ORCID Profile
0000-0002-1023-7795
Current Organisation
University of Wollongong
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Publisher: Springer Science and Business Media LLC
Date: 2007
DOI: 10.1080/13550280701258084
Abstract: Although neurological symptoms associated with cerebral malaria (CM) are largely reversible, recent studies suggest that lasting neurological sequelae can occur. This may be especially true for children, in whom persistent deficits include problems with memory and attention. Because the malaria parasite is not thought to enter the brain parenchyma, lasting deficits are likely related to factors including the host response to disease. Studies with a rodent model, and with human postmortem tissue, suggest that glial activation occurs with CM. In this review, the authors will highlight studies focused on such activation in CM. Likely causes will be discussed, which include ischemia and activation of blood brain barrier endothelial cells. The potential consequences of glial activation will also be discussed, highlighting the possibility that glial-derived proteinases contribute to structural damage of the central nervous system (CNS). Of note, for the purposes of this focused review, glial activation will refer to the activation of astrocytes and microglial cells discussion of oligodendroglial cells will not be included. In addition, although events thought to be critical to the pathogenesis of CM and glial activation will be covered, a comprehensive review of cerebral malaria will not be presented. Excellent reviews are already available, including Coltel et al (2004 Curr Neurovasc Res 1: 91-110), Medana and Turner (2006 Int J Parasitol 36: 555-568), and Hunt et al (2006 Int J Parasitol 36: 569-582).
Publisher: Wiley
Date: 03-1995
Abstract: Microglial cell activation, myelin alteration, and abundant tumor necrosis factor (TNF)-alpha message have been observed in the brains of some human immunodeficiency virus type 1 (HIV-1)-infected and demented patients. We therefore used cultures of purified human microglia and oligodendrocytes derived from adult human brain to examine the role of TNF-alpha in HIV-1 encephalopathy. Human microglia synthesize TNF-alpha message and protein in vitro. When these cells were infected with HIV-1 JrFL and maintained in the presence of TNF-alpha antibodies, soluble TNF-alpha receptors, or the TNF-alpha inhibitor pentoxifylline, viral replication was delayed or strongly inhibited. Both human microglia and oligodendrocytes express the two TNF receptors, TNF-R1, which has been implicated in cytotoxicity, and TNF-R2. While TNF-alpha may enhance HIV-1 replication in an autocrine manner, it is not toxic for microglia. In contrast, recombinant human TNF-alpha causes oligodendrocyte death in a dose-dependent manner. In situ detection of DNA fragmentation in some cells indicated that oligodendrocyte death may occur by apoptosis. Addition of live microglia or medium conditioned by these cells also resulted in 30 to 40% oligodendrocyte death, which was largely prevented by TNF-alpha inhibitors. We propose that TNF-alpha plays a dual role in HIV-1 encephalopathy, enhancing viral replication by activated microglia and damaging oligodendrocytes. Thus, TNF-alpha inhibitors may alleviate some of the neurological manifestations of acquired immunodeficiency syndrome.
Publisher: Society for Neuroscience
Date: 08-1994
DOI: 10.1523/JNEUROSCI.14-08-04571.1994
Abstract: Preoligodendrocytes have been described in cultures and tissue prints of adult human white matter (Armstrong et al., 1992). To characterize further these precursors of human oligodendrocytes, we have investigated whether they express genes playing a critical role in oligodendrocyte development. In the intact human brain, platelet- derived growth factor receptor alpha (PDGF alpha R) and myelin transcription factor 1 (MyTI) transcripts are expressed in 1–2% of cells of the oligodendrocyte lineage (OL), and clusters of such cells can be found in the periventricular region. Myelin basic protein transcripts containing exon 2 information (exon 2+ MBP), which are characteristic of the premyelinating stage, are detected in 15–20% of OL cells in vivo. When OL cells are separated from human white matter and allowed to regenerate in vitro, a much larger proportion of these cells express developmentally regulated genes, while exon 2- MBP and proteolipid protein (PLP) transcripts characteristic of mature OL cells appear transiently downregulated. Basic fibroblast growth factor (bFGF), even in the presence of PDGF, does not promote DNA synthesis in these cultured OL cells. Yet bFGF induces human oligodendrocytes