Neuroimaging as a selection tool and endpoint in preclinical and clinical trials

Standard imaging in acute stroke enables the exclusion of non-stroke structural CNS lesions and cerebral haemorrhage from clinical and pre-clinical ischaemic stroke trials. In this review, the potential benefit of imaging (e.g., angiography and penumbral imaging) as a translational tool for trial recruitment and the use of imaging endpoints are discussed for both clinical and pre-clinical stroke research. The addition of advanced imaging to identify a “responder” population leads to reduced sample size for any given effect size in phase 2 trials and is a potentially cost-efficient means of testing interventions. In pre-clinical studies, technical failures (failed or incomplete vessel occlusion, cerebral haemorrhage) can be excluded early and continuous multimodal imaging of the animal from stroke onset is feasible. Pre- and post-intervention repeat scans provide real time assessment of the intervention over the first 4–6 h. Negative aspects of advanced imaging in animal studies include increased time under general anaesthesia, and, as in clinical studies, a delay in starting the intervention. In clinical phase 3 trial designs, the negative aspects of advanced imaging in patient selection include higher exclusion rates, slower recruitment, overestimated effect size and longer acquisition times. Imaging may identify biological effects with smaller sample size and at earlier time points, compared to standard clinical assessments, and can be adjusted for baseline parameters. Mechanistic insights can be obtained. Pre-clinically, multimodal imaging can non-invasively generate data on a range of parameters, allowing the animal to be recovered for subsequent behavioural testing and/or the brain taken for further molecular or histological analysis

Hyperglycaemia does not increase perfusion deficits after focal cerebral ischaemia in male Wistar rats

Background: Hyperglycaemia is associated with a worse outcome in acute ischaemic stroke patients; yet the pathophysiological mechanisms of hyperglycaemia-induced damage are poorly understood. We hypothesised that hyperglycaemia at the time of stroke onset exacerbates ischaemic brain damage by increasing the severity of the blood flow deficit. Methods: Adult, male Wistar rats were randomly assigned to receive vehicle or glucose solutions prior to permanent middle cerebral artery occlusion. Cerebral blood flow was assessed semi-quantitatively either 1 h after middle cerebral artery occlusion using 99mTc-D, L-hexamethylpropyleneamine oxime (99mTc-HMPAO) autoradiography or, in a separate study, using quantitative pseudo-continuous arterial spin labelling for 4 h after middle cerebral artery occlusion. Diffusion weighted imaging was performed alongside pseudo-continuous arterial spin labelling and acute lesion volumes calculated from apparent diffusion coefficient maps. Infarct volume was measured at 24 h using rapid acquisition with refocused echoes T2-weighted magnetic resonance imaging. Results: Glucose administration had no effect on the severity of ischaemia when assessed by either 99mTc-HMPAO autoradiography or pseudo-continuous arterial spin labelling perfusion imaging. In comparison to the vehicle group, apparent diffusion coefficient–derived lesion volume 2–4 h post-middle cerebral artery occlusion and infarct volume 24 h post-middle cerebral artery occlusion were significantly greater in the glucose group. Conclusions: Hyperglycaemia increased acute lesion and infarct volumes but there was no evidence that the acute blood flow deficit was exacerbated. The data reinforce the conclusion that the detrimental effects of hyperglycaemia are rapid, and that treatment of post-stroke hyperglycaemia in the acute period is essential but the mechanisms of hyperglycaemia-induced harm remain unclear

Spectroscopy and Strong Decays of Charmed Baryons

Spectroscopy and strong decays of the charmed baryons are reviewed. Possible spin-parity quantum numbers of several newly observed charmed baryon resonances are discussed. Strong decays of charmed baryons are analyzed in the framework of heavy hadron chiral perturbation theory in which heavy quark symmetry and chiral symmetry are synthesized.Comment: 7 pages, to be published in the proceedings of CHARM07, Ithaca, NY, August 2007, eConf C07080

A Record Of Assimilation Preserved By Exotic Minerals In The Lowermost Platinum-Group Element Deposit Of The Bushveld Complex: The Volspruit Sulphide Zone

