ORCID Profile
0000-0002-1255-2350
Current Organisations
University of Adelaide
,
Macquarie University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.JFLM.2013.05.003
Abstract: Hypothermic fatalities in humans are characterized by a range of often subtle pathological findings that typically include superficial erosive gastritis (Wischnewski spots). Experimental studies have been successfully performed using animal models to replicate this finding, however study animals have inevitably been subjected to a variety of additional stressors including food deprivation, restraint and partial immersion in water while conscious. As it is recognised that stress on its own may cause superficial erosive gastritis, a model has been developed to enable the study of the effects of hypothermia in isolation. 42 Sprague-Dawley rats were allowed free social contact and were fed and watered ad libitum prior to being anaesthetized with isoflurane. Once unconscious, rats were placed on drape cloth covering metal mesh platforms in a styrofoam box packed with ice. The apparatus enabled both maintenance of a specific low temperature (26 °C) in 14 animals, and continued reduction of core temperatures in the remaining 28 (who all died of hypothermia under anaesthesia). Examination of the gastric mucosa in both groups macroscopically and microscopically failed to demonstrate typical Wischnewski spots in any of the 42 animals. Thus, in this model, death from hypothermia occurred without the development of these lesions. These results suggest that stress may be a significant effect modifier in the development of Wischnewski spots in lethal hypothermia.
Publisher: SAGE Publications
Date: 14-05-2018
Abstract: A wide variety of neuropathological abnormalities have been investigated in infants who have died of sudden infant death syndrome (SIDS). Issues which detracted from early studies included failure to use uniform definitions of SIDS and lack of appropriately matched control populations. Development of the triple risk model focused attention on the concept of an inherent susceptibility to unexpected death in certain infants, with research demonstrating a role for the neurotransmitter serotonin within the brainstem. However, it now appears that neuropathological abnormalities in SIDS infants are more complex than a simple serotonergic deficiency in certain medullary nuclei but instead could involve failure of an integrated network of neurochemical transmitters in a variety of subcortical locations. The following overview examines recent research developments looking particularly at the potential role of the peptide neurotransmitter substance P and its neurokinin-1 receptor in multiple nuclei within the brainstem, asymmetry and microdysgenesis of the hippoc us, and decreased orexin levels within dorsomedial, perifornical, and lateral levels in the hypothalamus. Whether such research will lead to identifiable biomarker for infants at risk of SIDS is yet to be established. Use of standardized and consistent methods of classifying and categorizing infant deaths will be pivotal in generating reproducible research results.
Publisher: Springer US
Date: 16-10-2021
Publisher: Informa UK Limited
Date: 19-02-2014
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.NPEP.2018.02.006
Abstract: Victims of sudden infant death syndrome (SIDS) are believed to have an underlying dysfunction in medullary homeostatic control that impairs critical responses to life threatening challenges such as hypoxia, hypercarbia and asphyxia, often during a sleep period. This failure is thought to result from abnormalities in a network of neural pathways in the medulla oblongata that control respiration, chemosensitivity, autonomic function and arousal. Studies have mainly focused on the role of serotonin, 5-hydroxytyptamine (5HT), although the neuropeptide substance P (SP) has also been shown to play an integral role in the modulation of medullary homeostatic function, often in conjunction with 5-HT. Actions of SP include regulation of respiratory rhythm generation, integration of cardiovascular control, modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may, therefore, also play a significant role in homeostatic dysfunction of the neurotransmitter network in SIDS. This review focuses on the pathways within the medulla involving SP and its tachykinin NK1 receptor, their potential relationship with the medullary 5-HT system, and possible involvement in the pathogenesis of SIDS.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.BRAINRESBULL.2018.01.009
