The impact of low-mode symmetry on inertial fusion energy output in the burning plasma state.

Indirect Drive Inertial Confinement Fusion Experiments on the National Ignition Facility (NIF) have achieved a burning plasma state with neutron yields exceeding 170 kJ, roughly 3 times the prior record and a necessary stage for igniting plasmas. The results are achieved despite multiple sources of degradations that lead to high variability in performance. Results shown here, for the first time, include an empirical correction factor for mode-2 asymmetry in the burning plasma regime in addition to previously determined corrections for radiative mix and mode-1. Analysis shows that including these three corrections alone accounts for the measured fusion performance variability in the two highest performing experimental campaigns on the NIF to within error. Here we quantify the performance sensitivity to mode-2 symmetry in the burning plasma regime and apply the results, in the form of an empirical correction to a 1D performance model. Furthermore, we find the sensitivity to mode-2 determined through a series of integrated 2D radiation hydrodynamic simulations to be consistent with the experimentally determined sensitivity only when including alpha-heating.

Alpha heating of indirect-drive layered implosions on the National Ignition Facility.

In order to understand how close current layered implosions in indirect-drive inertial confinement fusion are to ignition, it is necessary to measure the level of alpha heating present. To this end, pairs of experiments were performed that consisted of a low-yield tritium-hydrogen-deuterium (THD) layered implosion and a high-yield deuterium-tritium (DT) layered implosion to validate experimentally current simulation-based methods of determining yield amplification. The THD capsules were designed to reduce simultaneously DT neutron yield (alpha heating) and maintain hydrodynamic similarity with the higher yield DT capsules. The ratio of the yields measured in these experiments then allowed the alpha heating level of the DT layered implosions to be determined. The level of alpha heating inferred is consistent with fits to simulations expressed in terms of experimentally measurable quantities and enables us to infer the level of alpha heating in recent high-performing implosions.

Burning plasma achieved in inertial fusion.

Obtaining a burning plasma is a critical step towards self-sustaining fusion energy1. A burning plasma is one in which the fusion reactions themselves are the primary source of heating in the plasma, which is necessary to sustain and propagate the burn, enabling high energy gain. After decades of fusion research, here we achieve a burning-plasma state in the laboratory. These experiments were conducted at the US National Ignition Facility, a laser facility delivering up to 1.9 megajoules of energy in pulses with peak powers up to 500 terawatts. We use the lasers to generate X-rays in a radiation cavity to indirectly drive a fuel-containing capsule via the X-ray ablation pressure, which results in the implosion process compressing and heating the fuel via mechanical work. The burning-plasma state was created using a strategy to increase the spatial scale of the capsule2,3 through two different implosion concepts4-7. These experiments show fusion self-heating in excess of the mechanical work injected into the implosions, satisfying several burning-plasma metrics3,8. Additionally, we describe a subset of experiments that appear to have crossed the static self-heating boundary, where fusion heating surpasses the energy losses from radiation and conduction. These results provide an opportunity to study α-particle-dominated plasmas and burning-plasma physics in the laboratory.

Constraining physical models at gigabar pressures.

High-energy-density (HED) experiments in convergent geometry are able to test physical models at pressures beyond hundreds of millions of atmospheres. The measurements from these experiments are generally highly integrated and require unique analysis techniques to procure quantitative information. This work describes a methodology to constrain the physics in convergent HED experiments by adapting the methods common to many other fields of physics. As an example, a mechanical model of an imploding shell is constrained by data from a thin-shelled direct-drive exploding-pusher experiment on the OMEGA laser system using Bayesian inference, resulting in the reconstruction of the shell dynamics and energy transfer during the implosion. The model is tested by analyzing synthetic data from a one-dimensional hydrodynamics code and is sampled using a Markov chain Monte Carlo to generate the posterior distributions of the model parameters. The goal of this work is to demonstrate a general methodology that can be used to draw conclusions from a wide variety of HED experiments.

Energy Flow in Thin Shell Implosions and Explosions.