 This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record Low-grade platinum-group element mineralisation in the Volspruit Sulphide Zone is sulphide-poor (<5 vol. %), distributed over a ~60 m-thick horizon in the lowermost cumulates of the northern limb of the Bushveld Complex. Unlike any other platinum-group element (PGE) deposit of the Bushveld Complex, the Volspruit Sulphide Zone is hosted exclusively within harzburgitic and dunitic cumulates in the Lower Zone of the Rustenburg Layered Suite. Here, we present a petrological investigation on the distribution of PGEs and chalcophile metals in mineralised pyroxenite cumulates from the Volspruit Sulphide Zone, to determine the origin of the PGE mineralisation in ultramafic cumulates and evaluate whether Volspruit-style mineralisation could occur in the stratigraphically lowest, ultramafic portions of other layered intrusions. Electron microscopy of pyroxenite cumulates revealed (1) chromite inclusions containing dolomite, albite, monazite, Pb-chlorides, base metal sulphides and Pt-As minerals, (2) the presence of exotic microxenocrysts (<300 μm diameter) in the pyroxenite matrix such as grains of CaCO3, U-Th-oxide and Mn-ilmenite, and (3) base metal sulphide assemblages enclosing grains of primary galena, sphalerite and Pb-chlorides. Systematic mapping of high-density mineral assemblages in pyroxenite cumulates across the Volspruit Sulphide Zone identified 196 precious metal mineral grains (Pt-, Pd-, Rh-, Au- or Ag-minerals), 98 Pb-sulphide grains (± Se, Cl), 27 Pb-chloride grains (± K, Se, Te, S), as well as 1 grain of Pb-telluride, 1 monazite grain and 1 grain of U–Pb-Th oxide. Trace element analyses of base metal sulphides reveal the highest S/Se values in pyrrhotite and chalcopyrite yet recorded in the Bushveld Complex. While some base metal sulphides are enriched in PGEs, the overall low-grade of the deposit and inferred fertile ultramafic magma(s) require relatively low R-factors (mass of silicate to sulphide melt) compared to other sulphide-poor PGE deposits, with a calculated R factor of ~500–3000. We consider that the presence of exotic inclusions in chromite, exotic microxenocrysts, and Pb/Zn/Cl grains enclosed within primary base metal sulphide assemblages provide strong evidence for crustal contamination in the Volspruit Sulphide Zone. The Malmani dolomite and the Black Reef quartzite within the lower Chuniespoort Group (2.2–2.4 Ga) are the most likely source of xenocrysts, assimilated in a staging chamber beneath the main Grasvally chamber, in which the Volspruit Sulphide Zone developed. It is possible that the Malmani dolomite contained an enrichment of Pb, Zn, Cl, and S minerals prior to assimilation. The assimilation of dolomite and limestone would locally increase the fO2 of the magma, triggering chromite crystallisation. The sudden removal of Fe from the melt, coupled with the addition of external sulfur triggered saturation of an immiscible sulphide melt in the ultramafic Volspruit magma. Chromite and base metal sulphides were subsequently emplaced into the main Grasvally magma chamber as a crystal-bearing slurry. Therefore, we consider it is possible for PGE mineralisation to occur in the ultramafic portion of any layered intrusion intruding in the vicinity of carbonate units. Even if this style of mineralisation in the lowermost portions of layered intrusions is sub-economic, it may reduce the grade or opportunity for PGE mineralisation higher up in the local magmatic stratigraphy, or in later magma emplacement events sourced from the same reservoir. The technique of specifically searching for microxenocrysts could be applied beyond layered intrusion research, to identify the range of crustal contaminants in other magmatic systems where macro-scale xenoliths are neither sampled nor preserved.National Environment Research CouncilUniversity of WollongongClaude Leon FoundationCentre of Excellence for Integrated Mineral & Energy Resource Analysis (CIMERA) at the Universities of Witwatersrand and Johannesburg

Why Are People's Decisions Sometimes Worse with Computer Support?

In many applications of computerised decision support, a recognised source of undesired outcomes is operators' apparent over-reliance on automation. For instance, an operator may fail to react to a potentially dangerous situation because a computer fails to generate an alarm. However, the very use of terms like "over-reliance" betrays possible misunderstandings of these phenomena and their causes, which may lead to ineffective corrective action (e.g. training or procedures that do not counteract all the causes of the apparently "over-reliant" behaviour). We review relevant literature in the area of "automation bias" and describe the diverse mechanisms that may be involved in human errors when using computer support. We discuss these mechanisms, with reference to errors of omission when using "alerting systems", with the help of examples of novel counterintuitive findings we obtained from a case study in a health care application, as well as other examples from the literature

Potential use of oxygen as a metabolic biosensor in combination with T2*-weighted MRI to define the ischemic penumbra

We describe a novel magnetic resonance imaging technique for detecting metabolism indirectly through changes in oxyhemoglobin:deoxyhemoglobin ratios and T2* signal change during ‘oxygen challenge’ (OC, 5 mins 100% O2). During OC, T2* increase reflects O2 binding to deoxyhemoglobin, which is formed when metabolizing tissues take up oxygen. Here OC has been applied to identify tissue metabolism within the ischemic brain. Permanent middle cerebral artery occlusion was induced in rats. In series 1 scanning (n=5), diffusion-weighted imaging (DWI) was performed, followed by echo-planar T2* acquired during OC and perfusion-weighted imaging (PWI, arterial spin labeling). Oxygen challenge induced a T2* signal increase of 1.8%, 3.7%, and 0.24% in the contralateral cortex, ipsilateral cortex within the PWI/DWI mismatch zone, and ischemic core, respectively. T2* and apparent diffusion coefficient (ADC) map coregistration revealed that the T2* signal increase extended into the ADC lesion (3.4%). In series 2 (n=5), FLASH T2* and ADC maps coregistered with histology revealed a T2* signal increase of 4.9% in the histologically defined border zone (55% normal neuronal morphology, located within the ADC lesion boundary) compared with a 0.7% increase in the cortical ischemic core (92% neuronal ischemic cell change, core ADC lesion). Oxygen challenge has potential clinical utility and, by distinguishing metabolically active and inactive tissues within hypoperfused regions, could provide a more precise assessment of penumbra