to regenerate their processes rapidly in vitro and to express O4 antigens as well as exon 2+ MBP, MyTI, and PLP transcripts. While bFGF accelerates early regenerative processes, it also maintains high expression of exon 2+ MBP transcripts in OL cells for up to 2 weeks in vitro. In contrast, high levels of insulin in the absence of bFGF allow accumulation of exon 2- MBP and PLP transcripts in most OL cells at 2–3 weeks in vitro. We propose that the myelinated human brain harbors a small pool of precursors of oligodendrocytes and that growth factor- regulated phenotypic plasticity rather than mitogenic potential accounts for the regeneration of oligodendrocytes in the initial stages of demyelinating diseases such as multiple sclerosis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-04-2010
DOI: 10.1002/HEP.23712
Abstract: Iron and cholesterol are both essential metabolites in mammalian systems, and too much or too little of either can have serious clinical consequences. In addition, both have been associated with steatosis and its progression, contributing, inter alia, to an increase in hepatic oxidative stress. The interaction between iron and cholesterol is unclear, with no consistent evidence emerging with respect to changes in plasma cholesterol on the basis of iron status. We sought to clarify the role of iron in lipid metabolism by studying the effects of iron status on hepatic cholesterol synthesis in mice with differing iron status. Transcripts of seven enzymes in the cholesterol biosynthesis pathway were significantly up-regulated with increasing hepatic iron (R(2) between 0.602 and 0.164), including those of the rate-limiting enzyme, 3-hydroxy-3-methylglutarate-coenzyme A reductase (Hmgcr R(2) = 0.362, P < 0.002). Hepatic cholesterol content correlated positively with hepatic iron (R(2) = 0.255, P < 0.007). There was no significant relationship between plasma cholesterol and either hepatic cholesterol or iron (R(2) = 0.101 and 0.014, respectively). Hepatic iron did not correlate with a number of known regulators of cholesterol synthesis, including sterol-regulatory element binding factor 2 (Srebf2 R(2) = 0.015), suggesting that the increases seen in the cholesterol biosynthesis pathway are independent of Srebf2. Transcripts of genes involved in bile acid synthesis, transport, or regulation did not increase with increasing hepatic iron. This study suggests that hepatic iron loading increases liver cholesterol synthesis and provides a new and potentially important additional mechanism by which iron could contribute to the development of fatty liver disease or lipotoxicity.
Publisher: Springer Science and Business Media LLC
Date: 05-01-2016
DOI: 10.1038/MP.2015.192
Publisher: Springer Science and Business Media LLC
Date: 13-03-2011
DOI: 10.1007/S00401-011-0815-1
Abstract: Lewy bodies are made from insoluble, phosphorylated α-synuclein, but the earliest changes that precipitate such pathology still remain conjecture. In this study, we quantify and identify relationships between the levels of the main pathologic form of phosphorylated α-synuclein over the course of Parkinson's disease in regions affected early through to end-stage disease. Brain tissue s les from 33 cases at different disease stages and 13 controls were collected through the Australian Network of Brain Banks. 500 mg of frozen putamen (affected preclinically) and frontal cortex (affected late) was homogenized, fractionated and α-synuclein levels evaluated using specific antibodies (syn-1, BD Transduction Laboratories S129P phospho-α-synuclein, Elan Pharmaceuticals) and quantitative western blotting. Statistical analyses assessed the relationship between the different forms of α-synuclein, compared levels between groups, and determined any changes over the disease course. Soluble S129P was detected in controls with higher levels in putamen compared with frontal cortex. In contrast, insoluble α-synuclein occurred in Parkinson's disease with a significant increase in soluble and lipid-associated S129P, and a decrease in soluble frontal α-synuclein over the disease course. Increasing soluble S129P in the putamen correlated with increasing S129P in other fractions and regions. These data show that soluble non-phosphorylated α-synuclein decreases over the course of Parkinson's disease, becoming increasingly phosphorylated and insoluble. The finding that S129P α-synuclein normally occurs in vulnerable brain regions, and in Parkinson's disease has the strongest relationships to the pathogenic forms of α-synuclein in other brain regions, suggests a propagating role for putamenal phospho-α-synuclein in disease pathogenesis.
