ORCID Profile
0000-0002-0718-7934
Current Organisation
The University of Newcastle
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Publisher: MDPI AG
Date: 04-09-2022
DOI: 10.3390/V14091961
Abstract: Of in iduals who develop West Nile neuroinvasive disease (WNND), ~10% will die and % will develop long-term complications. Current treatment recommendations solely focus on supportive care therefore, we urgently need to identify novel and effective therapeutic options. We observed a correlation between substance P (SP), a key player in neuroinflammation, and its receptor Neurokinin-1 (NK1R). Our study in a wild-type BL6 mouse model found that SP is upregulated in the brain during infection, which correlated with neuroinvasion and damage to the blood–brain barrier. Blocking the SP/NK1R interaction beginning at disease onset modestly improved survival and prolonged time to death in a small pilot study. Although SP is significantly increased in the brain of untreated WNND mice when compared to mock-infected animals, levels of WNV are unchanged, indicating that SP likely does not play a role in viral replication but may mediate the immune response to infection. Additional studies are necessary to define if SP plays a mechanistic role or if it represents other mechanistic pathways.
Publisher: Informa UK Limited
Date: 10-2004
DOI: 10.1080/07315724.2004.10719398
Abstract: Magnesium (Mg) deficiency has been shown to increase substance P release and induce a pro-inflammatory response that can be attenuated with the administration of a substance P-antagonist. Neurogenic inflammation has also been implicated in traumatic brain injury (TBI), a condition where brain intracellular free magnesium (Mg(f)) decline is known to occur and has been correlated with functional outcome. We therefore examined whether a substance P antagonist restores brain intracellular free magnesium concentration following TBI. Male, adult Sprague-Dawley rats were injured using the Cernak impact acceleration model of diffuse TBI. At 30 min after injury, animals were administered either 0.25 mg/kg i.v. n-acetyl tryptophan or equal volume saline. Prior to and 4 h after induction of injury, phosphorus magnetic resonance spectra were acquired using a 7-tesla magnet interfaced with a Bruker console. Mg(f) was calculated from the chemical shift of the beta ATP. Before injury, Mg(f) was 0.51 +/- 0.05 mM (SEM). By 4 hr after injury, Mg(f) had significantly declined to 0.27 +/- 0.02 mM in saline treated rats. In contrast, rats treated with n-acetyl tryptophan had a Mg(f) of 0.47 +/- 0.06 mM at 4 h after injury, which was not significantly different from preinjury values. There were no significant differences in pH between the treatment groups. It seems that any beneficial effect of a substance P antagonist on functional outcome following TBI may be related to improvement in brain Mg homeostasis induced by the compound.
Publisher: Informa UK Limited
Date: 10-2004
DOI: 10.1080/07315724.2004.10719396
Abstract: Magnesium (Mg) declines after traumatic brain injury (TBI), a decline believed associated with ensuing neuronal cell death and subsequent functional impairment. While Mg's effects on motor and cognitive deficits following TBI have been well studied, few studies have addressed post-traumatic depression as an outcome parameter, despite its being a major clinical problem with an incidence of between 6 and 77%. We investigated the incidence of post-traumatic depression/anxiety in an animal model of diffuse TBI, and explored the use of magnesium sulfate (MgSO(4)) as an interventional treatment. Diffuse TBI was induced in 32 anesthetized, adult, male Sprague-Dawley rats, using the 2 m impact-acceleration model of injury. At 30 min after injury, half of the rats received 250 micromol/kg i.v. MgSO(4) the other half served as non-treated controls. Before and for 6 weeks after injury, the open-field, spontaneous activity test was used to determine post-traumatic depression/anxiety relative to pre-injury. In this test, animals are placed in a 1-meter square box with 100 squares marked on the base. The number of squares entered in a 5-min period is recorded. Incidence of post-traumatic depression/anxiety was defined as the number of animals demonstrating a reduction in spontaneous activity to less than 100 squares in 5 min. Prior to injury, rats typically entered a mean of 201 +/- 12 (SEM) squares over a 5 min observation period. At 1 week after injury, non-treated animals had a mean core of 62 +/- 13. The incidence of post-traumatic depression/anxiety in these animals was 61%, which is similar to that observed clinically. In contrast, animals treated with MgSO(4) had a mean activity score of 144 +/- 23 at 1 week after TBI and an incidence of depression/anxiety of less than 30%. The significant difference between groups persisted for the entire 6-week observation period. The improvement in post-traumatic depression/anxiety conferred by Mg adds further weight to available evidence of Mg's benefit as a neuroprotective agent after TBI.
