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.

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.

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.

Acute lung injury following treatment with high-dose cyclophosphamide, cisplatin, and carmustine: pharmacodynamic evaluation of carmustine.

BACKGROUND: Therapy with high-dose cyclophosphamide, cisplatin, and carmustine (BCNU) plus autologous bone marrow transplantation has been extensively studied as treatment for patients with stage II or III breast cancer who have a 70% or greater risk of developing metastatic disease. This therapy is being used in a cooperative intergroup phase III clinical trial. In the cyclophosphamide-cisplatin-BCNU regimen, cyclophosphamide and BCNU, but not cisplatin, have been reported to cause acute lung injury, suggesting that either cyclophosphamide or BCNU may contribute to this injury. PURPOSE: The purpose of this study was to analyze clinical and pharmacokinetic data from our ongoing phase II trials and to determine whether there is an association between BCNU pharmacokinetics and acute lung injury following cyclophosphamide-cisplatin-BCNU therapy. METHODS: We performed a retrospective study of 38 patients treated following induction therapy or relapse, 29 with stage II-IV breast cancer and nine with intermediate and high-grade stage III-IV non-Hodgkin's lymphoma. These patients received therapy with cyclophosphamide at a dose of 1875 mg/m2 daily as a 1-hour intravenous infusion for 3 days, cisplatin at 55 mg/m2 per day as a 72-hour continuous intravenous infusion, and BCNU at 600 mg/m2 as a 2-hour infusion immediately following completion of the cisplatin infusion. Data from analysis of blood samples were used to calculate pharmacokinetic parameters for BCNU, and acute lung injury was determined on the basis of pulmonary function test results and histologic examination of lung biopsy specimens. RESULTS: Our analysis showed that 20 (53%) of the 38 patients developed pulmonary injury following treatment. Twelve (60%) of the 20 had values for area under the curve (AUC) for BCNU concentration x time that exceeded 600 (micrograms/mL) x minute, whereas only two (11%) of the 18 without pulmonary injury had values above this level (P < .03). Thus, 12 (86%) of 14 patients with BCNU AUC greater than 600 (micrograms/mL) x minute developed lung injury. CONCLUSIONS: These results suggest that BCNU exposure greater than 600 (micrograms/mL) x minute is associated with increased risk of acute lung injury after cyclophosphamide-cisplatin-BCNU therapy and may be a major cause of pulmonary drug injury following this regimen. IMPLICATIONS: Strategies aimed at more uniform drug exposure or selective neutralization of chlorethylisocyanate, one of the two major hydrolysis products of BCNU, might reduce the incidence of acute lung injury following this regimen without major compromise of antitumor effect.

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.

cDNA and deduced amino acid sequence for the rat hydrophobic pulmonary surfactant-associated protein, SP-B.

Pulmonary surfactant prevents collapse of lung alveoli by lowering surface tension at the air/liquid interface. The hydrophobic surfactant associated proteins SP-B and SP-C have been shown to be important in surfactant function and metabolism. A cDNA clone for rat SP-B was isolated and sequenced. Northern analysis showed mRNA for SP-B was present in whole lung and was greatly enriched in alveolar type II cells, but was not present in brain, kidney, spleen or liver. A full length transcript of the rat SP-B cDNA clone consists of 1536 bases and encodes an open reading frame of 376 amino acids. The predicted molecular mass of the primary translation product is 42 kDa and the predicted molecular mass of the mature protein is 8 kDa. Extensive homology exists between the rat sequence for SP-B and those reported for human and canine SP-B. The position of 25 cysteine residues has been extremely well preserved across all three species. An N-linked glycosylation site in the COOH region has been conserved across all three species. A search of the NIH database revealed homology between rat SP-B and the active site for the mouse contrapsin serum proteinase inhibitor.

Nucleotide and deduced amino acid sequence of the hydrophobic surfactant protein SP-C from rat: expression in alveolar type II cells and homology with SP-C from other species.

Pulmonary surfactant lowers surface tension in the lung. Its deficiency leads to the severe physiologic abnormalities seen in the respiratory distress syndrome. The hydrophobic surfactant proteins, SP-B and SP-C, appear to be especially important in the surface-spreading characteristics of pulmonary surfactant. We report the nucleotide sequence of cDNA clones for rat SP-C and compare the deduced amino acid sequence for SP-C from several species. A highly conserved domain exists within the confines of mature human SP-C. An Eisenberg plot of this region predicts a membrane-associated helix. We also demonstrate by Northern analysis the tissue-specific expression of SP-C. A comparison of signal strength between total lung RNA and RNA derived from isolated type II cells supports the idea that most SP-C messenger RNA in total lung can be accounted for by that present in alveolar type II cells.

