Developing an Experimental Basis for Understanding Transport in NIF Hohlraum Plasmas.

We report on the first multilocation electron temperature (T_{e}) and flow measurements in an ignition hohlraum at the National Ignition Facility using the novel technique of mid-Z spectroscopic tracer "dots." The measurements define a low resolution "map" of hohlraum plasma conditions and provide a basis for the first multilocation tests of particle and energy transport physics in a laser-driven x-ray cavity. The data set is consistent with classical heat flow near the capsule but reduced heat flow near the laser entrance hole. We evaluate the role of kinetic effects, self-generated magnetic fields, and instabilities in causing spatially dependent heat transport in the hohlraum.

Cost-effectiveness of nonsteroidal anti-inflammatory drugs and opioids in the treatment of knee osteoarthritis in older patients with multiple comorbidities.

OBJECTIVE: To evaluate long-term clinical and economic outcomes of naproxen, ibuprofen, celecoxib or tramadol for OA patients with cardiovascular disease (CVD) and diabetes. DESIGN: We used the Osteoarthritis Policy Model to examine treatment with these analgesics after standard of care (SOC) - acetaminophen and corticosteroid injections - failed to control pain. NSAID regimens were evaluated with and without proton pump inhibitors (PPIs). We evaluated over-the-counter (OTC) regimens where available. Estimates of treatment efficacy (pain reduction, occurring in ∼57% of patients on all regimens) and toxicity (major cardiac or gastrointestinal toxicity or fractures, risk ranging from 1.09% with celecoxib to 5.62% with tramadol) were derived from published literature. Annual costs came from Red Book Online(®). Outcomes were discounted at 3%/year and included costs, quality-adjusted life expectancy, and incremental cost-effectiveness ratios (ICERs). Key input parameters were varied in sensitivity analyses. RESULTS: Adding ibuprofen to SOC was cost saving, increasing QALYs by 0.07 while decreasing cost by $800. Incorporating OTC naproxen rather than ibuprofen added 0.01 QALYs and increased costs by $300, resulting in an ICER of $54,800/QALY. Using prescription naproxen with OTC PPIs led to an ICER of $76,700/QALY, while use of prescription naproxen with prescription PPIs resulted in an ICER of $252,300/QALY. Regimens including tramadol or celecoxib cost more but added fewer QALYs and thus were dominated by several of the naproxen-containing regimens. CONCLUSIONS: In patients with multiple comorbidities, naproxen- and ibuprofen-containing regimens are more effective and cost-effective in managing OA pain than opioids, celecoxib or SOC.

Pharmacologic regimens for knee osteoarthritis prevention: can they be cost-effective?

OBJECTIVE: We sought to determine the target populations and drug efficacy, toxicity, cost, and initiation age thresholds under which a pharmacologic regimen for knee osteoarthritis (OA) prevention could be cost-effective. DESIGN: We used the Osteoarthritis Policy (OAPol) Model, a validated state-transition simulation model of knee OA, to evaluate the cost-effectiveness of using disease-modifying OA drugs (DMOADs) as prophylaxis for the disease. We assessed four cohorts at varying risk for developing OA: (1) no risk factors, (2) obese, (3) history of knee injury, and (4) high-risk (obese with history of knee injury). The base case DMOAD was initiated at age 50 with 40% efficacy in the first year, 5% failure per subsequent year, 0.22% major toxicity, and annual cost of $1,000. Outcomes included costs, quality-adjusted life expectancy (QALE), and incremental cost-effectiveness ratios (ICERs). Key parameters were varied in sensitivity analyses. RESULTS: For the high-risk cohort, base case prophylaxis increased quality-adjusted life-years (QALYs) by 0.04 and lifetime costs by $4,600, and produced an ICER of $118,000 per QALY gained. ICERs >$150,000/QALY were observed when comparing the base case DMOAD to the standard of care in the knee injury only cohort; for the obese only and no risk factors cohorts, the base case DMOAD was less cost-effective than the standard of care. Regimens priced at $3,000 per year and higher demonstrated ICERs above cost-effectiveness thresholds consistent with current US standards. CONCLUSIONS: The cost-effectiveness of DMOADs for OA prevention for persons at high risk for incident OA may be comparable to other accepted preventive therapies.

Disease-modifying drugs for knee osteoarthritis: can they be cost-effective?