Abstract: Substance P (SP) and its tachykinin NK1 receptor (NK1R) function within key medullary nuclei to regulate cardiorespiratory and autonomic control. We examined the normative distribution of SP and NK1R in the serotonergic (5-Hydroxytryptamine, [5-HT]) network of the human infant medulla during postnatal development, to provide a baseline to facilitate future analysis of the SP/NK1R system and its interaction with 5-HT within pediatric brainstem disorders in early life. [
Publisher: Springer Science and Business Media LLC
Date: 14-12-2017
DOI: 10.1007/S12024-017-9941-Y
Abstract: The prone (face down) sleeping position is known to be associated with a significantly increased risk of sudden and unexpected death in infancy (sudden infant death syndrome or SIDS), however, the reasons for this are unclear. Suggested mechanisms have involved suffocation from occlusion of the external airways by soft bedding illows or from flattening of the nose with backward displacement of the tongue, rebreathing of carbon dioxide, blunting of arousal responses with decreased cardiac responses to auditory stimulation, diaphragmatic splinting or fatigue, lowering of vasomotor tone with tachycardia, nasopharyngeal bacterial overgrowth, overheating, alteration of sleep patterns, compromise of cerebral blood flow and upper airway obstruction from distortion of nasal cartilages. Recent studies have, however, shown a significant reduction in substance P in the inferior portion of the olivo-cerebellar complex in SIDS infants which is crucial for the integration of motor and sensory information for the control of head and neck movement. This deficit may explain why some infants are not able to move their faces away from potentially dangerous sleeping environments.
Publisher: Elsevier BV
Date: 2013
Publisher: Oxford University Press (OUP)
Date: 08-2017
DOI: 10.1093/JNEN/NLX071
Abstract: Serotonin (5-hydroxytryptamine [5-HT]) neurons in the medulla oblongata project extensively to key autonomic and respiratory nuclei in the brainstem and spinal cord regulating critical homeostatic functions. Multiple abnormalities in markers of 5-HT function in the medulla in sudden infant death syndrome (SIDS) have been reported, informing the hypothesis that at least a subset of SIDS cases is caused by deficits in 5-HT function resulting in impaired homeostatic responses to potentially life-threatening events during sleep. To investigate medullary 5-HT defects in SIDS further, we undertook qualitative analysis immunohistochemical assessment of 5-HT neuron expression within the medulla of SIDS infants (n41) and nonSIDS controls (n = 28) in an independent cohort from Forensic Science South Australia. Compared with controls SIDS cases had significantly higher 5-HT neuron numbers and density in addition to significantly altered 5-HT neuron morphology. Thus, for the first time, we replicated and corroborated previous observations of a significant abnormality in medullary 5-HT neuron expression in SIDS in a separate independent SIDS cohort. This study further supports the hypothesis that medullary 5-HT defects contribute to the pathogenesis of a subset of SIDS victims and provides additional evidence of a more complex abnormality in 5-HT neuron dysfunction specifically within the different caudal and rostral medullary 5-HT domains.
Publisher: Elsevier BV
Date: 2015
Publisher: Springer Science and Business Media LLC
Date: 29-01-2018
Publisher: Wiley
Date: 08-04-2014
Abstract: Case files from Forensic Science South Australia and the Swedish National Forensic Database were reviewed over a 6-year period from 2006 to 2011 for cases where hypothermia either caused, or significantly contributed to, death. Data were analyzed for age, sex, time of year/season, place of discovery, circumstances of death, and underlying medical conditions. Despite the considerable demographic, geographic, and climatological differences, hypothermic deaths occurred at very similar rates in South Australia (3.9/100,000) and Sweden (3.3/100,000). Deaths from hypothermia in South Australia occurred predominantly indoors at home addresses, involving elderly females with multiple underlying illnesses and limited outside contacts. In contrast, Swedish hypothermic deaths generally occurred outdoors and involved middle-aged elderly males. These data show that hypothermia may be a risk in warmer climates particularly for elderly, socially isolated in iduals.