Publisher: Wiley
Date: 30-11-2001
DOI: 10.1046/J.1440-1681.2001.03548.X
Abstract: 1. Although a number of interventional pharmacotherapies have undergone clinical trial in traumatic brain injury (TBI), none has shown considerable promise. The present short review will examine some of the more novel compounds that have been proposed recently as potential therapeutic agents for use in TBI. 2. Previous experimental studies have demonstrated that brain intracellular free magnesium significantly declines following TBI and that the administration of magnesium salts attenuates the post-traumatic neurological deficits. More recent studies have established that magnesium salts administered after trauma enter the brain intracellular space and reduce the size of the lesion volume. Such protection could be afforded through attenuation of both necrotic and apoptotic cell death. Magnesium salts are currently on clinical trial in TBI. 3. Cyclosporine A is known to inhibit opening of the mitochondrial permeability transition pore. Administration of cyclosporine A after TBI has been shown to attenuate axonal injury and decrease the resultant lesion volume. Therefore, inhibitors of mitochondrial transition pore opening and resultant attenuation of apoptosis show some promise as neuroprotective agents. 4. Recent evidence has shown that substance P antagonists may decrease lesion volume and improve neurological outcome after ischaemia. Similar findings have recently been reported in TBI. The fact that substance P antagonists are known to reduce neurogenic inflammation, oedema formation and are clinically being trialed as both antidepressants and antinociceptive agents suggests that these agents warrant further investigation as therapeutic agents following TBI. 5. There are numerous contradictions in the literature regarding the potential neuroprotective effects of the hormones oestrogen and progesterone. Recent studies suggest that both hormones are protective in TBI and further studies are required to ascertain the mechanisms associated with this protection and any potential for clinical application.
Publisher: Portland Press Ltd.
Date: 04-1991
DOI: 10.1042/BST019181S
Publisher: Springer Vienna
Date: 2003
DOI: 10.1007/978-3-7091-0651-8_55
Abstract: The mechanisms associated with edema formation after traumatic brain injury (TBI) have not been fully elucidated. In peripheral tissue injury, the neurogenic component of inflammation plays a significant role in increased vascular permeability and edema formation. However, few studies have examined the role of neuropeptide induced neurogenic inflammation following TBI. Adult male Sprague-Dawley rats were either left untreated, or pre-treated with capsaicin (125 mg/kg s.c.) or equal volume vehicle, and injured 14 days later using the 2-meter impact-acceleration model. Subgroups of animals were assessed for blood brain barrier (BBB) permeability (Evans Blue), brain edema (wet weight/dry weight) and functional outcome (Barnes maze and Rotarod) for up to 2 weeks post-trauma. Increased BBB permeability was present in untreated animals between 3 and 6 h after injury but not at later time-points. Edema was maximal at 5 h after trauma, declined and then significantly increased over the 5 days post-trauma. In contrast, capsaicin pre-treated, neuropeptide-depleted animals exhibited no significant increase in BBB permeability or edema compared to vehicle treated animals after injury. Notably, motor and cognitive impairments were significantly reduced in the capsaicin-pretreated animals. We conclude that neurogenic inflammation contributes to the development of edema and posttraumatic deficits after diffuse TBI.
Publisher: Wiley
Date: 03-07-2002
DOI: 10.1046/J.1440-1681.2002.03712.X
Abstract: 1. Glucocorticoids are an effective treatment in the amelioration of chronic lung disease in neonates. However, systemic administration of glucocorticoids to neonates is associated with significant side-effects that preclude them as an early intervention to prevent onset of the condition. Conversely, local intratracheal administration of glucocorticoids may prevent inflammatory insult to the lungs without the development of systemic side-effects. We therefore investigated whether local intratracheal delivery of corticosteroids could be facilitated using surfactant as a vehicle. 2. Addition of dexamethasone to either diluted or commercial artificial surfactant, Survanta (Abbott Industries, Sydney, NSW, Australia), did not alter the surface properties of the surfactant. 3. After intratracheal instillation to rats, radiolabelled dexamethasone in Survanta was well distributed throughout all four lobes of the lungs. A concentration gradient of the steroid was observed between the root and the peripheral sections of all lobes. 4. Our results suggest that surfactant is an effective vehicle for intratracheal delivery of glucocorticoids. Moreover, we propose that prophylactic intratracheal administration of glucocorticoids administered shortly after birth may prevent inflammatory insult to the lungs and thereby reduce the likelihood of chronic lung disease developing.
Publisher: Mary Ann Liebert Inc
Date: 10-2003
DOI: 10.1089/089771503770195830
Abstract: A number of test paradigms have been used to determine acute and chronic motor and cognitive deficits after experimental traumatic brain injury (TBI). Some involve daily testing of either trained or untrained animals whereas others utilize periodic testing over extended time periods. Which test paradigm is the most appropriate for the assessment of motor and cognitive deficits is, however, unclear. In the current study, we have used both daily and weekly testing in trained and untrained animals to ascertain which assessment protocol is most suited for the detection of functional deficits after diffuse TBI in rats. Animals were subjected to severe injury using the impact-acceleration model of diffuse TBI. An equal number of animals were also prepared surgically but not subject to injury (shams). The rotarod device and the Barnes Maze were used for motor and cognitive assessment respectively, with half of the animals being pre-trained on each test for 10 days prior to injury. The open field test was used to assess spontaneous exploratory activity (stress). Following injury, animals were assessed for neurologic deficits either on a daily basis (for 10 days) or a weekly basis (for 4 weeks). In trained animals, the greatest differences in neurologic outcome between injured and sham animals were observed early after injury. In contrast, in untrained animals, greatest differences between injured and sham animals were observed at later time points. Pre-injury training did not improve the rate of cognitive recover, or the rate of motor recovery in the weekly test paradigm, but did improve the rate of motor recovery in the daily assessment paradigm. Daily assessment promoted rapid functional recovery whereas weekly assessments did not significantly affect outcome in injured animals over the 4-week assessment period. Spontaneous exploratory activity was decreased after TBI and was not influenced by task exposure. These studies demonstrate that the functional assessment paradigm needs to be considered when quantifying functional deficits following diffuse TBI in rats.
