Chronic Fatigue Syndrome (CFS) is an illness characterized by persistent debilitating fatigue of uncertain origin. Precipitating and perpetuating factors of this illness are thought to be distinct and the aim of this thesis was to gain greater insight into the role of cognitive factors which may maintain the condition. This work was guided by two central frameworks, the self-regulatory model of illness representations and the cognitive taxonomy of psychopathology. These were used to define the different cognitive constructs and to investigate the way they function as a system to maintain pathological schema and disability in CFS. Three studies using different methodologies were conducted to test the hypotheses. The first employed a descriptive comparative design to ascertain whether CFS patients have unique cognitions which contribute to their disability over time. The sample was comprised of CFS patients without depression (n=39), CFS patients with a concurrent diagnosis of depression (n=14), patients with a primary diagnosis of depression (n=20); and healthy controls (n=38). The groups were matched in aggregate for age, gender, race, and education. Subjects completed the Cognitive Errors Questionnaire-Revised, which measures cognitive distortions relevant to both general and somatic events, and the Illness Perception Questionnaire, which measures the five dimensions of the illness representation in conjunction with other standard measures. Between-group analyses confirmed that the depressed group was distinguished by a low self-esteem, feelings of guilt and self-recriminations, the propensity to make cognitive distortions across all situations, and to attribute their illness to internal, stable and global factors. In contrast, the CFS patients were characterized by low ratings of their current health status, a strong illness identity, external attributions for their illness, and distortion in thinking that were specific to somatic experiences. CFS depressed patients had lower self-esteem than non-depressed patients and had the most pessimistic illness beliefs. A six month follow-up showed that CFS patients' cognitive structures and level of disability remained remarkably stable. Illness identity, serious consequences, somatic errors, and limiting coping accounted for a substantial proportion of the variance in CFS patients’ disability scores over time. These results are discussed in terms of their support for both of the cognitive models. CFS patients appeared to have distinct cognitions which were associated with ongoing disability. The subsequent two quasi-experimental studies were conducted in a single laboratory session. The first of these used standardized neuropsychological tests to determine whether psychological variables, particularly somatic focus, interfere with CFS patients’ performance on high load attention tasks. The discrepancy between CFS patients’ subjective reports of concentration and memory difficulties and objective evidence of these deficits was also investigated. The subjects included 25 CFS patients matched for age, gender, and intelligence with two groups of healthy controls. One of these groups underwent a somatic induction procedure as part of the investigation of the effects of somatic preoccupation on attention tasks. The tests included the verbal memory subscales from the Wechsler Memory Scale-Revised and the Paced Auditory Serial Addition Task (PASAT), a measure of divided attention and speed of information processing. The analyses of the induction data failed to support the validity of this procedure resulting in the somatic control group being dropped from the analysis. Consistent with previous studies the principal deficit in the CFS group appeared to be on the PASAT. The CFS group appeared to be less accurate than healthy controls in their appraisal of their performance, which were related to negative mood rather than objective performance. Depression was also related to high performance expectations in the CFS group, but not the controls. The results did not support the original assumption that somatic preoccupation contributes to neuropsychological difficulties in CFS. However, mood factors were clearly shown to impact on both the objective and subjective experience of symptoms. The aim of the final study was to investigate the concordance between the self-report data collected in study one and information processing biases in CFS. Comparisons of the CFS patients and healthy controls on a modified Stroop attention task and a self-schema memory task, found no evidence of an illness-related bias in CFS patients’ processing of information. Rather, they demonstrated a significant tendency to be distracted by and remember depressed-relevant stimuli. The exception was their propensity to make somatic interpretations. These results are discussed in terms of the defensiveness hypothesis, which proposes that CFS patients’ negative, external illness perceptions and somatic distortions may act as a defence against underlying feelings of low self-esteem. The complex nature of CFS patients’ cognitive structures was revealed and the need to use measures which do not rely on self-reports was clearly demonstrated. These studies provided further support for the central role of cognitive factors and mood in perpetuating CFS.

