Search PubMed⌕ Search

Biomedical subjects

G A Donnan

Publications and source records attributed to G A Donnan.

At least 19 recordsLinked to original sources
PubMed2000

The functional neuroanatomy and long-term reproducibility of brain activation associated with a simple finger tapping task in older healthy volunteers: a serial PET study.

We examined long-term reproducibility of the functional organization of the brain associated with a simple finger tapping movement using positron emission tomography (PET). Repeat measurements of regional cerebral blood flow were obtained in 10 individuals, ages 35 to 82 years (mean 52 years), at scanning sessions separated by 6 months. Although the functional neuroanatomy of hand movements has previously been investigated with PET by a number of groups, none has reported systematic investigation of the consistency of brain activation over an extended time. As expected, we found significant activation in the left precentral gyrus [Talairach coordinate (-32, -34, 52)], postcentral gyrus (-22, -48, 56), and supplementary motor area (SMA) (-2, -18, 52) at the initial study, consistent with previous studies in younger subjects. For the follow-up study we also found significant activation in the left precentral (-36, -28, 52) and postcentral (-28, -36, 52) gyri and in the SMA (2, -16, 56). Our group results demonstrate consistent anatomical location and extent of motor activation over time. More importantly, analysis of individuals confirmed the presence of consistent sites of activation in primary sensorimotor cortex and SMA over the 6-month interval in most subjects. A high degree of consistency in location of activation in the group, and within individuals, over time suggests that changes in loci of activation may be confidently monitored using the PET method. Evidence of individual differences in extent of activation over time highlights the need for caution when interpreting similar changes in patient studies.

Adult↗
PubMed1999

No evidence of hypoxic tissue on 18F-fluoromisonidazole PET after intracerebral hemorrhage.

We studied six patients after intracerebral hemorrhage (ICH) and eight controls using positron emission tomography (PET) with to determine whether a zone of tissue hypoxia, possibly representing "penumbral" tissue, exists surrounding an intracerebral hemorrhage. None of the stroke patients, studied 24 to 43 hours after symptom onset, nor any of the controls exhibited areas of tissue hypoxia on 18F-fluoromisonidazole PET images. These findings may have implications for the treatment of intracerebral hemorrhage with neuroprotective strategies.

Aged↗
PubMed1999

Absent middle cerebral artery flow predicts the presence and evolution of the ischemic penumbra.

OBJECTIVES: In acute ischemic stroke the pattern of a perfusion-imaging (PI) lesion larger than the diffusion-weighted imaging (DWI) lesion may be a marker of the ischemic penumbra. We hypothesized that acute middle cerebral artery (MCA) occlusion would predict the presence of presumed "penumbral" patterns (PI > DWI), ischemic core evolution, and stroke outcome. METHODS: Echoplanar PI, DWI, and magnetic resonance angiography (MRA) were performed in 26 patients with MCA territory stroke. Imaging and clinical studies (Canadian Neurological Scale, Barthel Index, and Rankin Scale) were performed within 24 hours of onset and repeated at days 4 and 90. RESULTS: MCA flow was absent in 9 of 26 patients. This was associated with larger acute PI and DWI lesions, greater PI/DWI mismatch, early DWI lesion expansion, larger final infarct size, worse clinical outcome (p < 0.01) and provided independent prognostic information (multiple linear regression analysis, p < 0.05). Acute penumbral patterns were present in 14 of 26 patients. Most of these patients (9 of 14) had no MCA flow, whereas all nonpenumbral patients (PI < or = DWI lesion) had MCA flow (p < 0.001). Penumbral-pattern patients with absent MCA flow had greater DWI lesion expansion (p < 0.05) and worse clinical outcome (Rankin Scale score, p < 0.05). CONCLUSIONS: Absent MCA flow on MRA predicts the presence of a presumed penumbral pattern on acute PI and DWI and worse stroke outcome. Combined MRA, PI, and DWI can identify individual patients at risk of ischemic core progression and the potential to respond to thrombolytic therapy beyond 3 hours.

Adult↗
PubMed1999

Risk of primary intracerebral haemorrhage associated with aspirin and non-steroidal anti-inflammatory drugs: case-control study.

