A compact filtered x-ray diode array spectrometer for the National Ignition Facility: SENTINEL.

Sentinel is a 16-channel, filtered x-ray diode array spectrometer that has been developed to measure ∼1 keV-20 keV x-ray emission generated by the National Ignition Facility (NIF) laser. Unlike the large, fixed-port versions of this diagnostic that currently exist on the NIF (known as Dante), Sentinel is a Diagnostic Instrument Manipulator compatible such that it can be fielded along the polar or equatorial lines-of-sight-an essential new capability for characterizing the often anisotropic x-ray emission from laser-driven sources. We present the diagnostic design along with preliminary diode calibrations and performance results. The novel, small-form-factor x-ray diode design allows for ≳5×-25× increased channel areal density over that of Dante, simultaneously enabling improved diagnostic robustness and fidelity of spectral reconstructions. While the Sentinel diagnostic is anticipated to improve line-of-sight spectral characterization of x-ray sources for a wide variety of programs on the NIF, the compact and portable design is also attractive to small- and mid-scale facilities with limited diagnostic real estate.

Baseline characteristics and comorbidities in the CAnadian REgistry for Pulmonary Fibrosis.

BACKGROUND: The CAnadian REgistry for Pulmonary Fibrosis (CARE-PF) is a multi-center, prospective registry designed to study the natural history of fibrotic interstitial lung disease (ILD) in adults. The aim of this cross-sectional sub-study was to describe the baseline characteristics, risk factors, and comorbidities of patients enrolled in CARE-PF to date. METHODS: Patients completed study questionnaires and clinical measurements at enrollment and each follow-up visit. Environmental exposures were assessed by patient self-report and comorbidities by the Charlson Comorbidity Index (CCI). Baseline characteristics, exposures, and comorbidities were described for the overall study population and for incident cases, and were compared across ILD subtypes. RESULTS: The full cohort included 1285 patients with ILD (961 incident cases (74.8%)). Diagnoses included connective tissue disease-associated ILD (33.3%), idiopathic pulmonary fibrosis (IPF) (24.7%), unclassifiable ILD (22.3%), chronic hypersensitivity pneumonitis (HP) (7.5%), sarcoidosis (3.2%), non-IPF idiopathic interstitial pneumonias (3.0%, including idiopathic nonspecific interstitial pneumonia (NSIP) in 0.9%), and other ILDs (6.0%). Patient-reported exposures were most frequent amongst chronic HP, but common across all ILD subtypes. The CCI was ≤2 in 81% of patients, with a narrow distribution and range of values. CONCLUSIONS: CTD-ILD, IPF, and unclassifiable ILD made up 80% of ILD diagnoses at ILD referral centers in Canada, while idiopathic NSIP was rare when adhering to recommended diagnostic criteria. CCI had a very narrow distribution across our cohort suggesting it may be a poor discriminator in assessing the impact of comorbidities on patients with ILD.

X-ray transport and radiation response assessment (XTRRA) experiments at the National Ignition Facility.

Our team has developed an experimental platform to evaluate the x-ray-generated stress and impulse in materials. Experimental activities include x-ray source development, design of the sample mounting hardware and sensors interfaced to the National Ignition Facility's diagnostics insertion system, and system integration into the facility. This paper focuses on the X-ray Transport and Radiation Response Assessment (XTRRA) test cassettes built for these experiments. The test cassette is designed to position six samples at three predetermined distances from the source, each known to within ±1% accuracy. Built-in calorimeters give in situ measurements of the x-ray environment along the sample lines of sight. The measured accuracy of sample responses as well as planned modifications to the XTRRA cassette is discussed.

Recording EEG in immature rats with a novel miniature telemetry system.

Serial EEG recordings from immature rat pups are extremely difficult to obtain but important for analyzing animal models of neonatal seizures and other pediatric neurological conditions as well as normal physiology. In this report, we describe the features and applications of a novel miniature telemetry system designed to record EEG in rat pups as young as postnatal day 6 (P6). First, we have recorded electrographic seizure activity in two animal models of neonatal seizures, hypoxia- and kainate-induced seizures at P7. Second, we describe a viable approach for long-term continuous EEG monitoring of naturally reared rat pups implanted with EEG at P6. Third, we have used serial EEG recordings to record age-dependent changes in the background EEG signal as the animals matured from P7 to P11. The important advantages of using miniature wireless EEG technology are: 1) minimally invasive surgical implantation; 2) a device form-factor that is compatible with housing of rat pups with the dam and littermates; 3) serial recordings of EEG activity; and 4) low power consumption of the unit, theoretically allowing continuous monitoring for up to 2 yr without surgical reimplantation. The miniature EEG telemetry system provides a technical advance that allows researchers to record continuous and serial EEG recordings in neonatal rodent models of human neurological disorders, study the progression of the disease, and then assess possible therapies using quantitative EEG as an outcome measure. This new technical approach should improve animal models of human conditions that rely on EEG monitoring for diagnosis and therapy.

