Factors associated with NO2 and NOX concentration gradients near a highway.

The objective of this research is to learn how the near-road gradient, in which NO2 and NOX (NO + NO2) concentrations are elevated, varies with changes in meteorological and traffic variables. Measurements of NO2 and NOX were obtained east of I-15 in Las Vegas and fit to functions whose slopes (dCNO2 /dx and dCNOX /dx, respectively) characterize the size of the near-road zone where NO2 and NOX concentrations from mobile sources on the highway are elevated. These metrics were used to learn about the near-road gradient by modeling dCNO2 /dx and dCNOX /dx as functions of meteorological variables (e.g., wind direction, wind speed), traffic (vehicle count), NOX concentration upwind of the road, and O3 concentration at two fixed-site ambient monitors. Generalized additive models (GAM) were used to model dCNO2 /dx and dCNOX /dx versus the independent variables because they allowed for nonlinearity of the variables being compared. When data from all wind directions were included in the analysis, variability in O3 concentration comprised the largest proportion of variability in dCNO2 /dx, followed by variability in wind direction. In a second analysis constrained to winds from the west, variability in O3 concentration remained the largest contributor to variability in dCNO2 /dx, but the relative contribution of variability in wind speed to variability in dCNO2 /dx increased relative to its contribution for the all-wind analysis. When data from all wind directions were analyzed, variability in wind direction was by far the largest contributor to variability in dCNOX /dx, with smaller contributions from hour of day and upwind NOX concentration. When only winds from the west were analyzed, variability in upwind NOX concentration, wind speed, hour of day, and traffic count all were associated with variability in dCNOX /dx. Increases in O3 concentration were associated with increased magnitude near-road dCNO2 /dx, possibly shrinking the zone of elevated concentrations occurring near roads. Wind direction parallel to the highway was also related to an increased magnitude of both dCNO2 /dx and dCNOX /dx, again likely shrinking the zone of elevated concentrations occurring near roads. Wind direction perpendicular to the road decreased the magnitude of dCNO2 /dx and dCNOX /dx and likely contributed to growth of the zone of elevated concentrations occurring near roads. Thus, variability in near-road concentrations is influenced by local meteorology and ambient O3 concentration.

Reducing the saliency of intentional stimuli results in greater contextual-dependent performance.

Wright and Shea (1991) described intentional stimuli as explicitly identified information necessary to successfully perform a task, whereas incidental stimuli are not explicitly identified as crucial to task performance but have the potential to become associated with particular responses because of their selective presence in the training environment. Shea and Wright (1995), using a speeded-choice RT task, indicated that manipulating the strength of association between incidental information and the responses, by changing the discriminability of incidental stimuli while fixing the strength of the association between the intentional stimuli and each response, had a significant impact on task performance. The present experiment further examined the role played by incidental stimuli when the strength of association between the intentional stimuli and the associated responses was reduced, by minimising stimulus-response compatibility. It was assumed that this latter manipulation would have a similar impact as increasing the strength of incidental stimuli-response relationships. That is, the relative contribution of the incidental stimuli would increase, resulting in an increase in context-dependent behaviour during tests in which the intentional and incidental stimuli activated different responses. The results were in agreement with this prediction and consistent with a model for contextual-dependent performance proposed by Shea and Wright (1995) as well as with the outshining hypothesis forwarded by Smith (1988, 1994).

Neuroblastoma regression and immunity induced by transgenic expression of interleukin-12.

PURPOSE: Interleukin-12 (IL-12) is a cytokine with potent antitumor effects. The authors sought to assess its capacity to increase tumor immunogenicity when expressed by tumor cells in a murine model of neuroblastoma. METHODS: Syngeneic A/J mice were inoculated subcutaneously with 2 x 10(6) cells from a murine neuroblastoma-derived cell line (neuro-2a). In situ transduction of the neuroblastoma cells was achieved by intratumoral injection of an adenoviral vector encoding both subunits of the murine IL-12 heterodimer. Growth of the IL-12 gene-modified tumor cells was compared with untreated neuro-2a cells. Tumor immunity was assessed by rechallenging mice that had rejected their tumor with unmodified neuroblastoma cells. The contribution of cytotoxic T lymphocytes (CTLs) was evaluated through cytotoxicity assays. RESULTS: Eighteen (72%) of 25 tumor-bearing mice treated with the mlL-12 adenoviral vector exhibited tumor regression, with 12 mice (48%) completely rejecting their tumors over 2 to 3 weeks. None of the mice that had rejected their tumor and were rechallenged with unmodified neuro-2a cells subsequently developed new tumors. Pooled splenocytes from mice rejecting their tumors showed significant tumor killing (>20% cytolysis) in vitro in 51Cr release assays. CONCLUSIONS: Adenoviral-mediated IL-12 expression by tumor cells in a murine neuroblastoma model produced a significant antitumor response. Most treated tumors demonstrated at least transient regression, whereas many completely regressed. Cured mice exhibited protective immunity and CTL activity against the tumor. These data confirm the immunomodulatory efficacy of IL-12 as part of a vaccine-based antineuroblastoma strategy.

Increased transduction efficiency of primary hematopoietic cells by physical colocalization of retrovirus and target cells.

