25 results on '"Paterson DJ"'
Search Results
2. Evidence for multiple mechanisms in human ventricular fibrillation.
- Author
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Nash MP, Mourad A, Clayton RH, Sutton PM, Bradley CP, Hayward M, Paterson DJ, and Taggart P
- Published
- 2006
3. Should we still use nitrovasodilators to test baroreflex sensitivity?
- Author
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Casadei B, Paterson DJ, Casadei, B, and Paterson, D J
- Published
- 2000
- Full Text
- View/download PDF
4. Hypercapnic cerebral blood flow in spontaneously hypertensive rats.
- Author
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Heinert G, Casadei B, Paterson DJ, Heinert, G, Casadei, B, and Paterson, D J
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- 1998
- Full Text
- View/download PDF
5. Letter by Herring and Paterson regarding article, 'Common NOS1AP variants are associated with a prolonged QTc interval in the Rotterdam Study'.
- Author
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Herring N and Paterson DJ
- Published
- 2007
6. The Heart's Little Brain: Shedding New Light and CLARITY on the "Black Box".
- Author
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Herring N and Paterson DJ
- Subjects
- Heart Rate, Brain, Heart
- Published
- 2021
- Full Text
- View/download PDF
7. How Accurate Is Inverse Electrocardiographic Mapping? A Systematic In Vivo Evaluation.
- Author
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Bear LR, LeGrice IJ, Sands GB, Lever NA, Loiselle DS, Paterson DJ, Cheng LK, and Smaill BH
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- Animals, Arrhythmias, Cardiac diagnostic imaging, Arrhythmias, Cardiac physiopathology, Cardiac Pacing, Artificial, Disease Models, Animal, Heart Rate, Magnetic Resonance Imaging, Pericardium diagnostic imaging, Predictive Value of Tests, Reproducibility of Results, Sus scrofa, Action Potentials, Arrhythmias, Cardiac diagnosis, Body Surface Potential Mapping methods, Pericardium physiopathology
- Abstract
Background: Inverse electrocardiographic mapping reconstructs cardiac electrical activity from recorded body surface potentials. This noninvasive technique has been used to identify potential ablation targets. Despite this, there has been little systematic evaluation of its reliability., Methods: Torso and ventricular epicardial potentials were recorded simultaneously in anesthetized, closed-chest pigs (n=5), during sinus rhythm, epicardial, and endocardial ventricular pacing (70 records in total). Body surface and cardiac electrode positions were determined and registered using magnetic resonance imaging. Epicardial potentials were reconstructed during ventricular activation using experiment-specific magnetic resonance imaging-based thorax models, with homogeneous or inhomogeneous (lungs, skeletal muscle, fat) electrical properties. Coupled finite/boundary element methods and a meshless approach based on the method of fundamental solutions were compared. Inverse mapping underestimated epicardial potentials >2-fold ( P <0.0001)., Results: Mean correlation coefficients for reconstructed epicardial potential distributions ranged from 0.60±0.08 to 0.64±0.07 across all methods. Epicardial electrograms were recovered with reasonable fidelity at ≈50% of sites (median correlation coefficient, 0.69-0.72), but variation was substantial. General activation spread was reproduced (median correlation coefficient, 0.72-0.78 for activation time maps after spatio-temporal smoothing). Epicardial foci were identified with a median location error ≈16 mm (interquartile range, 9-29 mm). Inverse mapping with meshless method of fundamental solutions was better than with finite/boundary element methods, and the latter were not improved by inclusion of inhomogeneous torso electrical properties., Conclusions: Inverse potential mapping provides useful information on the origin and spread of epicardial activation. However the spatio-temporal variability of recovered electrograms limit resolution and must constrain the accuracy with which arrhythmia circuits can be identified independently using this approach., (© 2018 American Heart Association, Inc.)
- Published
- 2018
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8. Inhibition of Spleen Tyrosine Kinase Reduces Renal Allograft Injury in a Rat Model of Acute Antibody-Mediated Rejection in Sensitized Recipients.