Publisher: Elsevier BV
Date: 07-2005
Publisher: Wiley
Date: 2000
DOI: 10.1002/1098-1136(200012)32:3<264::AID-GLIA60>3.0.CO;2-Z
Publisher: Wiley
Date: 08-2002
DOI: 10.1046/J.1471-4159.2002.01038.X
Abstract: The matrix metalloproteinases (MMPs) are a family of structurally related metalloendopeptidases so named due to their propensity to target extracellular matrix (ECM) proteins. Accumulating evidence, however, suggests that these proteases cleave numerous non-ECM substrates including enzymes and cell surface receptors. MMPs may also bind to cell surface receptors, though such binding has typically been thought to mediate internalization and degradation of the bound protease. More recently, it has been shown that MMP-1 coimmunoprecipitates with the alpha2beta1 integrin, a receptor for collagen. This association may serve to localize the enzymatic activity of MMP-1 so that collagen is cleaved and cell migration is facilitated. In other studies, however, it has been shown that integrin engagement may be linked to the activation of signaling cascades including those mediated by Gialpha containing heterotrimers. As an ex le, alpha2beta1 can form a complex with CD47 that may associate with Gialpha. In the present study we have therefore investigated the possibility that MMP-1 may affect intracellular changes that are linked to the activation of a Gi protein-coupled receptor. We show that treatment of neural cells with MMP-1 is followed by a rapid reduction in cytosolic levels of cAMP. Moreover, MMP-1 potentiates proteinase activated receptor-1 (PAR-1) agonist-linked increases in intracellular calcium, an effect which is often observed when an agonist of a Gi protein-coupled receptor is administered in association with an agonist of a Gq coupled receptor. In addition, MMP-1 stimulates pertussis toxin sensitive release ofMMP-9 both from cultured neural cells and monocyte/macrophages. Together, these results suggest that MMP-1 signals through a pertussis toxin-sensitive G protein-coupled receptor.
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.BRAINRES.2012.02.006
Abstract: Severe disruption of brain iron homeostasis can cause fatal neurodegenerative disease, however debate surrounds the neurologic effects of milder, more common iron loading disorders such as hereditary hemochromatosis, which is usually caused by loss-of-function polymorphisms in the HFE gene. There is evidence from both human and animal studies that HFE gene variants may affect brain function and modify risks of brain disease. To investigate how disruption of HFE influences brain transcript levels, we used microarray and real-time reverse transcription polymerase chain reaction to assess the brain transcriptome in Hfe(-/-) mice relative to wildtype AKR controls (age 10 weeks, n≥4/group). The Hfe(-/-) mouse brain showed numerous significant changes in transcript levels (p<0.05) although few of these related to proteins directly involved in iron homeostasis. There were robust changes of at least 2-fold in levels of transcripts for prominent genes relating to transcriptional regulation (FBJ osteosarcoma oncogene Fos, early growth response genes), neurotransmission (glutamate NMDA receptor Grin1, GABA receptor Gabbr1) and synaptic plasticity and memory (calcium/calmodulin-dependent protein kinase IIα Camk2a). As previously reported for dietary iron-supplemented mice, there were altered levels of transcripts for genes linked to neuronal ceroid lipofuscinosis, a disease characterized by excessive lipofuscin deposition. Labile iron is known to enhance lipofuscin generation which may accelerate brain aging. The findings provide evidence that iron loading disorders can considerably perturb levels of transcripts for genes essential for normal brain function and may help explain some of the neurologic signs and symptoms reported in hemochromatosis patients.
Publisher: Informa UK Limited
Date: 2016
Publisher: Wiley
Date: 06-1989
DOI: 10.1111/J.1432-1033.1989.TB14849.X
Abstract: Previous studies have shown that insulin depresses the induction of tyrosine aminotransferase by glucocorticoids in cultured fetal rat hepatocytes. However, the site at which this inhibitory effect is exerted was not elucidated, since only enzyme activity was determined in such studies. Therefore, the effect of insulin on tyrosine aminotransferase synthesis, the level of its mRNA as well as the rate of transcription of the gene in isolated nuclei have been determined. The results obtained indicate that in cultures exposed to dexamethasone, Bt2cAMP, insulin and combinations of these additives, there is an excellent correlation between the enzyme activity, enzyme synthesis and the level of mRNA. Run-on transcription experiments indicate that the reduction in the level of mRNA by insulin in dexamethasone-supplemented cultures is the result of a diminished rate of gene transcription.
Publisher: Wiley
Date: 08-2009
DOI: 10.1111/J.1445-5994.2008.01789.X
Abstract: Lower testosterone levels are associated with anaemia in older men and women. The relation between testosterone and haemoglobin (Hb) in younger and middle-aged men is less well defined. The aim of the study was to examine the association between testosterone and Hb levels in men spanning middle to older ages. A cross-sectional analysis of 492 men aged 30.7-94.5 years from the Busselton Health Survey, Western Australia, was carried out. Haemoglobin (Hb), early-morning serum total testosterone and sex hormone-binding globulin (SHBG) were measured. Free testosterone was calculated using mass action equations. Haemoglobin correlated to total and free testosterone concentrations (r= 0.13, P= 0.003 and r= 0.20, P < 0.001, respectively). Hb and SHBG were inversely correlated (r=-0.14, P= 0.001). Hb increased across lowest to highest quartiles of total testosterone (P= 0.02) and free testosterone (P < 0.001), but not SHBG. After adjusting for age, waist circumference, smoking status, alcohol consumption, renal function and ferritin, total testosterone was associated with Hb (beta= 0.037, P= 0.003) as was free testosterone (beta= 2.32, P < 0.001), whereas SHBG was not associated. Testosterone concentration modulates Hb levels in community-dwelling men across a wide age range. Further studies are needed to clarify implications of this association between testosterone and Hb in men.