OBJECTIVE: To examine the association between use of aspirin or other non-steroidal anti-inflammatory drugs and intracerebral haemorrhage. DESIGN: Case-control study. SETTING: 13 major city hospitals in the Melbourne and metropolitan area. SUBJECTS: 331 consecutive cases of stroke verified by computed tomography or postmortem examination, and 331 age (+/- 5 years) and sex matched controls who were community based neighbours. INTERVENTIONS: Questionnaire administered to all subjects either directly or by proxy with the next of kin. Drug use was validated by reviewing prescribing records held by the participants' doctors. MAIN OUTCOME MEASURES: Previous use of aspirin or other non-steroidal anti-inflammatory drugs. RESULTS: Univariate analysis showed no increased risk of intracerebral haemorrhage with low dose aspirin use in the preceding 2 weeks. Using multiple logistic regression to control for possible confounding factors, the odds ratio associated with the use of aspirin was 1.00 (95% confidence interval 0.60 to 1. 66, P=0.998) and the odds ratio associated with the use of other non-steroidal anti-inflammatory drugs was 0.85 (0.45 to 1.61, P=0. 611) compared with respective non-users in the preceding fortnight. Moderate to high doses of aspirin (>1225 mg/week spread over at least three doses) yielded an odds ratio of 3.05 (1.02 to 9.14, P=0. 047). There was no evidence of an increased risk among subgroups defined by age, sex, blood pressure status, alcohol intake, smoking, and the presence or absence of previous cardiovascular disease. CONCLUSIONS: No increase in risk of intracerebral haemorrhage was found among aspirin users overall or among those who took low doses of the drug or other non-steroidal anti-inflammatory drugs. These data provide evidence that doses of aspirin usually used for prophylaxis against vascular disease produce no substantial increase in risk of intracerebral haemorrhage.

Adolescent↗
PubMed1999

Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor.

Nigrostriatal dopaminergic neurons undergo sprouting around the margins of a striatal wound. The mechanism of this periwound sprouting has been unclear. In this study, we have examined the role played by the macrophage and microglial response that follows striatal injury. Macrophages and activated microglia quickly accumulate after injury and reach their greatest numbers in the first week. Subsequently, the number of both cell types declines rapidly in the first month and thereafter more slowly. Macrophage numbers eventually cease to decline, and a sizable group of these cells remains at the wound site and forms a long-term, highly activated resident population. This population of macrophages expresses increasing amounts of glial cell line-derived neurotrophic factor mRNA with time. Brain-derived neurotrophic factor mRNA is also expressed in and around the wound site. Production of this factor is by both activated microglia and, to a lesser extent, macrophages. The production of these potent dopaminergic neurotrophic factors occurs in a similar spatial distribution to sprouting dopaminergic fibers. Moreover, dopamine transporter-positive dopaminergic neurites can be seen growing toward and embracing hemosiderin-filled wound macrophages. The dopaminergic sprouting that accompanies striatal injury thus appears to result from neurotrophic factor secretion by activated macrophages and microglia at the wound site.

Adrenergic Fibers↗
PubMed1999

Sprouting of dopaminergic axons after striatal injury: confirmation by markers not dependent on dopamine metabolism.

Striatal injury increases dopamine metabolism in the nigrostriatal system but it is unclear whether this response is due to increased synthesis and activation of tyrosine hydroxylase within existing dopamine terminals and/or branching and sprouting of new terminals. While monitoring the density of tyrosine hydroxylase immunoreactive fibers suggests that sprouting occurs, this technique alone cannot adequately answer this question since the intensity of staining and thus the visibility of individual fibers are intimately linked to dopaminergic activity. However, by examining axons and their branches using markers that are independent of dopamine metabolism it is possible to determine whether dopaminergic sprouting does in fact take place. One month after using a Scouten wire knife to create a small lesion in the left striatum of normal C57/bl-6 mice, silver staining revealed an increase in the total number of neuronal fibers throughout the injured striatum. This was accompanied by intense staining of tyrosine hydroxylase-positive fibers around the wound and an increased density of striatal fibers labeled with dextran-biotin after injection of this neuronal tracer into the substantia nigra 1 month after striatal surgery and 5 days prior to sacrifice. The increase in tyrosine hydroxylase immunoreactivity confirms previous observations of increased dopaminergic activity after striatal injury. The increases in silver staining and dextran-biotin transport provide independent evidence that this increase in dopaminergic activity occurs because of sprouting of new fibers originating in the substantia nigra.