Several studies have shown that non-cycling cells are resistant to the cytotoxic effects induced by amsacrine (m-AMSA; 4'-(9-acridinylamino)methanesulphon-m-anisidide). This resistance may limit the activity of m-AMSA and related 9-anilinoacridine antitumour agents against solid tumours. The biochemical mechanism(s) for this resistance have been investigated using spontaneously transformed Chinese hamster fibroblast (AA8 cells) in log- and plateau-phase spinner cultures. In early plateau phase most cells entered a growth-arrested state with a G1-G0 DNA content and showed a marked decrease in sensitivity to cytotoxicity after a 1-h exposure to m-AMSA or its solid tumour-active analogue, CI-921. Studies with radiolabelled m-AMSA demonstrated that changes in sensitivity to m-AMSA-induced cell killing were not due to a difference in uptake or retention of drug by log- and plateau-phase cells, and there was no significant metabolism of drug by either log- or plateau-phase cells. Thus, after a 1-h exposure to [3H]-m-AMSA at 37°C, a small proportion (1%) of cell-associated radioactivity was covalently bound to macromolecules, but most of the cell-associated radioactivity represented unchanged m-AMSA. There was no evidence for any oxidative metabolism to reactive quinoidal species in these tumour cells. However, studies with a fluorescence assay for DNA unwinding indicated that plateau-phase cells were 3 to 4 times less sensitive to m-AMSA-induced DNA breakage than log-phase cells, and changes in sensitivity to m-AMSA-induced DNA breakage correlated with changes in sensitivity to cell killing by m-AMSA as cell progressed from log to plateau phase. Further studies showed that the decrease in sensitivity to m-AMSA-induced DNA stand breakage correlated with a decrease in sensitivity to covalent DNA-protein complex formation in plateau-phase cells after m-AMSA treatment. Combined with evidence that the DNA lesions rapidly disappeared from both log- and plateau-phase cells following the removal of m-AMSA (half-time approx. 4 min), this indicated that the lesions detected by the FADU assay probably arose from the stimulation of DNA-topoisomerase II (topo II) cleavable complex formation by m-AMSA. K+/SDS precipitation assays with [32p] 3’-end-labelled pBR322 DNA indicated that nuclear extracts containing topo II activity from plateau-phase cells were 3- to 4-fold less sensitive to stimulation of DNA-topo II complex formation by m-AMSA than nuclear extracts from log-phase cells. This change in sensitivity to m-AMSA-induced DNA-topo II complex formation was therefore similar to that observed with intact cells. However, P4 unknotting assays indicated that topo II activity in nuclear extracts from plateau-phase cells was only 2-fold lower than that in nuclear extracts from log-phase cells. Resistance to treatment with m-AMSA may therefore reflect a decrease in topo II activity and/or a decrease in sensitivity of topo II enzymes to stimulation of cleavable complex formation by m-AMSA in non-cycling cells.

Members of the integrin superfamily of adhesion molecules are involved in cell to cell, cell to ECM, and cell to pathogen interactions, and are of fundamental importance in many biological processes. The β7 integrins α4β7 and αEβ7 have evolved to play specialized roles in gut mucosal immunity. α4β7 mediates the homing of lymphocytes to intestinal Peyer's patches, mesenteric lymph nodes, and the lamina propria by binding to the vascular addressin MAdCAM-1 (Fong et al., 1997). αEβ7 binds epithelial E-cadherin retaining lymphocytes at the intraepithelial compartment of the mucosa. The expression of αEβ7 is induced on migratory lymphocytes by TGF-β secreted by gut enterocytes. The signalling mechanisms responsible for basal and TGF-β-induced expression of β7 integrins are not well understood. Previous studies identified two TGF-β1 response regions in the β7 gene promoter termed TGFBRR-1 and TGFBRR-2 encompassing nucleotides -509 to -398 and -121 to -34. Here, TGF-β1 activation of the β7 gene proximal promoter is shown to be mediated by MAPK family members. TGF-β1 stimulation of TK-1 T cells increased the steady-state mRNA levels of the β7 gene relative to α4 transcripts, and led to enhanced phosphorylation of c-Jun. TGF-β1 stimulation induced rapid increases in the binding of nuclear protein complexes to TGFBRR-1 and -2. Sp1 and Sp3 which mediate TGF-β1 signalling were shown to bind to an Sp1 cis-element encompassing nucleotide positions -67 to -60 within TGFBRR-2. The interaction of Sp1 with its cognate binding site was c-Jun dependent. In contrast, there was no evidence for involvement of the Smad proteins. ATF-2 was identified to bind to a region encompassing nucleotide positions -699 to -689 just upstream of TGFBRR-1. Sp1 and ATF-2 expression vectors co-transfected into Sp1-deficient SL-2 cells synergized to drive the activity of a β7 gene luciferase reporter. Mutation of the ATF-2-binding site