Publisher: MDPI AG
Date: 21-05-2013
Publisher: Springer Science and Business Media LLC
Date: 06-2001
Abstract: This aim of the present study was to identify whether apoptotic features relate to the degree of cortical neuronal loss in cases with variable cortical degeneration. Neuronal apoptosis was assessed using histochemical and morphological criteria in cases with Alzheimer's disease (AD, n=7) or Lewy bodies (n= 11) compared with controls (n=11). AD cases had both significant plaque and tangle formation but no Lewy bodies, while cases with Lewy bodies had significant plaque formation but no tangles. Cortical sections were stained using (TdT)-mediated UTP nick end labelling (TUNEL), propidium iodide, and cell and pathology-specific labels. Cells identified as non-neuronal were excluded. Large cortical nuclei were classified as abnormal if they were TUNEL-positive with DNA condensation across the nucleus and no visible nucleolus, and further sub ided according to the presence or absence of visible neuronal cytoplasm. Nuclei were considered morphologically normal regardless of TUNEL staining if they possessed a clear nucleolus. Cortical fields containing the greatest density of TUNEL-positive nuclei were regionally s led and the proportion of all classified nuclei calculated. Analysis of variance was used to identify any significant relationships. Only AD cases had significant numbers of abnormal nuclei (23+/-6%, P=0.002) and a corresponding decrease in normal neurons (28+/-7% loss, P= 0.004). Absolute neuronal density was also decreased in AD (AD density 64+/-11% of other cases, P=0.02). Abnormal nuclei were not associated with plaque or tangle pathology. Our results suggest that nuclear abnormalities appear restricted to AD cases with substantial tau deposition and are related to the degree of neuronal degeneration.
Publisher: Elsevier BV
Date: 2008
Publisher: Public Library of Science (PLoS)
Date: 02-04-2012
Publisher: American Chemical Society (ACS)
Date: 11-1991
DOI: 10.1021/BI00108A027
Abstract: Amyloid deposits in the brains of patients with Alzheimer's disease (AD) contain a protein (beta A4) which is abnormally cleaved from a larger transmembrane precursor protein (APP). APP is believed to be normally released from membranes by the action of a protease referred to as APP secretase. Amyloid deposits have also been shown to contain the enzyme acetylcholinesterase (AChE). In this study, a protease activity associated with AChE was found to possess APP secretase activity, stimulating the release of a soluble 100K form of APP from HeLa cells transfected with an APP cDNA. The AChE-associated protease was strongly and specifically inhibited by soluble APP (10 nM) isolated from human brain. The AChE-associated protease cleaved a synthetic beta A4 peptide at the predicted cleavage site. As AChE is decreased in AD, a deficiency of its associated protease might explain why APP is abnormally processed in AD.
Publisher: Wiley
Date: 30-03-2020
DOI: 10.1002/PATH.5401
Publisher: Wiley
Date: 07-1995
DOI: 10.1111/J.1750-3639.1995.TB00607.X
Abstract: Transplantation of cells into the CNS of human patients with neurodegenerative disorders offers a radical new approach to the treatment of previously incurable diseases. Considerable success has been achieved in Parkinson's disease following transplantation of human fetal dopaminergic neurons. Disorders of myelination of the brain, of either inherited or acquired origin, might also be treated by glial cell transplantation although there are additional challenges. Cells of the oligodendrocyte lineage have been found to be capable of myelinating axons on transplantation into numerous experimental pathological environments, including the CNS of myelin mutants and focal areas of demyelination in normal animals made by injection of myelinotoxic chemicals. In general, primary cells and progenitors are likely to have the greatest myelinating capacity. Cell lines can also be used, but those driven by oncogenes may produce little myelin, and tumor formation is likely. Schwann cells are also a potential source of cells, possibly as a homograft, and may be primed by treatment ex vivo with glial growth factors. The variable CNS milieu seen in human myelin disease will mean that transplanted cells must be able to migrate appropriately and myelinate axons in an adult, pathological environment, and this awaits experimental confirmation. Physiological analysis of transplants in such situations in adult animals will provide the functional data which may expedite clinical trials.
