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<p>Catecholamine (CAT) secretion from adrenomedullary chromaffin cells (AMCs) is essential for survival of the fetus and for adaptation of the newborn to extrauterine life. CAT secretion protects the fetus from intrauterine hypoxia (low O₂) and is required for maintaining cardiac conduction and preparing the lungs for air breathing. Asphyxial stressors (e.g. hypoxia, hypercapnia (high PCO₂), and acidosis (low pH)) arising from labor contractions and postnatal apneas, are the main stimuli for the ‘non-neurogenic’ CAT release from perinatal AMCs. In the rat, the mechanisms of hypoxia chemosensitivity in AMCs involve inhibition of a variety of K⁺ channels, leading to membrane depolarization, voltage-gated Ca²⁺ entry, and CAT secretion. The magnitude of this depolarization is regulated by the simultaneous activation of ATP-sensitive K⁺ (K_ATP) channels, which tends to hyperpolarize the membrane potential during hypoxia. Interestingly, chemosensitivity of rat AMCs and CAT secretion in response to asphyxial stressors are markedly reduced postnatally following the development of functional innervation of these cells by the splanchnic nerve.</p> <p>The primary purpose of this thesis was to delineate molecular mechanisms involved in the suppression of hypoxia and hypercapnia chemosensitivity following splanchnic innervation in neonatal rat AMCs. Experiments were designed to test the general hypothesis that the ontogeny of O₂ and CO₂ sensitivity in AMCs is regulated by the activation of postsynaptic nicotinic ACh and opioid receptor signalling pathways following innervation. Previous studies in this laboratory showed that exposure of perinatal rat AMCs to nicotine <em>in utero </em>and <em>in vitro</em> resulted in the selective blunting of hypoxia (but <em>not</em> hypercapnia) chemosensitivity. The underlying mechanism was attributable to the increased membrane hyperpolarization caused by the functional upregulation of K_ATP channels. In Chapter 2, I report the results of investigations of molecular mechanisms involved in the nicotine-induced upregulation of K_ATP channels, using a rat fetal-derived, O₂- and CO₂-sensitive immortalized chromaffin cell line (MAH cells), as a model. Exposure of MAH cells to chronic nicotine (50 μM) for 7 days in culture caused an increase in the expression of the K_ATP channel subunit, Kir6.2. This effect was blocked by α-bungarotoxin, a blocker of homomeric α7 nicotinic acetylcholine receptors (α7 nAChRs). The upregulation of Kir6.2 in MAH cells was also dependent on the transcription factor, hypoxia inducible factor (HIF)-2α. First, whereas the upregulation of Kir6.2 was present in wild type and scrambled control MAH cells, it was absent in HIF-2α-deficient (shHIF-2α) MAH cells. Second, chronic nicotine caused a progressive, time-dependent increase in HIF-2α accumulation that occurred in parallel with the increase in Kir6.2 expression. Third, chromatin immunoprecipitation (ChIP) assays revealed the binding of HIF-2α to a hypoxia response element (HRE) in the promoter region of the Kir6.2 gene. These data suggest that chronic nicotine causes the accumulation of HIF-2α which results in the transcriptional upregulation of the Kir6.2 gene. These observations were validated in an <em>in vivo</em> model where rat pups were exposed to nicotine <em>in utero</em>. Western blot analysis of adrenal gland tissues from nicotine-exposed (relative to saline-exposed) pups revealed a significant increase in Kir6.2 subunit expression and HIF-2α accumulation, and both were restricted to the medullary (but not cortical) tissue.</p> <p>Chapter 3 tested the hypothesis that postnatal innervation causes the suppression of O₂- and CO₂-chemosensitivity in neonatal AMCs via opioid receptor signalling. It was found that chronic μ- and δ-opioid agonists (2 μM) <em>in vitro </em>led to the suppression of both O₂- and CO₂-chemosensitivity; this was correlated with the upregulation of K_ATP channel expression and the downregulation of carbonic anhydrase (CA) I and II respectively. The underlying molecular and signalling mechanisms were further investigated in Chapter 4. Using the MAH cell model, it was found that exposure to a combination of μ- and δ-opioid agonists for 7 days resulted in the naloxone-sensitive upregulation of Kir6.2 subunit and the downregulation of CAII. Similar to chronic nicotine exposure, the effects of chronic opioids on the upregulation of Kir6.2 and downregulation of CAII were HIF-2α-dependent. Western blot analysis revealed that HIF-2α accumulation in opioid-treated MAH cells occurred along a time-course that paralleled the upregulation of Kir6.2 subunit. ChIP assays demonstrated the binding of HIF-2α to the promoter region of the Kir6.2 subunit gene in opioid-treated MAH cells. Moreover, PKA activity (but not PKC or CaMK) was found to be required for the effects of opioids on Kir6.2 and CAII expression, but not HIF-2α accumulation. In complementary <em>in vivo</em> studies, adrenomedullary tissues from morphine-exposed rat pups showed an increased expression of both HIF-2α and Kir6.2, and decreased expression of CA1 and II protein. These findings have uncovered novel mechanisms by which postnatal innervation contributes to the ontogeny of O₂- and CO₂-chemosensitivity in rat adrenal chromaffin cells. They also suggest mechanisms by which exposure of the fetus to nicotine in cigarette smoke or opioids from drug abuse might contribute to abnormal arousal reflexes, and pathophysiological conditions such as Sudden Infant Death Syndrome (SIDS).<strong></strong></p> / Doctor of Philosophy (PhD)