- Author
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Ramessur Chandran S, Han Y, Tesch GH, Di Paolo J, Mulley WR, Kanellis J, Ma FY, and Nikolic-Paterson DJ
- Subjects
- Acute Disease, Animals, Blotting, Western, Disease Models, Animal, Graft Rejection enzymology, Graft Rejection immunology, Rats, Rats, Inbred Lew, Signal Transduction, Syk Kinase metabolism, Transplantation, Homologous, Antibodies immunology, Graft Rejection prevention & control, Kidney Transplantation adverse effects, Protein Kinase Inhibitors pharmacology, Syk Kinase antagonists & inhibitors, Transplant Recipients
- Abstract
Background: Organ transplantation into sensitized patients with preexisting donor-specific antibodies (DSA) is very challenging. Spleen tyrosine kinase (Syk) promotes leukocyte recruitment and activation via signaling through various cell surface receptors. We investigated whether a selective Syk inhibitor (GS-492429) could suppress antibody-mediated rejection (AMR) in a rat model of AMR in sensitized recipients., Methods: Recipient Lewis rats (RT1) were immunized with donor (Dark Agouti, RT1) spleen cells (day -5). Recipients underwent bilateral nephrectomy and orthotopic renal transplantation (day 0). Cellular rejection was minimized by tacrolimus treatment from day -1. Groups received GS-492429 (30 mg/kg, twice a day) (n = 11) or vehicle (n = 12) from 1 hour before transplantation until being killed on day 3., Results: Vehicle-treated recipients developed graft dysfunction on day 1 which rapidly worsened by day 3. Histology showed severe damage (thrombosis, acute tubular injury, capillaritis) and infiltration of many Syk leukocytes. GS-492429 did not affect graft dysfunction on day 1, but treatment reduced allograft damage and prevented the rapid deterioration of graft function on day 3. GS-492429 reduced the prominent macrophage infiltrate and reduced the M1 proinflammatory response. Neutrophil and NK cell infiltration and capillary thrombosis were also significantly reduced by GS-492429 treatment. Serum DSA levels and the deposition of IgG and C4d in the allograft were equivalent in the 2 groups., Conclusions: Treatment with a Syk inhibitor significantly reduced renal allograft injury in a model of severe antibody-mediated damage in highly sensitized recipients. Further studies are warranted to determine whether Syk inhibition is a potential adjunctive treatment in clinical AMR.
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- 2017
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9. Forward problem of electrocardiography: is it solved?
- Author
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Bear LR, Cheng LK, LeGrice IJ, Sands GB, Lever NA, Paterson DJ, and Smaill BH
- Subjects
- Action Potentials, Animals, Models, Animal, Models, Cardiovascular, Predictive Value of Tests, Reproducibility of Results, Signal Processing, Computer-Assisted, Swine, Body Surface Potential Mapping methods, Electrocardiography methods, Epicardial Mapping methods, Heart Conduction System physiology, Pericardium physiology
- Abstract
Background: The relationship between epicardial and body surface potentials defines the forward problem of electrocardiography. A robust formulation of the forward problem is instrumental to solving the inverse problem, in which epicardial potentials are computed from known body surface potentials. Here, the accuracy of different forward models has been evaluated experimentally., Methods and Results: Body surface and epicardial potentials were recorded simultaneously in anesthetized closed-chest pigs (n=5) during sinus rhythm, and epicardial and endocardial ventricular pacing (65 records in total). Body surface potentials were simulated from epicardial recordings using experiment-specific volume conductor models constructed from magnetic resonance imaging. Results for homogeneous (isotropic electric properties) and inhomogeneous (incorporating lungs, anisotropic skeletal muscle, and subcutaneous fat) forward models were compared with measured body surface potentials. Correlation coefficients were 0.85±0.08 across all animals and activation sequences with no significant difference between homogeneous and inhomogeneous solutions (P=0.85). Despite this, there was considerable variance between simulated and measured body surface potential distributions. Differences between the body surface potential extrema predicted with homogeneous forward models were 55% to 78% greater than observed (P<0.05) and attenuation of potentials adjacent to extrema were 10% to 171% greater (P<0.03). The length and orientation of the vector between potential extrema were also significantly different. Inclusion of inhomogeneous electric properties in the forward model reduced, but did not eliminate these differences., Conclusions: These results demonstrate that homogeneous volume conductor models introduce substantial spatial inaccuracies in forward problem solutions. This probably affects the precision of inverse reconstructions of cardiac potentials, in which this assumption is made., (© 2015 American Heart Association, Inc.)
- Published
- 2015
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10. Macrophages contribute to cellular but not humoral mechanisms of acute rejection in rat renal allografts.
