ORCID Profile
0000-0002-8667-203X
Current Organisation
University of Adelaide
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Physiology | Cell Development (Incl. Cell Division And Apoptosis) | Physiology Not Elsewhere Classified | Genetic Development (Incl. Sex Determination) | Animal Physiology - Cell | Systems Physiology | Gene Expression | Cardiology (Incl. Cardiovascular Diseases) | Genetics | Genetic Immunology | Cellular Nervous System | Animal Physiology—Systems | Nutritional Physiology |
ANZSRC Socio-Economic Objective (SEO)
Biological sciences | Clinical health not specific to particular organs, diseases and conditions | Livestock not elsewhere classified | Cardiovascular System and Diseases | Diabetes | Digestive System Disorders | Immune system and allergy | Cardiovascular system and diseases | Reproductive system and disorders | Treatments (e.g. chemicals, antibiotics) | Cancer and related disorders
Related Links
Publications
A non-canonical role for desmoglein-2 in endothelial cells: implications for neoangiogenesis
Publisher: Springer Science and Business Media LLC
Date: 23-06-2016
DOI: 10.1007/S10456-016-9520-Y
Abstract: Desmogleins (DSG) are a family of cadherin adhesion proteins that were first identified in desmosomes and provide cardiomyocytes and epithelial cells with the junctional stability to tolerate mechanical stress. However, one member of this family, DSG2, is emerging as a protein with additional biological functions on a broader range of cells. Here we reveal that DSG2 is expressed by non-desmosome-forming human endothelial progenitor cells as well as their mature counterparts [endothelial cells (ECs)] in human tissue from healthy in iduals and cancer patients. Analysis of normal blood and bone marrow showed that DSG2 is also expressed by CD34(+)CD45(dim) hematopoietic progenitor cells. An inability to detect other desmosomal components, i.e., DSG1, DSG3 and desmocollin (DSC)2/3, on these cells supports a solitary role for DSG2 outside of desmosomes. Functionally, we show that CD34(+)CD45(dim)DSG2(+) progenitor cells are multi-potent and pro-angiogenic in vitro. Using a 'knockout-first' approach, we generated a Dsg2 loss-of-function strain of mice (Dsg2 (lo/lo)) and observed that, in response to reduced levels of Dsg2: (i) CD31(+) ECs in the pancreas are hypertrophic and exhibit altered morphology, (ii) bone marrow-derived endothelial colony formation is impaired, (iii) ex vivo vascular sprouting from aortic rings is reduced, and (iv) vessel formation in vitro and in vivo is attenuated. Finally, knockdown of DSG2 in a human bone marrow EC line reveals a reduction in an in vitro angiogenesis assay as well as relocalisation of actin and VE-cadherin away from the cell junctions, reduced cell-cell adhesion and increased invasive properties by these cells. In summary, we have identified DSG2 expression in distinct progenitor cell subpopulations and show that, independent from its classical function as a component of desmosomes, this cadherin also plays a critical role in the vasculature.
Human adult dental pulp stem cells enhance poststroke functional recovery through non-neural replacement mechanisms
Publisher: Oxford University Press (OUP)
Date: 22-02-2012
Abstract: Human adult dental pulp stem cells (DPSCs), derived from third molar teeth, are multipotent and have the capacity to differentiate into neurons under inductive conditions both in vitro and following transplantation into the avian embryo. In this study, we demonstrate that the intracerebral transplantation of human DPSCs 24 hours following focal cerebral ischemia in a rodent model resulted in significant improvement in forelimb sensorimotor function at 4 weeks post-treatment. At this time, 2.3 ± 0.7% of engrafted cells had survived in the poststroke brain and demonstrated targeted migration toward the stroke lesion. In the peri-infarct striatum, transplanted DPSCs differentiated into astrocytes in preference to neurons. Our data suggest that the dominant mechanism of action underlying DPSC treatment that resulted in enhanced functional recovery is unlikely to be due to neural replacement. Functional improvement is more likely to be mediated through DPSC-dependent paracrine effects. This study provides preclinical evidence for the future use of human DPSCs in cell therapy to improve outcome in stroke patients.
Adult human dental pulp stem cells promote blood-brain barrier permeability through vascular endothelial growth factor-a expression
Publisher: SAGE Publications
Date: 02-10-2016
Abstract: Stem cell therapy is a promising new treatment option for stroke. Intravascular administration of stem cells is a valid approach as stem cells have been shown to transmigrate the blood–brain barrier. The mechanism that causes this effect has not yet been elucidated. We hypothesized that stem cells would mediate localized discontinuities in the blood–brain barrier, which would allow passage into the brain parenchyma. Here, we demonstrate that adult human dental pulp stem cells express a soluble factor that increases permeability across an in vitro model of the blood–brain barrier. This effect was shown to be the result of vascular endothelial growth factor-a. The effect could be lified by exposing dental pulp stem cell to stromal-derived factor 1, which stimulates vascular endothelial growth factor-a expression. These findings support the use of dental pulp stem cell in therapy for stroke.
Ischaemic stroke among young people aged 15 to 50 years in Adelaide, South Australia
Publisher: AMPCo
Date: 11-2011
DOI: 10.5694/MJA11.10558
Association of the phosphodiesterase 4D (PDE4D) gene and cardioembolic stroke in an Australian cohort
Publisher: SAGE Publications
Date: 11-10-2011
DOI: 10.1111/J.1747-4949.2011.00616.X
Abstract: Large-scale epidemiological studies support an important role for susceptibility genes in the pathogenesis of ischemic stroke, with phosphodiesterase 4D identified as the first gene predisposing to ischemic stroke. Several single nucleotide polymorphisms within the phosphodiesterase 4D gene have been implicated in the pathogenesis of stroke. Undertake a multivariate analysis of six single nucleotide polymorphisms within the phosphodiesterase 4D gene in a previously defined Australian stroke cohort, to determine whether these single nucleotide polymorphisms have an association with ischemic stroke. This case–control study was performed using an existing genetic database of 180 ischemic stroke patients and 301 community controls, evaluated previously for cerebrovascular risk factors (hypertension, hypercholesterolemia, diabetes, paroxysmal atrial fibrillation, smoking and history of stroke in a first-degree relative). Based on previously reported associations with large vessel disease, ischemic stroke, cardioembolic stroke or a mixture of these, six single nucleotide polymorphisms in the phosphodiesterase 4D gene were selected for study, these being single nucleotide polymorphisms 13, 19, rs152312, 45, 83 and 87, based on previously utilized DeCODE nomenclature. Single nucleotide polymorphisms were genotyped using a sequence-specific polymerase chain reaction method and gel electrophoresis. Logistic regression was undertaken to determine the relevance of each polymorphism to stroke. Further analysis was undertaken to determine the risk of stroke following stratification for stroke sub-type and etiology. Significant odds ratios were found to be associated with cardioembolic strokes in two single nucleotide polymorphisms: rs152312 and SNP 45 ( P ·05). Our findings demonstrated an association between cardioembolic stroke and phosphodiesterase 4D single nucleotide polymorphisms rs152312 and 45. No significant association was found for the other four single nucleotide polymorphisms investigated within the phosphodiesterase 4D gene. We propose that the results from this Australian population support the concept that a large prospective international study is required to investigate the role of phosphodiesterase 4D in the cardiogenic cause of ischemic stroke.
Significant increase in thrombolysis therapy rates for stroke in South Australia
Publisher: SAGE Publications
Date: 16-06-2015
DOI: 10.1111/IJS.12498
A case of presumptive primary lateral sclerosis with upper and lower motor neurone pathology
Publisher: Elsevier BV
Date: 08-2005
DOI: 10.1016/J.JOCN.2004.08.032
Abstract: Motor Neurone Disease (MND) is one of the commonest neurodegenerative disorders of adulthood. MND characteristically presents with a combination of both upper and lower motor neurone features. Primary Lateral Sclerosis (PLS) is thought to be a variant of MND presenting with purely upper motor neurone signs. Debate continues over whether PLS constitutes a distinct pathological entity or whether it is part of the spectrum of motor neurone diseases that present as an upper motor neurone-predominant form of MND. We present a case of MND with purely upper motor neurone features and a prominent pain component. A pre-mortem diagnosis of PLS was made, however autopsy findings demonstrated both upper and lower motor neurone involvement. We believe these findings support the view that PLS is not a discrete pathological entity, but that it is a part of the range of motor neurone diseases that present with predominant but not exclusive upper motor neurone involvement. This case also highlights the feature that pain may be associated with MND even though it is not appreciated to have a sensory pathology.
