published_or_final_version / Medicine / Master / Doctor of Medicine

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Stress and anxiety during pregnancy predict perinatal complications over the course of pregnancy and labor as well as premature birth and low infant birth weight. The current study examined whether relaxation training provided to women at the beginning of the 2nd trimester could reduce stress and anxiety and assessed the impact of the intervention on perinatal complications, premature delivery, and infant outcomes at birth. Twenty-six moderately anxious pregnant women between 14 and 20 weeks gestation participated in the treatment study. Women completed a baseline laboratory assessment that involved questionnaires and a psychophysiological assessment. They were randomized to receive either six weeks of relaxation training or a list of tips for reducing stress (control). Women repeated the laboratory tasks post-treatment (Time 2) and again between 34 and 36 weeks gestation (Time 3). The treatment condition did not lead to greater mood change than the control condition at either Time 2 or 3. Several analyses, however, suggest relaxation training has the potential for reducing negative mood and complications over the course of pregnancy. Moderator analyses also revealed the treatment more efficacious for those with greater physiological flexibility.

A study was done to examine factors that facilitate adherence to haemodialysis therapy amongst patients with chronic renal failure and the sources of support available to them. A self developed questionnaire was used to collect data from the respondents. The respondents were purposive and conveniently selected according to the set criteria. The sample consisted of 118 respondents that were selected from four hospitals, two provincial hospitals and two private hospitals. Permission to conduct the study was requested by means of written letters to all people concerned. Letters granting permission were obtained from the two provincial hospitals. The Heads of the Renal Units of the two private hospitals gave verbal permission. Data was analyzed using the Statistical Package for the Social Sciences (SPSS 11.5). Demographic data was analysed through frequency counts. Crosstabulations using Chi-square analysis was performed to test the relationship between the factors that facilitate adherence to haemodialysis therapy and the indicators for adherence. The results were presented in the form of Tables and Figures (Graphs). From the findings the researcher concluded that in order for a haemodialysis patient to adhere to therapy restrictions, the following should be adequate: physical factors, socio-economic factors, psychosocial factors which also encompasses cultural factors. Health education proved to be having a very good impact. Higher level of education is not that essential as long as the patient can read, write and understand the instructions. Religious factors did not have much effect on facilitation of adherence to haemodialysis therapy. / Thesis (M.A.)-University of KwaZulu- Natal, Durban, 2004.

Thesis (M.S.)--University of Hawaii at Manoa, 2007. / Includes bibliographical references (leaves 13-17). / vii, 17 leaves, bound ill. 29 cm

Increased levels of oestrogen and progesterone during pregnancy may lead to periodontal disease. The anaerobic Gram-negative bacteria called red complex (Porphyromonas gingivalis, Tannerella forsythensis and Treponema denticola) are frequently associated with periodontal disease. Periodontopathogens produce toxins and enzymes which can enter the bloodstream and cross the placenta to harm the foetus. The response of the mother&rsquo / s immune system to infection by these periodontopathogens, brings about the release of inflammatory mediators which may trigger preterm labour or result in low birth-weight infants. The purpose of this study was to examine the prevalence of red complex, using BANA and PCR in subginginval plaque samples from pregnant women. Subgingival plaque samples were obtained from pregnant women between the ages of 17 to 45 years attending a Mitchells Plain ante-natal clinic. Plaque samples were analyzed by the enzymatic BANA-test for detection of the presence of red complex and DNA was extracted and analyzed using 16 rDNA-Polymerase Chain Reaction (PCR).<br /> <br /> Seventy-nine percent of pregnant women showed gingival index scores of &ge / 1 of which 74.24% harboured by at least one of the members of the red complex. P.gingivalis was the most prevalent of the three members of the red complex. Findings of this study confirmed a need for dental preventive measures in pregnant women and microbial monitoring of suspected periodontopathogenes. This could be achieved by joint cooperation between Maternity Obstetric Units (MOU), Dentistry and oral microbiology departments. The results of this study revealed that although PCR is more sensitive than BANA in detecting members of the red complex, BANA showed a better association with the indices used to diagnose periodontal disease.