The purpose of this literature review is to describe nurses supportive function to families who lost their child in Sudden Infant Death Syndrome (SIDS) / Syftet med litteraturstudien är att beskriva sjuksköterskans stödjande funktion till familjer som förlorat sitt barn i plötslig spädbarnsdöd.

Yes / This chapter is an output from the PMI2 Project funded by the UK Department of Business, Innovation and Skills (BIS) for the benefit of the Malaysian Higher Education Sector and the UK Higher Education Sector. Any views expressed are not necessarily those of BIS, nor British Council.

Background: The death of a child has been found to have long term consequences for both individual and family functioning. This is particularly true for bereaved siblings who have been found to be at increased risk of developing mental health difficulties in later life. Literature on parental bereavement proposes that the parenting phenomenon, such as replacement child syndrome, subsequent child syndrome and the parenting paradox, which can emerge after the death of a child, may account for this. However, there is very little research on these labels of observed parenting phenomenon and, as a result, any hypothesis offered remains under elaborated. In addition, limited evidence suggests that, due to the sudden, unexpected and unexplained nature of the loss, SIDS parents are more likely to experience a greater degree of distress and adjustment difficulties than other perinatally bereaved populations. Given this, it could be hypothesised that SIDS parents may be likely to experience these parenting phenomena. Despite this, however, SIDS remains a neglected area of research. Aims: As a consequence of this research gap, the study aims to explore mothers’ experiences of parenting in their transition from being a parent unaffected by Sudden Infant Death Syndrome to a parent affected by Sudden Infant Death Syndrome. Methodology: Semi-structured interviews were conducted with seven mothers who had experienced an incident of Sudden Infant Death Syndrome. The interviews were then transcribed and analysed using Interpretative Phenomenological Analysis (IPA). Results: Five master themes emerged from the analysis: ‘Channelling the Parent Within’, a naturally developing and responsive parenting style that is facilitated by internal mechanisms, such as flexibility and confidence; ‘Parenting Outside of Yourself’, a parenting style that develops in the aftermath of a SIDS event, which is characterised by self doubt and a reliance on external mechanisms such as reassurance and restriction; ‘Restoration Through You’, the restorative effect of the subsequent and surviving children, which allows vindication and re-establishes happiness; ‘The Bitter Restoration’, a restoration that encompasses internal knowledge and external evidence of loss, including a disrupted family composition and a continued awareness of existential threat; ‘A Disruptive Appreciation’, the development of a greater appreciation for the subsequent and surviving children that impacts discipline and incorporates indulgence. These, along with the subthemes contributing to them, are presented as a narrative account. Conclusion: The results imply that mothers who have experienced a SIDS event shift into a permissive and anxious style of parenting which is characterised by safety behaviours. A model of parenting in the aftermath of SIDS has been proposed in order to explain the underlying cognitions and processes which drive this behaviour and the factors which serve to maintain it. By doing this it is hoped that, when working with bereaved parents and siblings, clinicians will be better positioned to frame parenting practices and intervene at a cognitive level.

<p>DNA samples from crime scenes or mass disasters are often limited and degraded which limits the possibility of successful traditional STR analysis. Moreover, there is a need to decrease the turnaround time in criminal investigations. These circumstances require a wider set of assays and technologies to be investigated for potential use in forensic DNA analysis, which has been explored in this thesis work. DNA analysis can also provide a useful tool in forensic pathology investigations. </p><p>In a search for mutations involved in The Sudden Infant death Syndrome (SIDS), the entire mitochondrial genome was sequenced in six SIDS infants and shorter mtDNA regions were analysed in paraffin-embedded tissues from an additional 14 SIDS cases. In this sample material no mutations associated with SIDS were found that could explain the death of these infants. </p><p>To reduce time, cost and effort related to sequencing of the mtDNA HVI/HVII regions in caseworks, a HVI/HVII mtDNA linear array assay was used as a pre-screening for exclusions of suspects or evidence samples. Using this assay, 56% of the samples involved in casework analysis could be excluded before sequencing was undertaken.</p><p>The possibility to use the new array technology was explored in a SNP assay targeting both mtDNA and nuclear SNPs. The system relies on minisequencing in solution prior to hybridisation to tag arrays. Using this system, we demonstrate a rapid, highly multiplexable and flexible array-format for SNP analysis.</p><p>The properties of the Pyrosequencing technology being a fast and user-friendly assay was utilised in a study to investigate the possibility to use this method for limited and degraded samples. Ten STR loci, overlapping with standardised kits, were genotyped in 114 Swedish individuals. We found additional variation and higher resolution of repeats at some of these loci that are not detected using standard fragment analysis.</p>