Animals↗
PubMed1999

Identification of major ischemic change. Diffusion-weighted imaging versus computed tomography.

BACKGROUND AND PURPOSE: Thrombolytic therapy is not recommended in patients with CT changes of recent major infarction, which has been defined as reduced attenuation or cerebral edema involving >33% of the middle cerebral artery territory (European Cooperative Acute Stroke Study [ECASS] criteria). Diffusion-weighted imaging (DWI) is more sensitive than CT in detecting acute ischemia, and the combination of DWI, MR perfusion imaging, and MR angiography provides additional information from a single examination. We sought to determine whether DWI could identify the presence and extent of major ischemia as well as CT in hyperacute stroke patients. METHODS: Seventeen suspected hemispheric stroke patients were studied with both CT and DWI within 6 hours of symptom onset. None received thrombolytic therapy. The scans were examined separately by 2 neuroradiologists in a blinded fashion for ischemic change and cerebral edema, graded as normal, <33%, or >33% of the MCA territory. Final diagnosis of stroke was determined with the use of standard clinical criteria and T2-weighted imaging at day 90. RESULTS: Sixteen of 17 patients had a final diagnosis of stroke. Acute ischemic changes were seen in all 16 on DWI (100% sensitivity) and in 12 of 16 on CT (75% sensitivity). DWI identified all 6 patients with major ischemia on CT, with excellent agreement between the 2 imaging techniques (kappa=0.88). One patient eligible for thrombolysis on the ECASS CT criteria had major ischemia on DWI. CONCLUSIONS: DWI is more sensitive than CT in the identification of acute ischemia and can visualize major ischemia more easily than CT.

Adult↗
PubMed1999

Nimodipine and perfusion changes after stroke.

BACKGROUND AND PURPOSE: Meta-analysis of previous trials of oral nimodipine in acute stroke has suggested a benefit when commenced within 12 hours of onset. We sought to study the effect of oral nimodipine on reperfusion after acute stroke and the relation between reperfusion and outcome. METHODS: Fifty patients with acute middle cerebral artery territory cortical infarction were blindly randomized within 12 hours of onset to either oral nimodipine (30 mg every 6 hours) or placebo. Treatment was continued for 2 weeks. Cerebral blood flow was assessed with the use of 99mTc-hexamethylpropyleneamine oxime single-photon emission CT before therapy, 24 hours later, and at 3 months. Hypoperfusion was measured by a validated volumetric technique. Neurological impairment and functional outcome were assessed with the Canadian Neurological Scale and Barthel Index, respectively. Tissue loss was measured with CT at 3 months. Four patients were excluded from analysis for technical reasons. RESULTS: Twenty-three patients received nimodipine, and 23 received placebo. In the nimodipine group, there was early reperfusion that was not maintained at outcome (P=0.01). In the placebo group, mean infarct hypoperfusion volumes showed no overall change. Nonnutritional reperfusion in nimodipine-treated patients was associated with adverse neurological (P=0.05) and functional outcome (P=0.06). There was, however, no difference in clinical outcome between the 2 groups. CONCLUSIONS: Oral nimodipine administered within 12 hours enhanced acute reperfusion, but this was largely nonnutritional. Larger studies using a shorter treatment delay are required to evaluate the clinical efficacy of nimodipine in acute ischemic stroke.

Acute Disease↗
PubMed1999

A long-term study to maximise migraine relief with zolmitriptan.

