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.

Studies on the anti-inflammatory action of 6-mercaptopurine.

The mechanism of action of 6-mercaptopurine (6-MP) on an egg albumin-induced inflammatory lesion in the skin has been studied in rabbits treated with 6-MP in a daily dosage of 18 mg/kg. Relative to control animals, significant decreases in the numbers of large lymphocytes and monocytes in the blood were observed in the 6-MP-treated animals by the 9th day of treatment, without significant decrease in the numbers of polymorphonuclear leukocytes and small and medium lymphocytes. Concurrently, a significant decrease was also seen in the percentage of tissue mononuclear cells in the inflammatory skin lesion. There was a highly significant correlation between the numbers of monocytes in the blood and the per cent of mononuclear cells in the lesion. A mean of 52% of the mononuclear cells in the tissue lesion phagocytosed carbon offering further evidence that the major cell involved was the blood monocyte. In vitro incorporation of (3)H-Tdr by blood mononuclear cells was significantly reduced in the 6-MP-treated animals as determined by scintillation counting and radioautography. The large lymphocyte was the predominant cell type which was labeled in vitro. Small lymphocytes and monocytes were rarely labeled. The data obtained suggest that the anti-inflammatory effect of 6-MP, reflected in these experiments by a decrease in mononuclear cells in a tissue lesion, results from suppression of a bone marrow response to local inflammation, affecting principally proliferating precursors of blood monocytes and large lymphocytes. The possible importance of this action of 6-MP in the treatment of inflammatory and immunologically mediated disease is discussed.

Immunohistologic studies of synoviocytes and synovial exudate cells.

Inclusions were demonstrated in normal polymorphonuclear cells incubated with rheumatoid factor-positive synovial fluid. These stained positively for IgG, IgM, and the beta(1)C component of complement. When normal polymorphonuclear cells were incubated with factor-negative rheumatoid fluid, inclusions were not obtained. However, after addition of IgM rheumatoid factor to such fluids, discrete inclusions were observed with similar staining properties. In a minority of nonrheumatoid fluids, inclusions were also obtained after addition of IgM rheumatoid factor. The phagocytosis of inclusions from synovial fluids after addition of IgM rheumatoid factor suggests the presence of aggregated IgG in these fluids. Immunofluorescent staining of phagocytic synovial lining cells, isolated from synovial tissue by trypsin digestion, demonstrated a diffuse staining pattern for IgG and the beta(1)C component of complement in cells from both seropositive and seronegative patients. In seropositive patients, discrete inclusions were also observed which stained positively for IgG, IgM, and beta(1)C. These findings provide evidence of in vivo phagocytosis of immune complexes from the synovial fluid.

The pathogenesis of chronic inflammation in experimental antigen-induced arthritis. II. Preferential localization of antigen-antibody complexes to collagenous tissues.

In an experimental arthritis induced by injection of bovine serum albumin or egg albumin into the joints of previously immunized animals, it has been demonstrated that the major portion of the radioactively labeled antigens injected was localized to avascular collagenous tissues in the joint, i.e., articular cartilage, menisci, and intra-articular ligaments. The antigens were partially eluted from the tissues with 5 M guanidine solution, but not with acid buffers or by 3 M magnesium chloride. The radioactive material eluted with guanidine was at least 80% precipitable by specific antisera. The radioactively labeled-inducing antigen was identified on the surface of articular collagenous tissues from arthritic joints by radioautography and immunofluorescence. Rabbit immunoglobulin and C3 were demonstrated in the same sites by immunofluorescence. The presence of specific antibody in collagenous tissues was demonstrated by the selective in vitro binding of (125)I-labeled-inducing antigen to menisci from arthritic joints of immunized animals. The evidence obtained indicates that in this model of chronic arthritis, the inducing antigen persists for long periods of time in the form of immune complexes in the surface layers of the intra-articular collagenous tissue. The antigen retained in this form may be responsible for the chronicity of the synovitis by serving as a direct stimulus for the maintenance of prolonged antibody synthesis in the synovium and by providing a source of complement-fixing antigen-antibody complexes for the mediation of joint inflammation.

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.

Immunoglobulin in clinically uninvolved skin in systemic lupus erythematosus: association with renal disease.

23 of 42, or 55%, of patients with systemic lupus erythematous had immunoglobulin deposits along the epidermal basement membrane of uninvolved skin (positive lupus band test [LBT]). In patients with low serum complement levels, 91% had a positive LBT), as compared with 15% in those with normal complement levels. The LBT was positive in 70% of patients with clinical and laboratory evidence of renal disease, but in only 31% of patients without renal disease. 81% of patients with the more severe histologic forms of lupus nephritis, i.e., proliferative glomerulonephritis and membranous glomerulonephritis, and positive tests, whereas only 23% with mesangial glomerulitis or normal histologic findings were positive. Immunoglobulins of the same class found in the skin were detected in the glomeruli of patients examined by renal biopsy. These results suggest that there is a relationship between the occurrence of immunoglobulin in the epidermal basement membrane and the presence of the more severe forms of lupus nephritis.

Prevention of glomerulonephritis and prolonged survival in New Zealand Black/New Zealand White F1 hybrid mice fed an essential fatty acid-deficient diet.