OBJECTIVE: Disease-modifying osteoarthritis drugs (DMOADs) are under development. Our goal was to determine efficacy, toxicity, and cost thresholds under which DMOADs would be a cost-effective knee OA treatment. DESIGN: We used the Osteoarthritis Policy Model, a validated computer simulation of knee OA, to compare guideline-concordant care to strategies that insert DMOADs into the care sequence. The guideline-concordant care sequence included conservative pain management, corticosteroid injections, total knee replacement (TKR), and revision TKR. Base case DMOAD characteristics included: 50% chance of suspending progression in the first year (resumption rate of 10% thereafter) and 30% pain relief among those with suspended progression; 0.5%/year risk of major toxicity; and costs of $1,000/year. In sensitivity analyses, we varied suspended progression (20-100%), pain relief (10-100%), major toxicity (0.1-2%), and cost ($1,000-$7,000). Outcomes included costs, quality-adjusted life expectancy, incremental cost-effectiveness ratios (ICERs), and TKR utilization. RESULTS: Base case DMOADs added 4.00 quality-adjusted life years (QALYs) and $230,000 per 100 persons, with an ICER of $57,500/QALY. DMOADs reduced need for TKR by 15%. Cost-effectiveness was most sensitive to likelihoods of suspended progression and pain relief. DMOADs costing $3,000/year achieved ICERs below $100,000/QALY if the likelihoods of suspended progression and pain relief were 20% and 70%. At a cost of $5,000, these ICERs were attained if the likelihoods of suspended progression and pain relief were both 60%. CONCLUSIONS: Cost, suspended progression, and pain relief are key drivers of value for DMOADs. Plausible combinations of these factors could reduce need for TKR and satisfy commonly cited cost-effectiveness criteria.

Numerical modeling of the sensitivity of x-ray driven implosions to low-mode flux asymmetries.

The sensitivity of inertial confinement fusion implosions, of the type performed on the National Ignition Facility (NIF) [1], to low-mode flux asymmetries is investigated numerically. It is shown that large-amplitude, low-order mode shapes (Legendre polynomial P(4), resulting from low-order flux asymmetries, cause spatial variations in capsule and fuel momentum that prevent the deuterium and tritium (DT) "ice" layer from being decelerated uniformly by the hot spot pressure. This reduces the transfer of implosion kinetic energy to internal energy of the central hot spot, thus reducing the neutron yield. Furthermore, synthetic gated x-ray images of the hot spot self-emission indicate that P(4) shapes may be unquantifiable for DT layered capsules. Instead the positive P(4) asymmetry "aliases" itself as an oblate P(2) in the x-ray images. Correction of this apparent P(2) distortion can further distort the implosion while creating a round x-ray image. Long wavelength asymmetries may be playing a significant role in the observed yield reduction of NIF DT implosions relative to detailed postshot two-dimensional simulations.

Onset of hydrodynamic mix in high-velocity, highly compressed inertial confinement fusion implosions.

Deuterium-tritium inertial confinement fusion implosion experiments on the National Ignition Facility have demonstrated yields ranging from 0.8 to 7×10(14), and record fuel areal densities of 0.7 to 1.3 g/cm2. These implosions use hohlraums irradiated with shaped laser pulses of 1.5-1.9 MJ energy. The laser peak power and duration at peak power were varied, as were the capsule ablator dopant concentrations and shell thicknesses. We quantify the level of hydrodynamic instability mix of the ablator into the hot spot from the measured elevated absolute x-ray emission of the hot spot. We observe that DT neutron yield and ion temperature decrease abruptly as the hot spot mix mass increases above several hundred ng. The comparison with radiation-hydrodynamic modeling indicates that low mode asymmetries and increased ablator surface perturbations may be responsible for the current performance.

Hot-spot mix in ignition-scale inertial confinement fusion targets.

Mixing of plastic ablator material, doped with Cu and Ge dopants, deep into the hot spot of ignition-scale inertial confinement fusion implosions by hydrodynamic instabilities is diagnosed with x-ray spectroscopy on the National Ignition Facility. The amount of hot-spot mix mass is determined from the absolute brightness of the emergent Cu and Ge K-shell emission. The Cu and Ge dopants placed at different radial locations in the plastic ablator show the ablation-front hydrodynamic instability is primarily responsible for hot-spot mix. Low neutron yields and hot-spot mix mass between 34(-13,+50) ng and 4000(-2970,+17 160) ng are observed.

Simple solution to the Fresnel-Kirchoff diffraction integral for application to refraction-enhanced radiography.