Publisher: Wiley
Date: 23-01-2010
DOI: 10.1002/MRM.22263
Abstract: Studies of iron overload in humans and animals suggest that brain iron concentrations may be related in a regionally specific way to body iron status. However, few quantitative studies have investigated the associations between peripheral and regional brain iron in a normal elderly cohort. To examine these relationships, we used MRI to measure the proton transverse relaxation rate (R(2)) in 13 gray and white matter brain regions in 18 elderly men (average age, 75.5 years) with normal cognition. Brain R(2) values were compared with liver iron concentrations measured using the FerriScan MRI technique and serum iron indices. R(2) values in high-iron gray matter regions were significantly correlated (positively) with liver iron concentrations (globus pallidus, ventral pallidum) and serum transferrin saturation (caudate nucleus, globus pallidus, putamen) measured concurrently with brain R(2), and with serum iron concentrations (caudate nucleus, globus pallidus) measured three years before the current study. Our results suggest that iron levels in specific gray matter brain regions are influenced by systemic iron status in elderly men.
Publisher: Springer Science and Business Media LLC
Date: 2005
DOI: 10.1007/BF03033777
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.NEUINT.2010.03.015
Abstract: The effects of systemic iron overload on the brain are unclear. Microarray analysis of brain gene expression in mice following short-term iron supplementation revealed altered expression of 287 genes, although most changes were small. Transcripts for the iron storage protein ferritin light chain increased 20% (p=0.002) and transcripts for iron regulatory protein 1, which negatively regulates ferritin translation, decreased 28% (p=0.048). There were expression changes for genes involved in important brain functions such as neurotransmission and nitric oxide signaling, which is dependent on iron. Few changes related to reactive oxygen species, inflammation or apoptosis, however expression changes were observed for genes causatively linked to neurological disorders, including Charcot-Marie-Tooth disease, neuronal ceroid lipofuscinosis and mucolipidosis. The latter involve intralysosomal lipofuscin build-up that may reflect lysosomal iron accumulation. The findings suggest that high iron intake may cause subtle brain effects of clinical relevance in some circumstances.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2006
DOI: 10.1002/HEP.21526
Abstract: Hereditary hemochromatosis, characterized by iron overload in multiple organs, is one of the most common genetic disorders among Caucasians. Hepcidin, which is synthesized in the liver, plays important roles in iron overload syndromes. Here, we show that a Cre-loxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most pronounced in liver, kidney, and pancreas. Transcript levels of genes involved in intestinal iron absorption, including Dcytb, DMT1, and ferroportin, are significantly elevated in the absence of hepcidin. We demonstrate that ectopic overexpression of SMAD4 activates the hepcidin promoter and is associated with epigenetic modification of histone H3 to a transcriptionally active form. Moreover, transcriptional activation of hepcidin is abrogated in SMAD4-deficient hepatocytes in response to iron overload, TGF-beta, BMP, or IL-6. Our study uncovers a novel role of TGF-beta/SMAD4 in regulating hepcidin expression and thus intestinal iron transport and iron homeostasis [corrected]
Publisher: Wiley
Date: 06-2010
DOI: 10.1111/J.1471-4159.2010.06697.X
Abstract: Iron is essential in the brain, yet too much iron can be toxic. Tight regulation of iron in the brain may involve intrinsic mechanisms that control internal homeostasis independent of systemic iron status. Iron abnormalities occur in various neurological disorders, usually with symptoms or neuropathology associated with movement impairment or behavioral disturbances rather than cognitive impairment or dementia. Consistent with this, polymorphisms in the HFE gene, associated with the iron overload disorder hemochromatosis, show stronger associations with the movement disorder amyotrophic lateral sclerosis (motor neuron disease) than with cognitive impairment. Such associations may arise because certain brain regions involved in movement or executive control are particularly iron-rich, notably the basal ganglia, and may be highly reliant on iron. Various mechanisms, including iron redistribution causing functional iron deficiency, lysosomal and mitochondrial abnormalities or oxidative damage, could underlie iron-related neuropathogenesis. Clarifying how iron contributes causatively to neurodegeneration may improve treatment options in a range of neurodegenerative disorders. This review considers how modern molecular genetic approaches can be applied to resolve the complex molecular systems and pathways by which brain iron homeostasis is regulated and the molecular changes that occur with iron dyshomeostasis and neuropathogenesis.