Female B/W mice spontaneously develop an autoimmune disease that is similar to systemic lupus erythematosus. Antibodies to doublestranded DNA (dsDNA) and antinuclear antibodies develop in aging animals; death from immune complex-mediated glomerulonephritis occurs from 8 to 12 mo of age. It has been reported that prostaglandin (PG)E(1) treatment of such mice prolongs survival. In the present study, four groups of female B/W mice were studied beginning at 6-11 wk of age on the following regimens: (a) a synthetic diet that contained 20% safflower oil, (b) a standard laboratory chow diet, (c) a standard diet together with injections of PGE(1), and (d) an essential fatty acid-deficient synthetic diet that contained 20% coconut oil. All animals were tested monthly for antinuclear antibodies and anti-dsDNA. Kidney tissue was obtained for light and immunofluorescence microscopy when animals were dying. All disease manifestations were altered strikingly in the essential fatty acid (EFA)-deficient animals. Intermediate benefit was seen in PGE(1)-treated animals. 7% of the control animals and 18% of safflower oil-fed animals survived to 10 mo. In contrast, the PGE(1)-treated and EFA-deficient mice had a similar survival rate (78-88%). At age 16 mo, 78% of EFA-deficient mice and 45% of PGE(1)-treated mice were alive. 25% of the PGE(1)-treated and 55% of the EFA-deficient animals survived to 20 mo. Serum anti-dsDNA appeared at age 5 mo in safflower oil-fed and control animals, but not until 9 and 12 mo for PGE(1)-treated and EFA-deficient animals, respectively. All kidneys from 7- to 9-mo-old safflower oil-fed and control animals and the majority of kidneys from PGE(1)-treated animals were abnormal by light and immunofluorescence microscopy. Kidneys from EFA-deficient animals were essentially normal at 10 mo. At 13 mo, all PGE(1)-treated animals examined had significant kidney involvement, whereas none of the EFA-deficient animals had glomerulonephritis. These findings demonstrate that an EFA-deficient diet has a beneficial effect on murine lupus erythematosus.

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.

Increased granulocyte adherence in psoriasis and psoriatic arthritis.

Circulating polymorphonuclear leukocytes (PMN) from patients with psoriasis and psoriatic arthritis were found to be significantly more adherent to nylon fiber columns when compared with both normal and nonpsoriatic patient control groups. The increased adherence correlated positively with the extent of disease and was highest in those patients with psoriatic arthritis. Total leukocyte and PMN counts were increased in psoriasis patients and were highest in the psoriatic arthritis group. No increase in cell counts was found for mononuclear leukocytes. PMN adherence was not increased in lithium-treated patients or a nonpsoriatic patient control group although such patients did have significant granulocytosis. PMN's are frequently present in lesions of psoriasis as are activated complement components and abnormal keratinocyte cyclic nucleotide levels. These factors or others may cause a generalized activation of PMN's in psoriasis leading to migration of neutrophils into the skin lesion. The present study demonstrates a systemic effector cell alteration in psoriasis and contradicts the general concept that uncomplicated psoriasis is limited to the skin.

Increased superoxide generation by normal granulocytes incubated in sera from patients with psoriasis.

Sera from patients with untreated psoriasis were found to induce increased superoxide anion (O-2) generation when incubated with normal granulocytes (PMNs) and zymosan. Sera from patients receiving systemic chemotherapy induced O-2 generation which was similar to that of normal sera and significantly lower than sera from the untreated patients. O-2 production was measured by superoxide dismutase inhibitable ferricytochrome C reduction and was dependent on the presence of both zymosan and a heat labile serum factor. Serum C3c and C5 levels were elevated in both treated and untreated groups of psoriasis patients while C4 was elevated only in untreated patients. serum ceruloplasmin, a O-2 scavenger, was not decreased in patients with psoriasis, and consequently does not account for the increased O-2 generation. These data suggest that sera from patients with psoriasis have an increased capacity to activate PMNs. Activation of PMNs in cutaneous and joint lesions may play a pathogenic role in psoriasis.

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.

Neurological complications of connective tissue and other "collagen-vascular" diseases.

A variety of neurological complications may occur in the various connective tissue and "collagen-vascular" diseases. Most of these complications are due to vasculitis affecting various sites in the central or peripheral nervous system. While the evidence for definitive vasculitis in SLE is not strong, small vessel damage usually is present in anatomic sites which correlate well with clinical features. Although patients with rheumatoid arthritis also may have vasculitis, neurological complications are usually related to nerve compression by rheumatoid nodules or the arthritic process itself. Considerable controversy exists regarding the accuracy of various diagnostic tests. While corticosteroids are the mainstay of therapy for these conditions, there are no definitive studies proving their efficacy.

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.

Effect of cyclophosphamide on interstitial nephritis and tubule cell proliferation in NZB/NZE mice.

The effect of cyclophosphamide on renal interstitial mononuclear cell infiltration and renal tubule cell (TC) proliferation has been examined in (NZB x NZW)F1 hybrid (B/W) and control mice. TC proliferation was measured by tritiated thymidine (3/Tdr) injection, autoradiographic examination of kidney sections, and enumeration of labeled tubular cells. Cyclophosphamide administered 2 months before sacrifice virtually obliterated interstitial infiltration and significantly decreased tubule cell proliferation at 3, 5, 7, 9, and 12 months of age.

Presence of leucocyte inclusions in spleen and bone marrow of patients with Felty's syndrome.

The spleens from two patients with Felty's syndrome and the bone marrow from one patient with Felty's syndrome were examined for the presence of intracytoplasmic inclusions in neutrophils when stained with antibodies to IgG, IgM, IgA, and betalc. Four normal spleens from trauma patients were similarly examined. In both spleens and the bone marrow from the Felty patients, large inclusions were noted. In none of the four normal spleens were large inclusions present. These studies suggest that phagocytosis of immune complexes by neutrophils in Felty patients may induce sequestration of these cells in the spleen and bone marrow.