Non-contrast-enhanced MRA of renal artery stenosis: validation against DSA in a porcine model.

OBJECTIVES: To compare 3D-inversion-recovery balanced steady-state free precession (IR-bSSFP) non-contrast-enhanced magnetic resonance angiography (MRA) with 3D-contrast-enhanced MRA (CE-MRA) for assessment of renal artery stenosis (RAS) using digital subtraction angiography (DSA) as the reference standard. METHODS: Bilateral RAS were surgically created in 12 swine. IR-bSSFP and CE-MRA were acquired at 1.5 T and compared to rotational DSA. Three experienced cardiovascular radiologists evaluated the IR-bSSFP and CE-MRA studies independently. Linear regression models were used to calibrate and assess the accuracy of IR-bSSFP and CE-MRA, separately, against DSA. The coefficient of determination and Cohen's kappa coefficient were also generated. RESULTS: Calibration of the three readers' RAS grading revealed R(2) values of 0.52, 0.37 and 0.59 for NCE-MRA and 0.48, 0.53 and 0.71 for CE-MRA. Inter-rater agreement demonstrated Cohen's kappa values ranging from 0.25 to 0.65. Distal renal artery branch vessels were visible to a significantly higher degree with NCE-MRA compared to CE-MRA (p < 0.001). Image quality was rated excellent for both sequences, although image noise was higher with CE-MRA (p < 0.05). In no cases did noise interfere with image interpretation. CONCLUSIONS: In a well-controlled animal model of surgically induced RAS, IR-bSSFP based NCE-MRA and CE-MRA accurately graded RAS with a tendency for stenosis overestimation, compared to DSA. KEY POINTS: • IR-bSSFP and CE-MRA are accurate methods for diagnosis of renal artery stenosis • IR-bSSFP and CE-MRA demonstrate excellent agreement with DSA • Both IR-bSSFP and CE-MRA have a tendency to overestimate renal artery stenosis.

Modelling and assessment of the impact of radiocesium and radiostrontium contamination in the Thermaikos Gulf, Greece.

A radiological model for (137)Cs and (90)Sr dispersion in the marine environment of the Thermaikos Gulf, Greece, and the river catchments draining into the Gulf, is presented. The model, developed and implemented within the MOIRA-PLUS decision support system, integrates appropriate site-specific information. The model's performance has been tested using the available empirical (137)Cs activity concentration data in abiotic and biotic components of the gulf since the Chernobyl accident. Further, this paper describes the results of a modelling exercise performed within the IAEA's EMRAS II international modelling programme to estimate the environmental sensitivity of this characteristic Mediterranean coastal marine environment following radioactive contamination. The radiation doses to humans after a single hypothetical instantaneous deposition of 1000 Bq m(-2), assuming that all of their food intake from the marine pathway comes from the local environment, were calculated. The obtained results are consistent with estimates from other models for different coastal marine environments in the frame of the above-mentioned EMRAS exercise.

Deep brain stimulation for tremor resulting from acquired brain injury.

OBJECTIVES: To evaluate the efficacy of deep brain stimulation (DBS) in the treatment of tremor resulting from acquired brain injury (ABI). METHODS: A series of eight consecutive patients with post-ABI tremor were treated with DBS of the ventro-oralis posterior (VOP)/zona incerta (ZI) region, and subsequently underwent blinded assessments using Bain's tremor severity scale. RESULTS: VOP/ZI DBS produced a mean reduction in tremor severity of 80.75% based on Bain's tremor severity scale, with significant reductions in all five component tremor subscores: rest, postural, kinetic, proximal and distal. No adverse neurological complications were reported, although one patient experienced exacerbation of pre-existing gait ataxia. CONCLUSION: VOP/ZI stimulation is demonstrated here to be an effective and safe approach for the treatment of post-ABI tremor in the largest series published at the time of writing.

The sensitivity of different environments to radioactive contamination.

