Time-resolved X-ray diffraction diagnostic development for the National Ignition Facility.

We present the development of an experimental platform that can collect four frames of x-ray diffraction data along a single line of sight during laser-driven, dynamic-compression experiments at the National Ignition Facility. The platform is comprised of a diagnostic imager built around ultrafast sensors with a 2-ns integration time, a custom target assembly that serves also to shield the imager, and a 10-ns duration, quasi-monochromatic x-ray source produced by laser-generated plasma. We demonstrate the performance with diffraction data for Pb ramp compressed to 150 GPa and illuminated by a Ge x-ray source that produces ∼7 × 1011, 10.25-keV photons/ns at the 400 µm diameter sample.

A study of space charge induced non-linearity in the Single Line Of Sight camera.

A new generation of gated x-ray detectors at the National Ignition Facility has brought faster, enhanced imaging capabilities. Their performance is currently limited by the amount of signal they can be operated with before space charge effects in their electron tube start to compromise their temporal and spatial response. We present a technique to characterize this phenomenon and apply it to a prototype of such a system, the Single Line Of Sight camera. The results of this characterization are used to benchmark particle-in-cell simulations of the electrons drifting inside the detector, which are found to well reproduce the experimental data. These simulations are then employed to predict the optimum photon flux to the camera, with the goal to increase the quality of the images obtained on an experimental campaign while preventing the appearance of deleterious effects. They also offer some insights into some of the improvements that can be brought to the new pulse-dilation systems being built at Lawrence Livermore National Laboratory.

Timing characterization of fast hCMOS sensors.

We describe a method of analyzing gate profile data for ultrafast x-ray imagers that allows pixel-by-pixel determination of temporal sensitivity in the presence of substantial background oscillations. With this method, systematic timing errors in gate width and gate arrival time of up to 1 ns (in a 2 ns wide gate) can be removed. In-sensor variations in gate arrival and gate width are observed, with variations in each up to 0.5 ns. This method can be used to estimate the coarse timing of the sensor, even if errors up to several ns are present.

Upgrade of the gated laser entrance hole imager G-LEH-2 on the National Ignition Facility.

A major upgrade has been implemented for the ns-gated laser entrance hole imager on the National Ignition Facility (NIF) to obtain high-quality data for Hohlraum physics study. In this upgrade, the single "Furi" hCMOS sensor (1024 × 448 pixel arrays with two-frame capability) is replaced with dual "Icarus" sensors (1024 × 512 pixel arrays with four-frame capability). Both types of sensors were developed by Sandia National Laboratories for high energy density physics experiments. With the new Icarus sensors, the new diagnostic provides twice the detection area with improved uniformity, wider temporal coverage, flexible timing setup, and greater sensitivity to soft x rays (<2 keV). These features, together with the fact that the diagnostic is radiation hardened and can be operated on the NIF for high neutron yield deuterium-triterium experiments, enable significantly greater return of data per experiment.

The dilation aided single-line-of-sight x-ray camera for the National Ignition Facility: Characterization and fielding.

Crystal x-ray imaging is frequently used in inertial confinement fusion and laser-plasma interaction applications as it has advantages compared to pinhole imaging, such as higher signal throughput, better achievable spatial resolution, and chromatic selection. However, currently used x-ray detectors are only able to obtain a single time resolved image per crystal. The dilation aided single-line-of-sight x-ray camera described here was designed for the National Ignition Facility (NIF) and combines two recent diagnostic developments, the pulse dilation principle used in the dilation x-ray imager and a ns-scale multi-frame camera that uses a hold and readout circuit for each pixel. This enables multiple images to be taken from a single-line-of-sight with high spatial and temporal resolution. At the moment, the instrument can record two single-line-of-sight images with spatial and temporal resolution of 35 µm and down to 35 ps, respectively, with a planned upgrade doubling the number of images to four. Here we present the dilation aided single-line-of-sight camera for the NIF, including the x-ray characterization measurements obtained at the COMET laser, as well as the results from the initial timing shot on the NIF.

Chromodomain proteins in development: lessons from CHARGE syndrome.

