Measuring respiratory symptoms in clinical trials of COPD: reliability and validity of a daily diary.

BACKGROUND: Although respiratory symptoms are characteristic features of COPD, there is no standardised method for quantifying their severity in stable disease. OBJECTIVE: To evaluate the EXACT-Respiratory Symptom (E-RS) measure, a daily diary comprising 11 of the 14 items in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT). METHODS: Qualitative: patient focus group and interviews to address content validity. Quantitative: secondary data analyses to test reliability and validity. RESULTS: Qualitative: n=84; mean (SD) age 65 (10) years, FEV1 1.2(0.4) L; 44% male. Subject descriptions of their respiratory symptoms were consistent with E-RS content and structure. Quantitative: n=188; mean (SD) age 66 (10) years, FEV1 1.2(0.5) L; 50% male. Factor analysis (FA) showed 3 subscales: RS-Breathlessness, RS-Cough & Sputum, and RS-Chest Symptoms; second-order FA supported a general factor and total score. Reliability (total and subscales): 0.88, 0.86, 0.73, 0.81; 2-day test-retest ICC: 0.90, 0.86, 0.87, 0.82, respectively. VALIDITY: Total scores correlated significantly (p < 0.0001) with SGRQ Total (r=0.75), Symptoms (r=0.66), Activity (r=0.57), Impact (r=0.70) scores; subscale correlations were also significant (r=0.26, p < 0.05 (RS-Chest Symptoms with Activity) to r=0.69, p < 0.0001 (RS-Cough & Sputum with Symptoms). RS-Breathlessness correlated with rescue medication use (r=0.32, p < 0.0001), clinician-reported mMRC (r=0.33, p < 0.0001), and FEV1% predicted (r=-0.17, p < 0.05). E-RS scores differentiated groups based on chronic bronchitis diagnosis (p < 0.01-0.001), smoking status (p < 0.05-0.001), and rescue medication use (p < 0.05-0.0001). CONCLUSIONS: Results suggest the RS-Total is a reliable and valid instrument for evaluating respiratory symptom severity in stable COPD. Further study of sensitivity to change is warranted.

A Contingency Plan for Catastrophic Loss of Bioassay Services.

The catastrophic loss of direct or indirect bioassay services can severely impact a site or facility's radiation protection program. While highly unlikely, circumstances such as fire, hurricane, other extreme weather conditions, unanticipated events, or contractual business decisions could result in the loss of either the onsite or offsite measurement capabilities for direct or indirect radiobioassay services. The process and elements that need to be addressed in obtaining alternate or replacement bioassay services can be described in relatively simple terms, but can be very complex and time consuming to implement. The contingency plan developed for one large, complex radiobioassay program is a good example for addressing these items.

Persistent activation of mitogen-activated protein kinases p42 and p44 and ets-2 phosphorylation in response to colony-stimulating factor 1/c-fms signaling.

An antibody that specifically recognized phosphothreonine 72 in ets-2 was used to determine the phosphorylation status of endogenous ets-2 in response to colony-stimulating factor 1 (CSF-1)/c-fms signaling. Phosphorylation of ets-2 was detected in primary macrophages, cells that normally express c-fms, and in fibroblasts engineered to express human c-fms. In the former cells, ets-2 was a CSF-1 immediate-early response gene, and phosphorylated ets-2 was detected after 2 to 4 h, coincident with expression of ets-2 protein. In fibroblasts, ets-2 was constitutively expressed and rapidly became phosphorylated in response to CSF-1. In both cell systems, ets-2 phosphorylation was persistent, with maximal phosphorylation detected 8 to 24 h after CSF-1 stimulation, and was correlated with activation of the CSF-1 target urokinase plasminogen activator (uPA) gene. Kinase assays that used recombinant ets-2 protein as a substrate demonstrated that mitogen-activated protein (MAP) kinases p42 and p44 were constitutively activated in both cell types in response to CSF-1. Immune depletion experiments and the use of the MAP kinase kinase inhibitor PD98059 indicate that these two MAP kinases are the major ets-2 kinases activated in response to CSF-1/c-fms signaling. In the macrophage cell line RAW264, conditional expression of raf kinase induced ets-2 expression and phosphorylation, as well as uPA mRNA expression. Transient assays mapped ets/AP-1 response elements as critical for basal and CSF-1-stimulated uPA reporter gene activity. These results indicate that persistent activation of the raf/MAP kinase pathway by CSF-1 is necessary for both ets-2 expression and posttranslational activation in macrophages.

Activation of the ras-mitogen-activated protein kinase pathway and phosphorylation of ets-2 at position threonine 72 in human ovarian cancer cell lines.