Publisher: Public Library of Science (PLoS)
Date: 20-09-2017
Publisher: AMPCo
Date: 12-2012
DOI: 10.5694/MJA12.11379
Publisher: MDPI AG
Date: 11-10-2022
Abstract: Cortical organoids are 3D structures derived either from human embryonic stem cells or human induced pluripotent stem cells with their use exploding in recent years due to their ability to better recapitulate the human brain in vivo in respect to organization differentiation and polarity. Adeno-associated viruses (AAVs) have emerged in recent years as the vectors of choice for CNS-targeted gene therapy. Here we compare the use of AAVs as a mode of gene expression in cortical organoids over traditional methods such as lipofectamine and electroporation and demonstrate its ease-of-use in generating quick disease models through expression of different variants of the central gene—TDP-43—implicated in amyotrophic lateral sclerosis and frontotemporal dementia.
Publisher: Oxford University Press (OUP)
Date: 15-09-2020
DOI: 10.1093/JNEN/NLAA100
Abstract: This study proposes a practical approach, using the minimum number of brain regions and stains, to consolidate previously published neuropathological criteria into one operationalized schema to differentiate subtypes of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau). This approach uses the superior frontal and precentral cortices and hippoc us stained for phosphorylated-tau, p62 and modified Bielschowsky silver, and the midbrain stained only for modified Bielschowsky silver. Accuracy of interrater reliability was determined by 10 raters in 24 FTLD-tau cases (Pick disease = 4, corticobasal degeneration = 9, progressive supranuclear palsy = 5, globular glial tauopathy = 6) including 4 with a mutation in MAPT collected with consent by Sydney Brain Bank. All brain regions and stains assessed proved informative for accurate pathological subtyping, and many neuropathological features were identified as common across the FTLD-tau subtypes. By identifying subtype-specific neuropathological features in the sections selected, 10 independent observers assigned the cases to a FTLD-tau subtype with almost perfect agreement between raters, emphasizing the requirement for the assessment of subtype-specific features for the accurate subtyping of FTLD-tau. This study consolidates current consensus diagnostic criteria for classifying FTLD-tau subtypes with an efficient, simple and accurate approach that can be implemented in future clinicopathological studies.
Publisher: Elsevier
Date: 2016
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.JFLM.2012.11.002
Abstract: An 86-year-old woman was found dead lying on her back on the floor of an unkempt kitchen. She had last been seen four days before. Her dress was pulled up and she was not wearing underpants. The house was noted to be in "disarray" with papers covering most surfaces and the floor. Rubbish was piled up against one of the doors. At autopsy the major findings were of a fractured left neck of femur, fresh pressure areas over her right buttock, Wischnewski spots of the stomach and foci of pancreatic necrosis, in keeping with hypothermia. No significant underlying organic diseases were identified and there was no other evidence of trauma. Death was due to hypothermia complicating immobility from a fractured neck of femur. This case confirms the vulnerability of frail, elderly and socially-isolated in iduals to death from hypothermia if a significant illness or injury occurs. Additional risk factors for hypothermia are also illustrated in this case that involve inadequate housing construction with absent insulation and window double glazing. The approach to hypothermic deaths should, therefore, include checking for these features as well as measuring room and environmental temperatures, evaluating the type and quality of heating and the nature of the floor and its coverings, Given the ageing population in many Western countries, increasing social isolation of the elderly, cost of fuel and electricity, and lack of energy efficient housing, this type of death may become an increasingly witnessed occurrence during the colder months of the year.