Transient Ischaemic Attack (TIA) Knowledge in General Practice: A cross-sectional study of Western Adelaide general practitioners
Publisher: Springer Science and Business Media LLC
Date: 07-06-2012
Plasma angiopoietin-1 is lower after ischemic stroke and associated with major disability but not stroke incidence
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2014
DOI: 10.1161/STROKEAHA.113.004339
Abstract: Studies in rodent models suggest that upregulating angiopoietin-1 (Angpt1) improves stroke outcomes. The aims of this study were to assess the association of plasma Angpt1 with stroke occurrence and outcome. Plasma Angpt1 was measured in 336 patients who had experienced a recent stroke and 321 healthy controls with no stroke history. Patients with stroke (n=285) were reassessed at 3 months and plasma Angpt1 concentration on admission compared between those with severe and minor disability as assessed by the modified Rankin scale. In a separate cohort of 4032 community-acquired older men prospectively followed for a minimum of 6 years, the association of plasma Angpt1 with stroke incidence was examined. Median plasma Angpt1 was 3-fold lower in patients who had experienced a recent stroke (6.42, interquartile range, 4.26–9.53 compared with 17.36 interquartile range, 14.01–22.46 ng/mL P .001) and remained associated with stroke after adjustment for other risk factors. Plasma Angpt1 concentrations on admission were lower in patients who had severe disability or died at 3 months (median, 5.52 interquartile range, 3.81–8.75 ng/mL for modified Rankin scale 3–6 n=91) compared with those with minor disability (median, 7.04 interquartile range, 4.75–9.92 ng/mL for modified Rankin scale 0–2 n=194), P =0.012, and remained negatively associated with severe disability or death after adjusting for other risk factors. Plasma Angpt1 was not predictive of stroke incidence in community-dwelling older men. Plasma Angpt1 concentrations are low after ischemic stroke particularly in patients with poor stroke outcomes at 3 months. Interventions effective at upregulating Angpt1 could potentially improve stroke outcomes.
Effects of Npas4 deficiency on anxiety, depression-like, cognition and sociability behaviour
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.BBR.2014.12.044
Abstract: The transcription factor neuronal PAS domain-containing protein 4 (Npas4), which regulates the formation of inhibitory synapses on excitatory neurons, has been suggested as a candidate gene for neurological and psychiatric conditions such as bipolar depression, autism spectrum and cognitive disorders. A mouse model of Npas4 deficiency has been developed to investigate any role in these disorders. Behavioural characterisation of Npas4(-/-), Npas4(+/-) and Npas4(+/+) mice has been conducted using the open field, elevated zero maze (EZM), Y-maze, sociability test and forced swim test (FST) to investigate a range of behaviours. Npas4(-/-) mice spent more time in the open arm of the EZM than other genotypes, suggesting decreased anxiety-like behaviour. Npas4(+/-) mice, however, were more immobile in the FST than other genotypes, suggesting increased depression-like behaviour, and also showed impaired spatial recognition memory in the Y-maze. There were no differences between genotype in social behaviour. These results suggest that differential levels of Npas4 expression in the brain may regulate anxiety, depression and cognition related disorders.
Response [2]
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2006
Human osteosarcoma expresses specific ephrin profiles
Publisher: Wiley
Date: 31-07-2002
DOI: 10.1002/CNCR.10749
Abstract: The molecular mechanisms underlying malignancy of osteosarcoma are unknown. It has been reported that eph receptor protein tyrosine kinases and their ligands, ephrins, are associated with increased tumorigenicity in patients with breast carcinoma and melanoma. The expression and role of eph/ephrins in human osteosarcoma has not yet been characterized. Ephrin-A1, ephrin-A3, ephrin-A4, ephrin-A5, ephrin-B1, ephrin-B2, and ephrin-B3 mRNA expression was examined by reverse transcription polymerase chain reaction analysis in nine specimens of human osteosarcoma tissue and five human osteosarcoma cell lines. Ephrin-B1 protein expression was detected immunohistochemically in human osteosarcoma tissue. Clinicopathologic correlation was made between the osteosarcoma specimens and their ephrin expression profiles. Normal bone specimens, osteosarcoma tissue specimens, and osteosarcoma cell lines expressed a distinct mRNA profile of ephrin-A1, ephrin-A4, and ephrin-B2. A second mRNA profile that included ephrin-A3, ephrin-A5, and ephrin-B1 was expressed by a subset of tumors. The expression of ephrin-B1 was correlated with a poorer clinical prognosis. Ephrin-B1 protein was expressed by osteosarcoma cells and blood vessels. The results of this study suggest that ephrin-B1 expressed by osteosarcoma may be a poor prognostic marker through increased tumorigenicity.
A reduction in Npas4 expression results in delayed neural differentiation of mouse embryonic stem cells
Publisher: Springer Science and Business Media LLC
Date: 08-05-2014
DOI: 10.1186/SCRT453
EphB/ephrin-B interactions mediate human MSC attachment, migration and osteochondral differentiation
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.BONE.2010.10.180
Abstract: Bone marrow derived mesenchymal stem/stromal cells (MSC) contribute to skeletal tissue formation and the regulation of haematopoiesis. The Eph/ephrin family of receptor tyrosine kinases is potentially important in the maintenance of the stem cell niche within neural, intestinal and dental tissues and has recently been shown to play a role in regulating bone homeostasis. However, the contribution of EphB/ephrin-B molecules in human MSC function remains to be determined. In the present study, EphB and ephrin-B molecules were expressed by ex vivo expanded human MSC populations and within human bone marrow trephine s les. To elucidate the contribution of EphB/ephrin-B molecules in MSC recruitment, we performed functional spreading and migration assays and showed that reverse ephrin-B signalling inhibited MSC attachment and spreading by activating Src-, PI3Kinase- and JNK-dependent signalling pathways. In contrast, forward EphB2 signalling promoted MSC migration by activating the Src kinase- and Abl-dependent signalling pathways. Furthermore, activation of ephrin-B1 and/or ephrin-B2 molecules expressed by MSC was found to increase osteogenic differentiation, while ephrin-B1 activation promoted chondrogenic differentiation. These observations suggest that EphB/ephrin-B interactions may mediate the recruitment, migration and differentiation of MSC during bone repair.
An essential function for the centrosomal protein NEDD1 in zebrafish development
Publisher: Springer Science and Business Media LLC
Date: 12-02-2010
DOI: 10.1038/CDD.2010.12
Abstract: The centrosome is the primary microtubule organising centre of the cell. It is composed of many proteins, some of which make up the core of the centrosome, whereas others are used for specific functions. Although the cellular roles of many centrosomal proteins are well defined, much less is known about their functions and the role of the centrosome in development. In this study we investigated the function of NEDD1, a critical component of the centrosome essential for microtubule nucleation, in zebrafish (Danio rerio) development. The zebrafish homologue of NEDD1 (zNEDD1) was cloned and found to have a similar localisation and function to mammalian NEDD1. We show that zNEDD1 is essential for survival, as a high level of knockdown was embryonic lethal. Partial knockdown of zNEDD1 caused abnormalities including an increase in mitotic and apoptotic cells. Pronounced phenotypic defects were seen in the brain, with a lack of defined brain structures, incomplete neural tube formation and a disorganisation of neurons. In addition, we show that a reduction in zNEDD1 resulted in the loss of gamma-tubulin at the centrosome. Our data thus demonstrate that zNEDD1 is critical for the recruitment of gamma-tubulin to the centrosome, and is essential for the proper development of zebrafish.
Nedd1 expression as a marker of dynamic centrosomal localization during mouse embryonic development
Publisher: Springer Science and Business Media LLC
Date: 02-2008
DOI: 10.1007/S00418-008-0392-0
Abstract: As the primary microtubule-organizing centre of the mammalian cell, the centrosome plays many important roles during cell growth and organization. This is evident across a broad range of cell types and processes, such as the proliferation, differentiation and polarity of neural cells. Additionally, given its localization and function, there are likely to be many more processes that rely on the centrosome that have not yet been characterized. Currently, little is known about centrosomal dynamics during mammalian development. In this study, we have analyzed Nedd1 protein expression to characterize the localization of the centrosome during some aspects of mouse embryogenesis. Using a Nedd1 antibody we have demonstrated the colocalization of Nedd1 with centrosomal markers. We found strong expression of Nedd1, and therefore the centrosome, in highly proliferating cells during neural development. Additionally, Nedd1 was found to have high expression in the cytoplasm of a subset of cells in the dorsal root ganglia. We have also shown a distinct, polarized centrosomal localization of Nedd1 in the developing lens, retina and other polarized tissues. This study reveals the localization of Nedd1 and the centrosome during important processes in mouse embryogenesis and provides a basis for further study into its role in development.