Publisher: MDPI AG
Date: 28-05-2016
Publisher: Springer Science and Business Media LLC
Date: 15-02-2010
DOI: 10.1007/BF03346645
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.PHARMTHERA.2012.08.008
Abstract: The advent of real-time macromolecular sequencing is opening the way for new levels of understanding of dynamic biological states and new approaches to point-of-care diagnosis and drug discovery. This fast-growing area promises unprecedented capacity to develop detailed descriptions of biosystems in health and disease that integrate features from both inherent trait analysis (e.g. by genotyping) and dynamic analysis of transient states (e.g. by transcriptome or proteome typing). This evolving, integrated 'pharmacomics' will facilitate the characterization and monitoring of disease states and drug responses in terms of perturbations of biosystems from optimal states. This review considers how the latest generation of advances in ultra-rapid macromolecular sequencing will accelerate the evolution of personalized medicine and more systematic, rational drug discovery.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2005
DOI: 10.1002/HEP.20652
Publisher: Informa UK Limited
Date: 2017
DOI: 10.2147/PGPM.S123719
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.BIOCEL.2017.05.003
Abstract: Iron is essential for many biological processes, however, too much or too little iron can result in a wide variety of pathological consequences, depending on the organ system, tissue or cell type affected. In order to reduce pathogenesis, iron levels are tightly controlled in throughout the body by regulatory systems that control iron absorption, systemic transport and cellular uptake and storage. Altered iron levels and/or dysregulated homeostasis have been associated with several lung diseases, including chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. However, the mechanisms that underpin these associations and whether iron plays a key role in the pathogenesis of lung disease are yet to be fully elucidated. Furthermore, in order to survive and replicate, pathogenic micro-organisms have evolved strategies to source host iron, including freeing iron from cells and proteins that store and transport iron. To counter these microbial strategies, mammals have evolved immune-mediated defence mechanisms that reduce iron availability to pathogens. This interplay between iron, infection and immunity has important ramifications for the pathogenesis and management of human respiratory infections and diseases. An increased understanding of the role that iron plays in the pathogenesis of lung disease and respiratory infections may help inform novel therapeutic strategies. Here we review the clinical and experimental evidence that highlights the potential importance of iron in respiratory diseases and infections.
Publisher: Oxford University Press (OUP)
Date: 27-09-2012
Abstract: up to 25% of older people in the USA and other Western countries are anaemic by World Health Organization (WHO) criteria. The objective of this study was to examine the long-term relationships of haemoglobin concentration with all-cause and cause-specific mortality in a community-based s le of Australian adults surveyed in 1978. a community survey of 2,194 adults aged 40+ years in Busselton, Western Australia in 1978 with mortality follow-up to 2001. Cox regression models were used to investigate the relationships of haemoglobin as a continuous measure and anaemia by WHO criteria (women <12 g/dl (7.5 mmol/l) men 10 g/dl) and normocytic. There was an increased risk of death from all causes and from cancer for men with low haemoglobin. Cancers were predominantly of the prostate and genito-urinary organs, and to a lesser extent the gastrointestinal tract. There was no increased risk of all cause or cancer death in women. mild, normocytic anaemia is associated with survival reductions in middle-aged and older men, where it often occurs with prostate, gastrointestinal and other cancers, and should be investigated to exclude treatable causes.
Publisher: Elsevier BV
Date: 07-1992
DOI: 10.1016/0896-6273(92)90228-6
Abstract: The beta A4 protein, the major component of the amyloid deposition characterizing Alzheimer's disease, derives from the amyloid protein precursor (APP), an integral membrane protein with soluble derivatives. The function of APP is unknown. Both soluble and membrane-associated human brain APP (10(-10) M) significantly increased (P less than 0.025) neurite length and branching in pheochromocytoma PC12 cells, but did not affect the number of neurites per cell. At higher concentrations, APP was cytotoxic, with a half-maximal concentration of 5 x 10(-9) M. Nerve growth factor (NGF) is known to affect APP expression in vivo and in vitro. Antibodies to APP specifically diminished the effects of NGF on neurite length and branching. Thus APP may act to mediate neurite outgrowth promotion by NGF.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1999
DOI: 10.1097/00001756-199908020-00029
Abstract: The present investigation aimed to examine associations of anaemia with dementia. Analysis of community-dwelling, elderly subjects characterized for different dementias failed to confirm a previously reported association of anaemia with Alzheimer's disease (AD) but revealed instead a significant association with vascular dementia (VAD). Nearly 45% of VAD subjects were anaemic, compared with 17% of controls. Close to one-third of all subjects with haemoglobin levels > 0.5 g/dl below reference anaemia levels had VAD. Co-existing VAD may explain previous links between AD and anaemia. The association was independent of age, dementia severity and a range of other factors including vitamin B 12 and folate levels. Anaemia can exacerbate focal cerebral ischaemia and could precipitate or lify VAD symptoms in elderly subjects with vasculopathy.