The activation status of the ras pathway was studied in eight ovarian tumor cell lines. Three biochemical parameters indicative of ras activation were tested: (a) the ratio of the ras-GTP:ras-GDP complex; (b) the activity of mitogen-activated protein kinases p42/p44; and (c) ets-2 phosphorylation at position threonine 72, a mitogen-activated protein kinase phosphorylation site in vivo. Four of the ovarian tumor cell lines had an activated ras pathway by these three parameters, whereas only one of these contained a mutated ras gene. In addition, ras/ets-2 responsive genes such as the urokinase plasminogen activator (uPA) were activated in these four cell lines. Transient transfection assays indicated that the compound ets-AP1 oncogene responsive enhancer present in the uPA gene was the target of ras signaling in ovarian tumor cells and that the combination of activated ras and ets-2 could superactivate the uPA enhancer element. Coexpression of the dominant-negative ras-Asn17 cDNA gene abrogated activity of this uPA element in ovarian tumor cells. These data indicate that ets-2 is a nuclear target of ras action in ovarian tumor cell lines and that ras signaling pathways may be activated in ovarian cancer by mechanisms independent of direct genetic damage to ras genes.

Quality-of-life questionnaire for patients taking antihypertensive medication.

This study was undertaken to construct a health-related quality-of-life (QOL) questionnaire for hypertensive patients from preexisting instruments and to validate its use in full form and in a shortened version. Two hundred seventy hypertensive patients who were stable while taking antihypertensive medication (control group), changing medication because of side effects, or newly treated for hypertension were enrolled in a prospective, observational, longitudinal study. At baseline and at months 1, 2, and 3, patients completed a questionnaire covering 7 domains of QOL. The criteria for evaluating the scales were internal consistency, test-retest reliability, construct validity, and responsiveness to change. Data were analyzed for the full questionnaire and the shortened version. Internal consistency and test-retest correlation values were 0.69 to 0.95 for scales in the full questionnaire and 0.57 to 0.92 in the shortened version. Construct validity was supported by statistically significant, positive correlations with a global QOL item for all but 1 scale in both versions. Responsiveness to change was supported by increases in scores between baseline and month 3 for all scales in patients changing their medication because of side effects; scores remained unchanged (on all but 1 scale) in the stable (control) group. By uniformly applying standard validation criteria to a set of preexisting instruments, we created a new QOL questionnaire. Results were similar in both the full form and shortened version.

Restraint, dieting, and the continuum model of bulimia nervosa.

The authors evaluated the continuity model of bulimia nervosa, which suggests that bulimia results from extreme weight concern and dieting practices. Individuals with bulimia, current dieters, restrained nondieters, and unrestrained nondieters were compared on measures of general psychopathology, eating-disorder-specific psychopathology, and overeating. Multiple methods, including questionnaires, clinical interviews, and food records, were used to collect data. The continuity and discontinuity models were tested with trend and regression analyses. The results of most analyses were consistent with the continuity perspective. However, binge eating behaviour exhibited a clear nonlinear trend, which occurred because binge eating was common in bulimic individuals but virtually non-existent in the other 3 groups. Current dieters scored higher than restrained nondieters on restraint/ weight concern, but not on psychopathology or binge eating. Overall, the results suggest that "normal" dieting is associated with psychological, but not consummatory, symptoms of bulimia.

Changing roles: the radiologist in management.

RATIONALE AND OBJECTIVES: Radiologists have rarely had direct administrative control of the hospital departments in which they practice. Several years ago, the administration of the medical school at the University of Texas Health Science Center at San Antonio and its county-owned principal teaching hospital agreed to integrate the physician and administrative management of the radiology department in an attempt to improve operations and reduce expenses. This integration is a pilot plan that will eventually be extended to most departments. MATERIALS AND METHODS: The authors have collected data that measure department function for the seven quarters of physician management and compared these data with those of the previous four quarters prior to physician management. RESULTS: There are substantial increases in department activity, together with reductions in expenses and waiting time for procedures. These changes have occurred while overall hospital activity has decreased. Bench-marking studies show favorable comparison with comparable radiology departments. CONCLUSION: Radiologists can have an important effect on department operations when given the responsibility and authority for managing these affairs.

Hmong folk remedies: limited acetylation of opium by aspirin and acetaminophen.

The traditional folk medicine of the Hmong and other Southeast Asian refugees has accompanied them during their immigration in this country over the past two decades. In two recent cases involving Hmong defendants, unknown solids, resembling charcoal in consistency and purported to be "backache remedies," were analyzed and found to be complex mixtures of aspirin, acetaminophen, caffeine and partly acetylated opium. In particular, significant amounts of acetylacetaminophen, 3-O-acetylmorphine, 6-O-acetylcodeine, 6-O-acetylmorphine, and heroin were identified by gas chromatography/mass spectrometry. Heating approximately equal weights of solid opium, aspirin, and acetaminophen at 130 degrees C for several hours produced a mixture of compounds showing a similar acetylation pattern.

Filtration removal of endotoxin (pyrogens) in solution in different states of aggregation.