This paper describes modelling calculations carried out to determine the sensitivity of various rural and semi-natural environments to radionuclide contamination by (137)Cs, (90)Sr, and (131)I released during a major nuclear accident. Depositions of 1000 Bq/m(3) were assumed for each radionuclide. Four broad types of environments were considered: agricultural, forest or tundra, freshwater aquatic, and coastal marine. A number of different models were applied to each environment. The annual dose to a human population receiving most or all of its food and drinking water from a given environment was taken as a broad measure of sensitivity. The results demonstrated that environmental sensitivity was highly radionuclide specific, with (137)Cs generally giving the highest doses during the first year, especially for adults, in terrestrial and freshwater pathways. However, in coastal marine environments, (131)I and (239)Pu were more significant. Sensitivity was time dependent with doses for the first year dominating those for the 2nd and 10th years after deposition. In agricultural environments the ingestion dose from (137)Cs was higher for adults than other age groups, whereas for (90)Sr and (131)I, the ingestion dose was highest for infants. The dependence of sensitivity on social and economic factors such as individual living habits, food consumption preferences, and agricultural practices is discussed.

Prevention of posttraumatic axon sprouting by blocking collapsin response mediator protein 2-mediated neurite outgrowth and tubulin polymerization.

Epileptogenesis following traumatic brain injury (TBI) is likely due to a combination of increased excitability, disinhibition, and increased excitatory connectivity via aberrant axon sprouting. Targeting these pathways could be beneficial in the prevention and treatment of posttraumatic epilepsy. Here, we tested this possibility using the novel anticonvulsant (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R)-lacosamide [LCM]), which acts on both voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP2), an axonal growth/guidance protein. LCM inhibited CRMP2-mediated neurite outgrowth, an effect phenocopied by CRMP2 knockdown. Mutation of LCM-binding sites in CRMP2 reduced the neurite inhibitory effect of LCM by ∼8-fold. LCM also reduced CRMP2-mediated tubulin polymerization. Thus, LCM selectively impairs CRMP2-mediated microtubule polymerization, which underlies its neurite outgrowth and branching. To determine whether LCM inhibits axon sprouting in vivo, LCM was injected into rats subjected to partial cortical isolation, an animal model of posttraumatic epileptogenesis that exhibits axon sprouting in cortical pyramidal neurons. Two weeks following injury, excitatory synaptic connectivity of cortical layer V pyramidal neurons was mapped using patch clamp recordings and laser scanning photostimulation of caged glutamate. In comparison with injured control animals, there was a significant decrease in the map size of excitatory synaptic connectivity in LCM-treated rats, suggesting that LCM treatment prevented enhanced excitatory synaptic connectivity due to posttraumatic axon sprouting. These findings suggest, for the first time, that LCM's mode of action involves interactions with CRMP2 to inhibit posttraumatic axon sprouting.

Pharmacodynamics, pharmacokinetics, and safety of AM211: a novel and potent antagonist of the prostaglandin D2 receptor type 2.

The prostaglandin D(2) receptor type 2 (DP2) and its ligand, PGD(2), have been implicated in the development of asthma and other inflammatory diseases. The authors evaluated the pharmacodynamics, pharmacokinetics and safety of [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid sodium salt (AM211), a novel and potent DP2 antagonist, in healthy participants. Single and multiple doses of AM211 demonstrated dose-dependent inhibition of eosinophil shape change in blood with near-complete inhibition observed at trough after dosing 200 mg once daily for 7 days. Maximum plasma concentrations and exposures of AM211 increased in a greater-than-dose-proportional manner after single and multiple dosing. After multiple dosing, the exposures on day 7 were higher than on day 1 with accumulation ratio values ranging from 1.4 to 1.5. Mean terminal half-life values ranged from 14 to 25 hours across the dose range of 100 to 600 mg. AM211 was well tolerated at all doses in both the single- and multiple-dose cohorts. These data support additional clinical studies to evaluate AM211 in asthma and other inflammatory diseases.

Computerised Decision Support Systems for the management of freshwater radioecological emergencies: assessment of the state-of-the-art with respect to the experiences and needs of end-users.

Assessment of the environmental and radiological consequences of a nuclear accident requires the management of a great deal of data and information as well as the use of predictive models. Computerised Decision Support Systems (CDSS) are essential tools for this kind of complex assessment and for assisting experts with a rational decision process. The present work focuses on the assessment of the main features of selected state-of-the-art CDSS for off-site management of freshwater ecosystems contaminated by radionuclides. This study involved both developers and end-users of the assessed CDSS and was based on practical customisation exercises, installation and application of the decision systems. Potential end-users can benefit from the availability of several ready-to-use CDSS that allow one to run different kinds of models aimed at predicting the behaviour of radionuclides in aquatic ecosystems, evaluating doses to humans, assessing the effectiveness of different kinds of environmental management interventions and ranking these interventions, accounting for their social, economic and environmental impacts. As a result of the present assessment, the importance of CDSS "integration" became apparent: in many circumstances, different CDSS can be used as complementary tools for the decision-making process. The results of this assessment can also be useful for the future development and improvement of the CDSS.

