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Biomedical subjects

G Donnan

Publications and source records attributed to G Donnan.

At least 19 recordsLinked to original sources
PubMed2007

Mycophenolate mofetil substitution for cyclosporine-dependent myasthenia gravis and nephrotoxicity.

Severe autoimmune myasthenia gravis is difficult to manage and may require immunosuppression with cyclosporine. However, cyclosporine dependency is associated with the risk of nephrotoxicity. Mycophenolate mofetil is a non-nephrotoxic alternative which should be considered to rescue cyclosporine-dependent, severe myasthenia gravis sufferers with renal impairment from progression to end-stage renal failure. However, the evidence is limited and studies have not assessed the outcome of a direct substitution in these cyclosporine-dependent patients. We study three such patients who successfully converted to mycophenolate mofetil, and briefly examine the evidence behind this option. We believe that total cyclosporine withdrawal is feasible, but strongly recommend overlapping mycophenolate mofetil treatment with cyclosporine.

Adult↗
PubMed2006

Treating the acute stroke patient as an emergency: current practices and future opportunities.

Developments in acute stroke therapy have followed advances in the understanding of the evolving pathophysiology in both ischaemic stroke and intracerebral haemorrhage (ICH). In ischaemic stroke, rapid reperfusion of the ischaemic penumbra with thrombolysis within 3 h of symptom onset is of proven benefit, but few patients currently receive therapy, mainly due to the short-time window and lack of stroke expertise. In ICH, a recent study indicated that a haemostatic agent can limit ongoing bleeding and improve outcomes when administered within 4 h of stroke onset. These advances in acute stroke therapy underlie the concept that 'time is brain' and that urgent intervention can limit cerebral damage. Neuroprotective therapy could offer the prospect of a greater proportion of stroke patients receiving treatment, potentially before imaging and even in the ambulance setting. Virtually all stroke patients would benefit from receiving multidisciplinary care in acute stroke units.

Emergencies↗
PubMed2005

Refining the perfusion-diffusion mismatch hypothesis.

BACKGROUND AND PURPOSE: The Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) tests the hypothesis that perfusion-weighted imaging (PWI)-diffusion-weighted imaging (DWI) mismatch predicts the response to thrombolysis. There is no accepted standardized definition of PWI-DWI mismatch. We compared common mismatch definitions in the initial 40 EPITHET patients. METHODS: Raw perfusion images were used to generate maps of time to peak (TTP), mean transit time (MTT), time to peak of the impulse response (Tmax) and first moment transit time (FMT). DWI, apparent diffusion coefficient (ADC), and PWI volumes were measured with planimetric and thresholding techniques. Correlations between mismatch volume (PWIvol-DWIvol) and DWI expansion (T2(Day 90-vol)-DWI(Acute-vol)) were also assessed. RESULTS: Mean age was 68+/-11, time to MRI 4.5+/-0.7 hours, and median National Institutes of Health Stroke Scale (NIHSS) score 11 (range 4 to 23). Tmax and MTT hypoperfusion volumes were significantly lower than those calculated with TTP and FMT maps (P<0.001). Mismatch > or =20% was observed in 89% (Tmax) to 92% (TTP/FMT/MTT) of patients. Application of a +4s (relative to the contralateral hemisphere) PWI threshold reduced the frequency of positive mismatch volumes (TTP 73%/FMT 68%/Tmax 54%/MTT 43%). Mismatch was not significantly different when assessed with ADC maps. Mismatch volume, calculated with all parameters and thresholds, was not significantly correlated with DWI expansion. In contrast, reperfusion was correlated inversely with infarct growth (R=-0.51; P=0.009). CONCLUSIONS: Deconvolution and application of PWI thresholds provide more conservative estimates of tissue at risk and decrease the frequency of mismatch accordingly. The precise definition may not be critical; however, because reperfusion alters tissue fate irrespective of mismatch.

Aged↗
PubMed2003

Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS Trial.

