Australian data do not support current pharmaceutical benefits scheme criteria for use of tumour necrosis factor-α inhibitors in ankylosing spondylitis

On the basis of local data, we write in support of the conclusions of Smith and Ahern that current Pharmaceu- tical Benefits Scheme (PBS) criteria for tumour necrosis factor (TNF)-a inhibitors in ankylosing spondylitis (AS) are not evidence-based. 1 As a prerequisite to the appropriate use of biological therapy in AS, three aspects of the disease need to be defined: (i) diagnosis, (ii) activity and (iii) therapeutic failure (Table 1)....

The effects of cholesterol inclusion on the vesicular membranes of cationic lipids

Small unilamellar vesicles formed from four cationic lipids in the absence and the presence of varying amounts of cholesterol were studied using fluorescence polarization and H-1-NMR techniques. The fluorescence polarization data clearly indicate that the packing order in the cationic lipid bilayers are affected by inclusion of cholesterol. importantly, this effect exists also with a cationic lipid that is devoid of any formal linkage region where the interaction of the lipid with cholesterol through hydrogen bonding is not feasible. The interactions of cholesterol with different types of cationic lipids in excess water have also been examined in multilamellar dispersions using proton magnetic resonance spectroscopy. In all the cases, the methylene proton linewidths in the NMR spectra respond to the addition of cholesterol to vesicles. Hydrophobic association of the lipid and cholesterol imposes restriction on the chain (CH2)(n) motions, leaving the terminal CH3 groups relatively mobile. On the basis of energy-minimized structural models, a rationale of the cholesterol-cationic lipid assembly has also been presented.

Rapid Synthesis And Properties Of Fevo4, Alvo4, Yvo4, And Eu3+-Doped Yvo4

Fine particle FeVO4, AIVO4, YVO4 and Yo.95Eu0.05VO4 have been prepared by the combustion of aqueous solutions containing corresponding metal nitrate, ammonium metavanadate, ammonium nitrate and 3-methyl-5-pyrazolone.The solutions containing the redox mixtures, when rapidly heated at 370 °C, ignite and undergo self-propagating,gas-producing, exothermic reactions to yield fine particle metal vanadates. Formation of crystalline vanadates was confirmed by powder X-ray diffraction patterns,27A1 nuclear magnetic resonance, IR and fluorescence spectra.

Functional activation during the Rapid Visual Information Processing task in a middle aged cohort: An fMRI study

The Rapid Visual Information Processing (RVIP) task, a serial discrimination task where task performance believed to reflect sustained attention capabilities, is widely used in behavioural research and increasingly in neuroimaging studies. To date, functional neuroimaging research into the RVIP has been undertaken using block analyses, reflecting the sustained processing involved in the task, but not necessarily the transient processes associated with individual trial performance. Furthermore, this research has been limited to young cohorts. This study assessed the behavioural and functional magnetic resonance imaging (fMRI) outcomes of the RVIP task using both block and event-related analyses in a healthy middle aged cohort (mean age = 53.56 years, n = 16). The results show that the version of the RVIP used here is sensitive to changes in attentional demand processes with participants achieving a 43% accuracy hit rate in the experimental task compared with 96% accuracy in the control task. As shown by previous research, the block analysis revealed an increase in activation in a network of frontal, parietal, occipital and cerebellar regions. The event related analysis showed a similar network of activation, seemingly omitting regions involved in the processing of the task (as shown in the block analysis), such as occipital areas and the thalamus, providing an indication of a network of regions involved in correct trial performance. Frontal (superior and inferior frontal gryi), parietal (precuenus, inferior parietal lobe) and cerebellar regions were shown to be active in both the block and event-related analyses, suggesting their importance in sustained attention/vigilance. These networks and the differences between them are discussed in detail, as well as implications for future research in middle aged cohorts.

Flow pattern analysis in a highly stenotic patient-specific carotid bifurcation model using a turbulence model

The aim of this study is to investigate the blood flow pattern in carotid bifurcation with a high degree of luminal stenosis, combining in vivo magnetic resonance imaging (MRI) and computational fluid dynamics (CFD). A newly developed two-equation transitional model was employed to evaluate wall shear stress (WSS) distribution and pressure drop across the stenosis, which are closely related to plaque vulnerability. A patient with an 80% left carotid stenosis was imaged using high resolution MRI, from which a patient-specific geometry was reconstructed and flow boundary conditions were acquired for CFD simulation. A transitional model was implemented to investigate the flow velocity and WSS distribution in the patient-specific model. The peak time-averaged WSS value of approximately 73Pa was predicted by the transitional flow model, and the regions of high WSS occurred at the throat of the stenosis. High oscillatory shear index values up to 0.50 were present in a helical flow pattern from the outer wall of the internal carotid artery immediately after the throat. This study shows the potential suitability of a transitional turbulent flow model in capturing the flow phenomena in severely stenosed carotid arteries using patient-specific MRI data and provides the basis for further investigation of the links between haemodynamic variables and plaque vulnerability. It may be useful in the future for risk assessment of patients with carotid disease.