The role of the subthalamic nucleus in response inhibition: evidence from deep brain stimulation for Parkinson's disease.

We measured reaction times during a stop-signal task while patients with Parkinson's disease were on and off unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). While reaction times to a "go" stimulus improved, there was no change in reaction times to the "stop" stimulus (SSRTs). However, changes in SSRTs induced by DBS were highly dependent on baseline SSRTs (measured off stimulation), with the greatest improvements being achieved by those with particularly slow reaction times. We therefore selected only those patients whose baseline SSRTs were within the limits of a control sample (N=10). In this group, SSRTs became slower when DBS was on. This finding suggests a role for the STN in response inhibition, which can be interrupted by DBS, observable only when more general improvements in Parkinson's function are minimised. We also compared the effects of unilateral left and right sided stimulation. We found a greater increase in SSRTs after DBS of the left STN.

Local field potentials reveal a distinctive neural signature of cluster headache in the hypothalamus.

Cluster headache (CH) is a debilitating neurovascular condition characterized by severe unilateral periorbital head pain. Deep brain stimulation of the posterior hypothalamus has shown potential in alleviating CH in its most severe, chronic form. During surgical implantation of stimulating macroelectrodes for cluster head pain, one of our patients suffered a CH attack. During the attack local field potentials displayed a significant increase in power of approximately 20 Hz. To the authors' knowledge, this is the first recorded account of neuronal activity observed during a cluster attack. Our results both support and extend the current literature, which has long implicated hypothalamic activation as key to CH generation, predominantly through indirect haemodynamic neuroimaging techniques. Our findings reveal a potential locus in CH neurogenesis and a potential rationale for efficacious stimulator titration.

Model testing of radioactive contamination by 90Sr, 137Cs and 239,240Pu of water and bottom sediments in the Techa River (Southern Urals, Russia).

This paper presents results of testing models for the radioactive contamination of river water and bottom sediments by (90)Sr, (137)Cs and (239,240)Pu. The scenario for the model testing was based on data from the Techa River (Southern Urals, Russia), which was contaminated as a result of discharges of liquid radioactive waste into the river. The endpoints of the scenario were model predictions of the activity concentrations of (90)Sr, (137)Cs and (239,240)Pu in water and bottom sediments along the Techa River in 1996. Calculations for the Techa scenario were performed by six participant teams from France (model CASTEAUR), Italy (model MARTE), Russia (models TRANSFER-2, CASSANDRA, GIDRO-W) and Ukraine (model RIVTOX), all using different models. As a whole, the radionuclide predictions for (90)Sr in water for all considered models, (137)Cs for MARTE and TRANSFER-2, and (239,240)Pu for TRANSFER-2 and CASSANDRA can be considered sufficiently reliable, whereas the prediction for sediments should be considered cautiously. At the same time the CASTEAUR and RIVTOX models estimate the activity concentrations of (137)Cs and (239,240)Pu in water more reliably than in bottom sediments. The models MARTE ((239,240)Pu) and CASSANDRA ((137)Cs) evaluated the activity concentrations of radionuclides in sediments with about the same agreement with observations as for water. For (90)Sr and (137)Cs the agreement between empirical data and model predictions was good, but not for all the observations of (239,240)Pu in the river water-bottom sediment system. The modelling of (239,240)Pu distribution proved difficult because, in contrast to (137)Cs and (90)Sr, most of models have not been previously tested or validated for plutonium.

Abnormal thalamocortical dynamics may be altered by deep brain stimulation: using magnetoencephalography to study phantom limb pain.

Deep brain stimulation (DBS) is used to alleviate chronic pain. Using magnetoencephalography (MEG) to study the mechanisms of DBS for pain is difficult because of the artefact caused by the stimulator. We were able to record activity over the occipital lobe of a patient using DBS for phantom limb pain during presentation of a visual stimulus. This demonstrates that MEG can be used to study patients undergoing DBS provided control stimuli are used to check the reliability of the data. We then asked the patient to rate his pain during and off DBS. Correlations were found between these ratings and power in theta (6-9) and beta bands (12-30). Further, there was a tendency for frequencies under 25 Hz to correlate with each other after a period off stimulation compared with immediately after DBS. The results are interpreted as reflecting abnormal thalamocortical dynamics, previously implicated in painful syndromes.

