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Biomedical subjects

David W Howells

Publications and source records attributed to David W Howells.

16 recordsLinked to original sources
PubMed2006

Characterization of fluoromisonidazole binding in stroke.

BACKGROUND AND PURPOSE: [18F]fluoromisonidazole (FMISO) positron emission tomography has been used to image hypoxia early after human stroke. To further study the role of hypoxia in stroke and the binding characteristics of FMISO, we aimed to develop [3H]FMISO autoradiography in an animal stroke model. We hypothesized that [3H]FMISO binding is prolonged, allowing correlation with 24-hour histology, and that there is no FMISO binding after effective reperfusion. METHODS: Temporary middle cerebral artery (MCA) occlusion was performed in rats, followed by [3H]FMISO administration. Tissue preparation for autoradiography and histology (from the same sections) was performed 2.5 hours after MCA occlusion (MCAo; replicating [18F]FMISO studies). Then, otherwise identical cohorts with tissue preparation at 2.5 or 24 hours were prepared. For reperfusion studies, animals had 1-hour MCAo, with [3H]FMISO administered 1 hour after reperfusion. RESULTS: [3H]FMISO autoradiography provided a high-resolution image of hypoxia throughout the ischemic territory. Delaying animal death from 2.5 to 24 hours allowed histological changes of stroke to develop, without significantly altering either relative intensity (1.88+/-0.06 and 2.02+/-0.11, respectively) or volume (25+/-6 mm3 and 28+/-5 mm3, respectively) of hypoxic binding. [3H]FMISO binding did not occur after effective reperfusion, despite histological injury from the preceding MCAo. CONCLUSIONS: [3H]FMISO autoradiography of hypoxia in experimental stroke offers several advantages. Bound FMISO is retained in tissues long term, enabling direct correlation with 24-hour histology. It is not bound after effective reperfusion. Therefore, positive [18F]FMISO positron emission tomography studies in stroke patients are indicative of ongoing tissue hypoxia, not merely recent tissue injury.

Animals↗
PubMed2006

Modification of the method of thread manufacture improves stroke induction rate and reduces mortality after thread-occlusion of the middle cerebral artery in young or aged rats.

Improving models of human stroke by the use of aged animals has been advocated; however the commonly used rat middle cerebral artery thread-occlusion model has produced suboptimal stroke induction and excess mortality in aged rats. We report the development of a modified method for silicone-coating the tip of occluding threads which produces a malleable silicone-coated tip which is firmly bonded and of highly consistent diameter, and overcomes problems of thread insertion through the narrowed carotid canal found in aged animals. Comparison of stroke outcomes and mortality were made between these threads and heat-treated poly-L-lysine coated threads. The rate of successful stroke induction in aged rats was significantly improved (from 14% to 86%). Similarly, mortality fell from 21-31% to 3-7% or less in both young and old rats with or without diabetes and hypertension. An occluding thread tip diameter of 0.35-0.38 mm was optimal for induction of mid-sized strokes in both young and old rats. This method of thread manufacture overcomes problems of inconsistency of diameter and bonding of the silicone-coated tip, and these threads produce significant improvements in stroke induction by MCA occlusion, particularly in aged animals and those with co-morbidities.

Aging↗
PubMed2006

1,026 experimental treatments in acute stroke.

OBJECTIVE: Preclinical evaluation of neuroprotectants fostered high expectations of clinical efficacy. When not matched, the question arises whether experiments are poor indicators of clinical outcome or whether the best drugs were not taken forward to clinical trial. Therefore, we endeavored to contrast experimental efficacy and scope of testing of drugs used clinically and those tested only experimentally. METHODS: We identified neuroprotectants and reports of experimental efficacy via a systematic search. Controlled in vivo and in vitro experiments using functional or histological end points were selected for analysis. Relationships between outcome, drug mechanism, scope of testing, and clinical trial status were assessed statistically. RESULTS: There was no evidence that drugs used clinically (114 drugs) were more effective experimentally than those tested only in animal models (912 drugs), for example, improvement in focal models averaged 31.3 +/- 16.7% versus 24.4 +/- 32.9%, p > 0.05, respectively. Scope of testing using Stroke Therapy Academic Industry Roundtable (STAIR) criteria was highly variable, and no relationship was found between mechanism and efficacy. INTERPRETATION: The results question whether the most efficacious drugs are being selected for stroke clinical trials. This may partially explain the slow progress in developing treatments. Greater rigor in the conduct, reporting, and analysis of animal data will improve the transition of scientific advances from bench to bedside.