Publisher: Springer Science and Business Media LLC
Date: 05-09-2017
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.JFLM.2013.10.020
Abstract: A review of hypothermic deaths was undertaken using cases from the Charité University, Berlin, Germany and Forensic Science South Australia, Australia. There were 16 cases from Berlin (age range 38-96 years average 68 years M:F = 13:3) Wischnewski spots were present in all 16 cases (100%), skin discolouration in nine (56%), and acute pancreatitis and muscle haemorrhage in one case each (6%). There were 62 Australian cases (age range 30-89 years average 67 years M:F = 13:18). Wischnewski spots were present in 57 (92%), skin discolouration in seven (11%), vacuolization of renal cells in six (10%), and acute pancreatitis in one (2%). Reporting of the pathological findings in hypothermia may vary among jurisdictions influenced by the location and nature of these deaths and also by reliance on particular features to make the diagnosis. In addition, it is possible that the aetiology of these markers is quite complex and involves not only a significant reduction in core temperature, but the variable and poorly-understood interaction of a number of other factors.
Publisher: MDPI AG
Date: 21-07-2021
DOI: 10.3390/IJMS22157781
Abstract: The abnormal mislocalisation and ubiquitinated protein aggregation of the TAR DNA binding protein 43 (TDP-43) within the cytoplasm of neurons and glia in the central nervous system (CNS) is a pathological hallmark of early-onset neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The pathomechanisms underlying abnormal mislocalisation and aggregation of TDP-43 remain unknown. However, there is a growing body of evidence implicating neuroinflammation and immune-mediated mechanisms in the pathogenesis of neurodegeneration. Importantly, most of the evidence for an active role of immunity and inflammation in the pathogenesis of ALS and FTD relates specifically to TDP-43, posing the question as to whether immune-mediated mechanisms could hold the key to understanding TDP-43’s underlying role in neurodegeneration in both diseases. Therefore, this review aims to piece together key lines of evidence for the specific association of TDP-43 with key immune and inflammatory pathways to explore the nature of this relationship and the implications for potential pathomechanisms underlying neurodegeneration in ALS and FTD.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2012
Publisher: Frontiers Media SA
Date: 09-2021
DOI: 10.3389/FIMMU.2021.736260
Abstract: Behavioral variant frontotemporal dementia (bvFTD) is a younger onset form of neurodegeneration initiated in the frontal and/or temporal lobes with a slow clinical onset but rapid progression. bvFTD is highly complex biologically with different pathological signatures and genetic variants that can exhibit a spectrum of overlapping clinical manifestations. Although the role of innate immunity has been extensively investigated in bvFTD, the involvement of adaptive immunity in bvFTD pathogenesis is poorly understood. We analyzed blood serum proteomics to identify proteins that are associated with autoimmune disease in bvFTD. Eleven proteins (increased: ATP5B, CALML5, COLEC11, FCGBP, PLEK, PLXND1 decreased: APOB, ATP8B1, FAM20C, LOXL3, TIMD4) were significantly altered in bvFTD with autoimmune disease compared to those without autoimmune disease. The majority of these proteins were enriched for glycoprotein-associated proteins and pathways, suggesting that the glycome is targeted in bvFTD with autoimmune disease.