Publisher: Acta Scientific Publications Pvt. Ltd.
Date: 18-01-2021
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.AJODO.2018.10.015
Abstract: This systematic review assesses the literature regarding the association between orthodontic tooth movement and external root resorption. By determining the evidence level supporting the association, the results could provide clinical evidence for minimizing the deleterious effect of orthodontic tooth movement. Electronic databases, including MEDLINE, PubMed, Embase, Scopus, CINAHL, Cochrane Library, and LILACS, were searched up to February 2018, with hand searching of selected orthodontic journals undertaken to identify any preelectronic publications. Searches were undertaken with no restrictions on year, publication status, or language. Selection criteria included randomized controlled trials conducted with the use of fixed orthodontic appliances or sequential thermoplastic aligners on human patients. The quality of included studies was assessed with the use of the Cochrane Risk of Bias Tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Inter-rater agreement of the review authors was used for the inclusion of primary articles, risk of bias assessment, and evaluation of the quality of evidence (GRADE), and it was calculated with the use of the Cohen kappa statistic. A total of 654 articles were retrieved in the initial search. After the review process, 25 articles describing 24 in idual trials met the inclusion criteria. S le sizes ranged from 6 to 154 patients. Most articles were classified as having unclear risks of bias and very low to low quality of evidence. There is very low to low evidence for supporting positive associations between root resorption and increased force levels, force continuity, intrusive forces, and treatment duration. Moreover, by including a pause in treatment for patients experiencing root resorption, it may be possible for the clinician to reduce the severity of the condition. Of the included studies, the most common methodologic flaws include the absence of a control group, appropriate randomization strategy, and adequate examinations before and after treatment.
Publisher: Oxford University Press (OUP)
Date: 06-2000
DOI: 10.1095/BIOLREPROD62.6.1661
Abstract: Regulated uterine contractions are important in many reproductive functions such as sperm transport and embryo positioning during implantation. The role of classical neurotransmitters including acetylcholine and norepinephrine in regulating myometrial contractility has been well studied however, the peripheral role of sensory neurotransmitters such as the neurokinins is less clear. The major neurokinins are substance P, neurokinin A, and neurokinin B, which predominantly activate neurokinin receptors (NK-Rs) 1, 2, and 3, respectively. This study utilized selective receptor agonists to examine the role of NK-Rs in uterine contractility. Uterine tissues, obtained from the major stages of the rat estrous cycle, were stimulated with selective NK-R agonists. Addition of each agonist resulted in a significant contractile response. However, the magnitude and nature of the response were dependent upon the stage of the estrous cycle, with responses to all agonists being significantly decreased in tissue from proestrus and estrus. Furthermore, the nature of NK3-R-mediated contraction was different in tissue from proestrus and estrus compared to metestrus and diestrus. The hormonal dependence of NK-R-mediated contractility was then examined in the ovariectomized estrogen-supplemented rat model. These studies confirmed that the magnitude and nature of uterine contractility in response to NK-R activation depend upon the hormonal environment.
Publisher: Wiley
Date: 26-11-2019
DOI: 10.1111/ADJ.12735
Publisher: Wiley
Date: 10-07-1989
DOI: 10.1113/EXPPHYSIOL.1989.SP003309
Abstract: The distribution of beta-adrenoceptors in sections of human cervix taken at the proliferative phase of the menstrual cycle was studied using light-microscopic autoradiography. The radioligand [125I]iodocyanopindolol (125ICYP) was used to identify specific binding sites. Moderate density of labelling by 125ICYP was seen over smooth muscle and blood vessels. The most intense labelling, however, was seen over glands and surface columnar epithelium. The association of beta-adrenoceptors with glands and surface columnar epithelium suggests a possible adrenergic regulation of secretory function in the cervix.
Publisher: Elsevier BV
Date: 02-2004
Publisher: CSIRO Publishing
Date: 2003
DOI: 10.1071/RD03021
Abstract: This study compared the nature and magnitude of the contractile response produced in vitro by selective NK1, NK2 and NK3 tachykinin receptor agonists in circularly and longitudinally oriented strips of myometrium from ovariectomised and ovariectomised oestrogen-treated rats. The nature of the responses produced upon stimulation of the tachykinin receptors varied between the different myometrial preparations and the hormonal environment from which the tissue was taken. Variations included: (i) sustained contraction until washout of agonist (ii) biphasic contraction until washout of agonist and (iii) monophasic contraction. The major differences in magnitude of contractions were seen in preparations from oestrogen-treated animals in which responses to stimulation of all tachykinin receptors were reduced in comparison to preparations from non-oestrogen treated animals. Furthermore, the responses in circularly oriented myometrium preparations from oestrogen-treated animals were all markedly reduced compared to responses in longitudinally oriented myometrium preparations. These results suggest that the tachykinin receptors in longitudinally and circularly oriented myometrial layers are differentially regulated, especially in tissue isolated from an oestrogen-dominated environment.