The x-ray source application test cassette for radiation exposures at the OMEGA laser.

We have designed a sample cassette that can be used to position up to six samples in the OMEGA laser chamber. The cassette accommodates round samples up to 38.1 mm (1.5(")) in diameter and square samples up to 27 mm on a side, any of which can be up to 12.7 mm thick. Smaller specimens are centered with spacers. The test cassette allows each sample to have a unique filter scheme, with multiple filter regions in front of each sample. This paper will present mechanical design considerations and operational aspects of the x-ray source application cassette.

Radiochromic film measurement of spatial uniformity for a laser generated x-ray environment.

An existing x-ray source application (XRSA) test cassette was modified to hold multiple x-ray filter materials followed by two radiochromic film types (FWT-60 and HD-810 Gafchromic® film) to qualitatively characterize the spectral-spatial uniformity over the XRSA sample field of view. Multiple sets of film were examined and nominal set was determined. These initial, qualitative measurements suggest a low-energy regime (E < 3 keV) spatial anisotropy and spatial isotropy at higher energies (E > 3 keV).

A test cassette for x-ray-exposure experiments at the National Ignition Facility.

We present the design and operation of a test cassette for exposure of samples to radiation environments at the National Ignition Facility. The cassette provides options for square and round samples and exposure areas; the cassette provides for multiple levels of filtration on a single sample, which allows dynamic range in experiments. The samples had normal lines of sight to the x-ray source in order to have uniform x-ray illumination. The incident x-radiation onto the samples was determined by the choice of filter thicknesses and materials. The samples were held at precise locations, accurate to within a few hundred microns, in the target chamber in order to have a known fluence incident. In the cassette, the samples were held in place in such a way that a minimal "line contact" allows them to have the maximal mechanical response to the x-ray load. We present postshot images of the debris found on films used for filters, and pre- and postexposure specimens.

The effectiveness and toxicity of cyclosporin A in rheumatoid arthritis: longitudinal analysis of a population-based registry.

OBJECTIVE: To determine factors associated with response or toxicity to cyclosporin A (CSA) in a population-based inception cohort with rheumatoid arthritis (RA). METHODS: Prospectively collected longitudinal measures including tender joint count (JC), duration of morning stiffness (MS), systolic and diastolic blood pressure (SBP, DBP), and serum creatinine (SCr) were modeled using generalized estimating equations. Survival methods were used to estimate CSA continuation time and its determinants. RESULTS: Of 133 patients (75% female, median RA duration 13 years), 37 discontinued CSA because of ineffectiveness (19) or because of toxicity (18) including increased SCr in 10, hypertension in 4, infections in 3, and gingival hyperplasia in 1. Patients remained on CSA a median of 75 months (95% confidence interval [CI] 38-112). Those receiving concomitant methotrexate (MTX) were more than 4 times as likely to continue on CSA therapy (hazard ratio 0.22, 95% CI 0.10-0.94). A lower final JC was predicted by a longer CSA treatment duration (relative risk [RR] 0.99 per month, 95% CI 0.98-0.99) and concomitant MTX therapy (RR 0.79, 95% CI 0.63-0.99); decreased MS was predicted only by longer CSA treatment duration (reduction of 2.0 minutes per month, 95% CI 1.1-3.0). Each previous disease-modifying antirheumatic drug (DMARD) exposure predicted a rise in SCr (35 micromole/liter, 95% CI 22-48), SBP (7.2 mm Hg, 95% CI 2.7-11.7), and DBP (3.8 mm Hg, 95% CI 3.0-6.4). CONCLUSIONS: Combination CSA/MTX prolongs therapy and reduces JC. Long-term CSA treatment was fairly well tolerated. Previous DMARD use appears to be a determinant for the development of toxicity.

Expression and localization of a novel Rab small G protein (Rab38) in the rat lung.