Reduction of common motoneuronal drive on the affected side during walking in hemiplegic stroke patients.

OBJECTIVE: The objective of this study was to use motor unit coupling in the time and frequency domains to obtain evidence of changes in motoneuronal drive during walking in subjects with stroke. METHODS: Paired tibialis anterior (TA) EMG activity was sampled during the swing phase of treadmill walking in eight subjects with unilateral stroke. RESULTS: On the unaffected side, short-term synchronization was evident from the presence of a narrow central peak in cumulant densities and from the presence of significant coherence between these signals in the 10-25 Hz band. Such indicators of short-term synchrony were either absent or very small on the affected side. Instead, pronounced 10 Hz coupling was observed. CONCLUSIONS: It is suggested that reduced corticospinal drive to the spinal motoneurones is responsible for the reduced short-term synchrony and coherence in the 10-25 Hz frequency band on the affected side in hemiplegic patients during walking. SIGNIFICANCE: This is of importance for understanding the mechanisms responsible for reduced gait ability and development of new strategies for gait restoration.

Local field potential beta activity in the subthalamic nucleus of patients with Parkinson's disease is associated with improvements in bradykinesia after dopamine and deep brain stimulation.

Parkinson's disease is treated pharmacologically with dopamine replacement medication and, more recently, by stimulating basal-ganglia nuclei such as the subthalamic nucleus (STN). Depth recordings after this procedure have revealed excessive activity at frequencies between 8 and 35 Hz (Brown et al., 2001; Kuhn et al., 2004; Priori et al., 2004) that are reduced by dopamine therapy in tandem with improvements in bradykinesia/rigidity, but not tremor (Kuhn et al., 2006). It has also been shown that improvements in motor symptoms after dopamine correlate with single unit activity in the beta range (Weinberger et al., 2006). We recorded local field potentials (LFPs) from the subthalamic nucleus of patients with Parkinson's disease (PD) after surgery to implant deep brain stimulating electrodes while they were on and off dopaminergic medication. As well as replicating Kuhn et al., using the same patients we were able to extend Weinberger et al. to show that LFP beta oscillatory activity correlated with the degree of improvement in bradykinesia/rigidity, but not tremor, after dopamine medication. We also found that the power of beta oscillatory activity uniquely predicted improvements in bradykinesia/rigidity, but again not tremor, after stimulation of the STN in a regression analysis. However improvements after STN stimulation related inversely to beta power, possibly reflecting the accuracy of the electrode placement and/or the limits of STN stimulation in patients with the greatest levels of beta oscillatory activity.

The alpha4beta1 integrin in sickle cell disease.

The alpha4beta1 integrin is an adhesion receptor expressed on reticulocytes in sickle cell disease (SCD) and mediates the adhesion of these cells to sub-endothelial matrix proteins and the endothelium. In this review, we describe the mechanism of activation of the alpha4beta1 integrin on sickle reticulocytes and discuss novel roles for this integrin in SCD as a result of this activation. We also illustrate novel therapies in SCD that may target the integrin and alleviate vaso-occlusion.

MR imaging of articular cartilage at 1.5T and 3.0T: comparison of SPGR and SSFP sequences.

OBJECTIVE: To compare articular cartilage signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and thickness measurements on a 1.5 T and a 3.0 T magnetic resonance (MR) scanner using three-dimensional spoiled gradient recalled echo (3D-SPGR) and two 3D steady-state free precession (SSFP) sequences. METHODS: Both knees of five volunteers were scanned at 1.5 T and at 3.0 T using a transmit-receive quadrature extremity coil. Each examination consisted of a sagittal 3D-SPGR sequence, a sagittal fat suppressed 3D-SSFP (FS-SSFP) sequence, and a sagittal Dixon 3D-SSFP sequence. For quantitative analysis, we compared cartilage SNR and CNR efficiencies, as well as average cartilage thickness measurements. RESULTS: For 3D-SPGR, cartilage SNR efficiencies at 3.0 T increased compared to those at 1.5 T by a factor of 1.83 (range: 1.40-2.09). In comparison to 3D-SPGR, the SNR efficiency of FS-SSFP increased by a factor of 2.13 (range: 1.81-2.39) and for Dixon SSFP by a factor of 2.39 (range: 1.95-2.99). For 3D-SPGR, CNR efficiencies between cartilage and its surrounding tissue increased compared to those at 1.5 T by a factor of 2.12 (range: 1.75-2.47), for FS-SSFP by a factor 2.11 (range: 1.58-2.80) and for Dixon SSFP by a factor 2.39 (range 2.09-2.83). Average cartilage thicknesses of load bearing regions were not different at both field strengths or between sequences (P>0.05). Mean average cartilage thickness measured in all knees was 2.28 mm. CONCLUSION: Articular cartilage imaging of the knee on a 3.0 T MR scanner shows increased SNR and CNR efficiencies compared to a 1.5 T scanner, where SSFP-based techniques show the highest increase in SNR and CNR efficiency. There was no difference between average cartilage thickness measurements performed at the 1.5 T and 3.0 T scanners or between the three different sequences.