Publisher: Wiley
Date: 09-1995
DOI: 10.1111/J.1464-410X.1995.TB07703.X
Abstract: To demonstrate the specific distribution of muscarinic receptors in the rat urinary bladder and to investigate the effects of afferent and efferent denervation on the density and distribution of muscarinic receptors. Urinary bladders were obtained from female rats which had been injected with vehicle (control), or neonatally with capsaicin (NC, afferent denervation) or which had their pelvic plexus removed (post-ganglionic denervation, PGD, efferent denervation). Tissue sections were used in radioligand-binding studies and for autoradiography with the muscarinic receptor ligand l-quinuclidinyl[phenyl-4-3H]benzilate (QNB). Binding of QNB was saturable and specific to a single population of binding sites, with a mean dissociation constant (Kd) of 1.05 +/- 0.14 nM in controls and 0.90 +/- 0.13 nM in rats with PGD. Post-ganglionic denervation caused a 37% increase in maximal binding (Bmax) of QNB from 437.1 +/- 39.1 fmol/mg protein (control group) to 599.1 +/- 4.5 fmol/mg protein (P < 0.02). Autoradiograms revealed muscarinic binding sites over the smooth muscle, but none over the epithelium. Smooth muscle binding sites were doubled after PGD but were unchanged after NC treatment. Muscarinic receptors were localized over the smooth muscle of the rat bladder and were increased after post-ganglionic denervation. This increase may be responsible for the increased sensitivity to muscarinic agonists reported to occur after bladder denervation.
Publisher: Wiley
Date: 12-11-1989
DOI: 10.1113/EXPPHYSIOL.1989.SP003368
Abstract: The binding of [125I] human alpha calcitonin gene-related peptide (hCGRP) and [125I]Bolton-Hunter-labelled substance P (BH-SP) to human fallopian tube tissue sections was characterized and the respective binding sites were localized by light-microscopic autoradiography. The hCGRP binding sites were associated with the muscularis, lamina propria and vascular smooth muscle, the latter being the most intensely labelled. BH-SP binding sites were associated only with blood vessels. This labelling was intense, and appeared to be restricted to the vascular endothelium. These results suggest that calcitonin gene-related peptide and substance P may act together to regulate local blood flow and plasma extravasation.
Publisher: Wiley
Date: 19-11-2019
DOI: 10.1111/ADJ.12732
Abstract: The aim of this study was to evaluate the knowledge of school professionals regarding the emergency management of dental avulsion. This cross-sectional study utilised a self-administered, pilot-tested questionnaire for school staff from primary schools. Descriptive statistics were used for the analysis - the prevalence and univariate associations between a categorical outcome and the variables under consideration, were evaluated using Pearson's Chi-squared test. This survey yielded a response rate of 43.5% (n = 313). Approximately 60% of participants held valid first-aid certificates and 23% had received avulsion advice previously. Over 80% of participants expressed an unwillingness to replant an avulsed tooth, and over 90% believed that there should be greater awareness in this area. This unwillingness to replant was influenced by respondents' age (x2 = 8.13 df = 3, P = 0.043) and receiving advice previously (x2 = 13.15, df = 1, P < 0.001). Under-preparedness was related to years of experience (x2 = 15.03, df = 5, P = 0.010), first-aid training (x2 = 6.41, df = 1, P = 0.011) and receiving advice previously (x2 = 43.47, df = 1, P < 0.001). It was also evident that first-aid training positively influenced appropriate dental referral in the management pathway (x2 = 10.49, df = 1, P = 0.001). This study suggests that there is an inadequate level of knowledge on the appropriate management of dental avulsion injuries amongst primary school professionals in Australia.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 2003
DOI: 10.1016/S0304-3940(02)01244-2
Abstract: Although a number of studies have demonstrated that magnesium improves acute motor and cognitive outcome after traumatic brain injury, others have failed to show positive effects on cognitive outcome and none have examined persistent functional deficits. The present study shows that severe impact-acceleration induced, diffuse traumatic brain injury in rats produced profound motor and cognitive deficits that persisted for at least 4 weeks after trauma. Intravenous administration of magnesium sulfate (250 micromoles/kg) at 30 min after injury significantly improved rotarod (sensorimotor) and open field (stress/anxiety) performance, and led to a faster rate of recovery in the Barnes maze (learning). We conclude that posttraumatic magnesium administration attenuates long-term motor and cognitive deficits after traumatic brain injury, and that this improvement may include some reduction of post-traumatic stress and anxiety.
Publisher: Elsevier BV
Date: 10-1991
DOI: 10.1016/0014-2999(91)90726-7
Abstract: The NK3 agonist, senktide, induced a potent contraction of rat uterus in the presence of tetrodotoxin, atropine and indomethacin, or the tachykinin receptor antagonists L-659877 and [D-Pro4,D-Trp7,9,10]substance P (4-11). Additional contractile and radioligand binding studies with receptor selective agonists and antagonists confirmed the presence of NK3 receptors and also revealed the presence of NK1 and NK2 receptors. The rat uterus is the second peripheral tissue in which a post-synaptic, non-neuronal NK3 receptor has been identified.