Animals↗
PubMed2006

Striatal dopaminergic neurons are lost with Parkinson's disease progression.

Increased numbers of dopaminergic neurons are described in the striatum of patients with Parkinson's disease. In postmortem striatal tissue from Parkinson's disease patients with short disease duration (< or =8 years), the number of dopaminergic neurons is approximately four times that in patients with long duration (> or =16 years). The data suggest the possibility that the presence of large numbers of these striatal dopaminergic neurons may be harmful and may accelerate the disease process. Alternatively, these neurons may be lost to the disease process.

Aged↗
PubMed2006

Inflammation following stroke.

Stroke is one of the leading causes of mortality and morbidity. The stroke process triggers an inflammatory reaction that may last up to several months. Suppression of inflammation using a variety of drugs reduces infarct volume and improves clinical outcomes in animal models of stroke. This benefit occurs even with the initiation of therapy after 3 hours of onset of stroke, beyond the therapeutic window for thrombolysis with tPA. The use of neuroprotectants to suppress inflammation may widen the therapeutic time window for tPA while lessening its side-effects. Suppression of inflammation may also improve outcomes in animal models of haemorrhagic stroke. To date, clinical trials with anti-inflammatory agents in acute ischaemic stroke have failed to improve clinical outcomes. However, because of the potential for broader applicability across all aspects of stroke, a better understanding of anti-inflammatory mechanisms is important.

Animals↗
PubMed2005

Vampire bat salivary plasminogen activator (desmoteplase) inhibits tissue-type plasminogen activator-induced potentiation of excitotoxic injury.

BACKGROUND AND PURPOSE: In contrast to tissue-type plasminogen activator (tPA), vampire bat (Desmodus rotundus) salivary plasminogen activator (desmoteplase [DSPA]) does not promote excitotoxic injury when injected directly into the brain. We have compared the excitotoxic effects of intravenously delivered tPA and DSPA and determined whether DSPA can antagonize the neurotoxic and calcium enhancing effects of tPA. METHODS: The brain striatal region of wild-type c57 Black 6 mice was stereotaxically injected with N-methyl-d-Aspartate (NMDA); 24 hour later, mice received an intravenous injection of tPA or DSPA (10 mg/kg) and lesion size was assessed after 24 hours. Cell death and calcium mobilization studies were performed using cultures of primary murine cortical neurons. RESULTS: NMDA-mediated injury was increased after intravenous administration of tPA, whereas no additional toxicity was seen after administration of DSPA. Unlike DSPA, tPA enhanced NMDA-induced cell death and the NMDA-mediated increase in intracellular calcium levels in vitro. Moreover, the enhancing effects of tPA were blocked by DSPA. CONCLUSIONS: Intravenous administration of tPA promotes excitotoxic injury, raising the possibility that leakage of tPA from the vasculature into the parenchyma contributes to brain damage. The lack of such toxicity by DSPA further encourages its use as a thrombolytic agent in the treatment of ischemic stroke.

Animals↗
PubMed2005

Systematic review and metaanalysis of the efficacy of FK506 in experimental stroke.

FK506 is a candidate drug for acute stroke. For such drugs, any decision to proceed to clinical trial should be based on a full and unbiased assessment of the animal data, and consideration should be given to the limitations of those data. Such an assessment should include not only the efficacy of a drug but also the in vivo characteristics and limits to that efficacy. Here we use systematic review and meta-analysis to assess the evidence for a protective effect of FK506 in animal models of stroke. In all, 29 studies were identified describing procedures involving 1759 animals. The point estimate for the effect of FK506 was a 31.3% (95% confidence interval 27.2% to 35.4%) improvement in outcome. Efficacy was higher with ketamine anaesthesia and temporary ischaemia and was lower in rats, in animals with comorbidities, and where outcome was measured as infarct size alone. Reported study quality was modest by clinical trial standards, and efficacy was lower in high-quality studies. These findings show a substantial efficacy for FK506 in experimental stroke, but raise concerns that our estimate of effect size might be too high because of factors such as study quality and possible publication bias.

Animals↗
PubMed2005

Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke.