DNA samples from crime scenes or mass disasters are often limited and degraded which limits the possibility of successful traditional STR analysis. Moreover, there is a need to decrease the turnaround time in criminal investigations. These circumstances require a wider set of assays and technologies to be investigated for potential use in forensic DNA analysis, which has been explored in this thesis work. DNA analysis can also provide a useful tool in forensic pathology investigations. In a search for mutations involved in The Sudden Infant death Syndrome (SIDS), the entire mitochondrial genome was sequenced in six SIDS infants and shorter mtDNA regions were analysed in paraffin-embedded tissues from an additional 14 SIDS cases. In this sample material no mutations associated with SIDS were found that could explain the death of these infants. To reduce time, cost and effort related to sequencing of the mtDNA HVI/HVII regions in caseworks, a HVI/HVII mtDNA linear array assay was used as a pre-screening for exclusions of suspects or evidence samples. Using this assay, 56% of the samples involved in casework analysis could be excluded before sequencing was undertaken. The possibility to use the new array technology was explored in a SNP assay targeting both mtDNA and nuclear SNPs. The system relies on minisequencing in solution prior to hybridisation to tag arrays. Using this system, we demonstrate a rapid, highly multiplexable and flexible array-format for SNP analysis. The properties of the Pyrosequencing technology being a fast and user-friendly assay was utilised in a study to investigate the possibility to use this method for limited and degraded samples. Ten STR loci, overlapping with standardised kits, were genotyped in 114 Swedish individuals. We found additional variation and higher resolution of repeats at some of these loci that are not detected using standard fragment analysis.

Title from PDF of title page. / Document formatted into pages; contains 62 pages. / Thesis (M.S.P.H.)--University of South Florida, 2003. / Includes bibliographical references. / Text (Electronic thesis) in PDF format. / ABSTRACT: Sudden Infant Death Syndrome (SIDS) is the third leading cause of infant mortality between birth and the first year of life in the United States. Along with the identication of various maternal risk factors, the role of fetal hypoxia has been hypothesized to be one of many causal factors associated with SIDS. The purpose of this study was to develop a profile of the SIDS infant and assess whether six pregnancy complications consistent with fetal hypoxia were associated with the increased outcome of SIDS. The secondary data analysis of Florida linked birth to death certificate data specific to Hillsborough County and Duval County were analyzed retrospectively for the period of time between 1998 and 2000. Of the 86, 342 births, 69 SIDS cases were identified, 34 in Hillsborough County and 35 in Duval County. / A majority of the infants were White males with an average age of death of 80 days. The Chi-Square test for Independence with Cramer's V, odds ratios and 95% confidence intervals were calculated to determine if an association existed between pregnancy complications, specific maternal risk factors and SIDS. Eclampsia was the only statistically significant prenatal complication found in this cohort (OR=4.67: 95% CI 1.49, 14.57). Maternal tobacco use (OR= 3.13: 95% CI 1.83, 5.36) and late initiation into prenatal care were also found to be significant in the SIDS cases, with the greatest risk occuring in women who did not receive prenatal care (OR=4.37: 95% CI 1.38, 13.89). These findings will assist with the development of a profile of infants who are at greater risk of dying of SIDS in Hillsborough County and Duval County as well as contribute to what is currently known about the association between fetal hypoxia and SIDS. / System requirements: World Wide Web browser and PDF reader. / Mode of access: World Wide Web.

A brainstem-related abnormality in respiratory control appears to be one of the most compelling mechanisms for sudden infant death syndrome (SIDS). The elements calcium, copper, iron, potassium, magnesium, sodium, phosphorus, sulfur, and zinc were analyzed by inductively coupled plasma atomic emission spectroscopy in the brainstem of 30 infants who died from SIDS and 10 infants who died from other causes (control). No differences were found between SIDS and control for any element except for more calcium in the SIDS group. A multivariate analysis of the data failed to group the majority of SIDS and control subjects in different clusters. Further research is required to determine the biological significance of the higher calcium found in the SIDS group.,

Sudden Infant Death (SIDS) has been associated with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, an inborn error of fatty acid oxidation. Blood and tissue samples from a large cohort of SIDS victims were analyzed for the presence of dodecanoic acid (C₁₂) by gas chromatography. A subgroup of these cases had a significantly higher blood concentration than age-matched controls, suggesting MCAD deficiency. An animal study using Sprague-Dawley rats was done to mimic the effects of MCAD deficiency. Significantly increased blood concentrations of dodecanoic acid were observed. Decreased values in heart and liver were puzzling findings. The data indicate that dodecanoic acid is a blood marker for MCAD deficiency.