and ethnic concentration). Associations between SDH, disease stage, treatment and outcome were explored using chi-square, log-rank and logistic regression. Results: 19530 patients were identified. 73% of cancers were confined to the uterus. Stage distribution differed across marginalization quintiles (p<0.001) with advanced disease found more frequently in highly marginalized patients (highest vs lowest quintile): OR=1.28 (95% CI 1.14-1.45) for deprivation, OR=1.2 (95% CI 1.06-1.35) for residential instability and OR=1.3 (95% CI 1.15-1.46) for ethnic concentration (<0.0001)). Highly marginalized patients also had less timely surgery (p<0.0001). Overall survival was shorter in patients in high deprivation and residential instability quintiles (log rank p-value<0.0001) but not in high ethnic concentration quintiles, with HR=1.4 for deprivation (p<0.0001) and HR=1.53 for instability (p<0.0001) for the highest marginalization quintile. Survival differences persisted in more uniform cohorts of early (stage I) disease and endometrioid tumors and on multivariable analysis. Conclusions: Marginalized populations diagnosed with uterine cancer present at more advanced stages, wait longer for surgery and have shorter overall survival. Associations of SDH with uterine cancer presentation and management in Ontario could shed light on the impact of these factors on disease trajectory, drive policies for patient advocacy and redistribution of resources and promote health equity in this population. / Thesis / Master of Public Health (MPH) / Conditions in the social environment in which people are born, live and work are powerful influencers of health and well-being. In fact, these circumstances have also been called Social Determinants of Health (SDH). Cancer outcomes are one of the domains impacted by SDH. In this study, we set out to investigate the association between SDH and uterine cancer outcomes in Ontario, Canada. We guessed that SDH may influence how soon patients with symptoms seek help from their doctors, how quickly their problem is investigated and how well they are able to undergo treatment. We used a tool called the Ontario Marginalization Index to break down Ontario’s uterine cancer patient population into groups according to degree of social, financial and ethnic marginalization. We found that more marginalized patients tended to present to care with more advanced cancers, that they took longer to have surgery for their cancer and that their survival was worse. These findings suggest there is more work to be done to promote health equity in cancer care.

The uterine immune system is down regulated when exposed to P4. Five experiments were conducted to determine the in vivo and in vitro role(s) of P4 and prostaglandins in immune function(s) associated with uterine infections. In Exp. 1, postpartum ewes (d 0 = parturition) were supplemented with either OIL or P4 (beginning on d 10) or were SHAM or OVEX. Vena caval blood and lymphocytes were collected on d 14, and 16 to 19. All ewes received intrauterine inoculations of bacteria on d 15 and uteri were collected on d 20. Ewes receiving P4 developed infections. Lymphocytes were incubated with mitogens, PGE2, indomethacin (INDO; a PG synthesis inhibitor) or both in a 3 x 2 x 2 arrangement. Concanavalin A-stimulated blastogenesis in P4-OVEX ewes and PGE2 and PGE2+INDO treated lymphocytes was inhibited (P < .05). Cyclic ewes in their follicular or luteal phase received either intrauterine inoculations of saline or bacteria, vena caval blood was collected for 3 d, and uteri were collected. Lymphocytes were incubated with mitogens, PGE2 (Exp. 2), PGF2alpha (Exp. 3) and(or) INDO in a 3 x 2 x 2 arrangement. Only luteal phase ewes that received bacteria developed infections. In Exp. 2, Con A- and LPS-stimulated blastogenesis was greater for luteal than for follicular phase ewes. T lymphocyte proliferation was inhibited in ewes inoculated with bacteria. T lymphocyte proliferation tended to be higher (P = .09) when incubated with INDO. In Exp. 3, T lymphocyte proliferation in response to PGF2alpha was greater for follicular than for luteal phase ewes. Neutrophils were lower in ewes inoculted with bacteria. In Exp. 4 and 5, uteri of luteal-phase (d 6) ewes were inoculated with bacteria. Ewes received either 15 mg of Lutalyse or saline on d 9, and uteri were collected on d 11. Lutalyse reduced P4, tended to decrease neutrophils, allowed ewes to clear infections, and had no effect on blastogenesis. Methods for modulating uterine prostaglandins seem to reduce susceptibility to uterine infections. / Ph. D.

Early pregnancy is characterized by complex interactions between blood vessels, leukocytes, and conceptus-derived trophoblasts within the gestational uterus. Uterine Natural Killer (uNK) cells become the most abundant leukocyte during decidualization and produce a wide array of angiogenic factors, yet little is known regarding their early pregnancy functions. To characterize the role(s) of uNK cells, whole mount in situ immunohistochemistry of live early implant sites was performed. A timecourse examination of murine early pregnancy (virgin, and gd4.5-9.5) implantation sites was performed. Comparison of Gd6.5, 8.5 and 9.5 implant sites from BALB/c+/+ controls (BALB/c) and BALB/c-Rag2-/-Il2rg-/- (alymphoid) identified anomalies that result from the absence of lymphocytes. In alymphoid decidua basalis, mesometrial angiogenesis was widespread but pruning of nascent vessels within alymphoid decidua basalis was deficient. As early gestation progressed, vessels of alymphoid decidua basalis showed no evidence for remodeling. Alymphoid implantation sites showed ~24h delay in uterine lumen closure and embryonic development. To determine if uNK cells would normalize the anomalies observed in alymphoid implantation sites, adoptive cell transfer of NK+ B- T- marrow to alymphoid mice was performed. All of the above anomalies were reversed by adoptive transfer of NK+B-T- marrow. My results suggest that uNK cells support vascular growth and development which ensures the decidua can support the growing conceptus early in pregnancy prior to formation and function of the placenta. Human decidual NK cells may fill similar roles and be important targets for strategies designed to correct intra-uterine growth restriction. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2013-08-02 08:42:06.487

Thesis (M.Sc.)--Memorial University of Newfoundland, 2000. / Restricted until November 2001. Bibliography: leaves 51-55.

This thesis investigates the origin of spontaneous activity in the uterus. This organ does not show any activity until shortly before delivery, where fast and efficient contractions are generated. The aim of this work is to provide insight into the origin of spontaneous oscillations and into the transition from asynchronous to synchronized activity in the pregnant uterus. One intriguing aspect in the uterus is the absence of any pacemaker cell. The organ is composed of muscular cells, which are excitable, and connective cells, whose behavior is purely passive; None of these cells, taken in isolation, spontaneously oscillates. We develop an hypothesis based on the observed strong increase in the electrical coupling between cells in the last days of pregnancy. The study is based on a mathematical model of excitable cells, coupled to each other on a regular lattice, and to a fluctuating number of passive cells, consistent with the known structure of the uterus. The two parameters of the model, the coupling between excitable cells, and between excitable and passive cells, grow during pregnancy.Using both a model based on measured electrophysiological properties, and a generic model of excitable cell, we demonstrate that spontaneous oscillations can appear when increasing the coupling coefficients, ultimately leading to coherent oscillations over the entire tissue. We study the transition towards a coherent regime, both numerically and semi-analytically, using the simple model of excitable cells. Last, we demonstrate that, the realistic model reproduces irregular action potential propagation patterns as well as the bursting behavior, observed in the in-vitro experiments.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.