BACKGROUND AND PURPOSE: The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) showed that blood pressure lowering reduced stroke risk in patients with a history of cerebrovascular events. Here, we report the consistency of treatment effects across different stroke subtypes and among major clinical subgroups. METHODS: PROGRESS was a randomized, double-blind trial among 6105 people with a prior history of cerebrovascular events. Participants were assigned to active treatment (perindopril for all participants and indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo(s). RESULTS: During a mean of 3.9 years of follow-up, active treatment reduced the absolute rates of ischemic stroke from 10% to 8% (relative risk reduction [RRR], 24%; 95% confidence interval [CI], 10 to 35) and the absolute rates of intracerebral hemorrhage from 2% to 1% (RRR, 50%; 95% CI, 26 to 67). The relative risk of any stroke during follow-up was reduced by 26% (95% CI, 12 to 38) among patients whose baseline cerebrovascular event was an ischemic stroke and by 49% (95% CI, 18 to 68) among those whose baseline event was an intracerebral hemorrhage. There was no evidence that treatment effects were modified by other drug therapies (antiplatelet or other antihypertensive agents), residual neurological signs, atrial fibrillation, or the time since the last cerebrovascular event. CONCLUSIONS: Beneficial effects of a perindopril-based treatment regimen were observed for all stroke types and all major clinical subgroups studied. These data suggest that effective blood pressure-lowering therapy should be routinely considered for all patients with a history of cerebrovascular events.

Aged↗
PubMed2003

Perfusion thresholds in acute stroke thrombolysis.

BACKGROUND AND PURPOSE: Perfusion-weighted MRI has been shown to be useful in the early identification of cerebral tissue at risk of infarction during acute ischemia. Identification of threshold perfusion measures that predict infarction may assist in the selection of patients for thrombolysis. METHODS: Mean transit time (MTT), regional cerebral blood flow (rCBF), and regional cerebral blood volume (rCBV) maps were generated in 35 acute stroke patients (17 treated with tissue plasminogen activator and 18 control patients) imaged within 6 hours from symptom onset. Day 90 outcome infarcts (T2-weighted MRI) were superimposed on acute MTT, rCBF, and rCBV maps. Perfusion-weighted MRI measures were then calculated for 2 regions: infarcted and salvaged tissue. RESULTS: MTT was prolonged by 22% in infarcted regions relative to salvaged tissue (P<0.001). rCBF was 10% lower in infarcted tissue than in salvaged regions (P<0.01). rCBV did not differ significantly between infarcted and salvaged regions. When reperfusion occurred, tissue with more severely prolonged MTT was salvaged from infarction relative to patients with persistent hypoperfusion (P<0.05). In contrast, rCBF in salvaged regions did not differ between patients with and without reperfusion. In reperfused patients, an inverse correlation (R=0.93, P<0.001) was found between time of initial MRI scan and MTT delay in salvaged tissue. CONCLUSIONS: Both increases in MTT and decreases in rCBF predict infarction. Differences in MTT also predict salvage in more severely hypoperfused tissue after reperfusion, suggesting that it is the most clinically useful quantitative perfusion measure. Perfusion thresholds for infarction need to be assessed in the context of symptom duration.

Acute Disease↗
PubMed2002

Reduced frequency of high cholesterol levels among patients with intracerebral haemorrhage.

To determine whether a relationship exists between high cholesterol levels and intracerebral haemorrhage (ICH) a case-control study was undertaken on 331 consecutive cases of first-episode primary ICH, verified by computed tomography, and 331 age- and sex-matched community controls. Using conditional logistic regression the adjusted odds ratio (OR) of ICH among individuals reporting a high cholesterol level was 0.45 [95% confidence interval (CI), 0.28-0.73]. A similar finding was observed when the analysis was limited to those using cholesterol-lowering drugs (OR 0.25; 95% CI, 0.08-0.80). These data provide support for an inverse relationship between high cholesterol levels and ICH. When considered together with previous findings, in which low cholesterol levels have been associated with an increased risk of haemorrhagic stroke, these data provide evidence that this inverse relationship may extend into a higher range of cholesterol values.