The Rab small G protein family participates in intracellular vesicle transport, including exocytosis and endocytosis. The cDNA encoding a novel Rab-related small G protein (Rab38) has been cloned from rat lung cDNA library and recorded in GenBank (accession no. M94043). However, the expression and localization of the protein in the lung remains primarily unknown. We produced polyhistidine-tagged recombinant Rab38 and a polyclonal antibody with a synthetic peptide. Immunohistochemistry demonstrated that the protein is specifically localized in alveolar type II cells and in bronchial epithelial cells. In situ hybridization using a digoxygenin-labeled RNA riboprobe clearly showed that the mRNA of the protein is localized in alveolar type II cells and bronchial epithelial cells, especially terminal airway epithelial cells. Western blot and reverse transcriptase-polymerase chain reaction showed distinct expression of the protein and mRNA in isolated alveolar type II cells, but not in alveolar macrophages. The native protein was predominantly hydrophobic and was enriched in a high-density vesicle fraction but was barely detectable in nuclear and lamellar body fractions in alveolar type II cells. Immunofluorescence cytochemistry performed on cultured alveolar type II cells showed that Rab38 distributed extensively in the cytoplasm with a distribution pattern similar to endoplasmic reticulum rather than other subcellular organelles. These results suggest that this novel rab small G protein (Rab38) mediates vesicular transport in terminal airway epithelium.

Distinct effects of surfactant protein A or D deficiency during bacterial infection on the lung.

Mice lacking surfactant protein (SP)-A (SP-A-/-) or SP-D (SP-D-/-) and wild-type mice were infected with group B streptococcus or Haemophilus influenzae by intratracheal instillation. Although decreased killing of group B streptococcus and H. influenzae was observed in SP-A-/- mice but not in SP-D-/- mice, deficiency of either SP-A or SP-D was associated with increased inflammation and inflammatory cell recruitment in the lung after infection. Deficient uptake of bacteria by alveolar macrophages was observed in both SP-A- and SP-D-deficient mice. Isolated alveolar macrophages from SP-A-/- mice generated significantly less, whereas those from SP-D-/- mice generated significantly greater superoxide and hydrogen peroxide compared with wild-type alveolar macrophages. In SP-D-/- mice, bacterial killing was associated with increased lung inflammation, increased oxidant production, and decreased macrophage phagocytosis. In contrast, in the absence of SP-A, bacterial killing was decreased and associated with increased lung inflammation, decreased oxidant production, and decreased macrophage phagocytosis. Increased oxidant production likely contributes to effective bacterial killing in the lungs of SP-D-/- mice. The collectins, SP-A and SP-D, play distinct roles during bacterial infection of the lung.

Standardization and decomposition of rates: useful analytic techniques for behavior and health studies.

Standardization and decomposition are widely used analytic techniques in population studies for adjusting the impact of compositional factors on rates. This study demonstrates the application of these methods to behavior and health studies. Bootstrapping is used to estimate standard errors of the component effects and to conduct significance tests for them. The authors have developed a Windows-based computer program that is demonstrated in the study for standardization and decomposition analysis by using empirical data on HIV seropositivity rates in two injection-drug-using populations in the northeastern United States.

Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice.

Targeted ablation of the surfactant protein D (SP-D) gene caused chronic inflammation, emphysema, and fibrosis in the lungs of SP-D (-/-) mice. Although lung morphology was unperturbed during the first 2 weeks of life, airspace enlargement was observed by 3 weeks and progressed with advancing age. Inflammation consisted of hypertrophic alveolar macrophages and peribronchiolar-perivascular monocytic infiltrates. These abnormalities were associated with increased activity of the matrix metalloproteinases, MMP2 and MMP9, and immunostaining for MMP9 and MMP12 in alveolar macrophages. Hydrogen peroxide production by isolated alveolar macrophages also was increased significantly (10-fold). SP-D plays a critical role in the suppression of alveolar macrophage activation, which may contribute to the pathogenesis of chronic inflammation and emphysema.

Pulmonary-specific expression of SP-D corrects pulmonary lipid accumulation in SP-D gene-targeted mice.