We present a simple solution to the Fresnel-Kirchoff diffraction integral that is appropriate for x-ray radiography of strongly absorbing and phase-shifting objects in the geometrical optics regime, where phase contrast enhancements can be considered to be caused by refraction by a semi-opaque object. We demonstrate its accuracy by comparison to brute-force numerical ray trace and diffraction calculations of a representative simulated object, and show excellent agreement for spatial scales corresponding to Fresnel numbers greater than unity. The result represents a significant improvement over approximate formulas typically used in analysis of refraction-enhanced radiographs, particularly for radiography of transient phenomena in objects that strongly refract and show significant absorption.

Direct measurement of energetic electrons coupling to an imploding low-adiabat inertial confinement fusion capsule.

We have imaged hard x-ray (>100 keV) bremsstrahlung emission from energetic electrons slowing in a plastic ablator shell during indirectly driven implosions at the National Ignition Facility. We measure 570 J in electrons with E>100 keV impinging on the fusion capsule under ignition drive conditions. This translates into an acceptable increase in the adiabat α, defined as the ratio of total deuterium-tritium fuel pressure to Fermi pressure, of 3.5%. The hard x-ray observables are consistent with detailed radiative-hydrodynamics simulations, including the sourcing and transport of these high energy electrons.

Observation of high soft x-ray drive in large-scale hohlraums at the National Ignition Facility.

The first soft x-ray radiation flux measurements from hohlraums using both a 96 and a 192 beam configuration at the National Ignition Facility have shown high x-ray conversion efficiencies of ∼85%-90%. These experiments employed gold vacuum hohlraums, 6.4 mm long and 3.55 mm in diameter, heated with laser energies between 150-635 kJ. The hohlraums reached radiation temperatures of up to 340 eV. These hohlraums for the first time reached coronal plasma conditions sufficient for two-electron processes and coronal heat conduction to be important for determining the radiation drive.

Genetic analysis of post-mating reproductive barriers in hybridizing European Populus species.

Molecular genetic analyses of experimental crosses provide important information on the strength and nature of post-mating barriers to gene exchange between divergent populations, which are topics of great interest to evolutionary geneticists and breeders. Although not a trivial task in long-lived organisms such as trees, experimental interspecific recombinants can sometimes be created through controlled crosses involving natural F(1)'s. Here, we used this approach to understand the genetics of post-mating isolation and barriers to introgression in Populus alba and Populus tremula, two ecologically divergent, hybridizing forest trees. We studied 86 interspecific backcross (BC(1)) progeny and >350 individuals from natural populations of these species for up to 98 nuclear genetic markers, including microsatellites, indels and single nucleotide polymorphisms, and inferred the origin of the cytoplasm of the cross with plastid DNA. Genetic analysis of the BC(1) revealed extensive segregation distortions on six chromosomes, and >90% of these (12 out of 13) favored P. tremula donor alleles in the heterospecific genomic background. Since selection was documented during early diploid stages of the progeny, this surprising result was attributed to epistasis, cyto-nuclear coadaptation, heterozygote advantage at nuclear loci experiencing introgression or a combination of these. Our results indicate that gene flow across 'porous' species barriers affects these poplars and aspens beyond neutral, Mendelian expectations and suggests the mechanisms responsible. Contrary to expectations, the Populus sex determination region is not protected from introgression. Understanding the population dynamics of the Populus sex determination region will require tests based on natural interspecific hybrid zones.

Late adverse effects after soft X-ray therapy of cutaneous malignancies: pruritus, burning, epiphora and insufficient occlusion of the mouth.

BACKGROUND: Pruritus, burning, epiphora and insufficient occlusion of the mouth have been less extensively studied than cosmetic changes in irradiated fields. OBJECTIVES: How frequent are these late adverse effects? Do they usually occur permanently? Are they influenced by treatment and tumour parameters, sex and age of the patients? METHODS: Patients were interviewed at least once later than 90 days after soft X-ray therapy. RESULTS: Pruritus has been reported in 18.5% of the interviews, burning in 7.7%, epiphora in 36.2% and insufficient occlusion of the mouth in 11.5%. Patients were usually not permanently troubled and irritated by these symptoms: pruritus more than once per week was reported in every interview for 0.6% of the fields, burning for 0.2%, epiphora for 6.4% and insufficient occlusion for 0%. Irritation by these symptoms has been stated in every interview for 5.1% of fields around the eye and for 1.4% of fields at other sites. Late pruritus, burning and epiphora were less frequently reported after irradiation with lower total doses, lower time-dose-fractionation factor (TDF) and by men. Patients older than 70 years of age experienced pruritus and burning less frequently. The largest diameter of the irradiated field influenced pruritus and the half value depth of the X-rays influenced burning and epiphora. CONCLUSIONS: Late pruritus, burning, epiphora and insufficient occlusion of the mouth do not considerably reduce the value of soft X-ray therapy because these adverse effects usually are not experienced permanently. Total dose and TDF should not be chosen higher than necessary.