In humans, heterozygous mutations in the adenosine triphosphate-dependent chromatin remodeling gene CHD7 cause CHARGE syndrome, a common cause of deaf-blindness, balance disorders, congenital heart malformations, and olfactory dysfunction with an estimated incidence of approximately 1 in 10,000 newborns. The clinical features of CHARGE in humans and mice are highly variable and incompletely penetrant, and most mutations appear to result in haploinsufficiency of functional CHD7 protein. Mice with heterozygous loss of function mutations in Chd7 are a good model for CHARGE syndrome, and analyses of mouse mutant phenotypes have begun to clarify a role for CHD7 during development and into adulthood. Chd7 heterozygous mutant mice have postnatal delayed growth, inner ear malformations, anosmia/hyposmia, and craniofacial defects, and Chd7 homozygous mutants are embryonic lethal. A central question in developmental biology is how chromodomain proteins like CHD7 regulate important developmental processes, and whether they directly activate or repress downstream gene transcription or act more globally to alter chromatin structure and/or function. CHD7 is expressed in a wide variety of tissues during development, suggesting that it has tissue-specific and developmental stage-specific roles. Here, we review recent and ongoing analyses of CHD7 function in mouse models and cell-based systems. These studies explore tissue-specific effects of CHD7 deficiency, known CHD7 interacting proteins, and downstream target sites for CHD7 binding. CHD7 is emerging as a critical regulator of important developmental processes in organs affected by human CHARGE syndrome.

Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine.

OBJECTIVE: To evaluate the ability of hydroxychloroquine sulfate (HCQ) to extend the response to combination therapy with HCQ and methotrexate (MTX) and the safety of longterm HCQ maintenance therapy in patients with active rheumatoid arthritis (RA). METHODS: Two-part study consisting of an open label segment evaluating combination HCQ/MTX therapy followed by a double blind segment evaluating maintenance therapy for a total of 60 weeks. First, all patients were treated with HCQ 400 mg/day and MTX 7.5 to 15 mg/week for 24 weeks. Then, responders were randomized into 3 groups: (1) HCQ with MTX as needed for disease flare (n = 40), (2) HCQ 400 mg/day (n = 41), or (3) placebo with MTX as needed for disease flare (n = 40), each for 36 weeks. RESULTS: Clinical disease and laboratory variables improved significantly during initial combination therapy with HCQ and MTX. After MTX withdrawal, HCQ-containing maintenance regimens delayed the onset of disease flare (p = 0.023). There were no unexpected adverse events at any time or between-group differences in the distribution of adverse events during the double blind segment. CONCLUSION: Combination of HCQ and MTX appeared to be effective and well tolerated for 24 weeks. After withdrawal of MTX, HCQ extended the response seen with combination therapy and was well tolerated for 36 weeks. Initial therapy with HCQ and MTX, followed by maintenance HCQ, may be a useful alternative for the treatment of RA.

The Colorado differentiated practice model.

The Colorado Differentiated Practice Model for Nurses has been implemented at a community hospital and is decreasing patient length of stay while simultaneously becoming a satisfaction factor for nurses, physicians, patients and families. Also, a new role, with more responsibility and authority, has evolved for the BSN-prepared staff nurse.

Severe restrictive pulmonary defect in a patient with adult-onset Still's disease.

Adult-onset Still's disease is characterized by seronegative arthritis, fever, and an evanescent skin rash. Earlier reports have described pneumonitis and pleuritis as manifestations of this disease. We report a patient with adult-onset Still's disease with severe restrictive ventilatory impairment and evidence of respiratory muscle weakness who responded to corticosteroid and aspirin therapy.

Kaposi's sarcoma in rheumatoid arthritis.

Cutaneous Kaposi's sarcoma developed eight months after initiation of prednisone treatment in a 58-year-old man with systemic rheumatoid disease (rheumatoid arthritis, Felty's syndrome, rheumatoid vasculitis, and myositis). This patient did not have the acquired immune deficiency syndrome. Review of the literature suggests that the onset of his Kaposi's sarcoma may have been related to immunosuppressive therapy with corticosteroids.

Benzo[a]pyrene diol epoxide induces viral reactivation at concentrations that block DNA elongation in mammalian cells.