Mucositis is the damage that occurs to the alimentary canal from anti - cancer therapies. It is caused by chemotherapy, radiotherapy and combination therapy and affects a large proportion of patients. Despite its prevalence, an effective anti - mucositis agent has yet to be developed that protects the whole tube, although the use of keratinocyte growth factor ( Amgen ' s Palifermin ) has recently been approved for the prevention of oral mucositis. It is important to understand mechanisms controlling mucositis so that treatment can be targeted appropriately. This thesis has investigated some of the key components identified as being involved in mucositis as well as identifying new genes which contribute to chemotherapy - induced intestinal injury. The research chapters investigated : 1 ) Gene expression of the apoptosis - regulating Bcl - 2 family, p53 and caspase - 3, and the changes which occur in the intestine following chemotherapy treatment for cancer. 2 ) The effect of different chemotherapeutic agents on intestinal cells in vitro and the role p53 plays. 3 ) The mucositis caused by single dose irinotecan in the rat with breast cancer and the role of p53 in induction of intestinal damage. 4 ) The early gene changes that occur in the small intestine of the rat with breast cancer following irinotecan treatment. Firstly, to investigate the difference in susceptibility to damage between the small and large intestine, the protein expression of 8 members of the Bcl - 2 family ( 4 pro - apoptotic ; Bax, Bak, Bid, Bim and 4 anti - apoptotic ; Bcl - 2, Bcl - xL, Bcl - w, Mcl - 1 ) was quantified in jejunal and colonic sections taken from rats inoculated with breast cancer. It was found that there was significantly higher expression of the pro - apoptotic proteins, Bax, Bak, Bim and Bid, in the crypts of the jejunum compared to the colon. Furthermore, expression of the anti - apoptotic proteins, Bcl - 2, Bcl - xL and Bcl - w, was significantly lower in jejunal crypts compared to colonic crypts. Mcl - 1 expression was similar in both regions. Thus, the small intestine is an environment balanced to favour apoptosis through specific Bcl - 2 family protein expression profiles. The Bcl - 2 family regulates apoptosis in response to a variety of chemotherapy agents. However, it is unknown how Bcl - 2 family gene expression changes along with other apoptogenic factors following cytotoxic therapy in the normal intestine. To investigate this, sections of rat jejunum treated with methotrexate and duodenal biopsies from chemotherapy patients treated with various regimens for cancer were subjected to quantitative immunohistochemistry to detect Bcl - 2 family proteins, p53 and caspase - 3. Treatment caused expression of p53 and caspase - 3 to increase within the crypts and follow a similar pattern to apoptosis levels. Pro - apoptotic Bcl - 2 family members, Bax and Bak, were increased, while the anti - apoptotic protein, Mcl - 1, was significantly reduced. A significant increase in mRNA expression for Bax and Bak was noticed at 6 h, without a concurrent decrease in Mcl - 1. Thus, Bcl - 2 family genes were altered in the small intestine in both humans and rats, and this was irrespective of chemotherapy agent or regimen used. The best characterised changes which occur during chemotherapy - induced damage in the intestine are in the epithelial layer, although it is thought that pan #45 mucosal alterations are involved. Two intestinal cell lines were chosen to investigate changes in apoptosis, proliferation and protein expression following cytotoxic treatment with various chemotherapeutic agents. These were the rat IEC - 6 and human FHs 74 cell lines, which represent untransformed epithelial cells. The human breast carcinoma cell line, MCF - 7, was also used as a positive control. Intestinal cells were resistant to the occurrence of methotrexate toxicities within 24 h of treatment, modestly affected by irinotecan and extremely sensitive to doxorubicin. Doxorubicin caused a marked increase in p53 and p21 