- Author
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Ma FY, Woodman N, Mulley WR, Kanellis J, and Nikolic-Paterson DJ
- Subjects
- Acute Disease, Animals, B-Lymphocytes drug effects, B-Lymphocytes immunology, Disease Models, Animal, Graft Rejection enzymology, Graft Rejection pathology, Graft Rejection prevention & control, Graft Survival, Immunosuppressive Agents pharmacology, Lymphocyte Activation drug effects, Macrophages drug effects, Macrophages enzymology, Protein Kinase Inhibitors pharmacology, Rats, Rats, Inbred Lew, Receptor, Macrophage Colony-Stimulating Factor antagonists & inhibitors, Receptor, Macrophage Colony-Stimulating Factor metabolism, T-Lymphocytes drug effects, T-Lymphocytes immunology, Time Factors, Graft Rejection immunology, Immunity, Cellular drug effects, Immunity, Humoral drug effects, Kidney Transplantation adverse effects, Macrophages immunology
- Abstract
Background: Cells of the monocyte/macrophage lineage have been implicated as effectors in acute allograft rejection based on short-term depletion studies. However, the therapeutic potential of targeting monocyte/macrophages in acute rejection is unknown. We investigated the potential of a c-fms kinase inhibitor (fms-I) in acute renal allograft rejection., Methods: Lewis rats underwent bilateral nephrectomy and received an orthotopic Dark Agouti renal allograft. Recipients received fms-I or vehicle from the time of transplantation until being killed on day 5., Results: Vehicle-treated rats developed severe allograft rejection with massive macrophage and T-cell infiltration. In contrast, fms-I substantially inhibited renal allograft dysfunction and structural damage with abrogation of macrophage and dendritic cell infiltration but had only a minor effect on the T-cell infiltrate. However, fms-I suppressed T-cell activation within the allograft, whereas systemic T- and B-cell activation was not affected. In a longer-term study to assess therapeutic potential, fms-I-treated rats developed severe antibody-mediated rejection on day 8 after transplantation. These transplants exhibited features of antibody-mediated rejection including capillaritis with thrombosis, acute tubular injury, IgG and C4d deposition, and neutrophil infiltration and activation. Interestingly, T-cell activation within these rejecting allografts remained suppressed, indicating separation of T-cell and antibody-mediated rejection., Conclusion: This study demonstrates the ability of c-fms kinase blockade to selectively deplete monocyte/macrophages in acute allograft rejection, although this did not result in significant prolongation of allograft survival. Furthermore, we identify contrasting roles for macrophages in cellular and humoral mechanisms of acute renal allograft rejection.
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- 2013
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11. Human ventricular fibrillation during global ischemia and reperfusion: paradoxical changes in activation rate and wavefront complexity.
- Author
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Bradley CP, Clayton RH, Nash MP, Mourad A, Hayward M, Paterson DJ, and Taggart P
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- Adult, Aged, Animals, Disease Models, Animal, Electrodes, Epicardial Mapping, Female, Humans, Male, Middle Aged, Pericardium physiopathology, Time Factors, Heart Conduction System physiopathology, Myocardial Ischemia physiopathology, Myocardial Reperfusion, Ventricular Fibrillation physiopathology
- Abstract
Background: Ischemic ventricular fibrillation in experimental models has been shown to progress through a series of stages. Progression of ischemic VF in the in vivo human heart has not been determined., Methods and Results: We studied 10 patients undergoing cardiac surgery. Ventricular fibrillation was induced by burst pacing. After 30 seconds, global myocardial ischemia was induced by aortic cross-clamp and maintained for 2.5 minutes, followed by coronary reflow. Epicardial activity was sampled (1 kHz) with a sock that contained 256 unipolar contact electrodes. Dominant frequencies were calculated with a fast Fourier transform with a moving window. The locations of phase singularities and activation wavefronts were identified at 10-ms intervals. Preischemic (perfused) ventricular fibrillation was maintained by a disorganized mix of large and small wavefronts. During global myocardial ischemia, mean dominant frequencies decreased from 6.4 to 4.7 Hz at a rate of -0.011±0.002 Hz s(-1) (P<0.001) and then increased rapidly to 7.4 Hz within 30 seconds of reflow. In contrast, the average number of epicardial phase singularities increased during ischemia from 7.7 to 9.7 at a rate of 0.013±0.005 phase singularities per second (P<0.01) and remained unchanged during reflow, at 10.3. The number of wavefronts showed a similar time course to the number of phase singularities., Conclusions: In human ventricular fibrillation, we found an increase in complexity of electric activation patterns during global myocardial ischemia, and this was not reversed during reflow despite an increase in activation rate.
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- 2011
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12. Stimulating the human midbrain to reveal the link between pain and blood pressure.
- Author
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Green AL, Wang S, Owen SLF, Xie K, Bittar RG, Stein JF, Paterson DJ, and Aziz TZ
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- Adult, Aged, Analgesia methods, Chronic Disease, Electrodes, Female, Humans, Linear Models, Male, Middle Aged, Pain Measurement, Prospective Studies, Sympathetic Nervous System physiology, Blood Pressure physiology, Deep Brain Stimulation, Pain physiopathology, Pain Management, Periaqueductal Gray physiology
- Abstract
The periaqueductal grey area (PAG) in the midbrain is an important area for both cardiovascular control and modulation of pain. However, the precise relationship between pain and blood pressure is unknown. We prospectively studied 16 patients undergoing deep brain stimulation of the rostral PAG for chronic pain. Pre-operatively, post-operatively, and at 1 year, pain scores were assessed using both visual analogue scores and the McGill Pain Questionnaire. Patients were tested post-operatively to determine whether electrical stimulation of the PAG would modulate blood pressure. We found that the degree of analgesia induced by deep brain stimulation of the rostral PAG in man is related to the magnitude of reduction in arterial blood pressure. We found that this relationship is linear and is related to reduced activity of the sympathetic nervous system. Thus stimulation of the PAG may partly control pain by reducing sympathetic activity as predicted by William James over a century ago.
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- 2006
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13. Deep brain stimulation can regulate arterial blood pressure in awake humans.