Activating mutation of the renal epithelial chloride channel ClC-Kb predisposing to hypertension [2]
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2006
Upregulation of the neuronal P er‐A rnt‐S im domain protein 4 (N pas4) in the rat corticolimbic system following focal cerebral ischemia
Publisher: Wiley
Date: 22-02-2013
DOI: 10.1111/EJN.12163
Abstract: The neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an important transcriptional regulator of synaptic plasticity and cognition. The present study characterises the in vivo neuroanatomical expression pattern of the Npas4 protein in a rat model of focal cerebral ischemia. Animals were subjected to unilateral middle cerebral artery occlusion for 2 h, after which the spatiotemporal and neuronal profiles of Npas4 protein expression were analysed by immunohistochemistry at different time points post-reperfusion. Focal cerebral ischemia induced an early, transient and robust upregulation of Npas4 in a brain region-dependent manner involving predominantly principal neurons. Interestingly, we observed a unique differential induction of Npas4 protein expression in corticolimbic regions of the rat brain that are critically linked to cognition and emotion. These findings suggest that stroke-induced Npas4 upregulation may be involved in a transcriptional regulatory program within the corticolimbic circuitry following an ischemic insult.
Role of vasodilation in cognitive impairment
Publisher: SAGE Publications
Date: 11-05-2011
Implanted adult human dental pulp stem cells induce endogenous axon guidance
Publisher: Oxford University Press (OUP)
Date: 04-06-2009
DOI: 10.1002/STEM.138
Abstract: The human central nervous system has limited capacity for regeneration. Stem cell-based therapies may overcome this through cellular mechanisms of neural replacement and/or through molecular mechanisms, whereby secreted factors induce change in the host tissue. To investigate these mechanisms, we used a readily accessible human cell population, dental pulp progenitor/stem cells (DPSCs) that can differentiate into functionally active neurons given the appropriate environmental cues. We hypothesized that implanted DPSCs secrete factors that coordinate axon guidance within a receptive host nervous system. An avian embryonic model system was adapted to investigate axon guidance in vivo after transplantation of adult human DPSCs. Chemoattraction of avian trigeminal ganglion axons toward implanted DPSCs was mediated via the chemokine, CXCL12, also known as stromal cell-derived factor-1, and its receptor, CXCR4. These findings provide the first direct evidence that DPSCs may induce neuroplasticity within a receptive host nervous system. Disclosure of potential conflicts of interest is found at the end of this article.
Group organization and communities of practice in translational research: A case study of a research team
Publisher: SAGE Publications
Date: 18-12-2014
Functional Health Literacy is Significantly Associated with Risk Factors for Stroke in a Population Sample
Publisher: SAGE Publications
Date: 16-03-2015
DOI: 10.1111/IJS.12425
Fibre-optic photochemical stroke: Generating and measuring photochemical changes inside the brain
Publisher: SPIE
Date: 02-06-2014
DOI: 10.1117/12.2071261
Growth factors: Potential therapeutic applications in neurology
Publisher: BMJ
Date: 12-1994
Polygenic overlap between kidney function and large artery atherosclerotic stroke.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
DOI: 10.1161/STROKEAHA.114.006609
Abstract: Epidemiological studies show strong associations between kidney dysfunction and risk of ischemic stroke (IS), the mechanisms of which are incompletely understood. We investigated whether these associations may reflect shared heritability because of a common polygenic basis and whether this differed for IS subtypes. Polygenic models were derived using genome-wide association studies meta-analysis results for 3 kidney traits: estimated glomerular filtration rate using serum creatinine (eGFRcrea: n=73 998), eGFR using cystatin C (eGFRcys: n=22 937), and urinary albumin to creatinine ratio (n=31 580). For each, single nucleotide polymorphisms passing 10 P value thresholds were used to form profile scores in 4561 IS cases and 7094 controls from the United Kingdom, Germany, and Australia. Scores were tested for association with IS and its 3 aetiological subtypes: large artery atherosclerosis, cardioembolism, and small vessel disease. Polygenic scores correlating with higher eGFRcrea were associated with reduced risk of large artery atherosclerosis, with 5 scores reaching P .05 (peak P =0.004) and all showing the epidemiologically expected direction of effect. A similar pattern was observed for polygenic scores reflecting higher urinary albumin to creatinine ratio, of which 3 associated with large artery atherosclerosis (peak P =0.01) and all showed the expected directional association. One urinary albumin to creatinine ratio–based score also associated with small vessel disease ( P =0.03). The global pattern of results was unlikely to have occurred by chance ( P =0.02). This study suggests possible polygenic correlation between renal dysfunction and IS. The shared genetic components may be specific to stroke subtypes, particularly large artery atherosclerotic stroke. Further study of the genetic relationships between these disorders seems merited.
Reasons for persistent disability in Guillain-Barre syndrome
Publisher: SAGE Publications
Date: 02-1993
DOI: 10.1177/026921559300700101
Abstract: The reasons for persistent disability in 10 Guillain-Barre syndrome patients were investigated. Patients were assessed between 11 and 35 months after disease onset with impairment, disability and handicap scales, a standard neurological examination and nerve conduction studies. All patients showed persistent limb weakness which affected independence in self-care in three patients and the pursuit of leisure and work activities in eight patients. The implications for clinical practice are discussed.
Cytokines which signal through the LIF receptor and their actions in the nervous system
Publisher: Elsevier BV
Date: 08-1997
DOI: 10.1016/S0301-0082(97)00020-8
Abstract: A number of different cytokines, each initially characterized on the basis of very different biological activities, all have very similar signalling pathways and share a similar tertiary structure. These cytokines include leukaemia inhibitory factor, ciliary neuronotrophic factor, oncostatin M, growth-promoting activity and cardiotrophin 1. They all have been found to regulate a number of properties of cells of the developing and mature nervous system in vitro and thus are neuroregulatory cytokines. The actions of these cytokines include regulation of neurotransmitter phenotype, differentiation of neuronal precursor cells both in the peripheral nervous system and in the spinal cord, survival of differentiated neurons, and regulation of development of both astrocytes and oligodendrocytes. In addition, studies in animal models show that these factors can rescue sensory and motor neurons from axotomy-induced cell death, which suggests that they can act as trauma factors for injured neurons. Analysis of the expression patterns of the different neuroregulatory cytokines and their receptors reveals that the receptors are expressed throughout nervous system development and following trauma, whereas the cytokines show temporal and spatial specific expression patterns. This is consistent with the idea that specific cytokines have specific roles in neural development and repair, but that their signalling pathways are shared. The phenotypes of the receptor knockouts show clear deficits in nervous system development, indicating a crucial role for LIF receptor signalling. Knockouts of in idual cytokines are less dramatic, but LIF and CNTF knockouts do reveal deficits in maintenance of motor neurons or following trauma. Thus, whereas LIF and CNTF have clear roles in maintenance and following trauma, it is unclear which of the cytokines is involved in nervous system development. In clinical terms, these findings add further support to the use of these cytokines in nervous system trauma and disease.
Motor axon pathfinding in the peripheral nervous system
Publisher: Elsevier BV
Date: 11-2000
DOI: 10.1016/S0361-9230(00)00381-6
Abstract: Functional motor performance is dependent upon the correct assemblage of neural circuitry, a process initiated during embryonic development. How is the complicated neural circuitry that underlies functional behavior formed? During early stages of development, motor neurons extend their axons in a precise manner to their target destinations where they form fine synaptic connections. This process is not random but rather, highly stereotyped and specific. Results of recent studies indicate that positive and negative molecules influence particular steps in the navigation of motor axons to their targets. These molecules include, but are not limited to, members of the Semaphorin family and their receptors, Neuropilins and Plexins, Slits and their Robo receptors, members of the Eph family, extracellular matrix molecules, Hepatocyte Growth Factor/Scatter Factor, peanut agglutinin-binding glycoproteins, and neural cell adhesion molecule. The developing avian peripheral nervous system has served as an excellent model system for many years for studies of the basic cellular interactions that underlie motor axon pathfinding. The principal advantage for the experimental use of the avian embryo is the ease of access to early developmental events. Fine microsurgical manipulations, difficult at best in mouse embryonic development, are readily accomplished in avian embryos and have provided a powerful approach to unraveling the cellular interactions that govern motor axon pathfinding. These approaches, combined in recent years with molecular biology, have begun to produce critical insights into the mechanisms that sculpt cellular architecture during neural development.