A new method for the in vivo identification of mechanical properties in arteries from cine MRI images: Theoretical framework and validation

Quantifying the stiffness properties of soft tissues is essential for the diagnosis of many cardiovascular diseases such as atherosclerosis. In these pathologies it is widely agreed that the arterial wall stiffness is an indicator of vulnerability. The present paper focuses on the carotid artery and proposes a new inversion methodology for deriving the stiffness properties of the wall from cine-MRI (magnetic resonance imaging) data. We address this problem by setting-up a cost function defined as the distance between the modeled pixel signals and the measured ones. Minimizing this cost function yields the unknown stiffness properties of both the arterial wall and the surrounding tissues. The sensitivity of the identified properties to various sources of uncertainty is studied. Validation of the method is performed on a rubber phantom. The elastic modulus identified using the developed methodology lies within a mean error of 9.6%. It is then applied to two young healthy subjects as a proof of practical feasibility, with identified values of 625 kPa and 587 kPa for one of the carotid of each subject.

MRI-based fatigue analysis predicts plaque vulnerability: A study comparing symptomatic and asymptomatic individuals

BACKGROUND: Rupture of atheromatous plaque in the carotid artery often leads to thrombosis and subsequent stroke. The mechanism of plaque rupture is not entirely clear but is thought to be a multi-factorial process involving thinning and weakening of the fibrous cap and biomechanical stress as the trigger leading to plaque rupture. As the cardiovascular system is a classic fatigue environment, the weakening of plaque leading to rupture may be a fatigue process, which is a symptomatically quiescent but potentially progressive failure process. In this study, we used a fatigue analysis based on in vivo magnetic resonance imaging (MRI) to investigate the rupture initiation location, crack propagation path and fatigue life within plaques of asymptomatic and symptomatic individuals. METHODS: Forty non-consecutive subjects (20 symptomatic and 20 asymptomatic) underwent high-resolution multi-sequence in vivo MRI of the carotid bifurcation. Fatigue analysis was performed based on the plaque geometry derived from in vivo MRI of the carotid artery at the point of maximum stenosis. Paris’ Law in fracture mechanics is adopted to determine the fatigue crack growth rate. Incremental crack propagation was dynamically simulated based on stress distributions. Plaque initiation location, crack propagation path and fatigue cycle of symptomatic and asymptomatic individuals were compared. RESULTS: Cracks were often found to begin at the lumen wall at areas of stress concentration. The preferred rupture direction was radial from the lumen center. The crack initially advanced slowly but accelerated as it developed, depending on plaque morphology. The fatigue cycles of symptomatic plaques were significantly less than those in the asymptomatic group (2.3 ± 0.9 vs 3.1 ± 0.7 (x106); p = 0.003). CONCLUSIONS: The number of cycles to rupture in symptomatic patients was higher than those predicted in asymptomatic patients by fatigue analysis, suggesting the possibility that plaques with a less fatigue life may be more prone to be symptomatic and rupture. If further validated by large-scale longitudinal studies, fatigue analysis based on high resolution in vivo MRI could potentially act as a useful tool for risk assessment of carotid atheroma.

Reduction in arterial wall strain with aggressive lipid-lowering therapy in patients with carotid artery disease

Background: Inflammation and biomechanical factors have been associated with the development of vulnerable atherosclerotic plaques. Lipid-lowering therapy has been shown to be effective in stabilizing them by reducing plaque inflammation. Its effect on arterial wall strain, however, remains unknown. The aim of the present study was to investigate the role of high- and low-dose lipid-lowering therapy using an HMG-CoA reductase inhibitor, atorvastatin, on arterial wall strain. Methods and Results: Forty patients with carotid stenosis >40% were successfully followed up during the Atorvastatin Therapy: Effects on Reduction Of Macrophage Activity (ATHEROMA; ISRCTN64894118) Trial. All patients had plaque inflammation as shown by intraplaque accumulation of ultrasmall super paramagnetic particles of iron oxide on magnetic resonance imaging at baseline. Structural analysis was performed and change of strain was compared between high- and low-dose statin at 0 and 12 weeks. There was no significant difference in strain between the 2 groups at baseline (P=0.6). At 12 weeks, the maximum strain was significantly lower in the 80-mg group than in the 10-mg group (0.085±0.033 vs. 0.169±0.084; P=0.001). A significant reduction (26%) of maximum strain was observed in the 80-mg group at 12 weeks (0.018±0.02; P=0.01). Conclusions: Aggressive lipid-lowering therapy is associated with a significant reduction in arterial wall strain. The reduction in biomechanical strain may be associated with reductions in plaque inflammatory burden.