Part 1 of this international study was a randomised, double-blind, placebo-controlled study of 2.5 mg and 5 mg zolmitriptan (Zomig) in the treatment of persistent migraine headache, two hours after an initial dose of 2.5 mg zolmitriptan. Part 2 was a non-comparative evaluation of long-term, unrestricted zolmitriptan use for treatment of initial, persistent and recurrent migraine headaches. In Part 1, following the treatment of moderate or severe persistent headache, two-hour headache response rates with 5 mg zolmitriptan (51.6%, n = 322), 2.5 mg zolmitriptan (49.7%, n = 324) and placebo (51.6%, n = 343) were not significantly different. However, the pain-free response rate following the treatment of persistent migraine headache of any intensity was significantly higher with 5 mg zolmitriptan than with placebo (36.0% vs. 25.5%; p < 0.001). This was predominantly due to effects in the subgroup of patients with mild headache. Thus, migraine relief in patients whose initial headache shows a partial response to 2.5 mg zolmitriptan may be maximised by a second 5 mg dose. In Part 2 (involving 2499 evaluable patients), 65.8% of attacks were treated with a single dose of zolmitriptan (2.5 mg or 5 mg). Of those migraine attacks initially treated with 2.5 mg zolmitriptan, 70.3% required no further dose, similarly 62.7% of migraine attacks treated initially with 5 mg zolmitriptan only required a single dose. Over the whole attack (i.e. initial and any persistent headache), headache response rates to one or two zolmitriptan doses were greater than 88.8%. 'Level of pain' was the primary factor influencing the choice of dose. Zolmitriptan provided consistent migraine headache relief in the majority of patients and was well tolerated.

Adolescent↗
PubMed1999

Ischemic stroke risk and passive exposure to spouses' cigarette smoking. Melbourne Stroke Risk Factor Study (MERFS) Group.

OBJECTIVES: This study investigated the association between ischemic stroke risk and passive exposure to cigarette smoking. METHODS: Risk factors among 452 hospitalized cases of first-episode ischemic stroke were compared with 452 age- and sex-matched "neighbor-hood" controls. RESULTS: The risk of stroke was twice as high for subjects whose spouses smoked as for those whose spouses did not smoke (95% confidence interval = 1.3, 3.1), after adjustment for the subject's own smoking, heart disease, hypertension, diabetes, and education level. These results were confirmed when analysis was limited to those who never smoked. CONCLUSIONS: These findings provide evidence that spousal smoking may be a significant risk factor for ischemic stroke.

Aged↗
PubMed1999

Limiting neurological damage after stroke: a review of pharmacological treatment options.

Acute ischaemic stroke is a leading cause of death and a major cause of long term disability worldwide. Effective treatments for limiting the neurological damage after stroke have proven elusive. An improved understanding of the complicated cascade of cellular events following the onset of cerebral ischaemia has led to exploration of a number of avenues for early intervention. Reperfusion of the ischaemic territory using thrombolytic drugs has shown promise in clinical trials as a method for achieving tissue salvage. Antithrombotic and antiplatelet agents have not demonstrated efficacy as acute therapies, although the early use of aspirin (acetylsalicylic acid) appears to produce a reduction in early stroke recurrence. A wide variety of drugs which interfere at various points in the ischaemic cascade, so-called 'neuroprotective agents', have also been studied, but with mixed success. Of these, antagonists of voltage-gated calcium channels, antagonists at the N-methyl-D-aspartate (NMDA) receptor and scavengers of free radicals have been most extensively studied. Despite proving effective in animal models of cerebral ischaemia, these drugs have largely failed to fulfil their promise in clinical trials. While individual compounds have proven ineffective, combinations of drugs with different mechanisms of action may yet provide the best treatment for acute ischaemic stroke.

Cerebrovascular Disorders↗
PubMed1999

Heavy drinking, but not moderate or intermediate drinking, increases the risk of intracerebral hemorrhage.