expression, which for irinotecan was less pronounced. The effect of cytotoxic treatment on Bcl - 2 family expression in intestinal cells varied, however the pro - apoptotic proteins, Bax and Bak, were generally upregulated following doxorubicin. Temporary inhibition of p53 using pifithrin alpha resulted in a significant improvement in cell survival in cancerous cell only and did not alter Bcl - 2 family expression. It was concluded that cultured epithelial cells exhibit varying sensitivities to different chemotherapeutic agents which is dependent on induction of p53 gene expression. The topoisomerase I inhibitor, irinotecan, is a chemotherapeutic agent commonly used in the treatment of colorectal cancer. It often induces severe mucositis with the most common symptom being diarrhoea. Previous research has shown that irinotecan damages the small and large bowel equally, which is unusual. This is characterised by an increase in apoptosis and a reduction in proliferation within epithelial crypts, an increase in inflammatory cell infiltrate in the lamina propria and excess mucin production. These investigations used two sequential doses of irinotecan. The early effect of a single dose of irinotecan on the intestine have yet to be studied. Thus the primary aim of this experiment was to examine in detail the changes caused by irinotecan at 6 and 48 h in the rat. A secondary aim was to investigate the role of p53 on induction of apoptosis and cell cycle arrest within intestinal crypts and the effect of temporary inhibition of the protein. Single dose irinotecan caused a decrease in body and small intestinal weight by 48 h after treatment. This was accompanied by crypt and villous degeneration, increased apoptosis and reduced proliferation within crypt epithelium as well as inflammatory infiltrate throughout lamina propria. An increase in Bax expression was seen at 6 h, however p53 protein levels remained relatively low until 48 h. Rats also treated with pifithrin alpha to inhibit p53 and had a significantly lower peak in apoptosis in the colon at 6 h, however did not show improvements in any other parameters tested. It was concluded that irinotecaninduced damage in the rat intestine is primarily p53 - independent, and that pifithrin alpha acts to inhibit apoptosis in the large intestine via a p53 - independent pathway. A study was designed to investigate the early genome - wide changes which occur following irinotecan treatment in the rat small intestine. Microarray analysis found that regulation of many genes was altered at 6 h following dual dose irinotecan. These genes were involved in apoptosis, cell cycle regulation, immune function, calcium homeostasis and protein turnover. Multiple genes from the MAP kinase pathway were also activated by irinotecan. The cystine protease, caspase - 1 was upregulated and was chosen for further investigations due to its role in apoptosis and inflammation. Real time PCR analysis confirmed the increase in gene expression at 6 h and also showed a return to baseline levels by 24 h which was followed by another modest increase at 48 h. It was concluded that irinotecan induces a wide range of gene changes within the intestine and that apoptosis and inflammatory damage pathways are activated during treatment. This thesis described key molecules in apoptosis and their role in induction of chemotherapy - induced intestinal mucositis. It has provided evidence of the importance of apoptosis in mucosal injury and also highlighted areas requiring further research. Results presented herein show that the Bcl - 2 family is involved in intestinal damage following many chemotherapy agents, whereas p53 is agent - specific. It has also shown that irinotecan causes intestinal damage via a mainly p53 - independent manner in the rat. It can be concluded that gastrointestinal mucositis is complex and activates multiple pathways to induce damage. Findings from this thesis will aid targeting of new anti - mucotoxic agents. / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2006.