Publisher: Bentham Science Publishers Ltd.
Date: 06-2009
DOI: 10.2174/157488909788452997
Abstract: In recent years, one of the major advances in terms of our understanding of the pathology underlying many neurological conditions has been the realisation that inflammation may play a major role in many acute and chronic conditions. Inflammation is not only involved in acute CNS conditions, such as stroke and traumatic injury, but it is also a central factor in chronic and neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease and multiple sclerosis. There are some key differences between inflammatory processes within the CNS (neuroinflammation) and peripheral inflammation, partly due to the natural compartmentation of the brain by the blood-brain barrier. As a result of these differences, the classical anti-inflammatory agents (steroids and NSAIDs) have not played a major role in the management of CNS inflammatory conditions. In order to address this clinical need, there is significant interest in developing novel anti-inflammatory agents that may help prevent or ameliorate CNS inflammation. In this review, the authors focus on disclosures from the patent literature to give a broad overview of the different approaches that are being taken to try and develop more effective and selective anti-inflammatory agents to manage acute and chronic inflammation in the CNS. A variety of approaches are discussed including modulating the activity of various inflammatory mediators such as cytokines, chemokines and kinins, targeting toll-like receptors as a possible therapeutic intervention, and novel approaches to managing the actions of eicosanoids in neuroinflammation.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2012
DOI: 10.1007/S10585-012-9487-Z
Abstract: It is not yet known how tumour cells traverse the blood-brain barrier (BBB) to form brain metastases. Substance P (SP) release is a key component of neurogenic inflammation which has been recently shown to increase the permeability of the BBB following CNS insults, making it a possible candidate as a mediator of tumour cell extravasation into the brain. This study investigated the properties of the BBB in the early stages of tumour cell invasion into the brain, and the possible involvement of SP. Male Wistar rats were injected with Walker 256 breast carcinoma cells via the internal carotid artery and euthanised at 1, 3, 6 and 9 days post tumour inoculation. Culture medium-injected animals served as controls at 1 and 9 days. Evidence of tumour cell extravasation across the BBB was first observed at 3 days post-inoculation, which corresponded with significantly increased albumin (p < 0.05) and SP immunoreactivity (p < 0.01) and significantly reduced endothelial barrier antigen labelling of microvessels when compared to culture medium control animals (p < 0.001). By day 9 after tumour cell inoculation, 100 % of animals developed large intracranial neoplasms that had significantly increased albumin in the peri-tumoral area (p < 0.001). The increased SP immunoreactivity and altered BBB properties at 3 days post-inoculation that coincided with early tumour invasion may be indicative of a mechanism for tumour cell extravasation into the brain. Thus, extravasation of tumour cells into the brain to form cerebral metastases may be a SP-mediated process.
Publisher: Wiley
Date: 25-09-1988
DOI: 10.1113/EXPPHYSIOL.1988.SP003200
Abstract: Binding of [125I]Bolton-Hunter labelled substance P (BH-SP) and [125I]human alpha-calcitonin gene-related peptide (h alpha CGRP) to rat bladder tissue sections was characterized and the respective binding sites localized by light-microscopic autoradiography. BH-SP binding sites were localized to epithelium, blood vessels and smooth muscle while hCGRP binding sites were present only over the epithelium. These results suggest that the range of biological actions of substance P and calcitonin gene-related peptide, which may be co-released from the same afferent terminals, might be determined by the different distributions of their respective receptors.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Springer Science and Business Media LLC
Date: 2009
Publisher: Elsevier BV
Date: 08-1984
Publisher: Frontiers Media SA
Date: 12-05-2023
DOI: 10.3389/FNMOL.2023.1128545
Abstract: Disruption of the blood-spinal cord barrier (BSCB) with subsequent edema formation and further neuroinflammation contributes to aggravation of spinal cord injury (SCI). We aimed to observe the effect of antagonizing the binding of the neuropeptide Substance-P (SP) to its neurokinin-1 (NK1) receptor in a rodent SCI model. Female Wistar rats were subjected to a T9 laminectomy with or without (Sham) a T9 clip-contusion/compression SCI, followed by the implantation of an osmotic pump for the continuous, seven-day-long infusion of a NK1 receptor antagonist (NRA) or saline (vehicle) into the intrathecal space. The animals were assessed via MRI, and behavioral tests were performed during the experiment. 7 days after SCI, wet & dry weight and immunohistological analyses were conducted. Substance-P inhibition via NRA showed limited effects on reducing edema. However, the invasion of T-lymphocytes and the number of apoptotic cells were significantly reduced with the NRA treatment. Moreover, a trend of reduced fibrinogen leakage, endothelial and microglial activation, CS-GAG deposition, and astrogliosis was found. Nevertheless, only insignificant general locomotion recovery could be observed in the BBB open field score and the Gridwalk test. In contrast, the CatWalk gait analysis showed an early onset of recovery in several parameters. Intrathecal administration of NRA might reinforce the integrity of the BSCB in the acute phase after SCI, potentially attenuating aspects of neurogenic inflammation, reducing edema formation, and improving functional recovery.