An in vitro study on 5-HT6 receptor antagonist induced hepatotoxicity based on biochemical assays and toxicogenomics.

We investigated the effects of two 5-HT(6) receptor antagonists on rat primary hepatocytes using a combined biochemical and toxicogenomics approach. Both compounds share the same pharmacological target, but displayed strikingly different toxicity profiles in pre-clinical animal studies: While R7199 caused hepatic steatosis in rats, no hepatotoxicity was observed with R0074. Here, we partially reproduced the steatosis findings seen in vivo using primary rat hepatocytes. Biochemical analyses and gene expression results generally supported the findings observed in the animal model and also allowed the differentiation of both compounds with regards to hepatotoxic potential. In particular, the induction of Cyp 2B and Cyp 3A1 directly correlates to the findings in the livers of treated animals. The effects on genes of the steroideogenic pathway relate to the deregulation of cholesterol homeostasis. We also observed the inhibition of beta-oxidation, indicating impaired lipid metabolism. Hence, gene expression analysis in combination with biochemical parameters can provide additional insight into the possible mechanisms underlying adverse events.

Progress towards a more predictive model for hohlraum radiation drive and symmetry.

For several years, we have been calculating the radiation drive in laser-heated gold hohlraums using flux-limited heat transport with a limiter of 0.15, tabulated values of local thermodynamic equilibrium gold opacity, and an approximate model for not in a local thermodynamic equilibrium (NLTE) gold emissivity (DCA_2010). This model has been successful in predicting the radiation drive in vacuum hohlraums, but for gas-filled hohlraums used to drive capsule implosions, the model consistently predicts too much drive and capsule bang times earlier than measured. In this work, we introduce a new model that brings the calculated bang time into better agreement with the measured bang time. The new model employs (1) a numerical grid that is fully converged in space, energy, and time, (2) a modified approximate NLTE model that includes more physics and is in better agreement with more detailed offline emissivity models, and (3) a reduced flux limiter value of 0.03. We applied this model to gas-filled hohlraum experiments using high density carbon and plastic ablator capsules that had hohlraum He fill gas densities ranging from 0.06 to 1.6 mg/cc and hohlraum diameters of 5.75 or 6.72 mm. The new model predicts bang times to within ±100 ps for most experiments with low to intermediate fill densities (up to 0.85 mg/cc). This model predicts higher temperatures in the plasma than the old model and also predicts that at higher gas fill densities, a significant amount of inner beam laser energy escapes the hohlraum through the opposite laser entrance hole.

Association with clinical outcome of expression of VLA-4 in primary cutaneous malignant melanoma as well as P-selectin and E-selectin on intratumoral vessels.

BACKGROUND: The process of tumor growth and metastasis is a complex multistep cascade. The ability of tumor cells to adhere to and detach from extracellular matrix and endothelial cells may be crucial in the metastatic process and may dramatically alter the clinical prognosis and outcome for patients with certain cancers. A number of adhesion molecules have been detected on human melanoma cells and have been associated with various properties in vitro including invasiveness. Recent findings from our laboratory have indicated an ordered change in integrin expression during the process of tumor progression. PURPOSE: This study was designed to identify molecular markers present on human melanoma cells and in intratumoral vessels that have prognostic significance regarding disease-free interval and survival time. METHODS: Specimens of primary cutaneous malignant melanoma were obtained from 60 patients who had been followed for at least 36 months, with development of metastases in 29 patients during that period of time, and were analyzed for their expression of VLA-4, VLA-6, ICAM-1, ELAM-1 (E-selectin), CD62 (P-selectin), and CD44v6 molecules on tumor and endothelial cells by immunostaining. Light microscopy was used to evaluate and categorize the number of positively stained cells. Statistical analyses were done to determine the relationship of the expression of individual adhesion molecules with time to disease progression (i.e., disease-free interval) and overall survival time. RESULTS: In each case, positive staining for ELAM-1 and CD62 on intratumoral vessels and for VLA-4 on human melanoma cells was negatively associated with disease-free interval (P < .01) and overall survival time (P < .01). The presence of VLA-6, CD44v6, and ICAM-1 on melanoma cells was not associated with clinical outcome. CONCLUSIONS: Immunohistochemical screening and detection of ELAM-1, CD62, and VLA-4 may help to define a subgroup of melanoma patients at risk of developing metastases.

Beyond the gain exponent: Effect of damping, scale length, and speckle length on stimulated scatter.