Mucositis is the damage that occurs to the alimentary canal from anti - cancer therapies. It is caused by chemotherapy, radiotherapy and combination therapy and affects a large proportion of patients. Despite its prevalence, an effective anti - mucositis agent has yet to be developed that protects the whole tube, although the use of keratinocyte growth factor ( Amgen ' s Palifermin ) has recently been approved for the prevention of oral mucositis. It is important to understand mechanisms controlling mucositis so that treatment can be targeted appropriately. This thesis has investigated some of the key components identified as being involved in mucositis as well as identifying new genes which contribute to chemotherapy - induced intestinal injury. The research chapters investigated : 1 ) Gene expression of the apoptosis - regulating Bcl - 2 family, p53 and caspase - 3, and the changes which occur in the intestine following chemotherapy treatment for cancer. 2 ) The effect of different chemotherapeutic agents on intestinal cells in vitro and the role p53 plays. 3 ) The mucositis caused by single dose irinotecan in the rat with breast cancer and the role of p53 in induction of intestinal damage. 4 ) The early gene changes that occur in the small intestine of the rat with breast cancer following irinotecan treatment. Firstly, to investigate the difference in susceptibility to damage between the small and large intestine, the protein expression of 8 members of the Bcl - 2 family ( 4 pro - apoptotic ; Bax, Bak, Bid, Bim and 4 anti - apoptotic ; Bcl - 2, Bcl - xL, Bcl - w, Mcl - 1 ) was quantified in jejunal and colonic sections taken from rats inoculated with breast cancer. It was found that there was significantly higher expression of the pro - apoptotic proteins, Bax, Bak, Bim and Bid, in the crypts of the jejunum compared to the colon. Furthermore, expression of the anti - apoptotic proteins, Bcl - 2, Bcl - xL and Bcl - w, was significantly lower in jejunal crypts compared to colonic crypts. Mcl - 1 expression was similar in both regions. Thus, the small intestine is an environment balanced to favour apoptosis through specific Bcl - 2 family protein expression profiles. The Bcl - 2 family regulates apoptosis in response to a variety of chemotherapy agents. However, it is unknown how Bcl - 2 family gene expression changes along with other apoptogenic factors following cytotoxic therapy in the normal intestine. To investigate this, sections of rat jejunum treated with methotrexate and duodenal biopsies from chemotherapy patients treated with various regimens for cancer were subjected to quantitative immunohistochemistry to detect Bcl - 2 family proteins, p53 and caspase - 3. Treatment caused expression of p53 and caspase - 3 to increase within the crypts and follow a similar pattern to apoptosis levels. Pro - apoptotic Bcl - 2 family members, Bax and Bak, were increased, while the anti - apoptotic protein, Mcl - 1, was significantly reduced. A significant increase in mRNA expression for Bax and Bak was noticed at 6 h, without a concurrent decrease in Mcl - 1. Thus, Bcl - 2 family genes were altered in the small intestine in both humans and rats, and this was irrespective of chemotherapy agent or regimen used. The best characterised changes which occur during chemotherapy - induced damage in the intestine are in the epithelial layer, although it is thought that pan #45 mucosal alterations are involved. Two intestinal cell lines were chosen to investigate changes in apoptosis, proliferation and protein expression following cytotoxic treatment with various chemotherapeutic agents. These were the rat IEC - 6 and human FHs 74 cell lines, which represent untransformed epithelial cells. The human breast carcinoma cell line, MCF - 7, was also used as a positive control. Intestinal cells were resistant to the occurrence of methotrexate toxicities within 24 h of treatment, modestly affected by irinotecan and extremely sensitive to doxorubicin. Doxorubicin caused a marked increase in p53 and p21 expression, which for irinotecan was less pronounced. The effect of cytotoxic treatment on Bcl - 2 family expression in intestinal cells varied, however the pro - apoptotic proteins, Bax and Bak, were generally upregulated following doxorubicin. Temporary inhibition of p53 using pifithrin alpha resulted in a significant improvement in cell survival in cancerous cell only and did not alter Bcl - 2 family expression. It was concluded that cultured epithelial cells exhibit varying sensitivities to different chemotherapeutic agents which is dependent on induction of p53 gene expression. The topoisomerase I inhibitor, irinotecan, is a chemotherapeutic agent commonly used in the treatment of colorectal cancer. It often induces severe mucositis with the most common symptom being diarrhoea. Previous research has shown that irinotecan damages the small and large bowel equally, which is unusual. This is characterised by an increase in apoptosis and a reduction in proliferation within epithelial crypts, an increase in inflammatory cell infiltrate in the lamina propria and excess mucin production. These investigations used two sequential doses of irinotecan. The early effect of a single dose of irinotecan on the intestine have yet to be studied. Thus the primary aim of this experiment was to examine in detail