Publisher: Informa Healthcare
Date: 10-2002
DOI: 10.1517/13543784.11.10.1375
Abstract: In industrialised countries, the mean per capita incidence of traumatic brain injury (TBI) that results in a hospital presentation is 250 per 100,000. In Europe and North America alone, this translates to > 2 million TBI presentations annually. Approximately 25% of these presentations are admitted for hospitalisation. Despite the significance of these figures, there is no single interventional pharmacotherapy that has shown efficacy in the treatment of clinical TBI. This lack of efficacy in clinical trials may be due, in part, to the inherent heterogeneity of the traumatic brain injury population. However, it is the multifactorial nature of secondary injury that also poses a major hurdle, particularly for those therapies that have been designed to specifically target an in idual injury factor. It is now becoming increasingly recognised that any successful TBI therapy may have to simultaneously affect multiple injury factors, somewhat analogous to other broad spectrum interventions. Recent efforts in experimental TBI have therefore focussed on developing novel pharmacotherapies that may affect multiple injury factors and thus improve the likelihood of a successful outcome. While a number of interventions are noteworthy in this regard, this review will focus on three novel compounds that show particular promise: magnesium, substance P antagonists and cyclosporin A.
Publisher: Wiley
Date: 6
DOI: 10.1113/EXPPHYSIOL.1993.SP003673
Abstract: Acidosis decreases the force of contraction of cardiac muscle in response to noradrenaline. The role of beta-adrenergic receptors in this response to acidosis was investigated. Radioligand techniques were used to determine beta-adrenergic receptor number and the degree of G-protein coupling, and to see whether these were altered in tissues subject to acidosis. The effect of pH on agonist and antagonist binding to these receptors was also investigated. Tissue pre-exposure to acidic conditions had no effect on numbers of beta-adrenergic receptors and no effect on the affinity of [125I]iodocyanopindolol (ICYP) for the receptors. Agonist competition experiments indicated that there was no change in the affinity of isoprenaline for these receptors, and there was no change in the relative proportions of high and low affinity binding sites. When radioligand experiments were performed under acidic conditions, however, the total number of beta-adrenergic receptors increased, and the affinity of these receptors for isoprenaline increased. This increase in agonist affinity might, therefore, minimize the shift to the right seen in the dose-response curve to noradrenaline during acidosis.
Publisher: Cambridge University Press (CUP)
Date: 08-1991
DOI: 10.1017/S0022215100116871
Abstract: The significance of the beta adrenergic system in the nasal mucosa isunclear. The authors have used the technique of autoradiography to localize and classify beta adrenoceptors in human nasal mucosa. The receptors have been found to beexclusively of thebeta-2 subtype and the highest density is found in the glandularducts. It is suggested that the beta-adrenergic system may have a physiologically important role in controlling the electrolyte composition of nasal secretions.
Publisher: Springer Science and Business Media LLC
Date: 17-07-2021
DOI: 10.1038/S41405-021-00082-5
Abstract: To comprehensively review the existing studies of articaine in dentistry and conduct a systematic review and meta-analysis to answer the following Population, Intervention, Comparison and Outcome question: “Is articaine a safe and efficacious local anaesthetic for routine dental treatment compared to lidocaine?” Database searches were conducted in Medline Ovid, Medline Pubmed, Scopus, Emcare, Proquest and the Cochrane Central register of Controlled Trials. Inclusion criteria were all existing English, human, randomised controlled trials of interventions involving 4% articaine and 2% lidocaine in routine dental treatment. Twelve studies were included for meta-analysis using Cochrane Review Manager 5 software. Anaesthetic success odds ratios were calculated using a random-effects model. Articaine had a higher likelihood of achieving anaesthetic success than lidocaine overall and in all subgroup analyses with varying degrees of significance. Overall (OR: 2.17, 95% CI: 1.50, 3.15, I 2 = 62%) articaine had 2.17 times the likelihood of anaesthetic success of lidocaine ( P 0.0001). For mandibular blocks (OR: 1.50, 95% CI: 1.14, 1.98, I 2 = 0%) articaine had 1.5 times the likelihood of anaesthetic success of lidocaine ( P = 0.004). For all infiltrations, maxillary and mandibular (OR: 2.78, 95% CI: 1.61, 4.79, I 2 = 66%) articaine had 2.78 times the likelihood of anaesthetic success of lidocaine ( P = 0.0002). None of the studies reported any major local anaesthetic-related adverse effects as a result of the interventions. Articaine is a safe and efficacious local anaesthetic for all routine dental procedures in patients of all ages, and more likely to achieve successful anaesthesia than lidocaine in routine dental treatment. Neither anaesthetic has a higher association with anaesthetic-related adverse effects.