Energy flow and balance in convergent systems beyond petapascal energy densities controls the fate of late-stage stars and the potential for controlling thermonuclear inertial fusion ignition. Time-resolved x-ray self-emission imaging combined with a Bayesian inference analysis is used to describe the energy flow and the potential information stored in the rebounding spherical shock at 0.22 PPa (2.2 Gbar or billions of atmospheres pressure). This analysis, together with a simple mechanical model, describes the trajectory of the shell and the time history of the pressure at the fuel-shell interface, ablation pressure, and energy partitioning including kinetic energy of the shell and internal energy of the fuel. The techniques used here provide a fully self-consistent uncertainty analysis of integrated implosion data, a thermodynamic-path independent measurement of pressure in the petapascal range, and can be used to deduce the energy flow in a wide variety of implosion systems to petapascal energy densities.

Clarification and confocal imaging of the nonhuman primate placental micro-anatomy.

Geometry of the placental villous vasculature is a key determinant of maternal-fetal nutrient exchange for optimal fetal growth. Recent advances in tissue clarification techniques allow for deep high-resolution imaging with confocal microscopy; however, the methodology lacks a signal:noise ratio of sufficient magnitude to allow for quantitative analysis. Thus, we sought to develop a reproducible method to investigate the 3D vasculature of the nonhuman primate placenta for subsequent data analysis. Fresh placental tissue was dissected, formalin fixed, clarified using a modified Visikol® protocol and immunolabeled for CD31 (fetal endothelium) and cytokeratin-7 (villous trophoblast) for confocal imaging of the microanatomy. We present a detailed clarification and staining protocol augmented for imaging of nonhuman primate placental tissue. The image stacks generated by this refined staining method and our data acquisition parameters can be analyzed quantitatively to provide insights regarding the villous and vascular micro-anatomy of the placenta.

Absolute Equation-of-State Measurement for Polystyrene from 25 to 60 Mbar Using a Spherically Converging Shock Wave.

We have developed an experimental platform for the National Ignition Facility that uses spherically converging shock waves for absolute equation-of-state (EOS) measurements along the principal Hugoniot. In this Letter, we present one indirect-drive implosion experiment with a polystyrene sample that employs radiographic compression measurements over a range of shock pressures reaching up to 60 Mbar (6 TPa). This significantly exceeds previously published results obtained on the Nova laser [R. Cauble et al., Phys. Rev. Lett. 80, 1248 (1998)PRLTAO0031-900710.1103/PhysRevLett.80.1248] at a strongly improved precision, allowing us to discriminate between different EOS models. We find excellent agreement with Kohn-Sham density-functional-theory-based molecular dynamics simulations.

Correlation between clinical and MRI disease activity scores in axial spondyloarthritis.

Magnetic resonance (MR) imaging-based disease activity scores (DAS) in axial spondyloarthritis (axSpA) are rarely employed in the normal clinical setting, whereas clinical DAS are used routinely to monitor disease activity and set thresholds for biologic treatment. The objectives of this study were to evaluate the correlation between MR and clinical DAS in a general axSpA outpatient population and to assess the difference in MR DAS in individuals with high and low clinical DAS. This was a prospective, cross-sectional observational study. Forty participants with axSpA who presented for MR of the whole spine and sacroiliac joints as part of ongoing management were included. Completion of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) was performed at the time of MR examination. MR images were scored by two independent observers using the Spondyloarthritis Research Consortium of Canada (SPARCC) MR DAS. There were weak, non-significant correlations between total SPARCC score and BASDAI (r = 0.18, p = 0.26), ASDAS using erythrocyte sedimentation rate (ASDAS-ESR) (r = 0.31, p = 0.07) and ASDAS using C-reactive protein level (ASDAS-CRP) (r = 0.31, p = 0.05). There was no significant difference in the SPARCC score of participants with high and low clinical DAS. MR DAS may provide information about disease activity not provided by the current standard of clinical DAS and may be considered as a useful adjunct in clinical practice.

Development and evaluation of The KIT: Keeping It Together™â€ for†Youth (the 'Youth KIT') to assist youth with disabilities in managing information.

BACKGROUND: This article presents findings from the development and evaluation of The KIT: Keeping It Together™â€…for Youth (the 'Youth KIT'). The Youth KIT is a resource intended to assist youth with disabilities during their teenage years and during the transition to adulthood to give information to others about themselves, get from others about themselves, and organize their own information to the best of their ability. METHODS: Thirty-six youth between the ages of 12 and 25 with physical and developmental disabilities were active participants in the development of the Youth KIT and partnered with a multidisciplinary team to conduct the qualitative evaluation. Focus groups and individual interviews were used in three phases of evaluation. RESULTS: The results of qualitative content analysis found the Youth KIT to be useful for a variety of youth in different contexts. The themes that emerged about the utility and impact of the Youth KIT were: (1) self-discovery for youth; and (2) the importance of the 'fit' between youth and mentors to support youth as they started to use the Youth KIT. CONCLUSION: Clinical implications for healthcare providers working with youth during the transition to adulthood include recognition that discussions about adult goals should be a continuous dialogue throughout adolescence rather than a 'special' conversation occurring at the time of discharge from paediatric services.

Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signalling pathways involving Cdc2 and gamma-adducin.

We used short-interfering RNA (siRNA) to knockdown the hyaluronan (HA) receptors CD44 and the receptor for hyaluronan-mediated motility (RHAMM) in vascular endothelial cells to investigate their role in angiogenesis. We showed that CD44 and RHAMM single knockdown inhibited low molecular weight hyaluronan (o-HA)-induced endothelial cell tube formation in Matrigel, but no change in the control, epidermal growth factor-induced tube formation was observed. Using a Kinexus phosphoprotein array and confirmational Western blotting we were able to show a differential effect on HA-induced protein expression after CD44 and RHAMM knockdown. CD44 knockdown abolished o-HA-induced membrane phospho-protein kinase C-alpha (PKC-alpha) and down-stream phospho-gamma-adducin expression. Using the PKC inhibitor Go6976, we demonstrated the involvement of PKC-alpha and gamma-adducin in o-HA-induced tube formation, whilst o-HA-induced enzymatic activity of MMP9 was also reduced. This suggests that endothelial tube formation involves activation of MMP9 via PKC-alpha. Furthermore, the involvement of gamma-adducin in o-HA-induced F-actin cytoskeleton rearrangement was CD44-dependent and the reduction of CD44 expression lead to a change in endothelial cell morphology. Both RHAMM and CD44 knockdown completely inhibited o-HA-induced Cdc2 (Cdk1) phosphorylation suggesting a possible involvement in cell cycle control. Although CD44 and RHAMM are both involved in o-HA-induced endothelial tube formation in Matrigel, they mediate distinct angiogenic signalling pathway and for the first time we demonstrated the specific involvement of gamma-adducin in CD44/o-HA-induced endothelial tube formation. The data presented here extend our understanding of key stages of the processes of o-HA-induced angiogenesis which may have relevance to tumour progression.

An investigation of the kinetic and anti-angiogenic properties of plant glycoside inhibitors of thymidine phosphorylase.

We investigated the potential of symplocomoside (1) and symponoside (2), glycosides isolated from the bark of Symplocos racemosa to inhibit thymidine phosphorylase (TP) activity and associated angiogenesis. Compound 1 was a reversible, noncompetitive inhibitor of deoxythymidine binding to TP (IC(50) = 65.45 +/- 5.08 microM; K(i) = 62.83 +/- 2.10 microM) and 2 was a reversible, uncompetitive inhibitor (IC(50) = 94.17 +/- 4.05 microM; K(i) = 101.95 +/- 1.65 microM). Molecular modeling analysis indicated that both compounds bound at the active site of the enzyme but not solely to amino acid residues involved in catalysis. Both compounds were active in in vitro angiogenic assays inhibiting endothelial cell migration and invasion in Matrigel, but did not inhibit growth factor-induced proliferation and were not cytotoxic. Compound 1 may have potential as an anti-angiogenic and anti-tumor agent.

New VEGF antagonists as possible therapeutic agents in vascular disease.

BACKGROUND: In this review we provide the reader with an analysis of the importance of VEGF in modulating the angiogenic process in vascular diseases. OBJECTIVES: We have described the key role of VEGF in the development of the major angiogenic diseases including ocular retinopathies, solid tumour growth and atherosclerotic plaque development. METHODS: Following a brief description of the disease, a detailed literature review of the mechanisms through which VEGF induces promotion of neovascularisation and current anti-VEGF therapies is provided for the reader. RESULTS/CONCLUSIONS: Current and future potential clinical therapies are discussed in particular concerning our thoughts on future directives involving adenoviral-mediated gene targeting, nanotechnology and combinational therapies.

Atherothrombosis and plaque heterology: different location or a unique disease?