modestly reduced β7 gene reporter activity. The involvement of c-Jun in TGF-β signalling and interaction of Sp1 with the β7 gene promoter suggested that MAP kinase pathways might mediate β7 gene transcription. Specific chemical inhibitors were used to ascertain which of the three MAPK pathways namely p38, JNK, and ERK were involved. Results obtained by nuclear run-on transcription analysis which measures nascent RNA synthesis showed that both the p38 and JNK pathways regulate β7 gene expression in TK-1 cells, whereas only the p38 pathway regulates α4 gene expression. Thus, treatment of TK-1 cells with the p38 inhibitor SB203580 and the JNK inhibitor SP600125 inhibited the synthesis of β7 transcripts, whereas only SB203580 inhibited the synthesis of α4 transcripts. Conversely, sodium arsenite which induces JNK and p38 upregulated nascent synthesis of α4 and β7 RNA transcripts. SB203580 blocked the binding of nuclear factors to TGFBRR-1, and ATF-2 binding to nucleotide position -699 to -689. Similarly, SP600125 blocked the binding of Sp1 and Sp3 to TGFBRR-2, whereas unexpectedly SB203580 enhanced their binding. Furthermore, both SB203580 and SP600125 decreased cell-surface expression of the β7 subunit and SB203580 inhibited TK-1 cell adhesion to MAdCAM-1. In contrast, the MEK inhibitor PD98059 had no effect on the expression of nascent β7 RNA transcripts and cell-surface expression of the β7 subunit, suggesting that the ERK pathway is not involved in regulation of β7 gene expression in TK-1 cells. In contrast to the results obtained with TK-1 cells, SB203580, SP600125, and PD98059 each inhibited the nascent synthesis of α4, β7, and αE transcripts in peripheral blood lymphocytes. In conclusion, this study has revealed for the first time that both the p38 and JNK pathways mediate TGF-β1-induced expression of the integrin β7 gene. Expression of the β7 gene is Sp1-dependent, and involves the synergistic cooperation of c-Jun and ATF-2. It is proposed that the p38 and JNK pathways play a role by triggering the activation and translocation of c-Jun and ATF-2 to the nucleus. / Whole document restricted, but available by request, use the feedback form to request access.

Lactose malabsorption (LM) in children was diagnosed by an elevated breath hydrogen (BH) level following a 10g lactose load. A portable gas chromatograph and a semiconductor detector, designed and constructed for use in the Pacific Islands is described. Following verification on known malabsorber and. normal subjects, the technique was used to determine the prevalence of LM in Europeans at Auckland and Rarotonga, and in Samoans at two locations in Auckland and two locations in Western Samoa. The prevalence of LM in Europeans was significantly (p<0.01) higher at Rarotonga than at Auckland. For Samoans, the prevalence of LM was significantly (p<0.01) higher in Western Samoa than at Auckland. The prevalence of LM was very highly significantly (p<0.001) related to race. Each child tested for LM filled in a questionaire to determine attitude, consumption of and perceived intolerance to milk, milk biscuits and ice cream. Lactose malabsorption was significantly (p<0.05) correlated to milk consumption and to attitude to dairy products, but not to sex, age, and perceived intolerance. The consumption of dairy products was very highly significantly (p<0.0001) correlated to attitude, and highly significantly (p<0.001) correlated to location and perceived intolerance. There was no significant correlation between consumption and race, sex or age. Perceived intolerance to individual dairy products was significantly correlated to attitude to milk (p<0.0001), milk biscuits (p<0.02) and ice cream (p<0.001). Perceived intolerance was not related to age, sex, race, location or the actual symptoms following the consumption of 10g lactose. The unexpected finding of increased LM in the Pacific Islands, was investigated further by studying the LM status of the Medical Team during a visit to western Samoa, and by performing a microbiological survey of water quality. It was found that half of the Medical Team 3/6, became malabsorbers during the week spent in Western Samoa. On returning to New Zealand it was shown that lactase levels took 3 months to normalise. The water supply in Western Samoa was shown to contain very high levels of coliform bacteria. The currently held hypothesis that genetic factors are solely involved in the onset of LM, was not supported. The evidence from the survey supported environmental factors are also involved in adult onset LM. The hypothesis suggesting that dietary lactose was a requirement for retaining elevated lactase levels, was tested using Galactosemic and Phenyl Ketonuria patients. None of the patients had developed LM although they had been on a low lactose diet for years, hence the theory was not supported. The BH method proved highly successful in diagnosing LM with many of the children actually enjoying it.