Targeted disruption of the surfactant protein (SP) D (SP-D) gene caused a marked pulmonary lipoidosis characterized by increased alveolar lung phospholipids, demonstrating a previously unexpected role for SP-D in surfactant homeostasis. In the present study, we tested whether the local production of SP-D in the lung influenced surfactant content in SP-D-deficient [SP-D(-/-)] and SP-D wild-type [SP-D(+/+)] mice. Rat SP-D (rSP-D) was expressed under control of the human SP-C promoter, producing rSP-D, SP-D(+/+) transgenic mice. SP-D content in bronchoalveolar lavage fluid was increased 30- to 50-fold in the rSP-D, SP-D(+/+) mice compared with the SP-D(+/+) parental strain. Lung morphology, phospholipid content, and surfactant protein mRNAs were unaltered by the increased concentration of SP-D. Likewise, the production of endogenous mouse SP-D mRNA was not perturbed by the SP-D transgene. rSP-D, SP-D(+/+) mice were bred to SP-D(-/-) mice to assess whether lung-selective expression of SP-D might correct lipid homeostasis abnormalities in the SP-D(-/-) mice. Selective expression of SP-D in the respiratory epithelium had no adverse effects on lung function, correcting surfactant phospholipid content and decreasing phosphatidylcholine incorporation significantly. SP-D regulates surfactant lipid homeostasis, functioning locally to inhibit surfactant phospholipid incorporation in the lung parenchyma and maintaining alveolar phospholipid content in the alveolus. Marked increases in biologically active tissue and alveolar SP-D do not alter lung morphology, macrophage abundance or structure, or surfactant accumulation.

Activation of the RON receptor tyrosine kinase inhibits inducible nitric oxide synthase (iNOS) expression by murine peritoneal exudate macrophages: phosphatidylinositol-3 kinase is required for RON-mediated inhibition of iNOS expression.

RON (recepteur d'origine nantais) is a receptor tyrosine kinase expressed in murine peritoneal resident macrophages and activated by macrophage-stimulating protein (MSP). The objectives of this investigation were to study the RON expression in exudate macrophages and the mechanisms by which RON inhibits inducible nitric oxide synthase (iNOS) expression induced by LPS and IFN-gamma. We found that mouse peritoneal resident and Con A-elicited macrophages collected on day 3 or day 5 express RON. Acute exudate macrophages collected on day 1 did not express RON. Activation of RON inhibited LPS- and IFN-gamma-induced macrophage nitric oxide production and iNOS mRNA accumulation. Similar inhibition was observed also in Raw264.7 macrophage cell lines transfected with human RON cDNA. In these cells, MSP induced RON phosphorylation concomitant with reduced iNOS mRNA expression and protein synthesis. Further, we show that activated RON inhibited the iNOS gene transcription activity as assessed by chloramphenicol acetyltransferase activity in Raw264.7 cells expressing RON. Wortmannin, a specific inhibitor of phosphatidylinositol-3 (PI-3) kinase, prevented the inhibitory effect of RON on the iNOS gene promoter activity and on the nitric oxide production induced by LPS and IFN-gamma. These effects were confirmed further by introducing a dominant-inhibitory PI-3 kinase p85 subunit in RON-expressing Raw264.7 cells. Taken together, our results suggest that RON is expressed in peritoneal macrophages at later stages of inflammation. Activation of RON by MSP in mature exudate macrophages inhibits LPS- and IFN-gamma-induced iNOS synthesis. PI-3 kinase is an important effector molecule required for RON-mediated inhibition of iNOS expression in macrophages.

Surfactant protein-D regulates surfactant phospholipid homeostasis in vivo.

Surfactant protein D (SP-D) is a 43-kDa member of the collectin family of collagenous lectin domain-containing proteins that is expressed in epithelial cells of the lung. The SP-D gene was targeted by homologous recombination in embryonic stem cells that were used to produce SP-D (+/-) and SP-D (-/-) mice. Both SP-D (-/-) and SP-D (+/-) mice survived normally in the perinatal and postnatal periods. Whereas no abnormalities were observed in SP-D (+/-) mice, alveolar and tissue phosphatidylcholine pool sizes were markedly increased in SP-D (-/-) mice. Increased numbers of large foamy alveolar macrophages and enlarged alveoli were also observed in SP-D (-/-) mice. Phospholipid composition was unaltered in SP-D (-/-) mice, but surfactant morphology was abnormal, consisting of dense phospholipid membranous arrays with decreased tubular myelin. The pulmonary lipoidosis in the SP-D (-/-) mice was not associated with accumulation of surfactant proteins B or C, or their mRNAs, distinguishing the disorder from alveolar proteinosis syndromes. Surfactant protein A mRNA was reduced and, SP-A protein appeared to be reduced in SP-D (-/-) compared with wild type mice. Targeting of the mouse SP-D gene caused accumulation of surfactant lipid and altered phospholipid structures, demonstrating a previously unsuspected role for SP-D in surfactant lipid homeostasis in vivo.