Stroke penumbra defined by an MRI-based oxygen challenge technique: 2. Validation based on the consequences of reperfusion

Magnetic resonance imaging (MRI) with oxygen challenge (T2* OC) uses oxygen as a metabolic biotracer to define penumbral tissue based on CMRO2 and oxygen extraction fraction. Penumbra displays a greater T2* signal change during OC than surrounding tissue. Since timely restoration of cerebral blood flow (CBF) should salvage penumbra, T2* OC was tested by examining the consequences of reperfusion on T2* OC-defined penumbra. Transient ischemia (109±20 minutes) was induced in male Sprague-Dawley rats (n=8). Penumbra was identified on T2*-weighted MRI during OC. Ischemia and ischemic injury were identified on CBF and apparent diffusion coefficient maps, respectively. Reperfusion was induced and scans repeated. T2 for final infarct and T2* OC were run on day 7. T2* signal increase to OC was 3.4% in contralateral cortex and caudate nucleus and was unaffected by reperfusion. In OC-defined penumbra, T2* signal increased by 8.4%±4.1% during ischemia and returned to 3.25%±0.8% following reperfusion. Ischemic core T2* signal increase was 0.39%±0.47% during ischemia and 0.84%±1.8% on reperfusion. Penumbral CBF increased from 41.94±13 to 116.5±25 mL per 100 g per minute on reperfusion. On day 7, OC-defined penumbra gave a normal OC response and was located outside the infarct. T2* OC-defined penumbra recovered when CBF was restored, providing further validation of the utility of T2* OC for acute stroke management

Stroke penumbra defined by an MRI-based oxygen challenge technique: 1. validation using [14C]2-deoxyglucose autoradiography

Accurate identification of ischemic penumbra will improve stroke patient selection for reperfusion therapies and clinical trials. Current magnetic resonance imaging (MRI) techniques have limitations and lack validation. Oxygen challenge T2* MRI (T2* OC) uses oxygen as a biotracer to detect tissue metabolism, with penumbra displaying the greatest T2* signal change during OC. [14C]2-deoxyglucose (2-DG) autoradiography was combined with T2* OC to determine metabolic status of T2*-defined penumbra. Permanent middle cerebral artery occlusion was induced in anesthetized male Sprague-Dawley rats (n=6). Ischemic injury and perfusion deficit were determined by diffusion- and perfusion-weighted imaging, respectively. At 147±32 minutes after stroke, T2* signal change was measured during a 5-minute 100% OC, immediately followed by 125 μCi/kg 2-DG, intravenously. Magnetic resonance images were coregistered with the corresponding autoradiograms. Regions of interest were located within ischemic core, T2*-defined penumbra, equivalent contralateral structures, and a region of hyperglycolysis. A T2* signal increase of 9.22%±3.9% (mean±s.d.) was recorded in presumed penumbra, which displayed local cerebral glucose utilization values equivalent to contralateral cortex. T2* signal change was negligible in ischemic core, 3.2%±0.78% in contralateral regions, and 1.41%±0.62% in hyperglycolytic tissue, located outside OC-defined penumbra and within the diffusion abnormality. The results support the utility of OC-MRI to detect viable penumbral tissue follow

High Energy Secondaries for the Quantitative Secondary Ion Mass Spectrometric Analysis of Minerals

The major hurdle in quantitative analysis by SIMS is the inconsistency and non-predictability of ion yields, particularly their sensitivity to sample matrix. High energy (100-500 eV) secondary ions have been shown to be considerably less susceptible to matrix effects than low energy secondary ions, particularly in mineral analysis. Therefore ion yields of some sixty elements were measured utilizing very high energy secondaries (~ 500 eV), from a standard silicate glass. They show a broad ionization potential dependence and a mass (or velocity) dependency which is not removed by the application of a M½ or M factor. The modification of yields with conventional thermodynamic partition functions, improves but does not clearly define agreement with the inverse exponential relationship observed by others, for low energy secondaries sputtered from oxygen rich matrices. The reproducibility of ion yields of high energy secondaries suggests empirical approaches to quantitative analysis are well justified; however the poor agreement of ion yields with an inverse exponential relationship, suggests that ion yielding mechanisms are somewhat different to those proposed in the low energy regime