The survival of UV-irradiated Simian virus 40 (SV40) in CV-1P African green monkey kidney cells treated with (+/-)7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BP-diol epoxide I) was studied. Enhanced survival of UV damaged SV40 was detected when CV-1P cells were treated with dose levels of BP-diol epoxide I corresponding to the exponential portion (0.33-1.11 microM) of a CV-1P cell survival curve. Dose levels of BP-diol epoxide I corresponding to the shoulder region (less than or equal to 0.16 microM) of a CV-1P survival curve did not induce viral reactivation. The shoulder region concentrations of BP-diol epoxide I selectively inhibited DNA initiation while the concentrations on the exponential portion of the curve preferentially inhibited DNA elongation. It was shown in a time course of enhanced viral survival at 0.66 microM BP-diol epoxide I that the reactivation response was fully induced by 24 h. In conclusion, the viral reactivation response was associated with concentrations of BP-diol epoxide I which induced lethal damage and preferentially inhibited DNA elongation.

Study of HLA antigens in ten multiple-case rheumatoid arthritis families.

We studied the inheritance of HLA haplotypes in 10 families with more than one member affected with adult onset rheumatoid arthritis (RA). The frequency of DR4 was 81% among these patients. Nine families had DR4 bearing haplotypes and homozygosity for DR4 existed in 4 families. In 6 of these families DR4 positive haplotypes were shared among affected members. All but one of the affected sibs shared at least one haplotype with their index case. Ten percent of the unaffected relatives had rheumatoid factor (RF). HLA-DR4 or associated genes appeared to confer susceptibility for RF production and development of RA. However, these haplotypes were inherited also by many sibs who did not develop any manifestations of disease.

Cytotoxicity of sera from patients with scleroderma. Effects on human endothelial cells and fibroblasts in culture.

Sera from patients with progressive systemic sclerosis were compared with sera from normal individuals and from patients with other connective tissue diseases for cytotoxic effects on cultured human cells. More than 40% of the sera from patients with active progressive systemic sclerosis were cytotoxic by several criteria for pulmonary arterial or umbilical venous endothelial cells, foreskin fibroblasts, and neuroblastoma cells. Cytotoxic sera caused morphologic changes, uptake of trypan blue dye, and a decrease in the incorporation of 3H-thymidine into DNA. In contrast, only 4 sera from normal individuals or patients with other rheumatic diseases affected cell morphology, staining, or uptake of 3H-thymidine. Partial characterization of the cytotoxic factor indicated that it is sensitive to proteolysis by trypsin. The molecular weight of the factor was estimated to be similar to that of albumin.

Increased endothelial cell adherence, aggregation, and superoxide generation by neutrophils incubated in systemic lupus erythematosus and Felty's syndrome sera.

The ability of sera from patients with systemic lupus erythematosus (SLE) and Felty's syndrome to induce increased adhesiveness of normal human neutrophils (PMN) was investigated. PMN from normal healthy donors were incubated in sera from 19 patients with active SLE, 12 with inactive SLE, 20 with Felty's, 24 with rheumatoid arthritis, and 34 normal persons. After incubation, the degree of adherence of the PMN to human endothelial cells in culture, their aggregation, and superoxide (O2-) generation were determined. Sera from patients with both active SLE and Felty's syndrome induced significantly increased PMN adherence to endothelial cells and PMN aggregation in vitro, compared with normal sera. This increased adherence to endothelial cells was maintained after heat treatment (56 degrees C for 30 minutes) of the sera. In O2- generation experiments, sera from patients with active SLE induced significantly increased O2- release from normal PMN using both fresh and heat-treated sera. Sera from Felty's patients demonstrated the same effect with heat-treated sera but not ith fresh sera. When sera from patients with active SLE and Felty's syndrome were used, all three parameters correlated significantly with each other in individual patients. In contrast, sera from the 12 patients with inactive SLE and 24 rheumatoid arthritis patients without Felty's failed to induce significant differences in the three parameters studied when compared with 34 normal controls. Fractionation of 3 SLE sera and 1 Felty's serum on Sephadex G-200 demonstrated that the adherence enhancing factor was present in both IgG and IgG-excluded fractions. The observed increased adhesiveness of PMN induced by SLE and Felty's sera may, at least in part, contribute to the neutropenia which is common in these diseases. Increased O2- release associated with PMN adherence may contribute to endothelial cell damage and vascular injury, which is also a common manifestation of these diseases.