Antibodies to gangliosides in guillain-Barré syndrome: Specificity and relationship to clinical features
Publisher: Oxford University Press (OUP)
Date: 02-1993
Endovascular Treatment for Acute Ischemic Stroke: Experience in South Australia
Publisher: SAGE Publications
Date: 23-07-2015
DOI: 10.1111/IJS.12580
The engraftment of transplanted primary neuroepithelial cells within the postnatal mouse brain
Publisher: Elsevier BV
Date: 11-1994
DOI: 10.1016/0304-3940(94)90576-2
Abstract: Primary neuroepithelial precursor cells carrying the reporter gene lacZ were transplanted into postnatal murine brain and assessed for their engraftment capacity. Freshly dissected precursors, derived from lacZ transgenic embryonic day 10 mouse brain, predominantly engrafted as discrete clusters, whereas the same precursors cultured in vitro with fibroblast growth factor-2, engrafted as single cells within the parenchyma of the hippoc us. Approximately 0.5% of the transplanted cells survived in the host brain for up to 3 months. Many of these cells displayed neuronal and astrocyte morphologies. These observations suggest that transplanted primary precursors derived from the embryonic brain can engraft and commit in situ to a variety of developmental fates.
Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues
Publisher: Oxford University Press (OUP)
Date: 22-05-2008
DOI: 10.1634/STEMCELLS.2007-0979
Abstract: Human adult dental pulp stem cells (DPSCs) reside within the perivascular niche of dental pulp and are thought to originate from migrating cranial neural crest (CNC) cells. During embryonic development, CNC cells differentiate into a wide variety of cell types, including neurons of the peripheral nervous system. Previously, we have demonstrated that DPSCs derived from adult human third molar teeth differentiate into cell types reminiscent of CNC embryonic ontology. We hypothesized that DPSCs exposed to the appropriate environmental cues would differentiate into functionally active neurons. The data demonstrated that ex vivo-expanded human adult DPSCs responded to neuronal inductive conditions both in vitro and in vivo. Human adult DPSCs, but not human foreskin fibroblasts (HFFs), acquired a neuronal morphology, and expressed neuronal-specific markers at both the gene and protein levels. Culture-expanded DPSCs also exhibited the capacity to produce a sodium current consistent with functional neuronal cells when exposed to neuronal inductive media. Furthermore, the response of human DPSCs and HFFs to endogenous neuronal environmental cues was determined in vivo using an avian xenotransplantation assay. DPSCs expressed neuronal markers and acquired a neuronal morphology following transplantation into the mesencephalon of embryonic day-2 chicken embryo, whereas HFFs maintained a thin spindle fibroblastic morphology. We propose that adult human DPSCs provide a readily accessible source of exogenous stem recursor cells that have the potential for use in cell-therapeutic paradigms to treat neurological disease. Disclosure of potential conflicts of interest is found at the end of this article.
Safety of Varenicline Tartrate and Counseling Versus Counseling Alone for Smoking Cessation: A Randomized Controlled Trial for Inpatients (STOP Study)
Publisher: Oxford University Press (OUP)
Date: 16-07-2014
DOI: 10.1093/NTR/NTU112
Abstract: Inpatient medical settings offer an opportunistic environment for initiating smoking cessation interventions to patients reflecting on their health. Current evidence has shown the superior efficacy of varenicline tartrate (VT) for smoking cessation compared with other tobacco cessation therapies however, recent evidence also has highlighted concerns about the safety and tolerability of VT. Given these apprehensions, we aimed to evaluate the safety and effectiveness of VT plus quitline-counseling compared to quitline-counseling alone in the inpatient medical setting. Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to 3 hospitals were randomized to receive either 12 weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice daily) plus quitline-counseling (VT+C), (n = 196) or quitline-counseling alone (n = 196). VT was well tolerated in the inpatient setting among subjects admitted with acute smoking-related illnesses (mean age 52.8±2.89 and 53.7±2.77 years in the VT+C and counseling alone groups, respectively). The most common self-reported adverse event during the 12-week treatment phase was nausea (16.3% in the VT+C group compared with 1.5% in the counseling alone group). Thirteen deaths occurred during the study period (n = 6 were in the VT+C arm compared with n = 7 in the counseling alone arm). All of these subjects had known comorbidities or developed underlying comorbidities. VT appears to be a safe and well-tolerated opportunistic treatment for inpatient smokers who have related chronic disease. Based on the proven efficacy of varenicline from outpatient studies and our recent inpatient evidence, we suggest it be considered as part of standard care in the hospital setting.
Reduction of the neuroprotective transcription factor Npas4 results in increased neuronal necrosis, inflammation and brain lesion size following ischaemia
Publisher: SAGE Publications
Date: 14-10-2015
Abstract: Stroke is the second leading cause of death and the most frequent cause of adult disability. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischaemia. Although previous studies have demonstrated that Npas4 plays a critical role in protecting neurons against neurodegenerative insults, the neuroprotective effect of Npas4 in response to ischaemic brain injury remains unknown. In this study, we used a loss-of-function approach to examine the neuroprotective potential of Npas4 in the context of ischaemic damage. Using oxygen and glucose deprivation, we demonstrated that the knockdown of Npas4 in mouse cortical neurons resulted in increased susceptibility to cell death. The protective effect of Npas4 was further investigated in vivo using a photochemically-induced stroke model in mice. We found a significantly larger lesion size and increased neurodegeneration in Npas4 knockout mice as compared to wild-type mice. Moreover, we also showed that ablation of Npas4 caused an increase in activated astrocytes and microglia, pro-inflammatory cytokines interleukin-6 and tumour necrosis factor alpha levels and a switch from apoptotic to necrotic cell death. Taken together, these data suggest that Npas4 plays a neuroprotective role in ischaemic stroke by limiting progressive neurodegeneration and neuroinflammation.
Tenascin-C is increased in atherothrombotic stroke patients and has an anti-inflammatory effect in the human carotid artery.
Publisher: Wiley
Date: 14-05-2014
DOI: 10.1002/BIOF.1170
Abstract: Tenascin-C (Tn-C) is an endogenous ligand of toll-like receptor-4 (TLR-4) a key signalling molecule associated with chronic inflammatory conditions. Both Tn-C and TLR-4 are increased in unstable human atheroma, but their effects on local inflammatory conditions have not been investigated. The aim of the present study was to investigate the association and functional implications of Tn-C/TLR-4 signalling in large artery atherosclerotic stroke. Plasma Tn-C was measured by ELISA and found to be higher in recent stroke patients (n = 336 median 12.77 µg/mL, inter-quartile range 10.23-15.74 µg/mL) than in controls (n = 321 median 11.31 µg/mL, inter-quartile range 8.89-13.90 µg/mL), P < 0.001. Plasma Tn-C was also independently positively associated with stroke (odds ratio for highest Tn-C quartile 2.27, 95% confidence interval 1.37-3.76). Assessment of Tn-C associated chronic cytokine secretion was performed in vitro using paired, human, macroscopically disease matched, carotid atheroma tissue biopsies obtained from five patients undergoing carotid endarterectomy. A 4-day incubation with specific Tn-C blocking antibodies (Abs) increased secretion of TLR-4-associated cytokines, interleukin (IL)-8, IL-1β, tumour necrosis factor and C-C motif chemokine (CCL)3 and expression of TLR-4 in the tissue. These results suggest with Tn-C blockade another endogenous TLR-4 ligand upregulates TLR-4 expression and subsequent cytokine secretion. Titration of the Tn-C Abs also dose dependently increased secretion of IL-6, IL-8, IL-1β, and CCL3 in mixed, healthy, primary vascular cell culture. In summary, circulating concentrations of Tn-C are higher in patients with a recent history of atherosclerotic stroke and may play an anti-inflammatory role by reducing pro-inflammatory cytokine release from atheroma.
Common variants at 6p21.1 are associated with large artery atherosclerotic stroke
Publisher: Springer Science and Business Media LLC
Date: 02-09-2012
DOI: 10.1038/NG.2397
Role of the angiotensin converting enzyme 1/angiotensin II/angiotensin receptor 1 axis in interstitial collagenase expression in human carotid atheroma
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.ATHEROSCLEROSIS.2013.05.022
Abstract: Angiotensin II (AII) receptor 1 (ATR1) and angiotensin converting enzyme 1 (ACE1) blockers have been shown to reduce acute cardiovascular events in patients, improve plaque stability and modify matrix metalloproteinase (MMP) expression. However, the role of the ACE1/AII/ATR1 axis in interstitial collagenase regulation has not been fully explored. In this study, we investigated the effect of ATR1 and ACE1 blockade on the expression and activity of MMP-1, -8 and -13 in human carotid atheroma. Atheroma s les (n = 24) were obtained from patients undergoing carotid endarterectomy. The effects of ATR1 (irbesartan), ACE1 (quinapril), ACE2 (DX600) and MMP (GM6001) blockade on the expression of AII, the interstitial collagenases and soluble elastin fragments were investigated in explant culture supernatants. Paired atheroma s les were incubated with intervention or media control for 4 days. Protein levels (AII, MMP-1, -8, -13 and soluble elastin) were determined by ELISA. ATR1, but not ACE1, blockade significantly reduced MMP-1 and -8 concentrations in atheroma supernatants. ACE2 blockade significantly increased MMP-1 and -8 concentrations in atheroma supernatants. AII concentration in atheroma supernatants significantly increased after ATR1, ACE1 and ACE2 blockade. Release of soluble elastin fragments increased after ATR1 and ACE1 blockade, but was not changed by an MMP inhibitor. Our findings suggest that ATR1 blockade alters AII, MMP-1, MMP-8 expression and a marker of elastin degradation in human atheroma, but that the elastin degradation response is not MMP driven. This data contributes to the recognised ability of ATR1 blockade to modify plaque stability.
