Regression calibration with instrumental variables for longitudinal models with interaction terms, and application to air pollution studies.

In this paper, we derive forms of estimators and associated variances for regression calibration with instrumental variables in longitudinal models that include interaction terms between two unobservable predictors and interactions between these predictors and covariates not measured with error; the inclusion of the latter interactions generalize results we previously reported. The methods are applied to air pollution and health data collected on children with asthma. The new methods allow for the examination of how the relationship between health outcome leukotriene E4 (LTE4, a biomarker of inflammation) and two unobservable pollutant exposures and their interaction are modified by the presence or absence of upper respiratory infections. The pollutant variables include secondhand smoke and ambient (outdoor) fine particulate matter. Simulations verify the accuracy of the proposed methods under various conditions.

The Denver Aerosol Sources and Health (DASH) Study: Overview and Early Findings.

Improved understanding of the sources of air pollution that are most harmful could aid in developing more effective measures for protecting human health. The Denver Aerosol Sources and Health (DASH) study was designed to identify the sources of ambient fine particulate matter (PM(2.5)) that are most responsible for the adverse health effects of short-term exposure to PM (2.5). Daily 24-hour PM(2.5) sampling began in July 2002 at a residential monitoring site in Denver, Colorado, using both Teflon and quartz filter samplers. Sampling is planned to continue through 2008. Chemical speciation is being carried out for mass, inorganic ionic compounds (sulfate, nitrate and ammonium), and carbonaceous components, including elemental carbon, organic carbon, temperature-resolved organic carbon fractions and a large array of organic compounds. In addition, water soluble metals were measured daily for 12 months in 2003. A receptor-based source apportionment approach utilizing positive matrix factorization (PMF) will be used to identify PM (2.5) source contributions for each 24-hour period. Based on a preliminary assessment using synthetic data, the proposed source apportionment should be able to identify many important sources on a daily basis, including secondary ammonium nitrate and ammonium sulfate, diesel vehicle exhaust, road dust, wood combustion and vegetative debris. Meat cooking, gasoline vehicle exhaust and natural gas combustion were more challenging for PMF to accurately identify due to high detection limits for certain organic molecular marker compounds. Measurements of these compounds are being improved and supplemented with additional organic molecular marker compounds. The health study will investigate associations between daily source contributions and an array of health endpoints, including daily mortality and hospitalizations and measures of asthma control in asthmatic children. Findings from the DASH study, in addition to being of interest to policymakers, by identifying harmful PM(2.5) sources may provide insights into mechanisms of PM effect.

The failure of STAT6-deficient mice to develop airway eosinophilia and airway hyperresponsiveness is overcome by interleukin-5.

While signal transducer and activator of transcription protein 6 (STAT6) is important in interleukin-4 (IL-4)-induced commitment of CD4(+) T cells to the T helper cell, type 2 (Th2) phenotype and IgE isotype switching in B cells, its role in other IL-4-mediated events and their impact upon the allergic response is less evident. In the present study we demonstrate the critical role of STAT6 in the development of allergic airway eosinophilia and airway hyperresponsiveness (AHR) after allergen sensitization and challenge. STAT6-deficient (STAT6-/-) mice did not develop a Th2 cytokine response or an allergen-specific IgE response. Further, STAT6-/- mice had a reduced constitutive and allergen-induced expression of CD23 as well as lower mucus production in the airway epithelium. Critically, we show that IL-5 alone can reconstitute airway eosinophilia and AHR in sensitized and challenged STAT6-/- mice. This emphasizes the essential nature of the IL-4-dependent signaling of T cells to the Th2 phenotype and secretion of IL-5, resulting in the airway eosinophilia and AHR. These observations underscore the importance of targeting this pathway in new antiallergic asthma drug development.

The role of immunoglobulin therapy in allergic diseases.