In newborn infants, birth asphyxia represents the predominant cause of brain injury. These infants will later exhibit neurodevelopmental disabilities or a more major cerebral palsy. Prevention of adverse outcomes requires an understanding of the way in which these deficits develop. Endogenous protective mechanisms arising from the insult have opened new insights in neuroprotective strategies. Neurotrophic factors such as IGF-1 and its N-terminal tripeptide GPE have been shown to confer some neuroprotection after HI injury in the adult rodent. In the P21 rat brain after moderate HI injury, exogenous intracerebral and intraperitoneal injections of GPE (30μg and 300μg respectively) were neuroprotective in the hippocampus and lateral cortex possibly through binding to glia as detected by autoradiography of 3H-GPE. In the preterm infant the mechanisms of white matter injury remain to be clearly elucidated. To mimic the pattern of diffuse cerebral injury of the very preterm infant, a transient moderate focal HI injury has been applied on the immature P3 rat. This new model showed a significant reduction in the lateral cortical volume with reduction and alteration of the myelination pattern in the cortical white matter (WM) at P21. These cortical alterations result from neuro-axonal damage 24h after the insult as shown with Fluoro-Jade B staining and β-APP accumulation. In addition activated astrocytes from 24h after HI up to P21 were present. This model should enable us to elucidate some of the pathogenic mechanisms involved in diffuse WM injury. Brain damage in the developing brain has two components: 1) the pattern and mechanisms of injury are correlated with the stage of development at the time of injury; 2) it will influence subsequent brain development.

Ischaemic cell death has been implicated in a number of retinal diseases, including glaucomatous neuropathy, proliferative diabetic retinopathy and a range of vascular diseases. The cascade of events leading to cell death involves both cellular metabolic changes and a functional component. However, it is yet unknown how long these changes persist, whether all cell classes are affected, and the characteristics of recovery. Moreover, there have been few studies correlating the neurochemical changes with the ensuing functional changes. The aim of this thesis was to track the metabolic and functional recovery of the ischaemic rat retina, given the premise that: (1) amino acid neurochemistry reflects metabolic integrity and cellular identity, and; (2) the permeation of a cation channel probe called agmatine reflects channel functionality. Quantitative pattern recognition analysis of overlapping amino acid and agmatine expression profiles were used to provide a statistically robust classification of cells according to metabolic and functional characteristics. This classification was spatially complete and with single cell resolution. Finally, the electroretinogram was used to also assess retinal function and corroborate the observed neurochemical changes. These measures were taken at intervals for up to two weeks of reperfusion. The results show that by 48 hours of reperfusion, amino acid metabolism had returned to near normal levels, although cell classes were missing, and there was persistant cation channel gating anomalies. Immunocytochemical labeling identified a preferential loss of cone bipolar cells, with all remaining rod bipolar cells showing increased cation channel gating. The electroretinogram and agmatine experiments showed that this dysfunction is likely due to abnormal glutamate release from pre-synaptic photoreceptors, detected by changes in post-synaptic agmatine permeation, and not due to the presence of anomalous metabotropic glutamate receptors. Cholinergic amacrine cells demonstrated persistant neurochemical labeling, but did not show cationic flux following stimulation by glutamate agonists. In conclusion, the retina shows remarkable recovery in the amino acid metabolism, although functional changes persist. Finally, structural integrity or immunocytochemical labeling does not necessarily imply that cells maintain functional receptors, or that neurotransmitter release is normal secondary to disease. / Whole document restricted, but available by request, use the feedback form to request access.