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.JNEUROIM.2007.04.010
Abstract: The matrix metalloproteinases (MMPs) are expressed in response to pro-inflammatory stimuli and other triggers. The MMPs cleave numerous substrates including extracellular matrix components, cytokines and growth factors. In the CNS, while most studied in the context of disease, the many physiological functions of the MMPs are now becoming appreciated. This review provides an overview of the growing body of evidence for physiological roles of MMPs both in CNS development and in CNS plasticity in normal brain functioning, including learning and memory, as well as in CNS repair and reorganization as part of the neuroimmune response to injury.
Publisher: Elsevier BV
Date: 03-2016
Publisher: Wiley
Date: 10-1992
DOI: 10.1111/J.1471-4159.1992.TB08465.X
Abstract: The major component of the amyloid deposition that characterizes Alzheimer's disease is the 4-kDa beta A4 protein, which is derived from a much larger amyloid protein precursor (APP). A procedure for the complete purification of APP from human brain is described. The same amino terminal sequence of APP was found in two patients with Alzheimer's disease and one control subject. Two major forms of APP were identified in human brain with apparent molecular masses of 100-110 kDa and 120-130 kDa. Soluble and membrane fractions of brain contained nearly equal amounts of APP in both humans and rats. Immunoprecipitation with carboxyl terminus-directed antibodies indicates that the soluble forms of APP are truncated. Carboxyl terminus truncation of membrane-associated forms of human brain APP was also found to occur during postmortem autolysis. The availability of purified human brain APP will facilitate the investigation of its normal function and the events that lead to its abnormal cleavage in patients with Alzheimer's disease.
Publisher: Informa UK Limited
Date: 15-03-2011
Publisher: Wiley
Date: 16-03-2009
DOI: 10.1002/IJC.24304
Abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by germline mutations in DNA mismatch repair genes however, variation in disease expression suggests that there are potential modifying factors. Polymorphisms of the HFE gene, which cause the iron overload disorder hereditary haemochromatosis, have been proposed as potential risk factors for the development of colorectal cancer (CRC). To understand the relationship between HNPCC disease phenotype and polymorphisms of the HFE gene, a total of 362 in iduals from Australia and Poland with confirmed causative MMR gene mutations were genotyped for the HFE C282Y and H63D polymorphisms. A significantly increased risk of developing CRC was observed for H63D homozygotes when compared with combined wild-type homozygotes and heterozygotes (hazard ratio = 2.93, p = 0.007). Evidence for earlier CRC onset was also observed in H63D homozygotes with a median age of onset 6 years earlier than wild type or heterozygous participants (44 vs. 50 years of age). This effect was significant by all tests used (log-rank test p = 0.026, Wilcoxon p = 0.044, Tarone-Ware p = 0.035). No association was identified for heterozygosity of either polymorphism and limitations on power-prevented investigation of C282Y homozygosity or compound C282Y/H63D heterozygosity. In the Australian s le only, women had a significantly reduced risk of developing CRC when compared with men (hazard ratio = 0.58, p = 0.012) independent of HFE genotype for either single nucleotide polymorphisms. In conclusion, homozygosity for the HFE H63D polymorphism seems to be a genetic modifier of disease expression in HNPCC. Understanding the mechanisms by which HFE interrelates with colorectal malignancies could lead to reduction of disease risk in HNPCC.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.NEUROSCIENCE.2013.01.014
Abstract: Iron abnormalities within the brain are associated with several rare but severe neurodegenerative conditions. There is growing evidence that more common systemic iron loading disorders such as hemochromatosis can also have important effects on the brain. To identify features that are common across different forms of hemochromatosis, we used microarray and real-time reverse transcription polymerase chain reaction (RT-PCR) to assess brain transcriptome profiles of transferrin receptor 2 mutant mice (Tfr2(mut)), a model of a rare type of hereditary hemochromatosis, relative to wildtype control mice. The results were compared with our previous findings in dietary iron-supplemented wildtype mice and Hfe(-/-) mice, a model of a common type of hereditary hemochromatosis. For transcripts showing significant changes relative to controls across all three models, there was perfect (100%) directional concordance (i.e. transcripts were increased in all models or decreased in all models). Comparison of the two models of hereditary hemochromatosis, which showed more pronounced changes than the dietary iron-supplemented mice, revealed numerous common molecular effects. Pathway analyses highlighted changes for genes relating to long-term depression (6.8-fold enrichment, p=5.4×10(-7)) and, to a lesser extent, long-term potentiation (3.7-fold enrichment, p=0.01), with generalized reductions in transcription of key genes from these pathways, which are involved in modulating synaptic strength and efficacy and are essential for memory and learning. The agreement across the models suggests the findings are robust and strengthens previous evidence that iron loading disorders affect the brain. Perturbations of brain phenomena such as long-term depression and long-term potentiation might partly explain neurologic symptoms reported for some hemochromatosis patients.