Generating and measuring photochemical changes inside the brain using optical fibers: Exploring stroke
Publisher: The Optical Society
Date: 16-10-2014
DOI: 10.1364/BOE.5.003975
Involvement of Angiotensin II Type 1 and 2 Receptors in Gelatinase Regulation in Human Carotid Atheroma <i>in vitro </i>
Publisher: Japan Atherosclerosis Society
Date: 2016
DOI: 10.5551/JAT.31401
FAST-IT:FindA SimpleTest —InTIA (transient ischaemic attack): a prospective cohort study to develop a multivariable prediction model for diagnosis of TIA through pro
Publisher: BMJ
Date: 04-2022
DOI: 10.1136/BMJOPEN-2020-045908
Abstract: Transient ischaemic attack (TIA) may be a warning sign of stroke and difficult to differentiate from minor stroke and TIA-mimics. Urgent evaluation and diagnosis is important as treating TIA early can prevent subsequent strokes. Recent improvements in mass spectrometer technology allow quantification of hundreds of plasma proteins and lipids, yielding large datasets that would benefit from different approaches including machine learning. Using plasma protein, lipid and radiological biomarkers, our study will develop predictive algorithms to distinguish TIA from minor stroke (positive control) and TIA-mimics (negative control). Analysis including machine learning employs more sophisticated modelling, allowing non-linear interactions, adapting to datasets and enabling development of multiple specialised test-panels for identification and differentiation. Patients attending the Emergency Department, Stroke Ward or TIA Clinic at the Royal Adelaide Hospital with TIA, minor stroke or TIA-like symptoms will be recruited consecutively by staff-alert for this prospective cohort study. Advanced neuroimaging will be performed for each participant, with images assessed independently by up to three expert neurologists. Venous blood s les will be collected within 48 hours of symptom onset. Plasma proteomic and lipid analysis will use advanced mass spectrometry (MS) techniques. Principal component analysis and hierarchical cluster analysis will be performed using MS software. Output files will be analysed for relative biomarker quantitative differences between the three groups. Differences will be assessed by linear regression, one-way analysis of variance, Kruskal-Wallis H-test, χ 2 test or Fisher’s exact test. Machine learning methods will also be applied including deep learning using neural networks. Patients will provide written informed consent to participate in this grant-funded study. The Central Adelaide Local Health Network Human Research Ethics Committee approved this study (HREC/18/CALHN/384 R20180618). Findings will be disseminated through peer-reviewed publication and conferences data will be managed according to our Data Management Plan (DMP2020-00062).
A Hot Topic – Heat Waves and Stroke
Publisher: SAGE Publications
Date: 18-09-2014
DOI: 10.1111/IJS.12319
Abstract: Following a heat wave in January 2014 in Adelaide, state capital of South Australia, we asked the question whether extreme heat was associated with an increase in stroke incidence. We found in the literature that the association between stroke presentation to hospital and meteorological factors has long been a topic of debate and subject to numerous studies. The literature indicated that an association between heat waves and an increase in admissions for stroke was unlikely in Australia and the United States. We suggest that it may be inappropriate to generalize this conclusion to other countries and rural areas. In view of the global climate change debate, we suggest that prospective studies be focused in developing countries and rural areas to assess the real impact of extreme heat on respective populations to better inform stroke physicians and health policy makers.
EphB/ephrin-B interaction mediates adult stem cell attachment, spreading, and migration: implications for dental tissue repair.
Publisher: Oxford University Press (OUP)
Date: 2007
DOI: 10.1634/STEMCELLS.2006-0373
Abstract: Human adult dental pulp stem cells (DPSCs) reside predominantly within the perivascular niche of dental pulp and are thought to originate from migrating neural crest cells during development. The Eph family of receptor tyrosine kinases and their ligands, the ephrin molecules, play an essential role in the migration of neural crest cells during development and stem cell niche maintenance. The present study examined the expression and function of the B-subclass Eph/ephrin molecules on DPSCs. Multiple receptors were primarily identified on DPSCs within the perivascular niche, whereas ephrin-B1 and ephrin-B3 were expressed by the surrounding pulp tissue. EphB/ephrin-B bidirectional signaling inhibited cell attachment and spreading, predominately via the mitogen-activated protein kinase (MAPK) pathway for forward signaling and phosphorylation of Src family tyrosine kinases via reverse ephrin-B signaling. DPSC migration was restricted through unidirectional ephrin-B1-activated EphB forward signaling, primarily signaling through the MAPK pathway. Furthermore, we observed that ephrin-B1 was downregulated in diseased adult teeth compared with paired uninjured controls. Collectively, these studies suggest that EphB/ephrin-B molecules play a role in restricting DPSC attachment and migration to maintain DPSCs within their stem cell niche under steady-state conditions. These results may have implications for dental pulp development and regeneration.
Concise Review: Preclinical Studies on Human Cell-Based Therapy in Rodent Ischemic Stroke Models: Where Are We Now after a Decade?
Publisher: Oxford University Press (OUP)
Date: 22-05-2013
DOI: 10.1002/STEM.1348
Abstract: Stroke, a debilitating brain insult, afflicts millions of in iduals globally each year. In the last decade, researchers have investigated cell-based therapy as an alternative strategy to improve neurological outcome following stroke. This concise review critically examines preclinical reports using human adult and fetal stem rogenitor cells in rodent models of ischemic stroke. As we enter the second decade of study, we should aim to optimize our collective likelihood to translational success for stroke victims worldwide. We advocate international consensus recommendations be developed for future preclinical research.
Are Myocardial Infarction–Associated Single-Nucleotide Polymorphisms Associated With Ischemic Stroke?
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2012
DOI: 10.1161/STROKEAHA.111.632075
Abstract: Ischemic stroke (IS) shares many common risk factors with coronary artery disease (CAD). We hypothesized that genetic variants associated with myocardial infarction (MI) or CAD may be similarly involved in the etiology of IS. To test this hypothesis, we evaluated whether single-nucleotide polymorphisms (SNPs) at 11 different loci recently associated with MI or CAD through genome-wide association studies were associated with IS. Meta-analyses of the associations between the 11 MI-associated SNPs and IS were performed using 6865 cases and 11 395 control subjects recruited from 9 studies. SNPs were either genotyped directly or imputed in a few cases a surrogate SNP in high linkage disequilibrium was chosen. Logistic regression was performed within each study to obtain study-specific βs and standard errors. Meta-analysis was conducted using an inverse variance weighted approach assuming a random effect model. Despite having power to detect odds ratio of 1.09–1.14 for overall IS and 1.20–1.32 for major stroke subtypes, none of the SNPs were significantly associated with overall IS and/or stroke subtypes after adjusting for multiple comparisons. Our results suggest that the major common loci associated with MI risk do not have effects of similar magnitude on overall IS but do not preclude moderate associations restricted to specific IS subtypes. Disparate mechanisms may be critical in the development of acute ischemic coronary and cerebrovascular events.
Transcranial magnetic stimulation of human adult stem cells in the mammalian brain
Publisher: Frontiers Media SA
Date: 17-03-2016
The role of tenascin C in cardiovascular disease
Publisher: Oxford University Press (OUP)
Date: 28-06-2011
DOI: 10.1093/CVR/CVR183
Abstract: The extracellular matrix protein tenascin C (TnC) is expressed in a variety of embryonic tissues, but its expression in adult arteries is co-incident with sites of vascular disease. TnC expression has been linked to the development and complications of intimal hyperplasia, pulmonary artery hypertension, atherosclerosis, myocardial infarction, and heart failure. This review identifies the growing collection of evidence linking TnC with cardiovascular disease development. The transient upregulation of this extracellular matrix protein at sites of vascular disease could provide a means to target TnC in the development of diagnostics and new therapies. Studies in TnC-deficient mice have implicated this protein in the development of intimal hyperplasia. Further animal and human studies are required to thoroughly assess the role of TnC in some of the other pathologies it has been linked with, such as atherosclerosis and pulmonary hypertension. Large population studies are also warranted to clarify the diagnostic value of this extracellular matrix protein in cardiovascular disease, for ex le by targeting its expression using radiolabelled antibodies or measuring circulating concentrations of TnC.