Ovine placental lactogen (oPL) is secreted by the placenta into both the fetal and maternal compartments. Its biological function(s) during pregnancy and the mechanisms involved are still unclear. A purification procedure was developed for oPL from sheep placental cotyledons of late gestation. Four procedures were attempted to obtain homogeneous oPL. Recoveries of oPL and total protein were measured throughout the several procedures using a specific oPL RIA and the Bradford protein estimation respectively. The third and fourth procedures resulted in homogeneous oPL and a partial amino acid sequence was obtained from the fourth procedure. In the successful procedures, the placental tissue was extracted with 0.1 M ammonium bicarbonate pH 8.5. A pH precipitation of the soluble fraction was performed, followed by 60% saturation with ammonium sulphate. Further separation steps involved chromatogaphic procedures. Carboxymethylcellulose (CM32) cation exchange was performed batchwise at pH 5.6. Subsequently chromatofocusing was performed to elute proteins in order of their isoelectric points. This was carried out using a pH gadient of 0.9 to 6.0. The final chromatographic step was reverse-phase high performance liquid chromatography (RP-HPLC) using a C4 column. To obtain homogeneous oPL in the third procedure, the partially purified oPL was subjected to SDS polyacrylamide gel electrophoresis and the separated proteins were transferred to nitrocellulose membrane. The homogeneous oPL was eluted from the membrane, however, sequencing was unsuccessful. It was assumed that the N terminal of oPL was blocked. Homogeneous oPL was obtained in the fourth procedure by electrophoretic elution from the Hunkapiller gel system performed at 4°C. The oPL was digested with trypsin, the fragments were separated by RP-HPLC chromatography and two peptides were sequenced. Peptide 1: F D E Q Y G Q G I Peptide 2: Y I N C H T Several strategies were attempted to provide more homogeneous oPL to enable more sequencing. The partially purified oPL fractions from each of these attempts were pooled and electrophoresed on an SDS polyacrylamide gel. The section of acrylamide containing the oPL band was homogenised and a trypsin digest was performed. The digested oPL was separated from the gel pieces, filtered through a Sep-Pak filter and the fragments were separated by RP-HPLC. The yield of oPL was low, but sufficient homogeneous oPL was obtained to provide a partial amino acid sequence from tryptic peptides. A further two peptides provided sequences. Peptide 3: (L) A G E M V N R F D E Q Y G Q G I Peptide 4: (L) Q P G K C Q I P L Q S L F Collaborators from Genentech Inc (San Francisco USA) used partially purified oPL produced from the present study and also obtained homogeneous oPL (Colosi et al., 1989). Complementary DNA clones of oPL were isolated and expressed in mammalian cells by recombinant DNA techniques (Colosi et al., 1989). These clones were sequenced, demonstrating that the full sequence of oPL consists of 198 amino acids preceded by a 38 amino acid sequence signal. Recombinant oPL was generated by Colosi et al. (1989) which provided sufficient material to perform physiological studies in vivo. The somatogenic effects of recombinant oPL were investigated in the growth hormone (GH) deficient dwarf rat and compared to identical doses of recombinant bovine GH (bGH) in 3 independent studies. Both oPL and bGH treatments resulted in an increase (p<0.05) in body weight gain compared to that in saline treated controls, with oPL treatment being more potent than bGH (p<0.05). In promoting linear growth, oPL was more potent (p<0.05) than bGH in some instances. Nitrogen content of dry carcass matter was increased with oPL treatment compared to saline (p<0.05), with a nonsignificant increase in bGH treated animals. Carcass fat was similarly reduced by both oPL and bGH treatment (p<0.05) compared to saline. Serum insulin-like growth factor I (IGF-I) concentrations were increased significantly (p<0.05) by both oPL and bGH treatments, with a significantly greater effect of oPL suggested in one study. No increase in hepatic IGF-I mRNA was evident with either treatment, suggesting that the increase in serum IGF-I is due to posttranscriptional mechanisms. The expression of IGF binding protein 3 (IGFBP-3) hepatic mRNA was increased (p<0.05) with bGH treatment compared to that after saline treatment, but was unaffected by opL treatment, indicating regulation by GH at the transcriptional level. The binding of [125I]bGH to hepatic membrane preparations demonstrated no difference in specific binding compared to that in saline controls. However, [125I]oPL specific binding was greater in oPL treated animals (p<0.05). Animals treated with bGH had reduced (p<0.05) hepatic GH receptor mRNA compared to saline controls, but oPL treatment had no effect. Thus, oPL is a potent anabolic and lipolytic agent in the dwarf rat, exerting greater somatogenic effects on some parameters than bGH. The studies in this thesis have described biochemical and biological characterisitics of oPL. The amino acid sequence of oPL is more closely related to prolactin (PRL) than to GH (Colosi et al., 1989). However, oPL has potent somatogenic activities in the GH deficient dwarf rat. Our data suggest differences in receptor binding and effects on GH receptor and IGFBP-3 expression with these two treatments, raising the possibility of actions through different pathways or differential effects at the GH receptor level. These results do not fully resolve whether GH and PRL exert all effects through a single receptor or whether there is a separate PL receptor.