Aged↗
PubMed2001

Inter-rater reliability of stroke sub-type classification by neurologists and nurses within a community-based stroke incidence study.

The stroke classification developed for use in the Oxfordshire Community Stroke Project (OCSP) is simple, clinically meaningful and requires no investigations. However, its inter-rater reliability in a community setting is unknown. We aimed to assess the inter-rater reliability of this classification among neurologists and nurses within a community-based stroke incidence study. Fifty-four stroke patients with cerebral infarction who were registered in the North East Melbourne Stroke Incidence Study (NEMESIS) were assigned OCSP classifications by two neurologists and one of seven research nurses. There was moderate agreement between neurologists (kappa = 0.53), fair agreement between neurologist 1 and nurse (kappa = 0.31) and moderate agreement between neurologist 2 and nurse (kappa = 0.45). Disagreement about the neurological signs was an important reason for classification differences. The OCSP classification can be easily applied in a community setting with moderate inter-rater reliability and is thus a useful instrument for commun ity-based epidemiological studies.

Australia↗
PubMed2000

Echoplanar magnetic resonance imaging in acute stroke.

Echoplanar magnetic resonance imaging (EPI) enables rapid, non-invasive imaging and analysis of cerebral pathophysiology in acute stroke. It represents an important clinical advance over computed tomography (CT) and conventional magnetic resonance (MR) scanning. It can rapidly delineate infarcted cerebral tissue and distinguish acute from chronic stroke. In addition, EPI has the potential to quickly determine the presence and degree of potentially viable brain tissue in the ischaemic penumbra. Thrombolysis is thought to reperfuse the penumbra and hence reduce infarct size. The thrombolytic agent tissue plasminogen activator (t-PA) improves outcome in ischaemic stroke when administered within the first 3 hours of onset. However, there is a significant risk of haemorrhage, and the time window for benefit may well exceed 3 hours in some patients. Hence, by facilitating diagnosis of 'at-risk' tissue in the ischaemic penumbra, a major clinical role of EPI may well become the rational selection of patients for acute interventional stroke therapy.

Brain↗
PubMed1999

Thrombolysis in acute ischemic stroke: controlled trials and clinical experience.

Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) is approved in the United States for treatment of acute ischemic stroke. Approval was granted after a large, randomized, placebo-controlled study by the National Institute of Neurological Disorders and Stroke (NINDS) showed a significant improvement in 3-month outcomes with rtPA despite a significant risk for symptomatic hemorrhage. Two other trials, the first and second European Cooperative Acute Stroke Study (ECASS I and II), have shown comparable results, but neither was statistically positive for the predefined primary end point. An analysis of the risk/benefit profile of rtPA therapy based on the results of these three trials indicates that the treatment is effective and, when administered within 3 hours of symptom onset at a dose of 0.9 mg/kg, the benefits by far outweigh the risks for eligible patients. Even with the 6-hour time window of the two ECASS trials, a combined analysis of the three studies shows the number of disabled or dead patients to be significantly reduced. Preliminary data collected on the use of rtPA outside of clinical trials in the United States and Europe suggest that, when rtPA is used according to the trial protocol, the risks and benefits are similar to those observed in clinical trials. However, even within the United States, rtPA is underutilized. The most substantial treatment barrier is the narrow time window, which may be expanded if long-term experience shows that this is possible. Most stroke patients arrive at the hospital too late to be eligible for screening and treatment. Education of the public and physicians may help to overcome this difficulty.

Acute Disease↗
PubMed1998

Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators.