Characterization of p75 neurotrophin receptor expression in human dental pulp stem cells
Publisher: Wiley
Date: 26-07-2016
DOI: 10.1016/J.IJDEVNEU.2016.07.007
Abstract: Human adult dental pulp stem cells (DPSC) are a heterogeneous stem cell population, which are able to differentiate down neural, chondrocyte, osteocyte and adipocyte lineages. We studied the expression pattern of p75 neurotrophin receptors (p75NTR), a marker of neural stem cells, within human DPSC populations from eight donors. p75NTR are expressed at low levels (<10%) in DPSC. Importantly, p75(+) DPSC represent higher expression levels of SOX1 (neural precursor cell marker), SOX2 (cell pluripotency marker) and nestin (neural stem cell marker) in comparison to p75(-) DPSC. Our results suggest that p75(+) hDPSC may denote a subpopulation with greater neurogenic potential.
Differences in Common Genetic Predisposition to Ischemic Stroke by Age and Sex.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2015
DOI: 10.1161/STROKEAHA.115.009816
Abstract: Evidence from epidemiological studies points to differences in factors predisposing to stroke by age and sex. Whether these arise because of different genetic influences remained untested. Here, we use data from 4 genome-wide association data sets to study the relationship between genetic influence on stroke with both age and sex. Using genomic-relatedness-matrix restricted maximum likelihood methods, we performed 4 analyses: (1) we calculated the genetic correlation between groups ided by age and (2) by sex, (3) we calculated the heritability of age-at-stroke-onset, and (4) we evaluated the evidence that heritability of stroke is greater in women than in men. We found that genetic factors influence age at stroke onset ( h 2 [SE]=18.0 [6.8] P =0.0038), with a trend toward a stronger influence in women (women: h 2 [SE]=21.6 [3.5] Men: h 2 [SE]=13.9 [2.8]). Although a moderate proportion of genetic factors was shared between sexes ( rG [SE]=0.68 [0.16]) and between younger and older cases ( rG [SE]=0.70 [0.17]), there was evidence to suggest that there are genetic susceptibility factors that are specific to sex ( P =0.037) and to younger or older groups ( P =0.056), particularly for women ( P =0.0068). Finally, we found a trend toward higher heritability of stroke in women although this was not significantly greater than in men ( P =0.084). Our results indicate that there are genetic factors that are either unique to or have a different effect between younger and older age groups and between women and men. Performing large, well-powered genome-wide association study analyses in these groups is likely to uncover further associations.
TOOTH (The Open study Of dental pulp stem cell Therapy in Humans): Study protocol for evaluating safety and feasibility of autologous human adult dental pulp stem cell therapy in patients with chronic
Publisher: SAGE Publications
Date: 30-03-2016
Abstract: Stroke represents a significant global disease burden. As of 2015, there is no chemical or biological therapy proven to actively enhance neurological recovery during the chronic phase post-stroke. Globally, cell-based therapy in stroke is at the stage of clinical translation and may improve neurological function through various mechanisms such as neural replacement, neuroprotection, angiogenesis, immuno-modulation, and neuroplasticity. Preclinical evidence in a rodent model of middle cerebral artery ischemic stroke as reported in four independent studies indicates improvement in neurobehavioral function with adult human dental pulp stem cell therapy. Human adult dental pulp stem cells present an exciting potential therapeutic option for improving post-stroke disability. TOOTH (The Open study Of dental pulp stem cell Therapy in Humans) will investigate the use of autologous stem cell therapy for stroke survivors with chronic disability, with the following objectives: (a) determine the maximum tolerable dose of autologous dental pulp stem cell therapy (b) define that dental pulp stem cell therapy at the maximum tolerable dose is safe and feasible in chronic stroke and (c) estimate the parameters of efficacy required to design a future Phase 2/3 clinical trial. TOOTH is a Phase 1, open-label, single-blinded clinical trial with a pragmatic design that comprises three stages: Stage 1 will involve the selection of 27 participants with middle cerebral artery ischemic stroke and the commencement of autologous dental pulp stem cell isolation, growth, and testing in sequential cohorts (n = 3). Stage 2 will involve the transplantation of dental pulp stem cell in each cohort of participants with an ascending dose and subsequent observation for a 6-month period for any dental pulp stem cell-related adverse events. Stage 3 will investigate the neurosurgical intervention of the maximum tolerable dose of autologous dental pulp stem cell followed by 9 weeks of intensive task-specific rehabilitation. Advanced magnetic resonance and positron emission tomography neuro-imaging, and clinical assessment will be employed to probe any change afforded by stem cell therapy in combination with rehabilitation. Nine participants will step-wise progress in Stage 2 to a dose of up to 10 million dental pulp stem cell, employing a cumulative 3 + 3 statistical design with low starting stem cell dose and subsequent dose escalation, assuming that an acceptable probability of dose-limiting complications is between 1 in 6 (17%) and 1 in 3 (33%) of patients. In Stage 3, another 18 participants will receive an intracranial injection with the maximum tolerable dose of dental pulp stem cell. The primary outcomes to be measured are safety and feasibility of intracranial administration of autologous human adult DPSC in patients with chronic stroke and determination of the maximum tolerable dose in human subjects. Secondary outcomes include estimation of the measures of effectiveness required to design a future Phase 2/3 clinical trial.
Angiotensin receptor 1 blockade reduces secretion of inflammation associated cytokines from cultured human carotid atheroma and vascular cells in association with reduced extracellular signal regulate
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.ATHEROSCLEROSIS.2014.06.011
Abstract: A number of studies have suggested that angiotensin II (AII) receptor type 1 (ATR1) blocking drugs (ARBs) have anti-inflammatory effects however the mechanisms responsible are poorly investigated. To determine the role of extracellular signal regulated kinase (ERK)1/2 in ARB induced anti-inflammatory effects within human carotid atherosclerosis. Atheroma s les obtained from patients undergoing carotid endarterectomy were cultured with and without ATR1 (irbesartan), ERK1/2 (PD98059), AII ([Sar(1), Ile(8)]-AII) and angiotensin converting enzyme (ACE)2 (DX600) blockade. The in vitro effects of ATR1 and ERK1/2 blockade and exogenous AII on serum stimulated healthy, primary vascular cells were also investigated. Outcome was assessed by measuring cytokine, (interleukin (IL)-6, IL-8, C-C motif chemokine (CCL)2, C-X-C motif chemokine (CXCL)5, osteoprotegerin (OPG), osteopontin (OPN), CXCL16), concentrations in supernatants and phosphorylated ERK1/2 in the tissue lysates using ELISA. ERK1/2 expression in the tissue was assessed using Western blotting. Irbesartan reduced concentrations of IL-6, IL-8, CCL2, CXCL5, OPG, OPN and CXCL16 in both atheroma and primary vascular cell culture supernatants. The reduction in cytokine levels in the atheroma supernatant was correlated to a reduction in ERK1/2 expression in the tissue. Inhibition of ERK1/2 downregulated IL-6, IL-8 and CXCL5 in both atheroma and cell culture supernatants. AII and ACE2 blockade had no impact on cytokine or active ERK1/2 levels in the atheroma culture. Our findings suggest that ATR1 blockade downregulates atheroma tissue ERK1/2 expression leading to a reduction in cytokine production and that a non-AII agonist ATR1 signalling response may induce expression of these inflammation associated cytokines in the atheroma.
Smoking Termination Opportunity for inPatients (STOP): superiority of a course of varenicline tartrate plus counselling over counselling alone for smoking cessation: a 12-month randomised controlled t
Publisher: BMJ
Date: 19-09-2012
DOI: 10.1136/THORAXJNL-2012-202484
Abstract: Smoking cessation interventions in outpatient settings have been demonstrated to be cost effective. Given this evidence, we aimed to evaluate the effectiveness of varenicline tartrate plus Quitline-counselling compared with Quitline-counselling alone when initiated in the inpatient setting. Adult patients (18-75 years) admitted with a smoking-related illness to three hospitals, were randomised to receive either 12-weeks of varenicline tartrate plus Quitline-counselling, (n=196) or Quitline-counselling alone, (n=196), with 12-months follow-up. For the primary analysis population (intention-to-treat), the proportion of subjects who remained continuously abstinent were significantly greater in the varenicline plus counselling arm (31.1%, n=61) compared with counselling alone (21.4%, n=42 RR 1.45, 95% CI 1.03 to 2.03, p=0.03). The combined use of varenicline plus counselling when initiated in the inpatient setting has produced a sustained smoking cessation benefit at 12-months follow-up, indicating a successful opportunistic treatment for smokers admitted with smoking related illnesses. www.clinicaltrials.gov/ ClinicalTrials.gov identification number: NCT01141855.