This thesis uses the concepts and methods of community psychology, and. applies them to what is called here a “comprehensive community project”. This is a project that undertakes to meet the needs of a community by fostering and strengthening the community’s own resources. The objectives of the research were : (1) to establish a comprehensive community project in the Auckland. suburbs of Birkdale and Beachhaven, and (2) to propose and. test a model for project organization and evaluation. The model was derived. from the systems approach to programme evaluation which provides a reasoned and. logical approach to all aspects of programme management. The model proposed involved systematic steps from initial programme planning to outcome measurement. The steps are, specifying the "system” or particular project, forming the values from which interventions would be derived, assessing needs and. resources, setting annual goals for activities from the foregoing steps, allocating available resources to activities, implementing and. reviewing activities, measuring outcome after one year, and feedback of this information for project improvement. Application of the model to the “Birkdale Project” showed that the model was relevant to management needs, and. Information yielded by application of the model was used. in day-to-day decision making. Thus the model was instrumental in establishing the Birkdale Project, and. in producing the vigorous project that resulted. in the first year a wide range of activities involving a significant portion of the population were provided. to meet community needs, and almost all the Project’s annual goals were attained. Although the project was established largely by paid professionally trained people, at the end. of the research period. the project was managed and run by non-professional residents. It was concluded. that the systems approach is highly appropriate to the development of comprehensive community projects, and has general advantages to the wider field of community psychology as a method for practice and research.

Investigations were undertaken to describe and quantitate the topographical abnormalities which develop in the organ of Corti as a result of acoustic trauma, and to determine their relationship to the associated losses of cochlear function assessed by the compound action Potential (N1) and cochlear microphonics (CM). Thirty guinea pigs were exposed, while anaesthetised, to a tone of 3 KHz at 125 dB SPL for 30 minutes. Both organs of Corti were examined by scanning electron microscopy either immediately or 1,3,7 or 14 days after exposure. In the second study 26 anaesthetised guinea pigs were exposed to 5 KHz at 125 dB SPL for 30 minutes. Cochlear potentials were recorded from the round window of the right cochlea and N1 audiograms (sound Pressure level required to elicit N1 Plotted against frequency) and 10 μv isopotential curves (sound pressure level required to produce 10 μv CM plotted against frequency) were produced for each animal either within one hour or 1,7,14 or 28 days later. The same organ of Corti was examined by scanning electron microscopy. Cochlear potentials were compared to mean values from 16 normal guinea pigs. Most animals developed topographical changes in one or both organs of Corti after exposure to 3 KHz (90%) and in the right organ of Corti after 5 KHz (92%). There was a wide variation in both the length (3 KHz: 0.1-4.15 mm; 5 KHz: 0.5-16.0 mm) of lesions and the number of hair cells affected. Both these indices of damage increased significantly (p <0.01) in the 24 hours following exposure to 5 KHz. Early damage to hair cells included either collapse, fusion or loss of stereocilia and there was an increase in the proportion of affected cells towards the centre of the lesions where supporting cells were damaged also. Subsequent to exposure, collapsed stereocilia appeared to become fused and some hair cells, particularly OHC, with stereocilia abnormalities were lost. However, others, particularly IHC, remained for up to 28 days despite abnormal stereocilia. Early changes occurred around the position of maximum displacement of the basilar membrane and subsequent extension of the lesions occurred equally in both apical and basal directions. Fusion was the only stereocilia change to develop after exposure. Regions of the organ of Corti showing supporting cell damage were replaced within 3-7 days by the proliferation of inner sulcus and Claudius’ cells. The substantial initial loss of both N1 thresholds and CM sensitivity partially recovered during the first 24 hours after exposure, but paradoxically, this was associated with the significant increase in the topographical changes in the organ of Corti. N1 threshold loss occurred over all frequencies and was maximum 1/2 – 1 octave