BACKGROUND: Thrombolysis for acute ischaemic stroke has been investigated in several clinical trials, with variable results. We have assessed the safety and efficacy of intravenous thrombolysis with alteplase (0.9 mg/kg bodyweight) within 6 h of stroke onset. METHODS: This non-angiographic, randomised, double-blind, trial enrolled 800 patients in Europe, Australia, and New Zealand. Computed tomography was used to exclude patients with signs of major infarction. Alteplase (n=409) and placebo (n=391) were randomly assigned with stratification for time since symptom onset (0-3 h or 3-6 h). The primary endpoint was the modified Rankin scale (mRS) at 90 days, dichotomised for favourable (score 0-1) and unfavourable (score 2-6) outcome. Analyses were by intention to treat. FINDINGS: 165 (40.3%) alteplase-group patients and 143 (36.6%) placebo-group patients had favourable mRS outcomes (absolute difference 3.7%, p=0.277). In a posthoc analysis of mRS scores dichotomised for death or dependency, 222 (54.3%) alteplase-group and 180 (46.0%) placebo-group patients had favourable outcomes (score 0-2; absolute difference 8.3%, p=0.024). Treatment differences were similar whether patients were treated within 3 h or 3-6 h. 85 (10.6%) patients died, with no difference between treatment groups at day 90+/-14 days (43 alteplase, 42 placebo). Symptomatic intracranial haemorrhage occurred in 36 (8.8%) alteplase-group patients and 13 (3.4%) placebo-group patients. INTERPRETATION: The results do not confirm a statistical benefit for alteplase. However, we believe the trend towards efficacy should be interpreted in the light of evidence from previous trials. Despite the increased risk of intracranial haemorrhage, thrombolysis with alteplase at a dose of 0.9 mg/kg in selected patients may lead to a clinically relevant improvement in outcome.

Adolescent↗
PubMed1996

Mitochondrial DNA polymorphism in substantia nigra.

Inefficiencies in mitochondrial respiration mainly affecting complex I and IV activities, occur with increasing age and have been suggested as a possible etiological factor in age-related neurodegenerative diseases. It has been suggested that this finding may be explained by an accumulation of mtDNA mutations. We hypothesise that some polymorphic mitochondrial genomes encode less efficient respiratory protein subunits and are therefore less tolerant of acquired mutations. If this hypothesis is correct, individuals with 'less efficient' mtDNA genotypes may be predisposed both to more rapid biological aging and to neurodegenerative disease. In this study we investigate the substantia nigra mtDNA composition from 4 elderly individuals (2 non-parkinsonian and 2 with idiopathic Parkinson's disease) to determine whether there is sufficient polymorphism to account for different possible respiratory efficiencies. THe mitochondrial tRNAArg, tRNAHis, tRNAScr, tRNALeu(CUN), ND4L, ND4 and ND5 genes as well as parts of the ND3 and ND6 subunit coding regions were analysed (4221 bp), revealing the presence of multiple deletions and 48 discrete polymorphic sites. These included 23 missense, two tRNA and one nonsense polymorphism. Eight of the missense polymorphisms caused nonconservative amino acid replacements at sites of moderate to high evolutionary constraint. These findings suggest that mtDNA diversity in the ageing brain may account for a range of bioenergetic outcomes. The variation in mtDNA genotype involves both inherited (fixed familial) polymorphism and superimposed acquired mutations.

Aged↗
PubMed1994

Dietary factors and the risk of glioma in adults: results of a case-control study in Melbourne, Australia.

In a population-based case-control study of 416 incident gliomas in adults carried out in Melbourne, Australia, between 1987 and 1991, 409 age-sex-matched case-control pairs (243 male and 166 female) had adequate data available to examine associations between the dietary intake of N-nitroso compounds, N-nitroso precursors, other nutrients including N-nitroso inhibitors, and the risk of glioma. Dietary intakes were based on the reported frequency of consumption of 59 food items. Increased odds ratio (OR) were observed in males who consumed high levels of bacon, corned meats, apples, melons and oil. OR less than unity were observed in men consuming cabbage and cola drinks, and in women who consumed wholegrain bread, pasta, corned meat, bananas, cauliflower, brocoli, cola drinks and nuts. Generally, N-nitroso associations were greater in men and micronutrient associations were greater in women. Elevated OR in men, but not women, were associated with the intake of N-nitroso dimethylamine (NDMA), retinol and vitamin E. The intake of nitrate (largely of vegetable origin) was protective in women but not in men. When analyzed using multiple logistic regression, the association with NDMA intake in males was not modified by dietary micronutrient intakes. In females, beta carotene alone, though not directly associated with risk, modified the effect of NDMA. On balance, this study added only limited support to the N-nitroso hypothesis of glial carcinogenesis.