Melatonin is a candidate neuroprotective drug for ischaemic stroke. Any decision to proceed to clinical trial for such drugs should be based on an unbiased assessment of all available data. Such an assessment should include not only the efficacy of a drug but also the in vivo characteristics and limits--in terms of time window, dose, species and model of ischaemia used--to that efficacy. Here we use a systematic approach to establish the limits to and characteristics of the neuroprotective efficacy of melatonin in experimental stroke. We have used systematic review and meta-analysis to assess the evidence for a protective effect of melatonin in animal models of focal cerebral ischaemia. Fourteen studies were identified describing procedures involving 432 animals. The point estimate for the effect of melatonin was a 42.8% (95% CI 39.3-46.3%) improvement in outcome. Efficacy was greater when ketamine anaesthesia was used, and melatonin was equally effective in permanent or temporary ischaemia. Study quality was generally poor by clinical trial standards, and no evidence was found regarding the efficacy of melatonin in focal cerebral ischaemia in aged, hypertensive or diabetic animals, in species other than rats, or at time windows beyond 2 hr. These findings demonstrate a marked efficacy of melatonin in animal models of focal cerebral ischaemia, identify priority areas for future animal research, and suggest melatonin as a candidate neuroprotective drug for human stroke.

Animals↗
PubMed2004

Pooling of animal experimental data reveals influence of study design and publication bias.

BACKGROUND AND PURPOSE: The extensive neuroprotective literature describing the efficacy of candidate drugs in focal ischemia has yet to lead to the development of effective stroke treatments. Ideally, the choice of drugs taken forward to clinical trial should be based on an unbiased assessment of all available data. Such an assessment might include not only the efficacy of a drug but also the in vivo characteristics and limits--in terms of time window, dose, species, and model of ischemia used--to that efficacy. To our knowledge, such assessments have not been made. Nicotinamide is a candidate neuroprotective drug with efficacy in experimental stroke, but the limits to and characteristics of that efficacy have not been fully described. METHODS: Systematic review and modified meta-analysis of studies of experimental stroke describing the efficacy of nicotinamide. The search strategy ensured ascertainment of studies published in full and those published in abstract only. DerSimonian and Laird random effects meta-analysis was used to account for heterogeneity between studies. RESULTS: Nicotinamide improved outcome by 0.287 (95% confidence interval 0.227 to 0.347); it was more effective in temporary ischemia models, after intravenous administration, in animals without comorbidities, and in studies published in full rather than in abstract. Studies scoring highly on a quality measure gave more precise estimates of the global effect. CONCLUSIONS: Meta-analysis provides an effective technique for the aggregation of data from experimental stroke studies. We propose new standards for reporting such studies and a systematic approach to aggregating data from the neuroprotective literature.

Animals↗
PubMed2004

Imaging the ischemic penumbra with 18F-fluoromisonidazole in a rat model of ischemic stroke.

BACKGROUND AND PURPOSE: The ischemic penumbra is a major focus of stroke research. 18F-fluoromisonidazole (18F-FMISO), a positron emission tomography (PET) marker of hypoxic cells, has shown promise as a technique to image the penumbra in humans. Our aim was to delineate the pattern of 18F-FMISO binding in a rat middle cerebral artery transient thread-occlusion model, and correlate this with tissue outcome at 24 hours. We hypothesized that the pattern of 18F-FMISO binding would mimic that seen in humans. METHODS: Thirty-eight rats underwent 2 hours transient middle cerebral artery (MCA) occlusion, and then received 18F-FMISO at time points from 0.5 to 22 hours post-MCA occlusion and were killed 2 hours later. Autoradiographic assessment of 18F-FMISO binding and assessment (triphenyltetrazolium chloride) of the area of infarction were performed on tissue slices. RESULTS: Until 1 hour after MCA occlusion, 18F-FMISO binding was increased in the entire MCA territory, with little or no infarction visible. Over the next 5 hours, the pattern of binding evolved to a small rim of intensely binding tissue surrounding the infarct core, which itself showed reduced binding compared with the contralateral hemisphere. By 24 hours, there was minimal accumulation of 18F-FMISO binding and a large area of infarction. CONCLUSIONS: The pattern of 18F-FMISO binding rats reproduced the pattern seen in humans, consistent with this tracer being a marker of the ischemic penumbra in both species. This technique may have application in studying the ischemic penumbra in animal models, and correlating this with similar studies in humans.

Animals↗
PubMed2004

The resistance to ischemia of white and gray matter after stroke.