- Author
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Green AL, Wang S, Owen SL, Xie K, Liu X, Paterson DJ, Stein JF, Bain PG, and Aziz TZ
- Subjects
- Adult, Aged, Analysis of Variance, Arteries physiology, Blood Pressure physiology, Electric Stimulation methods, Electrocardiography methods, Electrodes, Female, Humans, Male, Middle Aged, Pain Management, Periaqueductal Gray radiation effects, Arteries radiation effects, Blood Pressure radiation effects, Deep Brain Stimulation methods, Pain physiopathology
- Abstract
The periaqueductal grey matter is known to play a role in cardiovascular control in animals. Cardiovascular responses to electrical stimulation of the periventricular/periaqueductal grey matter were measured in 15 awake human study participants following implantation of deep brain stimulating electrodes for treatment of chronic pain. We found that stimulation of the ventral periventricular/periaqueductal grey matter caused a mean reduction in systolic blood pressure of 14.2+/-3.6 mmHg in seven patients and stimulation of the dorsal periventricular/periaqueductal grey matter caused a mean increase of 16.7+/-5.9 mmHg in six patients. A comparison between ventral and dorsal electrodes demonstrated significant differences (P<0.05). These changes were accompanied by analogous changes in diastolic blood pressure, pulse pressure, maximum dP/dt but not in the time interval between each R wave on the electrocardiogram.
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- 2005
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14. Targeting arterial chemoreceptor over-activity in heart failure with a gas.
- Author
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Paterson DJ
- Subjects
- Animals, Carotid Body enzymology, Cyclic GMP physiology, Nerve Tissue Proteins physiology, Nitric Oxide physiology, Nitric Oxide Synthase physiology, Nitric Oxide Synthase Type I, Rabbits, Carotid Body physiology, Chemoreceptor Cells physiology, Gene Transfer, Horizontal, Heart Failure physiopathology, Nerve Tissue Proteins genetics, Nitric Oxide Synthase genetics
- Published
- 2005
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15. Imaging electrocardiographic dispersion of depolarization and repolarization during ischemia: simultaneous body surface and epicardial mapping.
- Author
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Nash MP, Bradley CP, and Paterson DJ
- Subjects
- Animals, Arrhythmias, Cardiac diagnosis, Electrocardiography, Heart Ventricles physiopathology, Kinetics, Swine, Body Surface Potential Mapping, Myocardial Ischemia diagnosis, Pericardium physiopathology
- Abstract
Background: Myocardial ischemia creates abnormal electrophysiological substrates that result in life-threatening ventricular arrhythmias. Identifying patients at risk of such abnormalities by use of body surface electrical measures is controversial. We investigated the sensitivity of torso measures, recorded simultaneously with epicardial electrograms, to changes in dispersion of depolarization and repolarization during localized ventricular ischemia., Methods and Results: Ventricular epicardial electrograms were recorded from 5 anesthetized pigs with a 127-electrode sock. A controllable suture snare was used to ligate the left anterior descending coronary artery (LAD). The chest was reclosed, and a vest with 256 ECG electrodes was fitted to the torso. Simultaneous arrays of epicardial electrograms and torso ECGs were recorded during LAD occlusion and reperfusion. Activation-recovery intervals (ARIs), QTu and RTu dispersion (where u indicates upstroke), and QRST integrals were calculated, and these data were fitted to anatomically customized computational models of the swine ventricular epicardium and torso. LAD occlusion caused the epicardial ARI dispersion to steadily increase, whereas the location of shortest ARI shifted from the posterobasal ventricular tissue (control) to the anteroapical myocardium, distal to the suture snare. These changes were associated with a steady increase in the torso RTu dispersion as the shortest RTu interval moved from the right shoulder (control) to the sternum. QTu and RTu dispersion determined from the 12-lead ECG did not consistently reflect the myocardial changes., Conclusions: Although changes in myocardial repolarization dispersion resulting from localized ischemia are not reliably reflected in temporal indices derived from the 12-lead ECG, they can be readily identified with high-resolution torso ECG mapping.
- Published
- 2003
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16. Neuronal nitric oxide synthase gene transfer promotes cardiac vagal gain of function.