Bacterial lipopolysaccharides are recognized as the major cause of pyrogenic reactions from parenteral solutions. Molecular filtration was used to remove these pyrogenic molecules (endotoxins) from contaminated parenteral solutions. Because bacterial lipopolysaccharides can exist in different states of aggregation, depending on the composition of the solution they are suspended in, the full range of possible states of aggregation was examined by using filters with a wide range of pore sizes. Filters of different pore sizes retained endotoxin lipopolysaccharide presumed to be in the vesicle form, the micelle form, or the detergent-solubilized form in aqueous solutions. Endotoxins (pyrogens) were successfully removed from artificially contaminated solutions of concentrated antibiotics by using filters of 10,000-nominal-molecular-weight limit.

Use of synthetic polypeptides in the preparation of biodegradable delivery vehicles for narcotic antagonists.

Synthetic polypeptides consisting of copolymers of glutamic acid and leucine have been shown to be useful materials for the fabrication of practical, biodegradable delivery vehicles for narcotic antagonists. Model delivery vehicles in film form were prepared from copolymers containing 10 mole percent to 40 mole percent glutamic acid, and loaded with 10% to 40% naltrexone by weight. The naltrexone was found to be released by diffusion, exhibiting diffusion coefficients that varied as a function of the glutamic acid content and the initial naltrexone loading. A wide range in diffusion coefficients were achieved (0.31 x 10-7 cm2/hr to 120 x 10-7 cm2/hr), leading to release rates within practical ranges of interest for meeting the program goals. We have demonstrated that the polypeptides can be fabricated into dosage forms that are amenable to administration by trochar. For example, rods 0.4 mm to 0.8 mm in diameter containing as much as 40% naltrexone by weight were extruded using a simple compression mold and die arrangement. An in vitro evaluation of the rods showed that antagonist is released by diffusion at a continuously decreasing rate, a behavior similar to that observed with the film devices that were, nonetheless, capable of blocking an AD80 challenge of morphene sulfate in mice for more than 30 days. One of the most promising delivery vehicles that we have developed to date consists of a polypeptide tube filled with a naltrexone/polypeptide core. Preliminary experiments have shown that these devices may be capable of administering high, constant rates of release for prolonged periods of time. Additional work, however, is required to develop techniques for the preparation of reproducible delivery vehicles.

Use of synthetic polypeptides in the preparation of biodegradable delivery vehicles for narcotic antagonists.

Synthetic polypeptides consisting of copolymers of glutamic acid and leucine have been shown to be useful materials for the fabrication of practical, biodegradable delivery vehicles for narcotic antagonists. Model delivery vehicles in film form were prepared from copolymers containing 10 mole percent to 40 mole percent glutamic acid, and loaded with 10% to 40% naltrexone by weight. The naltrexone was found to be released by diffusion, exhibiting diffusion coefficients that varied as a function of the glutamic acid content and the initial naltrexone loading. A wide range in diffusion coefficients were achieved (0.31 x 10(-7) cm2/hr to 120 x 10(-7) cm2/hr), leading to release rates within practical ranges of interest for meeting the program goals. We have demonstrated that the polypeptides can be fabricated into dosage forms that are amenable to administration by trochar. For example, rods 0.4 mm to 0.8 mm in diameter containing as much as 40% naltrexone by weight were extruded using a simple compression mold and die arrangement. An in vitro evaluation of the rods showed that antagonist is released by diffusion at a continuously decreasing rate, a behavior similar to that observed with the film devices that were, nonetheless, capable of blocking an AD80 challenge of morphine sulfate in mice for more than 30 days. One of the most promising delivery vehicles that we have developed to date consists of a polypeptide tube filled with a naltrexone/polypeptide core. Preliminary experiments have shown that these devices may be capable of administering high, constant rates of release for prolonged periods of time. Additional work, however, is required to develop techniques for the preparation of reproducible delivery vehicles.

Prevention of vertical HIV transmission with zidovudine: projected impact of HIV testing and prenatal care.

We sought to estimate the impact of maternal HIV testing and prenatal care on the potential to reduce vertical transmission through zidovudine (AZT) use by HIV-infected mothers. We evaluated the prepartum maternal HIV diagnosis rate, prenatal care, disease stage, and vertical transmission rate (from a two-part mixture model) using New York State Medicaid and vital statistics data for HIV-infected mothers and their singletons in 1985-90. We used published data to estimate the effect of AZT on vertical transmission and expert input to define other parameters for the model. Our HIV-infected (N = 1514) had a vertical transmission rate of 27.0%. HIV was diagnosed prepartum for 39.5% of women in 1990. Transmission would have been 22.2% if AZT had been taken only by the subset of women diagnosed prepartum with HIV and receiving prenatal care by 34 weeks gestation (86.7%). Transmission would have dropped to 11.2% if all women had been diagnosed prepartum with HIV and received adequate prenatal care. The observed deficiencies in prenatal care and maternal HIV diagnosis rates in this Medicaid population-based cohort must be addressed to realize the promise of AZT to reduce vertical transmission.