Study of carotid arterial plaque stress for symptomatic and asymptomatic patients

Stroke is one of the leading causes of death in the world, resulting mostly from the sudden ruptures of atherosclerosis carotid plaques. Until now, the exact plaque rupture mechanism has not been fully understood, and also the plaque rupture risk stratification. The advanced multi-spectral magnetic resonance imaging (MRI) has allowed the plaque components to be visualized in-vivo and reconstructed by computational modeling. In the study, plaque stress analysis using fully coupled fluid structure interaction was applied to 20 patients (12 symptomatic and 8 asymptomatic) reconstructed from in-vivo MRI, followed by a detailed biomechanics analysis, and morphological feature study. The locally extreme stress conditions can be found in the fibrous cap region, 85% at the plaque shoulder based on the present study cases. Local maximum stress values predicted in the plaque region were found to be significantly higher in symptomatic patients than that in asymptomatic patients (200±43. kPa vs. 127±37. kPa, p=0.001). Plaque stress level, defined by excluding 5% highest stress nodes in the fibrous cap region based on the accumulative histogram of stress experienced on the computational nodes in the fibrous cap, was also significantly higher in symptomatic patients than that in asymptomatic patients (154±32. kPa vs. 111±23. kPa, p<0.05). Although there was no significant difference in lipid core size between the two patient groups, symptomatic group normally had a larger lipid core and a significantly thinner fibrous cap based on the reconstructed plaques using 3D interpolation from stacks of 2D contours. Plaques with a higher stenosis were more likely to have extreme stress conditions upstream of plaque throat. The combined analyses of plaque MR image and plaque stress will advance our understanding of plaque rupture, and provide a useful tool on assessing plaque rupture risk.

Stress analysis of carotid atheroma in transient ischemic attack patients: Evidence for extreme stress-induced plaque rupture

Plaque rupture has been considered to be the result of its structural failure. The aim of this study is to suggest a possible link between higher stresses and rupture sites observed from in vivo magnetic resonance imaging (MRI) of transient ischemic attack (TIA) patients, by using stress analysis methods. Three patients, who had recently suffered a TIA, underwent in vivo multi-spectral MR imaging. Based on plaque geometries reconstructed from the post-rupture status, six pre-rupture plaque models were generated for each patient dataset with different reconstructions of rupture sites to bridge the gap of fibrous cap from original MRI images. Stress analysis by fluid structure interaction simulation was performed on the models, followed by analysis of local stress concentration distribution and plaque rupture sites. Furthermore, the sensitivity of stress analysis to the pre-rupture plaque geometry reconstruction was examined. Local stress concentrations were found to be located at the plaque rupture sites for the three subjects studied. In the total of 18 models created, the locations of the stress concentration regions were similar in 17 models in which rupture sites were always associated with high stresses. The local stress concentration region moved from circumferential center to the shoulder region (slightly away from the rupture site) for a case with a thick fibrous cap. Plaque wall stress level in the rupture locations was found to be much higher than the value in non-rupture locations. The good correlation between local stress concentrations and plaque rupture sites, and generally higher plaque wall stress level in rupture locations in the subjects studied could provide indirect evidence for the extreme stress-induced plaque rupture hypothesis. Local stress concentration in the plaque region could be one of the factors contributing to plaque rupture.

Normalized wall index specific and MRI-based stress analysis of atherosclerotic carotid plaques: A study comparing acutely symptomatic and asymptomatic patients

Background: Biomechanical stresses play an important role in determining plaque stability. Quantification of these simulated stresses can be potentially used to assess plaque vulnerability and differentiate different patient groups. Methods and Results: 54 asymptomatic and 45 acutely symptomatic patients underwent in vivo multicontrast magnetic resonance imaging (MRI) of the carotid arteries. Plaque geometry used for finite element analysis was derived from in vivo MRI at the sites of maximum and minimum plaque burden. In total, 198 slices were used for the computational simulations. A pre-shrink technique was used to refine the simulation. Maximum principle stress at the vulnerable plaque sites (ie, critical stress) was extracted for the selected slices and a comparison was performed between the 2 groups. Critical stress in the slice with maximum plaque burden is significantly higher in acutely symptomatic patients as compared to asymptomatic patients (median, inter quartile range: 198.0 kPa (119.8-359.0 kPa) vs 138.4 kPa (83.8-242.6 kPa), P=0.04). No significant difference was found in the slice with minimum plaque burden between the 2 groups (196.7 kPa (133.3-282.7 kPa) vs 182.4 kPa (117.2-310.6 kPa), P=0.82). Conclusions: Acutely symptomatic carotid plaques have significantly high biomechanical stresses than asymptomatic plaques. This might be potentially useful for establishing a biomechanical risk stratification criteria based on plaque burden in future studies.