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Mohan RM, Heaton DA, Danson EJ, Krishnan SP, Cai S, Channon KM, and Paterson DJ
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- Acetylcholine metabolism, Adenoviridae genetics, Animals, Bradycardia chemically induced, Bradycardia enzymology, Bradycardia genetics, Electric Stimulation, Enzyme Inhibitors pharmacology, Gene Transfer Techniques, Genes, Reporter, Genetic Vectors genetics, Genetic Vectors pharmacology, Guinea Pigs, Heart Rate drug effects, Heart Rate physiology, In Vitro Techniques, Nitric Oxide Synthase antagonists & inhibitors, Nitric Oxide Synthase biosynthesis, Nitric Oxide Synthase Type I, Synaptic Transmission drug effects, Synaptic Transmission physiology, Up-Regulation drug effects, Up-Regulation physiology, Vagus Nerve drug effects, Heart Atria drug effects, Heart Atria innervation, Nitric Oxide Synthase genetics, Nitric Oxide Synthase pharmacology, Vagus Nerve physiology
- Abstract
Nitric oxide (NO) generated from neuronal nitric oxide synthase (NOS-1) in intrinsic cardiac ganglia has been implicated in parasympathetic-induced bradycardia. We provide direct evidence that NOS-1 acts in a site-specific manner to promote cardiac vagal neurotransmission and bradycardia. NOS-1 gene transfer to the guinea pig right atrium increased protein expression and NOS-1 immunolocalization in cholinergic ganglia. It also increased the release of acetylcholine and enhanced the heart rate (HR) response to vagal nerve stimulation (VNS) in vitro and in vivo. NOS inhibition normalized the HR response to VNS in the NOS-1-treated group compared with the control groups (enhanced green fluorescent protein and sham) in vitro. In contrast, an acetylcholine analogue reduced HR to the same extent in all groups before and during NOS inhibition. These results demonstrate that NOS-1-derived NO acts presynaptically to facilitate vagally induced bradycardia and that upregulation of NOS-1 via gene transfer may provide a novel method for increasing cardiac vagal function.
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- 2002
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17. Endothelial nitric oxide synthase and heart rate.
- Author
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Herring N and Paterson DJ
- Subjects
- Animals, Heart innervation, Heart physiology, Mice, Myocardium enzymology, Nitric Oxide metabolism, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Heart Rate, Nitric Oxide Synthase metabolism
- Published
- 2002
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18. Urine macrophage migration inhibitory factor concentrations as a diagnostic tool in human renal allograft rejection.
- Author
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Brown FG, Nikolic-Paterson DJ, Chadban SJ, Dowling J, Jose M, Metz CN, Bucala R, and Atkins RC
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- Adult, Cyclosporine poisoning, Diagnosis, Differential, Female, Humans, Immunosuppressive Agents poisoning, Kidney metabolism, Kidney pathology, Kidney Diseases chemically induced, Kidney Diseases diagnosis, Macrophage Migration-Inhibitory Factors blood, Macrophage Migration-Inhibitory Factors metabolism, Male, Middle Aged, Osmolar Concentration, Prospective Studies, Retrospective Studies, Transplantation, Homologous, Graft Rejection diagnosis, Graft Rejection urine, Kidney Transplantation, Macrophage Migration-Inhibitory Factors urine
- Abstract
Background: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is a potent activator of macrophages and T cells. Previous studies have shown that local MIF production is increased in acute renal allograft rejection, suggesting that it may play an important role in the rejection process., Aims: To determine if urine and serum MIF concentrations: (1) are increased in acute rejection, and (2) can be used as noninvasive tools to discriminate between acute rejection (AR) and cyclosporine nephrotoxicity (CyA toxicity)., Methods: In a prospective study of nine renal allograft patients (five acute rejection and four stable), serial urine MIF concentrations were measured by ELISA in the first 14 days after transplantation. In a retrospective study, MIF concentrations in urine and serum were measured in 24 patients who were biopsied for acute renal transplant dysfunction (11 AR, 13 CyA toxicity). Urine and serum MIF were also measured in 23 stable renal transplant patients and 10 normals., Results: MIF was readily detected in the urine of normal healthy controls (106+/-61 pg/micromol creatinine). In the prospective study, the urinary MIF concentration was increased substantially on day 1 posttransplantation and subsequently fell in parallel with the serum creatinine. However, urine MIF increased before episodes of biopsy proven acute rejection. The retrospective study showed that urine MIF concentrations in patients with AR were increased 5-fold compared to normal controls (439+/-313 pg/micromol Cr; P<0.01). In contrast, urine MIF concentrations in CyA toxicity were not significantly different to normal controls (145+/-119 pg/micromol Cr; P=NS). A marked increase in MIF immunostaining was seen in biopsies of AR, but not in CyA toxicity. No significant differences were evident in serum MIF levels between normals and any transplant patient group., Conclusions: These results suggest that measurement of urine MIF concentration may be useful in monitoring renal transplant patients for acute rejection and as a discriminator from cyclosporine nephrotoxicity.
- Published
- 2001
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19. Macrophage migration inhibitory factor expression in human renal allograft rejection.