Tissue plasminogen activator -7351C/T enhancer polymorphism is a risk factor for lacunar stroke
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2004
DOI: 10.1161/01.STR.0000124123.76658.6C
Abstract: Background and Purpose— Occlusive thrombosis is an important component of small- and large-vessel ischemic stroke. Endogenous tissue plasminogen activator (TPA) is the primary mediator of intravascular fibrinolysis and is predominantly expressed by the endothelium of small vessels. The acute release of TPA is influenced by the TPA −7351C/T polymorphism and therefore may play an important role in the pathogenesis of lacunar stroke. In this study, we investigated the risk of lacunar and nonlacunar ischemic stroke associated with the TPA −7351C/T polymorphism. Methods— We conducted a case-control study of 182 cases of ischemic stroke and 301 community controls. Participants were evaluated for known cerebrovascular risk factors, and the TPA −7351C/T genotype was established by a polymerase chain reaction (PCR) method. Logistic regression was used to determine the risk of lacunar and nonlacunar ischemic stroke associated with the TPA −7351C/T polymorphism. Results— The prevalence of the TPA −7351 CC, CT, and TT genotypes were 46%, 45%, and 9% for controls and 41%, 46%, and 13% for stroke patients, respectively. After adjustment for known cerebrovascular risk factors, the TT genotype was significantly associated with ischemic stroke (OR: 1.9 95% CI: 1.01 to 3.6). Stratification for stroke subtype showed a significant association between the TT genotype and lacunar stroke but not nonlacunar stroke (OR: 2.7 95% CI: 1.1 to 6.7). Conclusions— The TPA −7351C/T polymorphism is an independent risk factor for lacunar stroke. The findings suggest that impaired fibrinolysis may play a role in the pathogenesis of lacunar stroke.
Muscle-specific kinase antibody positive myaesthenia gravis and multiple sclerosis co-presentation: A case report and literature review
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.JNEUROIM.2013.08.016
Abstract: We present the first case of simultaneous muscle-specific kinase antibody positive myaesthenia gravis and relapsing-remitting multiple sclerosis to be reported in the English literature along with the inherent diagnostic and treatment challenges. There may be an association between myaesthenia and central nervous system demyelination. We identified 72 previously published cases of myaesthenia with central nervous system demyelination. Of 19 cases of myaesthenia with relapsing-remitting multiple sclerosis, nine (47%) were acetylcholine receptor antibody negative, but there were no previously published cases with muscle-specific kinase antibody. Further research is required to clarify this association and optimal treatment in such cases.
Pleural mesothelioma with extension into the thoracic spinal cord
Publisher: Wiley
Date: 25-02-2005
Hashimoto's thyroiditis associated with acquired idiopathic demyelinating polyradiculoneuropathy
Publisher: Oxford University Press (OUP)
Date: 07-1991
Eph/ephrinB mediate dental pulp stem cell mobilization and function
Publisher: SAGE Publications
Date: 09-2009
Abstract: Damage to the dentin matrix instigates the proliferation and mobilization of dental progenitor cells to the injury site, the mechanisms of which are not defined. EphB receptors and ephrin-B ligands expressed within the perivascular niche of dental pulp have been implicated following tooth injury. We propose that elevated levels of ephrin-B1 following injury may prevent the proliferation and migration of dental pulp stem cell (DPSC), while EphB/ephrin-B interaction facilitates odontoblastic differentiation. The migration, proliferation, and differentiation of DPSC in response to Eph/ephrin-B molecules was assessed in an established ex vivo tooth injury model and by in vitro assays for the assessment of colony formation and differentiation. Analysis of our data demonstrated that EphB forward signaling promoted DPSC proliferation, while inhibiting migration. Conversely, reverse signaling enhanced DPSC mineral production. These observations suggest that EphB/ephrin-B molecules are important for perivascular DPSC migration toward the dentin surfaces and differentiation into functional odontoblasts, following damage to the dentin matrix.
Endovascular therapy after stroke in a patient treated with dabigatran
Publisher: AMPCo
Date: 04-2012
DOI: 10.5694/MJA11.11617
High EphA3 expressing ophthalmic trigeminal sensory axons are sensitive to ephrin-A5-Fc: Implications for lobe specific axon guidance
Publisher: Elsevier BV
Date: 2005
An investigation of cortical neuroplasticity following stroke in adults: is there evidence for a critical window for rehabilitation?
Publisher: Springer Science and Business Media LLC
Date: 11-07-2015
REGULATION OF NEURAL PRECURSOR DIFFERENTIATION IN THE EMBRYONIC AND ADULT FOREBRAIN
Publisher: Wiley
Date: 08-1995
DOI: 10.1111/J.1440-1681.1995.TB02066.X
Abstract: 1. Precursors form the neuroepithelium of the developing cortex and also from the adult sub-ventricular zone, can be cloned in vitro after stimulation with fibroblast growth factor (FGF)-2 and have the potential to give rise to both neurons and glia. The generation of neurons from these clones can be stimulated by either a factor derived from an astrocyteprecursor line, Ast-1, or FGF-1. 2. Neuronal differentiation stimulated by FGF-1 can be inhibited by diacylglycerol-lipase inhibitor and mimicked by arachidonic acid, suggesting that the neuronal differentiation is signalled through the PCL gamma pathway. 3. The sequential expression of FGF-2 and FGF-1 within the developing forebrain neuroepithelium fits with the different functions the two FGF play in precursor regulation. 4. We have shown that the precursor response to FGF-1 is regulated by a heparan sulphate proteoglycan (HSPG) expressed within the developing neuroepithelium. Precursors restricted to the astrocyte cell lineage can be stimulated by epidermal growth factor or FGF-2 however, the differentiation into GFAP positive astrocytes appears to require a cytokine acting through the leukaemia inhibitory factor beta receptor.
Early glycogen synthase kinase‐3β and protein phosphatase 2A independent tau dephosphorylation during global brain ischaemia and reperfusion following cardiac arrest and the role of the adenosine monophosphate kinase pathway
Publisher: Wiley
Date: 08-06-2016
DOI: 10.1111/EJN.13277
Neurogenic potential of dental pulp stem cells isolated from murine incisors
Publisher: Springer Science and Business Media LLC
Date: 27-02-2014
DOI: 10.1186/SCRT419
Letter by benedict et al regarding article, what causes disability after transient ischemic attack and minor stroke? Results from the CT and MRI in the triage of TIA and minor cerebrovascular events to identify high-risk patients (CATCH) study
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2013
EphA4 constitutes a population-specific guidance cue for motor neurons
Publisher: Elsevier BV
Date: 07-2002
A patient with anaphylaxis after alteplase infusion
Publisher: Elsevier BV
Date: 02-2012
Alterations in anxiety and social behaviour in Npas4 deficient mice following photochemically-induced focal cortical stroke
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.BBR.2016.08.050
Abstract: In addition to causing widespread cell death and loss of brain function, cerebral ischaemia also induces extensive neuroplasticity. In humans, stroke is often accompanied by severe cognitive and psychiatric changes that are thought to arise as a consequence of this infarct-induced remodelling. A candidate for producing these post-stroke neuropsychiatric changes is Npas4, an activity-dependent transcription factor involved in synaptic plasticity whose expression is aberrantly up-regulated following ischaemic injury. In this study we investigated the role of Npas4 in modulating these stroke-induced neuropsychiatric responses by comparing the performance of wildtype and Npas4
Peripheral nervous system and central nervous system pathology in rapidly progressive lower motor neuron syndrome with immunoglobulin M anti-GM1 ganglioside antibody
Publisher: Wiley
Date: 22-04-2004
Activity-dependent expression of neuronal PAS domain-containing protein 4 (npas4a) in the developing zebrafish brain
Publisher: Frontiers Media SA
Date: 04-12-2014
Developing a multivariable prediction model for functional outcome after reperfusion therapy for acute ischaemic stroke: study protocol for the Targeting Optimal Thrombolysis Outcomes (TOTO) multicentre cohort study.