Formation of unstable plaques frequently results in atherothrombosis, the major cause for ischaemic stroke, myocardial infarction and peripheral arterial disease. Patients who have symptomatic thrombosis in one vascular bed are at increased risk of disease in other beds. However, the development of the disease in carotid, coronary and peripheral arteries may have different pathophysiology suggesting that more complex treatment protocols may have to be designed to reduce plaque development at different locations. In this review we describe the known risk factors, compare the developmental features of coronary and carotid plaque development and determine their association with end-point ischaemic events. Differences are also seen in the genetic contribution to plaque development as well as in the deregulation of gene and protein expression and cellular signal transduction activity of active cells in regions susceptible to thrombosis. Differences between carotid and coronary artery plaque development might help to explain the differences in anatomopathological appearance and risk of rupture.

Anti-angiogenic activity of sesterterpenes; natural product inhibitors of FGF-2-induced angiogenesis.

Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is of physiological and pathological importance. We have investigated the anti-angiogenic potential of two naturally occurring sesterterpenes, leucosesterterpenone (compound 1) and leucosterlactone (compound 2) isolated from the Himalayan plant Leucosceptrum canum and identified as having biological activity in preliminary screening. Compound 1 inhibited fibroblast growth factor-2-induced proliferation, migration in a wounding assay, chemotaxis and tube formation with small vessel (human dermal) and large vessel (bovine aortic) endothelial cells while compound 2 was largely inactive. Both compounds were also active in an in vivo angiogenic model using the chick chorioallantoic membrane. Neither compounds showed inhibitory activity in the absence of fibroblast growth factor-2. We were able to demonstrate in a binding assay that compounds 1 and 2 bound to the fibroblast growth factor-2 receptor-1 with IC(50) values of 1.4 +/- 0.956 and 132.47 +/- 7.90 muM, respectively, with a concomitant down regulation of phosphorylated ERK1/2 but did not bind to receptor-2. Compound 1 was less hydrophobic than compound 2 and this may contribute to its increased activity. Compound 1 is a new addition to the small number of inhibitors of fibroblast growth factor-2-induced angiogenesis. The compound was a specific inhibitor in that it had no effect on vascular endothelial growth factor or epithelial growth factor-induced angiogenesis. Since angiogenesis is essential for tumour development we conclude that these compounds may have potential as anti-tumour agents.

Leukaemia inhibitory factor is over-expressed by ischaemic brain tissue concomitant with reduced plasma expression following acute stroke.

Leukaemia inhibitory factor (LIF) is a glycoprotein of the interleukin-6 family, which has potent pro-inflammatory properties and is involved in regulation of neuronal differentiation. We have previously identified its upregulation in gene microarrays following acute ischaemic stroke in man. LIF expression and localization was measured in human ischaemic stroke autopsy specimens, in a rat model of middle cerebral artery occlusion (MCAO) and in human foetal neural cell cultures following oxygen-glucose deprivation (OGD) by Western blotting and immunohistochemistry. Circulating LIF was determined in the plasma of patients in the hyper-acute stroke phase using a multiplex enzyme-linked-immunosorbent serologic assay system. Patients demonstrated an increase in LIF expression in peri-infarcted regions with localization in neurons and endothelial cells of microvessels surrounding the infarcted core. The rat MCAO model showed similar upregulation in neurons with a peak increase at 90 min. Circulating serum LIF expression was significantly decreased in the hyper-acute phase of stroke. Brain-derived neurons and glia cultured in vitro demonstrated an increase in gene/protein and protein expression respectively following exposure to OGD. Increased LIF expression in peri-infarcted regions and sequestration from the peripheral circulation in acute stroke patients are characteristic of the pathobiological response to ischaemia and tissue damage.

Pathophysiology of acute ischaemic stroke: an analysis of common signalling mechanisms and identification of new molecular targets.

Stroke continues to be a major cause of death and disability. The currently available therapies have proven to be highly unsatisfactory (except thrombolysis) and attempts are being made to identify and characterize signalling proteins which could be exploited to design novel therapeutic modalities. The pathophysiology of stroke is a complex process. Delaying interventions from the first hours to days or even weeks following blood vessel occlusion may lead to worsening or impairment of recovery in later stages. The objective of this review is to critically evaluate the major mechanisms underlying stroke pathophysiology, especially the role of cell signalling in excitotoxicity, inflammation, apoptosis, neuroprotection and angiogenesis, and highlight potential novel targets for drug discovery.

Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults.

BACKGROUND: Cough is a very common symptom presenting to medical practitioners. Gastroesophageal reflux disease (GORD) is said to be the causative factor in up to 41% of adults with chronic cough. However cough and GORD are common ailments and their co-existence by chance is high. Also cough can induce reflux episodes. Treatment for GORD includes conservative measures (diet manipulation), pharmaceutical therapy (motility or prokinetic agents, H(2) antagonist and proton pump inhibitors (PPI)) and fundoplication. OBJECTIVES: To evaluate the efficacy of GORD treatment on chronic cough in children and adults with GORD and prolonged cough that is not related to an underlying respiratory disease i.e. non-specific chronic cough. SEARCH STRATEGY: The Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Specialised Register Collaboration and Cochrane Airways Group, MEDLINE and EMBASE databases, review articles and reference lists of relevant articles were searched. The date of last search was 7th April 2006. SELECTION CRITERIA: All randomised controlled trials on GORD treatment for cough in children and adults without primary lung disease. DATA COLLECTION AND ANALYSIS: Results of searches were reviewed against pre-determined criteria for inclusion. Two independent reviewers selected, extracted and assessed data for inclusion. Authors were contacted for further information. Data was analysed as "intention to treat" as well as "treatment received". Paediatric and adults data were considered separately. Sensitivity analyses were performed. MAIN RESULTS: Thirteen studies (3 paediatric, 10 adults) were included. Data from six were available for analysis. None of the paediatric studies could be included in meta-analysis. In adults, analysis on use of H(2) antagonist, motility agents and conservative treatment for GORD were not possible (from lack of data) and there were no controlled studies on fundoplication as an intervention. Six adult studies comparing PPI (2-3 months) to placebo were analysed for various outcomes in the meta-analysis. Enrolment of subjects for two studies were primarily from medical clinics and another 4 studies were otolaryngology clinic patients or patients with laryngitis. Using "intention to treat", pooled data from 4 studies resulted in no significant difference between treatment and placebo in total resolution of cough, Odds Ratio 0.46 (95% CI 0.19 to 1.15). Pooled data revealed no overall significant improvement in cough outcomes (end of trial or change in cough scores). Significant differences were only found in sensitivity analyses. A significant improvement in change of cough scores was found in end of intervention (2-3 months) in those receiving PPI with a standardised mean difference of -0.41 (95%CI -0.75, -0.07) using GIV analysis on cross over trials. Two studies reported improvement in cough after 5 days to 2 weeks of treatment. AUTHORS' CONCLUSIONS: There is insufficient evidence to definitely conclude that GORD treatment with PPI is universally beneficial for cough associated with GORD in adults. The beneficial effect was only seen in sub-analysis and its effect was small. The optimal duration of such a trial of therapy to evaluate response could not be ascertained in the meta-analysis although two RCTs reported significant change by 2 weeks of therapy. Clinicians should be cognisant of a period (natural resolution with time) and placebo effect in studies that utilise cough as an outcome measure. Data in children are inconclusive. Future paediatric and adult studies are needed whereby studies should be double blind, randomised controlled, parallel design, using treatments for at least two months, with validated subjective and objective cough outcomes and include ascertainment of time to respond as well as assessment of acid and/or non acid reflux whilst on therapy.

HIV, sexually transmitted infections, and risk behaviours in male sex workers in London over a 10 year period.

OBJECTIVES: To describe changing characteristics of men who sold sex in London between 1994 and 2003. METHODS: A baseline survey of 823 male sex workers attending a specialist clinic, plus follow up of 628 men for 1379 person years. RESULTS: Men recruited earlier (1994 to 1996) were more likely than those recruited later (2000 to 2003) to be UK born and to self define as homosexual. Later recruits included more men from South/Central America and eastern Europe and a higher proportion reported regular female partners. Baseline prevalence of HIV was 9% (59/636), and multivariate analysis showed an associated with injecting drug use and unprotected sex with a casual partner. During follow up there were 49 incident cases of HIV. Survival analysis showed earlier recruitment (1994-6) to be associated with a higher incidence of HIV. The prevalence of gonorrhoea increased over time. CONCLUSIONS: Men who sell sex are at risk of HIV and other STIs, but these risks do not appear to be directly linked to sex work. The changing demographics of these men is associated with different patterns of infection and poses challenges for service delivery.