Publisher: MDPI AG
Date: 07-09-2023
Publisher: Springer Science and Business Media LLC
Date: 26-09-2019
DOI: 10.1007/S10585-019-09994-X
Abstract: Metastasis, whether regional or distant, remains the main cause of morbidity and recurrence in oral cancer. The accumulating evidence suggests that inflammatory mediators are strong drivers for cancer progression and spread. However, the precise role of these inflammatory mediators in mediating specific metastatic stage is poorly understood due to lack of integration/validation of experimental research data and the clinical trials, i.e., the data produced from research is not translated to clinical therapeutic targets. This, in turn, results in the lack of developing reliable biomarker that can be used for accurate diagnosis rognosis of the tumour spread. We have performed a systematic review to assess the role of inflammatory mediators as potential markers for diagnosis rognosis of oral squamous cell carcinoma (OSCC) metastasis. We carried out a systematic search the PubMed, Web of Science, Embase and Scopus databases under the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Australian National Health and Medical Research Council (NHMRC). Articles were ided into two groups experimental (in-vivo) and clinical studies. The REporting recommendations for tumour MARKer prognostic studies Scale (REMARK) was used to assess the quality of the studies for the clinical search while Animal research: Reporting In-vivo experiments (ARRIVE) guidelines were used to assess the quality of the animal studies. Sixteen articles in the clinical group and four articles in the experimental group were included in the final review. We identified nine inflammatory mediators CXCR4, CXCL12 (SDF-1), CCR7, IL-6, IL-18, CCL20 (MIP-3), CXCL1 (GRO-1), CCL3, CXCR2. This panel of inflammatory mediators can provide a framework for hypothesis testing of the potential value of these mediators in metastatic prognosis. We recommend carrying a large cohort study with data pooling for adequate assessment and testing of the inflammatory panel of mediators.
Publisher: Oxford University Press (OUP)
Date: 11-2002
DOI: 10.1095/BIOLREPROD.101.002022
Abstract: The receptors for neurokinin 1 (NK1-R), neurokinin 2 (NK2-R), and neurokinin 3 (NK3-R) are expressed and functionally active in the uterus, promoting strong contractions of the myometrium. Previously, we demonstrated that myometrial contractility activated by the NK-Rs is regulated by estrogen. In the current study, we furthered our investigations of the role of estrogen in the regulation of NK3-R-mediated myometrial contractility. Estrogen promotes both heterologous and homologous desensitization of NK3-R-mediated uterine contractility. In tissue obtained from estrogen-dominated rats (ovariectomized estrogen-treated rats and rats in estrus), the magnitude of uterine contractions decreased in response to consecutive additions of the NK3-R-selective agonist senktide. By addition of the fourth dose of agonist, the contractile response was routinely barely above baseline. In contrast, in tissue obtained from non-estrogen-dominated rats consecutive doses of senktide resulted in contractions of identical magnitude. The homologous desensitization was specific to the NK3-R, and the desensitization of the NK3-R-mediated response did not affect the magnitude or nature of uterine contractions in response to NK1-R or NK2-R activation. Furthermore, heterologous and homologous desensitization of NK3-R-mediated contractility is dependent upon the duration of exposure to estrogen. This complex mechanism appears to be important in intact tissue capsaicin-mediated release of endogenous neuropeptides resulted in a desensitization of response to subsequent stimulation with senktide in estrogen-dominated uterine tissue.
Publisher: MDPI AG
Date: 22-12-2020
DOI: 10.3390/DJ9010002
Abstract: This review sheds light on the recent published scientific evidence relating to the use of professionally delivered local antimicrobial agents (LA’s). The review also analyses drug delivery systems available to date and provides an update on the latest scientific evidence about the benefits, limitations, and clinical results obtained by use of local drugs in the treatment of periodontal disease. The search strategy revealed randomized controlled trials (RCTs) that compared the efficacy of adjunctive LA’s to mechanical therapy alone. Based on the available evidence gathered from this review, we can infer that the use of local antimicrobial agents in conjunction to scaling and root debridement (SRD) delivers significant benefits in periodontal therapy and it is a useful aid, avoiding many of the side effects that systemic antibiotic therapy may involve. Local drug delivery (LDD) is an efficient and effective means of delivering drugs based on the evidence presented in the review. The authors of this review would suggest the use of local antimicrobials in cases of localized periodontitis or in idual areas that do not respond to the usual mechanical therapy alone. This review summarizes the current use of local drug delivery in periodontal management ensuring that the general practitioners are able to choose an appropriate local antimicrobial.
Publisher: Portland Press Ltd.
Date: 11-1991
DOI: 10.1042/BST019357S
Publisher: SAGE Publications
Date: 13-05-2009
Abstract: Brain edema and swelling is a critical factor in the high mortality and morbidity associated with traumatic brain injury (TBI). Despite this, the mechanisms associated with its development are poorly understood and interventions have not changed in over 30 years. Although neuropeptides and neurogenic inflammation have been implicated in peripheral edema formation, their role in the development of central nervous system edema after brain trauma has not been investigated. This study examines the role of the neuropeptide, substance P (SP), in the development of edema and functional deficits after brain trauma in rats. After severe diffuse TBI in adult male rats, neuronal and perivascular SP immunoreactivity were increased markedly. Perivascular SP colocalized with exogenously administered Evans blue, supporting a role for SP in vascular permeability. Inhibition of SP action by administration of the neurokinin-1 (NIC,) antagonist, N-acetyl-l-tryptophan, at 30 mins after trauma attenuated vascular permeability and edema formation. Administration of the NIC, antagonist also improved both motor and cognitive neurologic outcomes. These findings suggest that SP release is integrally linked to the increased vascular permeability and edema formation after brain trauma, and that treatment with an NIC, receptor antagonist reduces edema and improves neurologic outcome.