Surfactant proteins A and D increase in response to intratracheal lipopolysaccharide.

Surfactant proteins A (SP-A) and D (SP-D) are "collectins": proteins with collagen-like region and lectin domain that bind carbohydrates in a calcium-dependent manner. Mannose-binding protein, a serum collectin, is an acute-phase protein. We hypothesized that SP-A and SP-D would respond to an acute stress, such as lung inflammation, in the same manner as does mannose-binding protein, with increased messenger ribonucleic acid (mRNA) and protein production. Rats received intratracheal lipopolysaccharide (LPS; 0.5 mg/kg) or vehicle and were killed 1, 6, 24, and 72 h later. Their lungs were lavaged and the lung tissue homogenized and analyzed for SP-A, SP-D, and phospholipids. Tissue levels of SP-A were increased by 6 h, peaked at 24 h, and were still elevated at 72 h in LPS-treated animals as compared with those given vehicle. SP-A and SP-D levels in lavage fluid were significantly elevated at 72 h. Message levels for SP-A and SP-D, but not SP-B, were significantly increased at 24 h. Lavage phospholipid levels first increased, then decreased in both the control and LPS-treated animals, and significantly less phospholipid was recovered in the lavage fluid of the LPS-treated animals than in that of controls at 72 h. Although other mechanisms, including altered surfactant metabolism, may be involved, these data are consistent with our hypothesis that SP-A and SP-D are upregulated by an acute inflammatory stress in a manner analogous to that of the structurally and functionally related serum acute-phase reactant, mannose-binding protein. We speculate that this upregulation may be a protective response for the lungs.

Enhancing substance abuse treatment with case management. Its impact on employment.

This article examines the effectiveness of strengths-based case management in assisting persons with substance abuse problems improve employment-related functioning. In a study of 632 veterans seeking treatment for substance abuse problems, Wright State University's Enhanced Treatment Project found that veterans in substance abuse treatment had improved in several areas of employment functioning, including number of days employed. Among clients who expressed interest in receiving assistance with employment-related issues, those who received strengths-based case management demonstrated additional improvement in employment functioning including more days employed, fewer employment problems and being less troubled about their employment situation. Correlations between improved employment functioning and improved functioning in other life areas further support the value of case management. The implications of these findings for the inclusion of case management services in substance abuse treatment programs will be discussed.

Presenting problems of substance abusers in treatment: implications for service delivery and attrition.

This study used the Addiction Severity Index (ASI) to identify the various problems substance abuse clients present when seeking treatment at a Department of Veterans Affairs Medical Center. The sample was 98% male and 73% African-American, with a mean age of 37 years. Cluster analysis was used to identify commonalities and divergences in self-reported employment, legal, family, substance abuse, psychological, and medical problems. Four distinct clusters emerged, each of which could be characterized by a dysfunctional pattern. The utility of this approach in designing treatment regimens, addressing client problems in addition to their substance abuse, increasing client satisfaction with service provided, and decreasing treatment attrition is discussed.

Expression of pulmonary surfactant protein D in rat gastric mucosa.

Gastric mucosa is protected from an acidic lumenal environment by an extracellular layer composed in part of phospholipids that are similar in composition to the phospholipids of lung surfactant. The function and metabolic processing of lung surfactant is regulated, in part, by surfactant specific proteins. We speculated that the gastric extracellular acid barrier might be regulated by such proteins. We demonstrate by RNA blot analysis, RT-PCR, and immunostaining and protein blot the synthesis of surfactant protein D (SP-D) in mucus-secreting cells of the gastric mucosa. SP-D protein and mRNA were not detected in the duodenum and the remainder of the gastrointestinal tract. We speculate that SP-D may participate in the regulation of secretion or assembly of the gastric acid barrier. Alternatively, SP-D may participate in gastric mucosal host defense.

The strengths perspective of case management: a promising inpatient substance abuse treatment enhancement.

The medical model or disease concept approach to substance abuse treatment is practiced in most residential substance abuse treatment programs. Despite wide acceptance, many of the factors inherent in this approach may actually increase patient noncompliance with treatment regimens. These factors are related to the pathology-based nature of substance abuse treatment, an overemphasis on patient denial, and the paternalistic role that treatment staff often take in the treatment of substance abusers. The Strengths Perspective of Case Management/Advocacy has demonstrated usefulness as an adjunct to treatment that remedies these detrimental factors and improves compliance with, and retention in, treatment. The specific activities that lead to this improvement are discussed.