Rat pulmonary surfactant protein A is expressed as two differently sized mRNA species which arise from differential polyadenylation of one transcript.

In rat, the surfactant-associated glycoprotein A, SP-A, is encoded by two mRNA species of 0.9 and 1.6 kb. Each transcript is polyadenylated and is found in approximately the same ratio in total cellular RNA isolated from either alveolar type II cells or from whole lung. The two mRNA species have identical coding regions and differ only in the length of the 3' untranslated sequences. Restriction analysis and partial sequence analysis of rat genomic clones indicate that each mRNA species arises from one gene, with the difference in size most easily accounted for by differential polyadenylation. During fetal development, the accumulation of mRNA encoding SP-A is detectable by day 18 but increases many-fold on day 19. However, there are no apparent alterations in the prevalence of either mRNA species during fetal development or in the early postnatal period.

Expression and characterization of rat surfactant protein A synthesized in Chinese hamster ovary cells.

Rat surfactant protein A (SP-A) was expressed in a Chinese hamster ovary (CHO-K1) cell line and characterized for biologic activity using assays for receptor binding and modulation of phospholipid secretion from isolated type II cells. The CHO-K1 cell line was cotransfected with separate plasmids encoding for the rat SP-A, dihydrofolate reductase and neomycin phosphotransferase, respectively. Antibiotic (Geneticin-G418)-resistant transformants were screened by ELISA for the secretion of recombinant SP-A into the media. Northern analysis of the transfected cell lines demonstrated the expression of both 1.6 kb and 0.9 kb mRNA species for SP-A, consistent with the proposed differential polyadenylation of the primary transcript. Amplification with methotrexate resulted in a dose-dependent increase in mRNA for SP-A and a 20-fold increase in the production of recombinant SP-A relative to untreated cells. Maximum production of SP-A was 370 micrograms of SP-A/l of media in a 4-day incubation. Recombinant SP-A was purified from the serum-free media of large scale cultures of transfected, amplified CHO cells by affinity chromatography on mannose-Sepharose. The recombinant SP-A migrated similarly to native SP-A by NaDodSO4-PAGE analysis under reducing and nonreducing conditions and under reducing conditions after digestion with N-glycanase. Recombinant SP-A effectively competed with 125I-native SP-A for binding to the high affinity receptor for SP-A on isolated plasma membranes from rat alveolar type II cells. The recombinant SP-A was as effective as native SP-A in the inhibition of secretion of phospholipid from isolated type II cells. We conclude that recombinant rat SP-A produced in Chinese hamster ovary cells is physically and functionally similar to native rat SP-A.

Fulminant respiratory failure and death in a patient with idiopathic bronchiolitis obliterans.

A middle-aged man with fulminant respiratory failure was found to have idiopathic bronchiolitis obliterans with organizing pneumonia on lung biopsy specimen. His course was atypical in that it was not altered by steroid therapy and led to fulminant respiratory failure and death.

The endoscopic diagnosis of an aortoduodenal fistula.

An aortoduodenal fistula is a serious complication of aortic reconstructive surgery. This artile describes a case in which the diagnosis of an aortoduodenal fistula was made by upper gastrointestinal endoscopy. The endoscopic finding of a vascular prosthesis within the duodenum allowed immediate surgical intervention and control of the gastrointestinal hemorrhage.

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.

Use of cytomegalovirus (CMV) hyperimmune globulin for prevention of CMV disease in CMV-seropositive lung transplant recipients.

Our data suggest that CMVIG in combination with ganciclovir effectively reduces the incidence, and delays the onset of CMV infections in seropositive lung transplant recipients. In addition, its use may be associated with less severe CMV infection and a lower incidence of bacterial or fungal opportunistic infection. Although the number of patients in the study is small, high-titer CMVIG may be more effective than standard titer immunoglobulin in the prevention of CMV disease in lung transplant recipients. Several questions remain in addition to these: What is the optimal dosage and duration of treatment with CMVIG for prophylaxis of CMV infection and disease in lung transplant recipients; Is this strategy cost-effective; Will it reduce the incidence of obliterative bronchiolitis following lung transplantation and enhance allograft survival? A prospective, random-assignment trial is warranted to answer these questions.

Esophageal adenocarcinoma 20 years after esophageal atresia repair.

We report a case of esophageal adenocarcinoma 20 years after esophageal atresia repair. From one case report it is premature to recommend cancer surveillance for all esophageal atresia patients. However, the first survivors are now reaching an age when esophageal cancer related to chronic esophagitis may become more prevalent.

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.

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.