Intravenous immunoglobulin (IVIG) has been used for many years to treat patients with primary immunodeficiencies. More recently, IVIG has been shown to have anti-inflammatory activity when used at substantially higher concentrations. A number of studies have examined the efficacy of IVIG in allergic diseases. For patients with severe refractory asthma, sinusitis, atopic dermatitis, and urticaria, IVIG offers an alternative therapy with relatively few side-effects. Although the mechanism by which IVIG may attenuate the allergic response is still undetermined, clinical studies have shown that immunoglobulin therapy can decrease serum IgE levels and increase glucocorticoid binding affinity, while in vitro studies have shown that IVIG can decrease T-cell secretion of TH2 cytokines. Further studies are needed to confirm the initial encouraging results seen in allergic patients with severe, resistant disease.

New approaches to the treatment of childhood asthma.

In the past year, a number of important advances were made in the treatment of asthma, particularly with regard to children. New guidelines stress anti-inflammatory treatment early after diagnosis for patients who have persistent symptoms. Recent studies confirmed that inhaled steroids are the most efficacious therapy for children with mild asthma, although these same studies demonstrate the potential for adverse effects as well. Combination therapy with theophylline or salmeterol may allow clinicians to minimize the dose of inhaled steroids while controlling symptoms. New high-potency inhaled steroid preparations are clearly effective in the treatment of severely asthmatic patients, but they may cause significant side effects at higher doses. Anti-leukotriene medications may be helpful in the management of persistent asthma because they have been shown to improve asthma symptoms and pulmonary function. New directions in asthma therapy include treatment with monoclonal antibodies directed against IgE and specific cytokines involved in the inflammatory response in asthma.

Viral inhibition of lymphocyte proliferative responsiveness in patients suffering from recurrent lesions caused by herpes simplex virus.

Herpes simplex viruses (HSV) are able to prevent the lectin-driven mitogenesis of coincubated human peripheral blood lymphocytes. This abrogation of responsiveness is independent of infection and can be obtained by using ultraviolet-inactivated as well as live virus particles. Lymphocytes from patients prone to frequent recurrences of HSV-induced lesions were more susceptible to inhibition of proliferative responsiveness than were cells from either individuals seronegative for HSV type 1 and HSV type 2 or individuals subject only to infrequent recurrences of HSV-induced disease. Lymphocytes from all patients tested were more susceptible to viral abrogation of mitogen responsiveness during preepisodic and acute as opposed to convalescent and postepisodic periods. When exogenous T cell growth factor was added to lymphoid cell cultures that had been coincubated with HSV, the cells were generally able to overcome the inhibition of responsiveness that would otherwise occur. However, this restoration of responsiveness occurred less efficiently in cells from patients with acute HSV-induced lesions and in cells from patients with frequent recurrences of lesions.

Oligoclonal immunoglobulins, light chain ratios and free light chains in cerebrospinal fluid and serum from patients affected with various neurological diseases.

Several immunological parameters, of which the most important are the kappa-lambda ratios, the presence of free light chains and the double ring formation for kappa-chains in single radial immunodiffusion, were investigated in the cerebrospinal fluid and serum of patients affected with different neurological diseases. Parallels were run either with multiple sclerosis or subacute sclerosing panencephalitis. There seems to be a correlation between the frequency of the presence of free light chains and the degree of severity of the immunological process.

Imbalance of k/lambda ratios associated with high measles antibody titers in fractionated serum immunoglobulins of patients affected with subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a neurological disease which is characterized not only by the appearance of oligoclonal immunoglobulins in cerebrospinal fluid (CSF) and serum but also by high measles antibody titers and disturbed k/lambda ratios, as well in serum as in CSF. These findings lead to the hypothesis that specific immunoglobulins are produced by hyperimmunisation against measles and/or measles-like virus. Therefore the serum IgG from subacute sclerosing panencephalitis patients were fractionated by column isoelectric focusing and the k/lambda light chain ratio and the measles antibody titer of each fration were determined. The highest k/lambda ratios and the highest measles antibody titers were found mainly in two fractions at a pH ranging from 8.94-8.51 for the first and 8.88-8.24 for the second.