Australia↗
PubMed1992

Propofol induction for laryngeal mask airway insertion: dose requirement and cardiorespiratory effects.

The dosage, haemodynamic and respiratory effects of propofol for laryngeal mask airway (LMA) insertion were investigated. Fifty patients (ASA I-II) were randomly assigned one of four induction doses of propofol (1.5-2.5 mg/kg) delivered over 30 seconds and the first attempt at LMA insertion was made at 90 seconds. The LMA was inserted at 90 seconds in 35 patients and by 300 seconds in 13 others (mean plasma concentration at 90 seconds was 7.7 mcg/ml (no delay) versus 5.2 mcg/ml (insertion delayed), P < 0.01). Insertion was less successful after 1.5 mcg/kg (failed at 90 seconds in 6 of 12 patients), but did not vary with the other doses. Additional propofol (0.5 mg/kg/30s) was required in 22 patients for LMA insertion or to prevent movement, resulting in propofol concentrations at 120-180 seconds above 7 mcg/ml. Respiratory effects were minor, but MAP decreased by 18 +/- 1.4 mmHg at 90 seconds. Cardiovascular effects did not differ significantly between dosage groups or with the use of additional propofol.

Adult↗
PubMed1989

Interpleural administration of bupivacaine after cholecystectomy: a comparison with intercostal nerve block.

Pethidine requirements and verbal pain scores were recorded in 36 patients after cholecystectomy via subcostal incision. All patients also received 20 ml 0.5% bupivacaine with adrenaline 1/200,000. Group 1 (12 patients) received unilateral intercostal nerve blocks. Interpleural catheters were inserted through the 8th intercostal space in the remaining patients; 12 received local anaesthetic via the catheter immediately after surgery (Group 2) and 12 were given local anaesthetic at three hours (Group 3). Small asymptomatic pneumothoraces were noted on chest X-ray in six of the 24 patients with interpleural catheters. Both types of local anaesthesia produced lower pain scores than pethidine alone (P less than 0.05) with 25% of intercostal nerve blocks and 63% of interpleural catheters requiring no pethidine in the following three hours. The provision of catheter 'top-ups' between six and 18 hours after surgery also resulted in lower pain scores and a reduction in pethidine requirements (P less than 0.05).

Adult↗
PubMed1988

Cardiovascular effects of sedative infusions of propofol and midazolam after spinal anaesthesia.

The cardiovascular effects of intravenous sedation were studied in fifty patients after spinal anaesthesia for lower limb or pelvic surgery. Twenty patients received propofol (mean dosage 74 (SD 4) micrograms/kg/min for 0-20 minutes and 51 (SD 7) micrograms/kg/min for 20-40 minutes), twenty received midazolam (35 micrograms/kg + 2.54 (SD 0.2) micrograms/kg/min for 0-20 minutes and 1.35 (SD 0.2) micrograms/kg/min for 20-40 minutes) and ten patients received saline infusion only. The forearm vasoconstriction in response to the spinal anaesthesia was measured by strain gauge plethysmography. Spinal anaesthesia lowered systolic and diastolic blood pressure by 18 (SED 4) mmHg and 9 (SED 2) mmHg respectively. (SED = standard error of the difference.) This was associated with a 32% decrease in mean forearm blood flow. Propofol and midazolam caused similar additional reductions in systolic and diastolic blood pressure (10 (SED 4) mmHg and 4 (SED 2) mmHg) and a decrease in heart rate (P less than 0.005), but forearm vasoconstriction was not altered. In the control group, however, forearm vasoconstriction increased during 40 minutes in theatre (P less than 0.05). Recovery from propofol was far more rapid than after midazolam and was virtually complete in ten minutes. This was reflected by an increase in blood pressure and in forearm vasoconstriction in the recovery period.

Aged↗