Arterial luminal curvature and fibrous-cap thickness affect critical stress conditions within atherosclerotic plaque: An in vivo MRI-based 2D finite-element study

High mechanical stress in atherosclerotic plaques at vulnerable sites, called critical stress, contributes to plaque rupture. The site of minimum fibrous cap (FC) thickness (FCMIN) and plaque shoulder are well-documented vulnerable sites. The inherent weakness of the FC material at the thinnest point increases the stress, making it vulnerable, and it is the big curvature of the lumen contour over FC which may result in increased plaque stress. We aimed to assess critical stresses at FCMIN and the maximum lumen curvature over FC (LCMAX) and quantify the difference to see which vulnerable site had the highest critical stress and was, therefore, at highest risk of rupture. One hundred patients underwent high resolution carotid magnetic resonance (MR) imaging. We used 352 MR slices with delineated atherosclerotic components for the simulation study. Stresses at all the integral nodes along the lumen surface were calculated using the finite-element method. FCMIN and LCMAX were identified, and critical stresses at these sites were assessed and compared. Critical stress at FC MIN was significantly lower than that at LCMAX (median: 121.55 kPa; inter quartile range (IQR) = [60.70-180.32] kPa vs. 150.80 kPa; IQR = [91.39-235.75] kPa, p < 0.0001). If critical stress at FCMIN was only used, then the stress condition of 238 of 352 MR slices would be underestimated, while if the critical stress at LCMAX only was used, then 112 out of 352 would be underestimated. Stress analysis at FCMIN and LCMAX should be used for a refined mechanical risk assessment of atherosclerotic plaques, since material failure at either site may result in rupture.

Stress analysis of carotid plaque based on in vivo MRI of acute symptomatic and asymptomatic patients

Stress analysis within carotid plaques based on in vivo MR imaging has shown to be useful for the identification of vulnerable atheroma. This study is to investigate whether magnetic resonance imaging (MRI) based-biomechanical stress analysis of carotid plaques can differentiate acute symptomatic and asymptomatic patients. 54 asymptomatic and 45 acute symptomatic patients underwent in vivo multi-contrast MRI of the carotid arteries. Plaque geometry used for finite element analysis was derived from in vivo MR images at the site of maximum and minimum plaque burden. In total 198 slices were used for the computational simulations. A pre shrink technique was used to refine the simulation. Maximum principle stress at the vulnerable plaque sites (i.e. critical stress) was extracted for the selected slices and a comparison was performed between the two groups. Critical stress at the site of maximum plaque burden is significantly higher in acute symptomatic patients as compared to asymptomatic patients [median: 198.0kPa (inter quartile range (IQR) = (119.8 - 359.0) vs. 138.4kPa (83.8, 242.6), p=0.04]. No significant difference was found at the minimum plaque burden site between the two groups [196.7kPa (133.3- 282.7) vs. 182.4kPa (117.2 - 310. 6), p=0.82). Stress analysis at the site of maximal plaque burden can be effectively used for differentiating acute symptomatic carotid plaques from asymptomatic plaques. This maybe potentially used for development of biomechanical risk stratification criteria based on plaque burden in future studies.

Invasive and non-invasive modalities of imaging carotid stenosis

Despite recent therapeutic advances, acute ischemic complications of atherosclerosis remain the primary cause of morbidity and mortality in Western countries, with carotid atherosclerotic disease one of the major preventable causes of stroke. As the impact of this disease challenges our healthcare systems, we are becoming aware that factors influencing this disease are more complex than previously realized. In current clinical practice, risk stratification relies primarily on evaluation of the degree of luminal stenosis and patient symptomatology. Adequate investigation and optimal imaging are important factors that affect the quality of a carotid endarterectomy (CEA) service and are fundamental to patient selection. Digital subtraction angiography is still perceived as the most accurate imaging modality for carotid stenosis and historically has been the cornerstone of most of the major CEA trials but concerns regarding potential neurological complications have generated substantial interest in non-invasive modalities, such as contrast-enhanced magnetic resonance angiography. The purpose of this review is to give an overview to the vascular specialist of the current imaging modalities in clinical practice to identify patients with carotid stenosis. Advantages and disadvantages of each technique are outlined. Finally, limitations of assessing luminal stenosis in general are discussed. This article will not cover imaging of carotid atheroma morphology, function and other emerging imaging modalities of assessing plaque risk, which look beyond simple luminal measurements.