- Author
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Lan HY, Yang N, Brown FG, Isbel NM, Nikolic-Paterson DJ, Mu W, Metz CN, Bacher M, Atkins RC, and Bucala R
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- Acute Disease, Adult, Biopsy, Chronic Disease, Female, Gene Expression physiology, Graft Rejection genetics, Graft Rejection pathology, Humans, Kidney pathology, Kidney Transplantation pathology, Macrophage Migration-Inhibitory Factors physiology, Male, Middle Aged, RNA, Messenger metabolism, Severity of Illness Index, Up-Regulation, Kidney Transplantation immunology, Macrophage Migration-Inhibitory Factors genetics
- Abstract
Background: Macrophage migration inhibitory factor (MIF) plays a pivotal role in immune-mediated diseases. Despite the long-standing association of MIF with the delayed-type hypersensitivity response, the potential role of MIF in allograft rejection is unknown., Methods: MIF expression was assessed by in situ hybridization and immunohistochemistry staining in 62 biopsies of human renal allograft rejection and in normal human kidney., Results: MIF mRNA and protein is constitutively expressed in normal kidney, being largely restricted to tubular epithelial cells, some glomerular epithelial cells, and vascular smooth muscle cells. In both acute and chronic renal allograft rejection, there was marked up-regulation of MIF mRNA and protein expression by intrinsic kidney cells such as tubular epithelial cells and vascular endothelial and smooth muscle cells. There was also MIF expression by infiltrating macrophages and T cells. Of note, macrophage and T cell infiltrates were largely restricted to areas with marked up-regulation of MIF expression, potentially contributing to the development of severe tubulitis and intimal or transmural arteritis. Quantitative analysis found that increased MIF expression in allograft rejection gave a highly significant correlation with macrophage and T cell accumulation in both the glomerulus and interstitium (P<0.001). In addition, the number of MIF+ tubules and interstitial MIF+ cells correlated significantly with the severity of allograft rejection (P<0.01), and the loss of renal function (P<0.01). In contrast, no up-regulation of renal MIF expression and no leukocyte accumulation was seen in allograft biopsies without evidence of rejection., Conclusions: This is the first study to demonstrate that local MIF expression is up-regulated during allograft rejection. The association between up-regulation of MIF expression, macrophage and T cell infiltration and the severity of renal allograft rejection suggests that MIF may be an important mediator in the process of allograft rejection.
- Published
- 1998
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20. Ultrastructural localisation of CD44 in the rat lung in experimental Goodpasture's syndrome.
- Author
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Hill PA, Lan HY, Atkins RC, and Nikolic-Paterson DJ
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- Animals, Endothelium, Vascular metabolism, Gold Colloid, In Situ Hybridization, Leukocytes metabolism, Lung metabolism, Macrophages metabolism, Male, Microscopy, Immunoelectron, RNA, Messenger analysis, Rats, Rats, Sprague-Dawley, Time Factors, Anti-Glomerular Basement Membrane Disease immunology, Hyaluronan Receptors metabolism, Lung ultrastructure
- Abstract
Although CD44 is known to be involved in a wide array of cell to cell and cell to matrix interactions, its role in immune-mediated disease is not well understood. Therefore, using immunogold electron microscopy we have determined the precise localisation of CD44 in the rat lung in experimental Goodpasture's (GP) syndrome, a model of immune-mediated pulmonary disease. In normal rat lung CD44 was present on the surface of alveolar macrophages but was not detectable on endothelium. In GP syndrome there was strong CD44 expression on all infiltrating inflammatory leucocytes, both adherent to endothelium and within the alveolar spaces and interstitium. However the most striking finding was the progressively strong antibody staining for CD44 on pulmonary endothelium of alveolar capillaries and larger vessels over the 21 days of GP syndrome. In situ hybridisation confirmed that the endothelial CD44 staining was due to local protein synthesis. All epithelial cell surfaces, including bronchial epithelium and type I and II alveolar epithelial cells, were negative in normal rat lung and GP syndrome. De novo CD44 expression by endothelial cells during the progression of GP syndrome may contribute to leucocyte recruitment and cell-mediated lung injury.
- Published
- 1997
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21. Nitric oxide can increase heart rate by stimulating the hyperpolarization-activated inward current, I(f).
- Author
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Musialek P, Lei M, Brown HF, Paterson DJ, and Casadei B
- Subjects
- Animals, Cyclic GMP pharmacology, Data Interpretation, Statistical, Female, Guinea Pigs, Heart Rate drug effects, In Vitro Techniques, Ion Channels drug effects, Male, Molsidomine analogs & derivatives, Molsidomine pharmacology, Nitroprusside pharmacology, Rabbits, Sinoatrial Node drug effects, Superoxide Dismutase pharmacology, Time Factors, Vasodilator Agents pharmacology, Heart Rate physiology, Ion Channels physiology, Nitric Oxide physiology, Sinoatrial Node physiology
- Abstract
We investigated the chronotropic effect of increasing concentrations of sodium nitroprusside (SNP, n = 8) or 3-morpholinosydnonimine (SIN-1, n = 6) in isolated guinea pig spontaneously beating sinoatrial node/atrial preparations. Low concentrations of NO donors (nanomolar to micromolar) gradually increased the beating rate, whereas high (millimolar) concentrations decreased it. The increase in rate was (1) enhanced by superoxide dismutase (50 to 100 U/mL, n = 6), (2) prevented by the guanylyl cyclase inhibitors 6-anilino-5,8-quinolinedione (5 mumol/L, n = 6) or 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (10 mumol/L, n = 6), and (3) mimicked by 8-bromo-cGMP (n = 6) with no additional positive chronotropic effect of SIN-1 (n = 5). The response to 10 mumol/L SNP (n = 28) or 50 mumol/L SIN-1 (n = 16) was unaffected by IcaL antagonism with nifedipine (0.2 mumol/L) but was abolished after blockade of the hyperpolarization-activated inward current (I(f)) by Cs+ (2 mmol/L) or 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride (1 mumol/L). The effect on I(f) was further evaluated in rabbit isolated patch-clamped sinoatrial node cells (n = 21), where we found that 5 mumol/L SNP or SIN-1 caused a reversible Cs(+)-sensitive increase in this current (+130% at -70 mV and +250% at -100 mV). In conclusion, NO donors can affect pacemaker activity in a concentration-dependent biphasic fashion. Our results indicate that the increase in beating rate is due to stimulation of I(f) via the NO-cGMP pathway. This may contribute to the sinus tachycardia in pathological conditions associated with an increase in myocardial production of NO.