Efficient gene transfer into hematopoietic stem cells offers a number of potential therapeutic applications. However, the relatively low titer of retroviral supernatants and the requirement for cell division to ensure integration have meant that transduction efficiency has been low. We have modified a flowthrough approach to cell transduction and have been able consistently to increase gene transfer efficiency into human hematopoietic progenitor cells. We transduced CD34 cells with retroviral vectors encoding a truncated nerve growth factor receptor (NGFR) or neo. Retroviral supernatant was pulled through 0.2-micron polycarbonated membranes, followed by placement of cells on the filter. In the absence of cytokines, the transduction efficiency of CD34 cells with a NGFR vector was increased 3-11-fold over that obtained at an identical MOI in liquid culture to produce 11%-44% transduction. Furthermore, both Thy1+ and Thy1- subsets in a total CD34 population were transduced with similar efficiency, and transduction with a neo vector, as measured by G418 resistance in clonogenic assays, increased 1.5-5-fold. The mechanism by which gene transfer is improved may reflect colocalization of cells and retrovirus. Costaining of cells transduced on the filter with an NGFR retrovirus with both an NGFR antibody and a gp70 antibody that recognizes viral coat protein revealed high-level coexpression. The levels of in vitro gene transfer we obtain are equivalent to those observed when CD34 cells are cocultured in liquid culture with cytokines. However, culture with cytokines may commit CD34 cells to differentiation and has produced disappointingly low levels of subsequent in vivo gene transfer. Gene marking studies using distinguishable retroviral vectors will provide a means of learning whether the effects of flowthrough transduction genuinely enhance the efficiency of gene transfer to human marrow-repopulating cells.

Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the treatment of patients with EBV-positive relapsed Hodgkin's disease.

Adoptive transfer of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) is effective prophylaxis and treatment of EBV-positive immunoblastic lymphoma in immunocompromised patients. In 50% of patients with Hodgkin's disease, the tumor cells are EBV antigen-positive and may therefore also be suitable targets for treatment with virus-specific CTLs. However, Hodgkin's disease may produce several inhibitory effects on immune induction and effector function in vivo, which may preclude the generation or effector function of CTLs reactive against EBV viral proteins, including those expressed by the tumor cells. We have investigated whether EBV-specific CTLs could be generated ex vivo from 13 patients with Hodgkin's disease: nine with active relapsed disease and four who were in clinical remission after a first or subsequent relapse. CTL lines were successfully generated from nine of 13 patients (five active disease, four remission). Although these lines had an abnormal pattern of expansion comparable to EBV-specific CTLs generated from normal donors, their phenotype was normal except for reduced expression of the zeta chain of the T-cell receptor (TCR). Their cytotoxicity was also compared to EBV-specific lines generated from normal donors and included activity against LMP2a, one of the three weakly immunogenic viral antigens expressed by Hodgkin's tumor cells. To assess the activity of the CTLs in vivo, they were gene-marked and infused into three patients with multiply relapsed disease. The CTLs persisted for more than 13 weeks postinfusion and retained their potent antiviral effects in vivo, thereby enhancing the patient immune response to EBV. This approach may therefore have value in the treatment of EBV-positive Hodgkin's disease.

Assay for beta-glucuronidase in cerebrospinal fluid: usefulness for the detection of neoplastic meningitis.

The specificity and sensitivity of the assay for beta-glucuronidase in cerebrospinal fluid were evaluated to determine the usefulness of this test for the detection of neoplastic meningitis. The enzyme activity was first measured in cerebrospinal fluid from 131 patients with various disorders and was then prospectively measured in cerebrospinal fluid from 30 patients with cytologic results that were positive for or suggestive of malignant disease. Within the first group, elevated levels of beta-glucuronidase were found only among patients with neoplastic processes in the central nervous system, including neoplastic meningitis. Among 26 patients with neoplastic processes in the central nervous system, including neoplastic meningitis. Among 26 patients with positive cytologic results, 13 had elevated beta-glucuronidase activities. Elevated values were more frequent among patients with adenocarcinoma (75%) and myelogenous leukemia (60%). The patients with these two disorders also had the highest enzyme activities. The correlation of th beta-glucuronidase level with other cerebrospinal fluid values, including total protein, glucose content, and cell count, was not significant. The findings of this study indicate that measurement of beta-glucuronidase in cerebrospinal fluid can be used as an adjunctive diagnostic test for neoplastic meningitis. The results should be interpreted with caution, however, because of the possibility that the elevated enzyme levels may be due to acute or subacute bacterial or fungal meningitis.

A cost-effectiveness analysis of screening for carcinoma of the prostate by digital examination.

While screening for carcinoma of the prostate by digital examination has been promoted as low in cost, safe, and effective, recent reviews have questioned its cost-effectiveness. Critical analysis has been lacking because of limited understanding of the preclinical phase of the disease and because of the absence of pertinent large-cohort data. We conducted a cost-effectiveness analysis of digital examination for prostate cancer using computer simulation of a large-cohort study. The simulation allowed for study of variations in critical assumptions about the disease and the screening procedure and keeps track of outcome descriptors such as total cost of the screening program and total years of life saved over the life of the cohort. Under assumptions favoring demonstrations of benefit from screening, modest increases in life expectancy were found in direct proportion to frequency and increasing costs of screening.

Lupus myositis.

Eleven patients met rigid criteria for having both polymyositis and systemic lupus erythematosus (SLE). The patients differed little in clinical features when compared with patients who had SLE and polymyositis in a previously reported series. The overall mortality rate of 18% and the finding that 56% of survivors were asymptomatic at latest follow-up (average four years) suggest that the prognosis for this subgroup of patients may be more favorable than that for patients with rheumatoid arthritis and scleroderma complicated by polymyositis and may be comparable to the prognosis of the overall group of patients with polymyositis.