the changes caused by irinotecan at 6 and 48 h in the rat. A secondary aim was to investigate the role of p53 on induction of apoptosis and cell cycle arrest within intestinal crypts and the effect of temporary inhibition of the protein. Single dose irinotecan caused a decrease in body and small intestinal weight by 48 h after treatment. This was accompanied by crypt and villous degeneration, increased apoptosis and reduced proliferation within crypt epithelium as well as inflammatory infiltrate throughout lamina propria. An increase in Bax expression was seen at 6 h, however p53 protein levels remained relatively low until 48 h. Rats also treated with pifithrin alpha to inhibit p53 and had a significantly lower peak in apoptosis in the colon at 6 h, however did not show improvements in any other parameters tested. It was concluded that irinotecaninduced damage in the rat intestine is primarily p53 - independent, and that pifithrin alpha acts to inhibit apoptosis in the large intestine via a p53 - independent pathway. A study was designed to investigate the early genome - wide changes which occur following irinotecan treatment in the rat small intestine. Microarray analysis found that regulation of many genes was altered at 6 h following dual dose irinotecan. These genes were involved in apoptosis, cell cycle regulation, immune function, calcium homeostasis and protein turnover. Multiple genes from the MAP kinase pathway were also activated by irinotecan. The cystine protease, caspase - 1 was upregulated and was chosen for further investigations due to its role in apoptosis and inflammation. Real time PCR analysis confirmed the increase in gene expression at 6 h and also showed a return to baseline levels by 24 h which was followed by another modest increase at 48 h. It was concluded that irinotecan induces a wide range of gene changes within the intestine and that apoptosis and inflammatory damage pathways are activated during treatment. This thesis described key molecules in apoptosis and their role in induction of chemotherapy - induced intestinal mucositis. It has provided evidence of the importance of apoptosis in mucosal injury and also highlighted areas requiring further research. Results presented herein show that the Bcl - 2 family is involved in intestinal damage following many chemotherapy agents, whereas p53 is agent - specific. It has also shown that irinotecan causes intestinal damage via a mainly p53 - independent manner in the rat. It can be concluded that gastrointestinal mucositis is complex and activates multiple pathways to induce damage. Findings from this thesis will aid targeting of new anti - mucotoxic agents. / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2006.

Records of all neurosurgical inpatients admitted to Royal North Shore Hospital since 1976 have been prospectively kept in a relational database. Demographic details, diagnoses, operations and complications have been entered continuously since 1982 by the author of this study. Complications are monitored at monthly review meetings attended by medical staff. The recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) at these meetings, despite continual improvements in patient care, prompted this study. It aims to use the database to study changes in the incidence of DVT and PE over the previous twenty years; to find what database variables predict these complications; and whether use of mechanical and pharmacological agents has had an impact on DVT and PE rate. Univariate analysis of the incidence of DVT and PE by age, sex, length of stay (LOS), admission month, diagnosis, operation and surgeon over time was run. Any significant variables were then analysed by multivariate logistic regression. The DVT rate was low by world standards, but rose from 0.6% in 1979-83 to 1.2% in 1984-88, then rose exponentially to 3.60% in 1994-98 with a significantly increasing trend over the twenty years (c2 MH =114.20, with IDF, P<0.001). PE rate doubled significantly over the twenty years from 0.6% to 1.2% (c2 MH =17.94 with 1DF, P<0.001). Age, LOS, diagnosis, operation and surgeon were significant predictors of DVT and PE. After adjustment for LOS, time period and age, vascular surgery was found to be the strongest predictor of DVT (OR=2.82, 95% CI: 2.08-3.82, c2 =43.91, P<0.01). Vascular diagnosis was the strongest diagnosis predictor. No effect of sex or month of admission was shown. After adjustment for LOS, time period and age, spinal fusion was the strongest predictor of PE (OR=4.04, 95% CI: 1.81-9.03). Anterior communicating artery aneurysm was the diagnosis most highly associated with PE. The rise in DVT rate may be due to increased complexity of surgical and nursing management, and some screening of patients with the introduction of duplex scanning. The doubling of PE rate is unexplained. The risk of brain or spinal cord haemorrhage makes prophylactic anticoagulation a difficult choice. This study reveals groupings which can be used to determine appropriate prophylaxis. Use of mechanical and pharmaceutical agents is not recorded consistently in the database, but it is known approximately when they were introduced. No impact on the rate of DVT and PE can be demonstrated by these agents. More vigilant and widespread use of mechanical prophylaxis might be just as effective in controlling DVT and PE.