Publisher: University of Adelaide Press
Date: 2018
DOI: 10.20851/SIDS-26
Publisher: Springer Science and Business Media LLC
Date: 13-08-2020
DOI: 10.1038/S41598-020-70687-7
Abstract: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that are considered to be on the same disease spectrum because of overlapping genetic, pathological and clinical traits. Changes in serum proteins in FTD and ALS are poorly understood, and currently no definitive biomarkers exist for diagnosing or monitoring disease progression for either disease. Here we applied quantitative discovery proteomics to analyze protein changes in FTD (N = 72) and ALS (N = 28) patient serum compared to controls (N = 22). Twenty three proteins were significantly altered in FTD compared to controls (increased—APOL1, C3, CTSH, EIF5A, MYH2, S100A8, SUSD5, WDR1 decreased—C1S, C7, CILP2, COMP, CRTAC1, EFEMP1, FBLN1, GSN, HSPG2, IGHV1, ITIH2, PROS1, SHBG, UMOD, VASN) and 14 proteins were significantly altered in ALS compared to controls (increased—APOL1, CKM, CTSH, IGHG1, IGKC, MYH2 decreased—C7, COMP, CRTAC1, EFEMP1, FBLN1, GSN, HSPG2, SHBG). There was substantial overlap in the proteins that were altered in FTD and ALS. These results were validated using western blotting. Gene ontology tools were used to assess functional pathways potentially dysregulated in the two diseases, and calcium ion binding and innate immunity pathways were altered in both diseases. When put together, these results suggest significant overlap in pathophysiological peripheral changes in FTD and ALS. This study represents the first proteomics side-by-side comparison of serum changes in FTD and ALS, providing new insights into under-recognized perturbed pathways and an avenue for biomarker development for FTD and ALS.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.JFLM.2013.10.014
Abstract: A rodent model was used to evaluate the association between hypothermia and basal vacuolization in renal tubular epithelial cells. 28 Sprague Dawley rats were anaesthetized in non-stressful conditions and placed two at a time into a cooling chamber. Body core temperatures dropped to a minimum of 7-10 °C, causing death under anaesthesia at times varying from 120 to 240 min. The animals were then subjected to necropsy the kidneys were removed and placed in 10% buffered formalin. Examination of haematoxylin and eosin-stained renal sections failed to reveal basal vacuolization of renal tubular epithelial cells in any of the 28 animals. In this model, no evidence of subnuclear lipid vacuolization of renal tubular cells could be demonstrated despite significant and eventually lethal hypothermia. These results lend support to the hypothesis that the basal vacuolization in hypothermia may be a manifestation of a more complex pathophysiological pathway rather than being due simply to low body core temperatures.
Publisher: MDPI AG
Date: 28-06-2019
DOI: 10.3390/IJMS20133161
Abstract: Neuroinflammation is an inflammatory response in the brain and spinal cord, which can involve the activation of microglia and astrocytes. It is a common feature of many central nervous system disorders, including a range of neurodegenerative disorders. An overlap between activated microglia, pro-inflammatory cytokines and translocator protein (TSPO) ligand binding was shown in early animal studies of neurodegeneration. These findings have been translated in clinical studies, where increases in TSPO positron emission tomography (PET) signal occur in disease-relevant areas across a broad spectrum of neurodegenerative diseases. While this supports the use of TSPO PET as a biomarker to monitor response in clinical trials of novel neurodegenerative therapeutics, the clinical utility of current TSPO PET radioligands has been h ered by the lack of high affinity binding to a prevalent form of polymorphic TSPO (A147T) compared to wild type TSPO. This review details recent developments in exploration of ligand-sensitivity to A147T TSPO that have yielded ligands with improved clinical utility. In addition to developing a non-discriminating TSPO ligand, the final frontier of TSPO biomarker research requires developing an understanding of the cellular and functional interpretation of the TSPO PET signal. Recent insights resulting from single cell analysis of microglial phenotypes are reviewed.
Publisher: Springer Science and Business Media LLC
Date: 19-07-2019
DOI: 10.1038/S41582-019-0231-Z
Abstract: Frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative disorders with different pathological signatures, genetic variability and complex disease mechanisms, for which no effective treatments exist. Despite advances in understanding the underlying pathology of FTD, sensitive and specific fluid biomarkers for this disease are lacking. As in other types of dementia, mounting evidence suggests that neuroinflammation is involved in the progression of FTD, including cortical inflammation, microglial activation, astrogliosis and differential expression of inflammation-related proteins in the periphery. Furthermore, an overlap between FTD and autoimmune disease has been identified. The most substantial evidence, however, comes from genetic studies, and several FTD-related genes are also implicated in neuroinflammation. This Review discusses specific evidence of neuroinflammatory mechanisms in FTD and describes how advances in our understanding of these mechanisms, in FTD as well as in other neurodegenerative diseases, might facilitate the development and implementation of diagnostic tools and disease-modifying treatments for FTD.
Publisher: Elsevier BV
Date: 2013
No related grants have been discovered for Fiona Bright.