Publisher: Springer Science and Business Media LLC
Date: 12-11-2021
DOI: 10.1186/S12889-021-12016-9
Abstract: The prevalence of the oral-systemic relationship has accounted for potentially preventable chronic conditions and morbidity worldwide. Health literacy is a large contributing factor. This systematic review investigates the knowledge and awareness of patients with major systemic conditions, regarding the oral associations to their condition. Electronic databases including Medline (Ovid), CINAHL, The Cochrane Library, Web of Science, Informit Health Databases and Scopus were searched. All articles from 2011 to 2020, investigating knowledge of the oral-systemic link, of adult patients with the following major system conditions were searched: diabetes mellitus (DM), respiratory disease, cardiovascular disease (CVD), pregnancy and bone disease. Two independent reviewers completed screening, data extraction and quality assessment. A synthesis without meta-analysis was conducted. Twenty-four studies, from 14 different countries, were included in the systematic review. Analysis showed that globally, patients with major systemic conditions have poor knowledge and awareness ( 50%) of the oral health associations to their condition. Improvements in health education are particularly necessary for patients with heart disease, bone disease and diabetes. Dentists and the media were the most common source of information. There were no relevant studies investigating the knowledge of patients with respiratory disease. To improve the global burden of preventable chronic conditions, it is essential to address inequalities in the dissemination of health education to at-risk populations. Improvements in patient education rely on an increase in patient-practitioner communication on the oral-systemic link, implementation of oral health educational programs and greater interdisciplinary collaboration.
Publisher: Oxford University Press (OUP)
Date: 2006
Abstract: A high-performance liquid chromatography (HPLC) assay is described for the determination of indomethacin in porcine plasma using acetonitrile to precipitate plasma proteins and for the one-step extraction. Calibration curves (using the internal standard method) are linear (r2 > 0.98) over the concentration range of 50.0 to 3000 ng/mL in both mobile phase and plasma. Precision, expressed as the inter- and intraday coefficient of variation (n = 5), is < 7% on the same day and < 5% between days at each plasma control s le of 300, 1000, and 3000 ng/mL, respectively. System precision, calculated as the coefficient of variation (n = 5), is < 7% at 3000 ng/mL of indomethacin, and the limit of quantitation in plasma is 50 ng/mL. The absolute recovery for both indomethacin and the internal standard (mefenamic acid) from plasma is over 97% (n = 3), and the concentrations do not deviate more than -2.9% to 2.4% from their actual values. The specificity of the method is confirmed. This technique is thus reported to be both rapid and specific. The real advantage is the small s le volume required (500 microL), which allows it to be considered for the quantitation of indomethacin in plasma from paediatric patients.
Publisher: Bioscientifica
Date: 11-1995
Abstract: The inhibitory effects of catecholamines on rat myometrium mediated by β-adrenoceptors are modulated by ovarian steroids. Previously reported findings of radioligand binding studies on myometrial membranes have demonstrated changes in the numbers of β-adrenergic binding sites following ovarian steroid treatment. However, these changes were not accompanied by parallel functional changes. In the present study, we have investigated possible mechanisms of heterologous β-adrenoceptor regulation by ovarian steroids. Binding studies were performed on myometrial membrane and cytosolic preparations from rats which had been ovariectomized and subsequently received no hormonal treatment or had been treated with oestradiol, progesterone or combined oestradiol and progesterone. The β-adrenergic antagonist [ 125 I]iodocyanopindolol and the unlabelled competing agonist, isoprenaline, were used in the present studies. Hormonal treatment had no effect on the concentration of β-adrenergic binding sites in the myometrium (i.e. the number of membrane-bound and cytosolic binding sites per mg protein). However, significant changes were found in the total number of binding sites these were associated with the hormone-induced tissue hypertrophy. In myometrium from ovariectomized-alone rats, approximately 50% of β-adrenergic binding sites were present in the cytosolic fraction. Oestradiol treatment, either on its own or in combination with progesterone, resulted in the translocation of binding sites to the cell membrane. However, in the absence of progesterone only 33% of the membrane-bound binding sites bound the β-adrenergic agonist, isoprenaline, with a high affinity, suggesting that the majority of these membrane-bound binding sites represented non-functional β-adrenoceptors. Progesterone treatment resulted in a doubling in number of the high affinity membrane-bound receptors. As a result of our findings we propose that oestrogen and progesterone act together in regulating β-adrenoceptor function: it is proposed that oestrogens increase the number of β-adrenergic binding sites associated with the cell membrane while progesterone promotes the coupling of these binding sites to their effector mechanisms thus leading to an increase in the number of functional β-adrenoceptors. Journal of Endocrinology (1995) 147, 303–309
No related grants have been discovered for Alan Nimmo.