- Published
- 1997
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22. Effects of high potassium and the bradycardic agents ZD7288 and cesium on heart rate of rabbits and guinea pigs.
- Author
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Leitch SP, Sears CE, Brown HF, and Paterson DJ
- Subjects
- Animals, Atrioventricular Node drug effects, Bradycardia chemically induced, Cardiotonic Agents therapeutic use, Cesium therapeutic use, Female, Guinea Pigs, In Vitro Techniques, Male, Potassium metabolism, Potassium therapeutic use, Pyrimidines therapeutic use, Rabbits, Species Specificity, Cesium pharmacology, Heart drug effects, Heart Rate drug effects, Potassium pharmacology, Pyrimidines pharmacology
- Abstract
The effects of 2 mM cesium (Cs+) and a novel selective bradycardic agent ZD7288 (0.64 microM) on sinoatrial Node (SAN) pacing rate were investigated in an isolated guinea pig SAN/atrial preparation, rabbit SAN preparation, and isolated working rabbit heart preparation. The effect of Cs+ and ZD7288 on the response of the preparations to increased extracellular potassium concentration ([K+]o) was also studied. Cs+ reduced beating frequency by 24% in isolated rabbit SAN (n = 16, p < 0.01) and by 21% in isolated working rabbit heart (n = 9, p < 0.01). ZD7288 decreased beating rate by 53% in guinea pig SAN (n = 7, p < 0.01) and by 38% in isolated working rabbit heart (n = 6, p < 0.01). In all three preparations, increased [K+]o significantly decreased the rate (p < 0.01) in normal Tyrode's solution but had no effect in the presence of Cs+ and caused tachycardia (p < 0.01) in the presence of ZD7288. We conclude that Cs+ and ZD7288 decrease pacing rate in rabbits and guinea pigs, possibly through modulation of the hyperpolarization-activated current (I(f)). ZD7288 is a more effective bradycardic agent than Cs+.
- Published
- 1995
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23. Deoxyspergualin suppresses local macrophage proliferation in rat renal allograft rejection.
- Author
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Kerr PG, Nikolic-Paterson DJ, Lan HY, Tesch G, Rainone S, and Atkins RC
- Subjects
- Animals, Base Sequence, Cell Division drug effects, Cytokines biosynthesis, Cytokines genetics, Gene Expression drug effects, Humans, Macrophages cytology, Male, Molecular Sequence Data, Rats, Rats, Inbred Strains, T-Lymphocytes cytology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Graft Rejection immunology, Graft Rejection prevention & control, Guanidines therapeutic use, Immunosuppressive Agents therapeutic use, Kidney Transplantation immunology, Macrophages drug effects, Macrophages physiology
- Abstract
Deoxyspergualin (DSP) is a potent immunosuppressive drug that is able to both prevent and reverse acute allograft rejection. Although there is good evidence that DSP can inhibit T and B lymphocyte responses, the effect of this drug upon monocyte function is controversial. In the current study, substantial local proliferation of inflammatory macrophages (41.6 +/- 5.5% of ED1+ cells) within acutely rejecting rat renal allografts was identified by expression of the proliferating cell nuclear antigen. Treatment of animals with DSP not only reduced macrophage accumulation within the tissue, but it also significantly inhibited local proliferation of macrophages within the graft (26.4 +/- 5.6% of ED1+ cells, P < 0.05 vs. untreated). This appeared to be, at least in part, a direct effect of DSP upon macrophages since the drug also inhibited growth of 2 monocytic cell lines (RC-2A and U937) in vitro. However, DSP treatment had no effect upon LPS-induced monocyte IL-1 beta, TNF alpha, and IL-6 mRNA and protein production, indicating that this drug is not a general inhibitor of monocyte function. In conclusion, this study has demonstrated that local proliferation of macrophages within the kidney is a prominent feature of acute allograft rejection and that inhibition of this response is one mechanism whereby DSP exerts its potent immunosuppressive actions.
- Published
- 1994
- Full Text
- View/download PDF
24. Effect of physical training on exercise-induced hyperkalemia in chronic heart failure. Relation with ventilation and catecholamines.