higher than the exposure frequency (5 KHz). All lesions occurred within regions corresponding to changes in N1 thresholds. In the first 24 hours topographical changes occurred over a much smaller area of the organ of Corti than indicated by changes in N1 thresholds. Seven or more days later the longer lesions (30%) reflected the extent of changes in N1 but the remainder were smaller than indicated by this functional loss. This suggests that functionally important damage to the cochlea is more extensive than indicated by hair cell loss, stereocilia abnormality or supporting cell changes in the organ of Corti. Therefore, investigations of the effects of noise should not be based simply on topographical changes in the organ of Corti as these often underestimate the extent of injury to the cochlea.

The introduction to this thesis is a literature review. Kramer, in a study commissioned by WHO, reviewed the literature prior to 1985 on low birthweight. This is extended, mainly in respect to infants who are small for gestational age with emphasis on important findings in relation to birthweight since that time. Work in New Zealand on birthweight is also summarised. The literature is also reviewed in respect to the mechanisms in the pathway between the placenta and the fetus, and in respect to recent work suggesting a link between birthweight and disease in adult life. This thesis examines factors that influence birthweight and placental weight. Birthweight for gestational age percentile curves for the New Zealand population were firstly defined. small for gestational age (SGA) infants could then be categorised. The thesis considers two sources of data, the first a cross-sectional sample of the New Zealand population from 1987 to 1990 (the control subjects of the New Zealand cot Death study, a national case-control study on sudden infant death syndrome), and the second a hospital population in Auckland (National Womens Hospital (l992)). These two datasets are investigated to determine factors that influence birthweight in a univariate situation and then in the multivariate situation. Independent variables are considered using a priori categorisations and where appropriate Quantile-Quantile (Q-Q) derived categorisations determined by producing plots of the quantiles of cases versus controls. A number of variables under the headings of socio-demographic, lifestyle, genetic, obstetric and nutrition are examined and found to be associated with the outcomes of interest at the univariate level. After controlling in multivariate analyses a number of variables are found to be no longer significant, however some show strong relationships. The variable relating to smoking in both datasets shows the greatest detrimental effect on the outcomes considered in respect to birthweight. This confirms that in New Zealand, as in other places in the world, smoking has significant consequences on birthweight. The data is also investigated for the timing of insult to the fetus from smoking, and is found to be most important during pregnancy. comparison of the results comparing those obtained using a binary outcome for SGA, and those obtained using birthweight continuously, show relatively consistent results. The odds ratios and the decreases in birthweight obtained from both datasets show a relatively linear relationship between the two. An examination into whether a distinct group of individuals exists in respect to having large placentae for birthweight, indentified an artefact in the dataset relating to recording of placental weight for twins. After removal of twins from the dataset, examination of factors that influence placental weight showed that the factors that influence placental weight are not the same as those that influence birthweight. In particular smoking is found not to influence placental weight, and haemoglobin, which has no influence on birthweight, is found to be inversely associated with placental weight. other factors such as parity are found to influence placental weight in the same proportion in which birthweight is affected. In conclusion this thesis shows that factors investigated in New Zealand are consistent with findings in the international literature in relation to birthweight. The results on factors that influence placental weight add to the international literature on a topic on which little work has been carried out. The results of this thesis point to areas where future research needs to be carried out, in particular in relation to maternal nutrition during pregnancy and maternal energy expenditure during pregnancy. There is also a need for further research into the relationships of factors on placental weight and the ratio of birthweight to placental weight, and how these relationships affect health outcomes in childhood and adult life.