Publisher: BMJ
Date: 04-2020
DOI: 10.1136/BMJOPEN-2020-038180
Abstract: Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) is the only approved pharmacological reperfusion therapy for acute ischaemic stroke. Despite population benefit, IVT is not equally effective in all patients, nor is it without significant risk. Uncertain treatment outcome prediction complicates patient treatment selection. This study will develop and validate predictive algorithms for IVT response, using clinical, radiological and blood-based biomarker measures. A secondary objective is to develop predictive algorithms for endovascular thrombectomy (EVT), which has been proven as an effective reperfusion therapy since study inception. The Targeting Optimal Thrombolysis Outcomes Study is a multicenter prospective cohort study of ischaemic stroke patients treated at participating Australian Stroke Centres with IVT and/or EVT. Patients undergo neuroimaging using multimodal CT or MRI at baseline with repeat neuroimaging 24 hours post-treatment. Baseline and follow-up blood s les are provided for research use. The primary outcome is good functional outcome at 90 days poststroke, defined as a modified Rankin Scale (mRS) Score of 0–2. Secondary outcomes are reperfusion, recanalisation, infarct core growth, change in stroke severity, poor functional outcome, excellent functional outcome and ordinal mRS at 90 days. Primary predictive models will be developed and validated in patients treated only with rt-PA. Models will be built using regression methods and include clinical variables, radiological measures from multimodal neuroimaging and blood-based biomarkers measured by mass spectrometry. Predictive accuracy will be quantified using c-statistics and R 2 . In secondary analyses, models will be developed in patients treated using EVT, with or without prior IVT, reflecting practice changes since original study design. Patients, or relatives when patients could not consent, provide written informed consent to participate. This study received approval from the Hunter New England Local Health District Human Research Ethics Committee (reference 14/10/15/4.02). Findings will be disseminated via peer-reviewed publications and conference presentations.
Editorial
Publisher: SAGE Publications
Date: 02-2008
Advanced management services for transient ischaemic attacks and minor stroke
Publisher: Wiley
Date: 06-05-2016
Association between glycoconjugate antibodies and Campylobacter infection in patients with Guillain-Barré syndrome
Publisher: Elsevier BV
Date: 10-1991
DOI: 10.1016/0165-5728(91)90097-Q
Abstract: In a retrospective study, we have analysed sera from a well-characterised Guillain-Barré syndrome (GBS) patient group for antibodies that react with gangliosides. Of 95 GBS patients and 85 control patients analysed, we found that 14 (15%) of GBS patients but only one control patient had antibodies that react with the gangliosides GM1 and/or GD1b but not GM2, GD1a and GT1b using a sensitive enzyme-linked immunosorbent assay (ELISA). This pattern of reactivity suggests binding to the carbohydrate structure Gal(beta 1-3)GalNAc which is shared between some glycolipids and glycoproteins. Similar antibodies have been found previously in a subpopulation of patients with lower motor neuron disease. In the present study, the predominant immunoglobulin class of these anti-glycoconjugate antibodies was IgG rather than IgM. A correlation was found between the presence of these antibodies and prognosis in terms of disability at 3 and 12 months after presentation. Patients with anti-glycoconjugate antibodies also had a higher incidence of previous C ylobacter infections than the rest of the patient group, although the significance of this remains to be determined.
The Role of the Neuroprotective Factor Npas4 in Cerebral Ischemia
Publisher: MDPI AG
Date: 04-12-2015
Eph receptor and ephrin signaling in developing and adult brain of the honeybee (Apis mellifera)
Publisher: Wiley
Date: 2007
DOI: 10.1002/DNEU.20341
miR-744 and miR-224 Downregulate Npas4 and Affect Lineage Differentiation Potential and Neurite Development During Neural Differentiation of Mouse Embryonic Stem Cells
Publisher: Springer Science and Business Media LLC
Date: 17-05-2016
DOI: 10.1007/S12035-016-9912-4
Abstract: Neuronal PAS domain protein 4 (Npas4) is a brain-specific transcription factor whose expression is enriched in neurogenic regions of the brain. In addition, it was demonstrated that Npas4 expression is dynamic and highly regulated during neural differentiation of embryonic stem cells (ESCs). While these findings implicate a role for Npas4 in neurogenesis, the underlying mechanisms of regulation remain unknown. Given that growing evidence suggests that microRNAs (miRNAs) play important roles in both embryonic and adult neurogenesis, we reasoned that miRNAs are good candidates for regulating Npas4 expression during neural differentiation of ESCs. In this study, we utilized the small RNA sequencing method to profile miRNA expression during neural differentiation of mouse ESCs. Two differentially expressed miRNAs were identified to be able to significantly reduce reporter gene activity by targeting the Npas4 3'UTR, namely miR-744 and miR-224. More importantly, ectopic expression of these miRNAs during neural differentiation resulted in downregulation of endogenous Npas4 expression. Subsequent functional analysis revealed that overexpression of either miR-744 or miR-224 delayed early neural differentiation, reduced GABAergic neuron production and inhibited neurite outgrowth. Collectively, our findings indicate that Npas4 not only functions at the early stages of neural differentiation but may also, in part, contribute to neuronal subtype specification and neurite development.
Stem Cell-Based Therapy for Experimental Stroke: A Systematic Review and Meta-Analysis
Publisher: SAGE Publications
Date: 12-06-2012
DOI: 10.1111/J.1747-4949.2012.00797.X
Abstract: Stem cell therapy holds great promise in medicine, but clinical development should be based on a sound understanding of potential weaknesses in supporting experimental data. The aim of this article was to provide a systematic overview of evidence relating to the efficacy of stem cell-based therapies in animal models of stroke to foster the clinical application of stem cell-based therapies and to inform the design of large-scale clinical trials. We conducted a systematic search for reports of experiments using stem cells in animal models of cerebral ischaemia, and performed DerSimmonian and Laird random effects meta-analysis. We assessed the impact of study characteristics, of publication bias and of measures to reduce bias. We identified 6059 publications, 117 met our prespecified inclusion criteria. One hundred eighty-seven experiments using 2332 animals described changes in structural outcome and 192 experiments using 2704 animals described changes in functional outcome. Median study quality score was 4 (interquartile range 3 to 6) and less than half of studies reported randomization or blinded outcome assessment only three studies reported a s le size calculation. Nonrandomized studies gave significantly higher estimates of improvement in structural outcome, and there was evidence of a significant publication bias. For structural outcome autologous (i.e. self-derived) stem cells were more effective than allogeneic (donor-derived) cells, but for functional outcome, the reverse was true. A significant dose–response relationship was observed only for structural outcome. For structural outcome, there was an absolute reduction in efficacy of 1.5% (−2.4 to −0.6) for each days delay to treatment functional outcome was independent of the time of administration. While stem cells appear to be of some benefit in animal models of stroke the internal and external validity of this literature is potentially confounded by poor study quality and by publication bias. The clinical development of stem cell-based therapies, in stroke and elsewhere, should acknowledge these potential weaknesses in the supporting animal data.
Nxf and Fbxo33: novel seizure‐responsive genes in mice
Publisher: Wiley
Date: 14-09-2004
EphB4 enhances the process of endochondral ossification and inhibits remodeling during bone fracture repair
Publisher: Wiley
Date: 18-03-2013
DOI: 10.1002/JBMR.1821
Abstract: Previous reports have identified a role for the tyrosine kinase receptor EphB4 and its ligand, ephrinB2, as potential mediators of both bone formation by osteoblasts and bone resorption by osteoclasts. In the present study, we examined the role of EphB4 during bone repair after traumatic injury. We performed femoral fractures with internal fixation in transgenic mice that overexpress EphB4 under the collagen type 1 promoter (Col1-EphB4) and investigated the bone repair process up to 12 weeks postfracture. The data indicated that Col1-EphB4 mice exhibited stiffer and stronger bones after fracture compared with wild-type mice. The fractured bones of Col1-EphB4 transgenic mice displayed significantly greater tissue and bone volume 2 weeks postfracture compared with that of wild-type mice. These findings correlated with increased chondrogenesis and mineral formation within the callus site at 2 weeks postfracture, as demonstrated by increased safranin O and von Kossa staining, respectively. Interestingly, Col1-EphB4 mice were found to possess significantly greater numbers of clonogenic mesenchymal stromal progenitor cells (CFU-F), with an increased capacity to form mineralized nodules in vitro under osteogenic conditions, when compared with those of the wild-type control mice. Furthermore, Col1-EphB4 mice had significantly lower numbers of TRAP-positive multinucleated osteoclasts within the callus site. Taken together, these observations suggest that EphB4 promotes endochondral ossification while inhibiting osteoclast development during callus formation and may represent a novel drug target for the repair of fractured bones.
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