A contributing factor to the failure of trials of neuroprotectants in acute ischemic stroke may be the differing vulnerability to ischemia of white compared with gray matter. To address this issue, we determined to establish the existence of potentially viable tissue in white matter and its evolution to infarction or salvage in both gray and white matter compartments in patients with ischemic stroke. Twenty-seven patients (mean age, 73.4 years) at a median of 16.5 hours after symptom onset were studied using the hypoxic marker 18F-misonidazole with positron emission tomography (PET). Tissue was segmented using an magnetic resonance probabilistic map. Although there was a greater volume of initially "at-risk tissue" in gray matter (58.3 cm3, 29.9-93.0 cm3 than white matter (42.0 cm3, 15.8-74.0 cm3; p <0.001) at the time of PET imaging, a higher proportion of this was still potentially viable in white matter (41.4%, 4.6-74.5%) than in gray matter (23.6%, 3.2-61.1%; p <0.05). However, a similar proportion in each compartment spontaneously survived. These data provide evidence for the existence of potentially salvageable tissue in human white matter and is consistent with it having a similar or even greater resistance to ischemia than gray matter. For the latter possibility, alternative therapeutic strategies may be required for its salvage.

Adult↗
PubMed2003

Stem cell therapies: a tale of caution.

One of the most exciting possibilities in human therapeutics is that stem cells (embryonic or adult) may compensate for cell loss in disease, with functional recovery. This has received considerable publicity in the lay press. Much work remains to be done to turn stem cell therapy into a practical reality for major degenerative diseases, especially those affecting the nervous system. Medical scientists and journalists should work together in ensuring that the general public has a realistic understanding of the likely time frame in which benefits from stem cell therapies will be realised.

Central Nervous System Diseases↗
PubMed2003

CNS regeneration: clinical possibility or basic science fantasy?

Following injury to the CNS, severed axons undergo a phase of abortive sprouting in the vicinity of the wound, but do not spontaneously re-grow or regenerate. From a long history of attempts to stimulate regeneraion, a major strategy that has been developed clinically is the implantation of tissue into denervated target regions. Unfortunately trials have so far not borne out the promise that this would prove a useful therapy for disorders such as Parkinson's disease. Many strategies have also been developed to stimulate the regeneration of axons across sites of injury, particularly in the spinal cord. Animal data have demonstrated that some of these approaches hold promise and that the spinal cord has a remarkable degree of intrinsic plasticity. Attempts are now being made to utilize experimental techniques in spinal patients.

Animals↗
PubMed2003

Can the time window for administration of thrombolytics in stroke be increased?

Level 1 evidence now shows that thrombolysis in cases of acute ischaemic stroke is effective if administered within 3 hours of stroke onset. This benefit has been shown to be time dependent and potentially extends beyond 3 hours, with evidence that potentially viable penumbral tissue may be present in a significant proportion of cases well beyond 3-6 hours and, in isolated cases, perhaps up to 48 hours. This exposes a "stroke recovery gap", the difference observed between the clinical response to thrombolytic therapy in a given population of patients presenting with ischaemic stroke and the potential clinical recovery if all of the penumbra were salvaged under ideal circumstances. The means of bridging this "stroke recovery gap" using thrombolysis must involve extending the therapeutic time window (i.e. the time between stroke onset and administration of thrombolytics). Approaches to do this include the use of: (i) improved patient selection with modern neuroimaging techniques, particularly magnetic resonance imaging using perfusion-weighted image/diffusion-weighted image mismatch; (ii) newer thrombolytic agents; (iii) lower doses of these agents; (iv) varied methods of administration of thrombolytic therapy including combined intravenous and intra-arterial approaches; and (v) adjunctive therapies such as neuroprotectants. Should these means of extending the time window for thrombolysis prove successful, a more widespread use of this form of acute stroke therapy will be possible.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

Salvaging the ischaemic penumbra: more than just reperfusion?

1. The ischaemic penumbra is defined as a moderately hypoperfused region that retains structural integrity but has lost function. In animal models of ischaemic stroke, this region is prone to recurrent anoxic depolarization and will become infarcted if reperfusion does not occur. In the macaque model, an ischaemic penumbra has been identified for up to 3 h after ischaemic stroke onset, whereas in selected human patients it may exist for up to 48 h. 2. Although most definitions of the ischaemic penumbra stress a time-brain volume concept, few incorporate the idea that selective and delayed neuronal injury plays an important role. Thus, in addition to necrotic cell death caused by acute injury, it is important to also consider delayed death mediated by caspase-dependent and -independent apoptotic pathways. 3. Salvage of penumbral tissue is possible if reperfusion (e.g. after thrombolysis) occurs. However, neurons within this salvaged region may be still at risk of further delayed neuronal injury. 4. In the present review, we aim to revisit the concept of the ischaemic penumbra and explore the role of selective and delayed neuronal injury in enlargement of the volume of infarction, as well as pathogenic mechanisms of white matter ischaemia. Both animal and human models of cerebral ischaemia imaged using magnetic resonance and positron emission tomography techniques will be discussed.

Animals↗