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.4065/83.5.543
Abstract: To investigate whether citrus fruit, noncitrus fruit, and other dietary factors act as environmental modifiers of iron status in the absence or presence of hemochromatotic HFE gene mutations. Iron studies, HFE genotypic analyses, and dietary data from a survey conducted from March 21, 1994, through December 15, 1995, were analyzed for a group of 2232 residents (1105 men, 1127 women) aged 20 to 79 years recruited from the community electoral roll of Busselton in Western Australia. Data were analyzed by linear regression analysis and analysis of covariance. Higher levels of fresh fruit intake (excluding citrus fruits and citrus juices) had a significant protective effect (P=.002) against high body iron status as gauged by ferritin levels in men, irrespective of HFE genotype. Consumption of 2 or more pieces of fruit per day on average reduced mean serum ferritin levels by 20% compared with average consumption of less than 1 piece of fruit per day. This effect was not observed in women. Consumption of citrus fruits and citrus juices had no significant effects in either sex. No protective effects were observed for tea consumption or any other dietary factors studied. Red meat and alcohol consumption correlated with high body iron stores (P .05). Noncitrus fruits are environmental modifiers of iron status independent of HFE genotype. This could have important implications for the provision of evidence-based dietary advice to patients with other iron-storage disorders.
Publisher: European Respiratory Society (ERS)
Date: 17-03-2020
DOI: 10.1183/13993003.01340-2019
Abstract: Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma. We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild–moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV 1 ). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV 1 /forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules alent metal transporter 1 ( DMT1 ) and transferrin receptor 1 ( TFR1 ) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1 + macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo , including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses. Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.
Publisher: Wiley
Date: 10-1997
DOI: 10.1111/J.1460-9568.1997.TB01389.X
Abstract: Oligodendrocytes originate in different neural tube domains, within boundaries of expression of a series of patterning genes which condition the erse morphogenetic programme of each area. Although neuronal and astrocyte heterogeneity are widely accepted, and despite accumulating evidence for oligodendrocyte heterogeneity in vivo, oligodendrocytes in vitro are currently considered as a homogeneous cell population. The present investigation demonstrates that oligodendrocyte ersity can be detected in vitro and characterizes a novel morphological class of O4-positive oligodendrocyte which is consistently identifiable in rat central nervous system cultures. These cells have a very characteristic epithelioid, unbranched and often lobulated morphology which enables their identification within 2 h of plating. Immunostaining shows that this morphological type is sometimes positive for GD3, A2B5 and vimentin, and most of the time positive for Ranscht antibody, O1 and Rip but negative for glial fibrillary acidic protein, OX-42, neuron-specific enolase, nestin and erbB2. The apparent levels and/or distributions of (i) microtubules, (ii) surface glycolipids recognized by O4, O1 and Ranscht antibody, and (iii) the less specific marker carbonic anhydrase II, typically differ from those of nearby classical, branched oligodendrocytes. Cells with this epithelioid morphology also express myelin basic protein and O10 (a proteolipid protein epitope), both of which are markers for mature oligodendrocytes. Conversely, O4+/O1- cells with this membranous appearance were also seen. Although these atypical oligodendrocytes were most abundant in spinal cord cultures (representing >10% of the O4+ population), they were not exclusive to this region and occurred at a low frequency in neonatal optic nerve cultures.
Publisher: Wiley
Date: 10-03-2005
DOI: 10.1002/IJC.20983
Abstract: The MYH gene has recently been shown to be associated with a recessive form of colorectal adenomatous polyposis. Two common mutations in the MYH gene have been identified that lend themselves to rapid screening. We have examined a series of 302 in iduals comprising 120 control subjects, 120 patients diagnosed with adenomatous polyposis but without germline mutations in the APC gene and 62 patients diagnosed with familial adenomatous polyposis all harbouring confirmed causative APC germline mutations. The results reveal that MYH accounts for 16 percent of polyposis patients without germline mutations in the APC gene and that it does not appear to be a modifier gene in FAP patients diagnosed with APC germline mutations.
No related grants have been discovered for Adrienne Milward.