Aquatic mosses as a monitoring tool for 137Cs contamination in streams and rivers-a field study from central southern Norway.

Mosses are frequently used as biomonitors for trace element pollution in the aquatic environment. The purpose of this study was to assess their usefulness as a tool in monitoring and in regional surveys of radioactive contamination. Specimens of the aquatic mosses, Fontinalis antipyretica and F. dalecarlica, were transplanted from non-contaminated areas to streams and rivers in the Norwegian Jotunheimen Mountains and neighbouring lowland areas that had received radioactive fallout after the Chernobyl accident. Equilibrium concentrations of 137Cs in the exposed mosses were reached after a few weeks. Two series from 20 streams in 1994 and 1996 show linear correlations between activities in water and moss samples and biomagnification ratios of 10(4) - 10(5). We conclude that mosses are better suited for monitoring purposes than water samples, because they provide values integrated over weeks while the radioactivity in surface waters can be subject to rapid variations according to hydrological events. The activity concentrations in aquatic mosses can be easily measured with good precision even when aqueous concentrations are below the limit of detection. Use of aquatic mosses also reduces the logistic problems of transporting large volumes of water, especially in areas inaccessible by road.

Activation of sickle red blood cell adhesion via integrin-associated protein/CD47-induced signal transduction.

Peripheral human red blood cells (RBCs) are not generally known to become activated and adhesive in response to cell signaling. We show, however, that soluble thrombospondin via integrin-associated protein (IAP; CD47) increases the adhesiveness of sickle RBCs (SS RBCs) by activating signal transduction in the SS RBC. This stimulated adhesion requires occupancy of IAP and shear stress and is mediated by the activation of large G proteins and tyrosine kinases. Reticulocyte-enriched RBCs derived from sickle-cell disease (SCD) patients are most responsive to IAP-induced activation. These studies therefore establish peripheral SS RBCs as signaling cells that respond to a novel synergy between IAP-induced signal transduction and shear stress, suggesting new therapeutic targets in SCD.

Integrin-associated protein is an adhesion receptor on sickle red blood cells for immobilized thrombospondin.

The adhesive protein thrombospondin (TSP) potentially mediates sickle (SS) red blood cell (RBC) adhesion to the blood vessel wall, thereby contributing to vaso-occlusive crises in sickle cell disease. We previously reported that SS RBCs bind to immobilized TSP under flow conditions, whereas normal (AA) red cells do not. However, the SS RBC receptors that mediate this interaction are largely unknown. Here it is reported that integrin-associated protein (IAP), or CD47, mediates the adhesion of these cells to immobilized TSP under both flow and static conditions. A peptide derived from the C-terminal IAP binding site of TSP also supports sickle cell adhesion; adhesion to this peptide or to TSP is inhibited specifically by the anti-IAP monoclonal antibody, 1F7. Furthermore, these data suggest that IAP on SS RBCs is structurally different from that expressed on AA RBCs but that IAP expression levels do not vary between AA and SS RBCs. This structural difference may contribute to the enhanced adhesion of SS RBCs to immobilized TSP. These results identify IAP as a TSP receptor on SS RBCs and suggest that this receptor and its binding site within TSP represent potential therapeutic targets to decrease vaso-occlusion. (Blood. 2001;97:2159-2164)

Delivery of health informatics education and training.

An overview is provided of education and training in health information management in the context of national information strategies. Although the article focuses upon British programmes, there are examples from North America, Australasia and other countries. Reference is made to international activities in the development of generic courses for education and training, the need for education and training, the content of courses, and methods of delivery, including Internet-based training and education. Governments and health authorities in many countries have recognized the urgent need for a highly educated and trained workforce in information management, but universities have been slow to respond, until the last few years. However, there is now a plethora of education and training programmes in North America, most European countries, and Australasia.