- Author
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Barlow CW, Qayyum MS, Davey PP, Conway J, Paterson DJ, and Robbins PA
- Subjects
- Epinephrine blood, Exercise Test, Heart Failure blood, Heart Failure rehabilitation, Homeostasis, Humans, Lactates blood, Lactic Acid, Male, Middle Aged, Norepinephrine blood, Potassium metabolism, Time Factors, Ventricular Function, Left physiology, Exercise Therapy, Exercise Tolerance physiology, Heart Failure physiopathology, Potassium blood, Respiration physiology
- Abstract
Background: The exercise-induced rise in arterial potassium concentration ([K+]a) may contribute to exercise hyperpnea and could play a role in exertional fatigue. This study was designed to determine whether the exercise-induced rise in [K+]a is altered in patients with chronic heart failure (CHF) and whether physical training affects K+ homeostasis., Methods and Results: We evaluated 10 subjects with CHF (ejection fraction, 23 +/- 3.9%) and 10 subjects with normal left ventricular function (NLVF) who had undergone previous coronary artery graft surgery (ejection fraction, 63 +/- 8.6%). Subjects performed an incremental cycle ergometer exercise test before and after a physical training or detraining program. Changes in [K+]a and ventilation (VE) during exercise were closely related in both groups. Subjects with CHF did less absolute work and had reduced maximal oxygen consumption (VO2max) compared with subjects with NLVF (P < .01). Exercise-induced rises in [K+]a, VE, norepinephrine, lactate, and heart rate were greater at matched absolute work rates in subjects with CHF than in subjects with NLVF (P < .01). However, when the rise in [K+]a was plotted against percentage of VO2max to match for relative submaximal effort, there were no differences between the two groups. Physical training resulted in reduced exercise-induced hyperkalemia at matched submaximal work rates in both groups (P < .01) despite no associated change in the concentration of arterial catecholamines. At maximal exercise when trained, peak increases in [K+]a were unaltered, but peak concentrations of catecholamines were raised (P < .05). The decrease in VE at submaximal work rates after training was not significant with this incremental exercise protocol, but both groups had an increased peak VE when trained (P < .01)., Conclusions: Exercise-induced rises in [K+]a, catecholamines, and VE are greater at submaximal work rates in subjects with CHF than in subjects with NLVF. Physical training reduces the exercise-induced rise in [K+]a but does not significantly decrease VE during submaximal exercise with this incremental cycle ergometry protocol. The reduction in exercise-induced hyperkalemia after training is not the result of altered concentrations of arterial catecholamines. The pathophysiological significance of the increased exercise-induced hyperkalemia in CHF and the mechanisms of improved K+ homeostasis with training have yet to be established.
- Published
- 1994
- Full Text
- View/download PDF
25. Immune events in lymphoid tissues during experimental glomerulonephritis.
- Author
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Lan HY, Nikolic-Paterson DJ, and Atkins RC
- Subjects
- Acute Disease, Animals, Glomerulonephritis pathology, Immunoglobulin G analysis, Lymph Nodes pathology, Male, Rats, Rats, Sprague-Dawley, Receptors, Interleukin-2 analysis, Serum Sickness pathology, Spleen pathology, T-Lymphocyte Subsets, Glomerulonephritis immunology, Lymph Nodes immunology, Lymphocyte Activation, Serum Sickness immunology, Spleen immunology
- Abstract
To investigate immune events within lymphoid tissues and their role in relation to glomerular disease, systemic lymphoid tissues from rats with accelerated experimental anti-GBM glomerulonephritis or with primed serum sickness glomerulopathy were studied. Following disease induction, changes in leukocytic populations within lymphoid tissues were analysed over a 28 day time course by immunoperoxidase labelling with monoclonal antibodies. In anti-GBM glomerulonephritis there was rapid and severe renal injury and pulmonary hemorrhage (Good-pasture's syndrome). In these rats, antigen (rabbit IgG) was deposited on the GBM and within germinal centres of lymphoid tissues. From day 3 onwards, there was a significant increase in the number of T cells, presumably CD4+ T helper cells, present within enlarged germinal centres of kidney draining lymph nodes, axillary lymph nodes and spleen (p < 0.05) which peaked at day 14 (up to 28% of total cells) when there was intense deposition of rat IgG and C3 on the GBM. Similarly, increased numbers of ED1+ macrophages were evident in both germinal centres and T cell areas (paracortex and periarteriolar lymphoid sheath). Notably, the appearance of IL-2R expression in germinal centres and T cell areas was apparent from day 7 onwards. This was the time when widespread renal interstitial infiltration, cellular immune activation and severe renal functional and histological injury developed. In addition, antigen deposited in germinal centres was found to be associated with CD4+, CD5-, ED1- cells, most probably antigen presenting dendritic cells. In contrast, in acute serum sickness there was no antigen deposited in germinal centres and only mild renal injury and minor changes within lymphoid tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1993
- Full Text
- View/download PDF
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