NAD+-dependent 15-hydroxyprostaglandin dehydrogenase activity in kidney tissue from NZB/NZW F1 hybrid mice.

Prostaglandins, or related compounds, as well as estrogen and androgen are believed to be involved in the processes that lead to the development of murine lupus erythematosus (LE) in NZB/NZW F1 hybrid mice. In this investigation we measured NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) activity in kidney tissue of male and female NZB/NZW F1 hybrid mice and in kidney tissue of male and female mice of other strains. In each case the specific activity of PGDH was significantly greater in kidney tissue of male than in kidney tissue of female mice. However, the specific activities of PGDH in kidney tissues of males of various strains of mice were similar, and the specific activities of PGDH in kidney tissues of females of various strains-including the NZB/NZW F1 hybrid- were similar. Thus, while the lower activity of PGDH in kidney tissues of the female may be important in the pathogenesis of LE, the lower activity of this enzyme is not unique to the kidney of the female NZB/NZW F1 hybrid mouse.

Beneficial effect of an essential fatty acid deficient diet in NZB/NZW F1 mice.

New Zealand Black by White (B/W) hybrid mice spontaneously develop a disease similar to systemic lupus erythematosus (SLE). Subepidermal immunoglobulin deposits (Se-Ig) and antibodies to double-stranded DNA (anti-dsDNA) develop in aging mice. Death from glomerulonephritis occurs at 8 to 12 mo. Previous findings suggest that epidermal DNA:anti-dsDNA complexes form in situ since Se-Ig correlates with anti-ds DNA and Se-Ig accumulation is augmented by increased epidermal proliferation (presumably due to enhanced epidermal DNA release). Since essential fatty acid (EFA) deficiency is known to increase epidermal proliferation we have studied the effect of an essential fatty acid deficient EFA-d diet on: (1) Se-Ig, anti-dsDNA, and (3) survival. Ten-mo B/W mice on an EFA-d diet were compared with 14 controls on a calorically equivalent standard diet. Both groups were initiated on their diets at 2 mo of age. Only female mice were used. All were weighed weekly; tested for anti-ds DNA (Crithidia luciliae assay) each month; and biopsied for direct immunofluorescence (IF) staining of skin at 6, 7.5, 9, 10.5, and 12 mo. Tissue (skin and kidney) was also obtained for light and IF microscopy. Weights in the 2 study groups were essentially identical. All disease manifestations examined were strikingly altered in the EFA-d animals. Only 2 of 14 (14%) control animals survived to 9 mo and both had anti-dsDNA and Se-Ig. In contrast, 8 of 10 (80%) EFA-d mice were alive at 9 mo and none had anti-dsDNA or Se-Ig. The kidneys from EFA-d mice at 10 mo were normal; however, all kidneys from 7 to 9 mo control mice were abnormal by both light and IF microscopy. Eight of the 10 EFA-d mice were alive at 10 mo. None had Se-Ig but one had anti-dsDNA. At 16 mo (4 mo after controls had died) 7 of 10 EFA-d mice were living and 60% were anti-ds DNA positive. These findings strongly suggest that (1) SE-Ig is present in mice with anti-dsDNA and severe renal disease and (2) EFA-d produces a profoundly beneficial effect in the disease process.

Human neutrophil swelling induced by immune complexes and aggregated IgG.

Using a Coulter counter method, the effects of various types of IgG-dependent phagocytic stimuli on human neutrophil (PMN) swelling were determined. Human heat aggregated IgG, ovalbumin-antiovalbumin (OV-anti-OV) immune complexes, and opsonized latex particles all induced PMN swelling. The OV-anti-OV immune complexes were effective, whether prepared at antigen-antibody equivalence (insoluble) or at 4 or 9 times antigen excess (soluble). Swelling of PMN occurred at 37 degrees C, but not at 4 degrees C. Complement was not present in any of the experiments. In contrast to the above results, native IgG, OV-anti-OV F(ab')2 immune complexes and unopsonized latex particles did not induce PMN swelling. These results suggest that the PMN swelling observed in this study is due to Fc-dependent, complement-independent membrane stimulation and/or phagocytosis.