An increased risk of intracerebral hemorrhage among heavy consumers of alcohol has been demonstrated in several epidemiologic studies. The effect of moderate or intermediate intakes is, however, unclear. Although several studies provide evidence for a protective effect, this conclusion may be spurious, resulting from the inclusion, within the zero intake (reference) group, of past drinkers who have recently abstained for health reasons. The present study describes the relation between alcohol consumption and intracerebral hemorrhage among 331 case-control pairs recruited in Melbourne, Australia. Heavy drinking was associated with an increased risk of intracerebral hemorrhage (odds ratio (OR) 3.4, 95% confidence interval (CI) = 1.4-8.4). The odds ratio of intracerebral hemorrhage with moderate drinking, when compared with never drinkers, was 0.7, (95% CI = 0.4-1.2) and was 0.6 (95% CI = 0.4-1.0) when compared with nondrinkers (never drinkers plus past drinkers). Wine drinkers were apparently protected from intracerebral hemorrhage (OR 0.5, 95% CI = 0.2-0.9). These results are consistent with the possibility that moderate drinking may confer protection from intracerebral hemorrhage, but this protection may be less than that previously reported.

Adult↗
PubMed1998

Three important subgroups of hypertensive persons at greater risk of intracerebral hemorrhage. Melbourne Risk Factor Study Group.

Hypertension as a risk factor for intracerebral hemorrhage (ICH) is poorly quantified, particularly in the setting of the use of modern antihypertensive agents. To investigate this, we studied 331 consecutive hospital cases of primary ICH verified by computed tomography or autopsy, occurring during the period 1990 through 1992, and 331 age- and sex-matched community-based control subjects in a city-wide study involving 13 hospitals. Hypertension approximately doubled the risk of ICH (adjusted odds ratio [OR], 2.45; 95% confidence interval [CI], 1.61 to 3.73). The OR associated with hypertension was significantly greater among those who had ceased taking medications, supervised and unsupervised (OR, 4.98; 95% CI, 2.25 to 11.02), compared with those who had not (OR, 1.95; 95% CI, 1.20 to 3.16), were under the age of 55 years (OR, 7.68; 95% CI, 2.65 to 22.5), or were current smokers (OR, 6.12; 95% CI, 2.29 to 16.35). The presence of hypertension did not influence size or location of the hemorrhage. However, those dying from ICH displayed a greater risk of ICH due to hypertension than survivors, with the ratio of the two ORs being 5.47 (95% CI, 1.23 to 24.44). These findings provide evidence for a greater increase in risk of ICH due to hypertension among younger persons, current smokers, and those discontinuing antihypertensive therapy. This is the first direct evidence for a link between stopping antihypertensive medication use and stroke risk; targeting these individuals for more intensive monitoring and education on the importance of risk factor modification may help to reduce the impact of this form of stroke.

Adolescent↗
PubMed1998

Spontaneous reperfusion after ischemic stroke is associated with improved outcome.

BACKGROUND AND PURPOSE: The rationale behind thrombolytic therapy in acute ischemic stroke is penumbral salvage by rapid restoration of cerebral blood flow. The relationship, however, between early reperfusion (potentially composed of both nutritional and nonnutritional components) and outcome remains unclear. METHODS: To establish the relationship between reperfusion parameters and outcome variables (Canadian Neurological Scale, Barthel Index, outcome CT scans), we used 99Tc-hexamethylpropyleneamine oxime (99Tc-HMPAO) single-photon emission CT (SPECT) to examine 41 acute ischemic stroke patients. All patients had at least 2 SPECT studies (24 with 3 studies), and none had been treated with thrombolytic or other acute investigational drugs. RESULTS: A total of 106 studies were performed. Mean time to acute study was 9.2 hours; that for subacute study was 42 hours and for outcome study was 150 days. Hypoperfusion (HP) volumes at each of the 3 time points correlated with outcome clinical state and final infarct size. Both early reperfusion (61% of patients) and nutritional reperfusion alone (56%), which is early reperfusion maintained at outcome, were associated with improvement in clinical state and better functional outcome. Early HP volume change (acute minus subacute HP volume) and total HP volume change (acute minus outcome HP volume) also correlated with clinical improvement and better outcome. CONCLUSIONS: This study establishes the benefit of spontaneous reperfusion after ischemic stroke and emphasizes the prognostic value of HP deficit volumes. 99Tc-HMPAO SPECT may be used to screen patients and group them according to perfusion deficit in acute stroke trials, thereby decreasing patient numbers required to show drug effect.

Adult↗