Three-dimensional wave propagation simulations and experiments show that the gain exponent, an often used metric to assess the likelihood of stimulated Brillouin scatter, is insufficient and must be augmented with another parameter, Nr, the ratio of the resonance length, Lres, to the laser speckle length. The damping rate of ion acoustic waves, ν, and thus Lres, which is proportional to ν, are easily varied with plasma species composition, e.g., by varying the ratio of hydrogen and carbon ions. As Nr decreases, stimulated Brillouin scattering increases despite the same gain exponent.

DNA aneuploidy in congenital melanocytic nevi: suggestive evidence for premalignant changes.

Nuclei with abnormal (aneuploid) DNA content were detected by flow cytometric analysis in 4 of 39 congenital melanocytic nevi and in 0 of 62 acquired nevi. Three of the 4 nevi with DNA-aneuploidy were greater than 20 cm in their largest diameter. We suggest that DNA aneuploidy is an indicator of a premalignant condition in congenital nevi in cases where histologic examination does not reveal any evidence for malignant melanoma. Cells with abnormal DNA content (aneuploid cells) are not uniformly distributed in giant congenital nevi: in one lesion we observed an area with a high percentage of cells with DNA aneuploidy, areas with a low percentage of aneuploid cells, and parts that were found to be normal by flow cytometric analysis. Nuclear pleomorphism was found histologically in the area with the high percentage of aneuploid cells while the areas with the low percentage of aneuploid cells were histologically normal. Thus, flow cytometry seems to be an additional sensitive method for the detection of nuclear abnormalities that are not always apparent by conventional histology. Increase in the relative amount of growth phase (S-phase cells), indicating elevated proliferative activity, was detected in 6 of 39 congenital pigmented nevi and in 6 of 62 acquired nevi.

HLA-DR antigen expression in primary melanomas of the skin.

Ninety-three primary malignant melanomas of the skin were typed immunohistologically for the expression of HLA-DR on tumor cells. HLA-DR-positive stroma cells were HLA-DR-negative or only locally positive in most cases. In 36 (39%) of the lesions more than 10% of the tumor cells were stained by two monoclonal antibodies against the nonpolymorphic portion of HLA-DR. HLA-DR-positive tumor cells were often accumulated at the advancing front of the melanoma. The occurrence of HLA-DR-positive tumor cells was related to tumor thickness and level of invasion. Substantial numbers of HLA-DR-positive tumor cells were found in half of the tumors thicker than 1.5 mm and in only 18% of flatter lesions. The highest percentage of HLA-DR-positive tumors was found in the group of melanomas invading the reticular dermis (level IV). The majority of tumors (18/24) that had metastasized within an observation period of 0-32 months were HLA-DR-positive. Regarding the mononuclear cell infiltrate, no correlation between the degree of overall infiltrate and the expression of HLA-DR by the tumor cells was found. The infiltrate within the tumor, however, was more often marked in HLA-DR-positive than in HLA-DR-negative melanomas.

Use of an enzyme-linked immunosorbent assay (ELISA) for screening of hybridoma antibodies against cell surface antigens.

A micro-ELISA for screening of antibodies from hybridoma cultures against surface antigens of human melanoma is described. The technique employs alkaline phosphatase-conjugated protein A and target cells attached to poly-L-lysine-coated microtiter plates. The micro-ELISA is equally sensitive as the radioimmunoassay. Mild glutaraldehyde treatment of cells did not lead to an appreciable loss of antigen activity. The fixed cells can be stored at 4 degrees C for at least 6 weeks. It is concluded that the ELISA is superior to the radioimmunoassay in the following aspects: (1) exclusion of radioactive hazards, (2) speed of performance, and (3) lower costs.

p-glycoprotein expression in malignant melanoma.

In some human malignancies resistance to chemotherapy is caused by an energy-dependent efflux system, responsible for the removal of chemotherapeutics out of the resistant tumor cells. A major component of this efflux system is the permeability glycoprotein (p-glycoprotein), which depends on the multidrug-resistance gene MDR1. We have tested p-glycoprotein in primary and metastatic human melanoma by use of the monoclonal antibody C219; a substantial expression was only observed in 1/37 primary melanomas and in 1/27 melanoma metastases. None of the patients with negative metastases responded to chemotherapy. Moreover a complete remission of metastatic growth was observed in the patient with the metastasis significantly expressing the p-glycoprotein. Sequential studies revealed no significant increase of p-glycoprotein-positive cells during and after chemotherapy. We conclude that drug resistance in human melanoma does not usually depend on the p-glycoprotein-related efflux system. Other mechanisms are obviously responsible for drug resistance in this human malignancy.