Predictors of asthma exacerbation among patients with poorly controlled asthma despite inhaled corticosteroid treatment.

BACKGROUND: Asthma exacerbations are associated with decreased quality of life and increased health care usage. Identification of characteristics that predict increased risk of future exacerbations in patients with suboptimal control of asthma could guide treatment decisions. OBJECTIVE: To examine patient characteristics associated with risk of asthma exacerbations in patients with uncontrolled persistent asthma. METHODS: A retrospective analysis of adults and children with inadequately controlled asthma despite asthma controller therapy and enrolled in 2 randomized trials was conducted. Baseline characteristics of subjects who experienced an asthma exacerbation during the treatment period were compared with those of subjects who did not experience an exacerbation. RESULTS: Of 718 subjects (402 adults and 295 children), 108 adults (27%) and 110 children (37%) experienced an asthma exacerbation during the study period. Unscheduled health care visits for asthma or use of oral corticosteroids in the previous year were significantly associated with asthma exacerbation during the study period (P < .01). Adult subjects who experienced an exacerbation had significantly lower forced expiratory volume in 1 second compared with those who did not (2.3 vs 2.5 L, respectively, P = .02). Children who experienced an exacerbation had lower baseline pre- and post-bronchodilator ratios of forced expiratory volume in 1 second to forced vital capacity (77% vs 81%, P < .01; 82% vs 86%, P < .001, respectively). Symptom scores on validated questionnaires were significantly worse in adults but not in children who developed an exacerbation. CONCLUSION: Spirometric measurements can help identify adults and children at increased risk for asthma exacerbation. Symptom scores could be helpful in identifying adults who are at high risk for exacerbations but could be less helpful in children.

Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt.

In the setting of high salt intake, aldosterone stimulates fibrosis in the heart, great vessels, and kidney of rats. We used uninephrectomized rats treated with angiotensin II and placed on a high salt diet to exaggerate renal fibrosis. We then tested whether mineralocorticoid receptor blockade by spironolactone or aldosterone synthase inhibition by FAD286 have similar effects on end-organ damage and gene expression. Individually, both drugs prevented the hypertensive response to uninephrectomy and high salt intake but not when angiotensin II was administered. Following 4 weeks of treatment with FAD286, plasma aldosterone was reduced, whereas spironolactone increased aldosterone at 8 weeks of treatment. Angiotensin II and high salt treatment caused albuminuria, azotemia, renovascular hypertrophy, glomerular injury, increased plasminogen activator inhibitor-1 (PAI-1), and osteopontin mRNA expression, as well as tubulointerstitial fibrosis in the kidney. Both drugs prevented these renal effects and attenuated cardiac and aortic medial hypertrophy while reducing osteopontin and transforming growth factor-beta mRNA expression in the aorta. The two drugs also reduced cardiac interstitial fibrosis but had no effect on that of the perivascular region. Although spironolactone enhanced angiotensin II and salt-stimulated PAI-1 mRNA expression in aorta and heart, spironolactone and FAD286 prevented renal PAI-1 mRNA protein expression. Our study shows that mineralocorticoid receptor antagonism and aldosterone synthase inhibition similarly decrease hypertrophy and interstitial fibrosis of the kidney and heart caused by angiotensin II and high salt.

Manipulating the optical properties of pyramidal nanoparticle arrays.

This paper reports the orientation-dependent optical properties of two-dimensional arrays of anisotropic metallic nanoparticles. These studies were made possible by our simple procedure to encapsulate and manipulate aligned particles having complex three-dimensional (3D) shapes inside a uniform dielectric environment. Using dark field or scattering spectroscopy, we investigated the plasmon resonances of 250-nm Au pyramidal shells embedded in a poly(dimethylsiloxane) (PDMS) matrix. Interestingly, we discovered that the scattering spectra of these particle arrays depended sensitively on the direction and polarization of the incident white light relative to the orientation of the pyramidal shells. Theoretical calculations using the discrete dipole approximation support the experimentally observed dependence on particle orientation with respect to incident field. This work presents an approach to manipulate--by hand--ordered arrays of particles over cm(2) areas and provides new insight into the relationship between the shape of well-defined, 3D particles and their supported plasmon resonance modes.

Packaging of gold particles in viral capsids.

In-vitro self-assembly conditions known to result in generating infectious virions have been used in vitro to reassemble bromovirus capsid proteins around negatively charged gold nanoparticles cores. We discuss here the optical properties (elastic light scattering) and the influence of the core size and of the functional moiety on the resulting virus-like particles. Our results indicate that the formation of a closed shell, as opposed to an amorphous protein coat, does occur and that the shell/core interactions can be tuned using different coatings on the nanoparticle core. Such studies may lead to real-time monitoring of viral traffic on the scale of a single virus, as well as to the possibility of chemical sensing along the intracellular and intercellular viral pathways and contribute to a better understanding of the virus transport and cellular compartmentalization.

Phthalates, Pesticides, and Bisphenol-A Exposure and the Development of Nonoccupational Asthma and Allergies: How Valid Are the Links?

Phthalates, pesticides, and bisphenol-A (BPA) are three groups of chemicals, implicated in endocrine disruption and commonly found in the local environment, that have been implicated in the pathogenesis of asthma and allergies [1-3]. Multiple observational studies have demonstrated an association between exposure to phthalates and the development of asthma and allergies in humans. Associations with exposure to pesticides and BPA and the development of respiratory disease are less clear. However, recent evidence suggests that prenatal or early postnatal exposure to BPA may be deleterious to the developing immune system. Future cohort-driven epidemiological or translational research should focus on determining whether these ubiquitous chemicals contribute to the development of asthma and allergies in humans, and attempt to establish the routes and mechanisms by which they operate. Determining dose-response relationships will be important to establishing safe levels of these chemicals in the environment and in consumer products. Attempts to reduce exposures to chemicals such as phthalates, pesticides, and BPA may have environmental repercussions as well as public health impact for the developing child.

The emergence of ErbB2 expression in cultured rat hepatocytes correlates with enhanced and diversified EGF-mediated signaling.

The proliferative effects of EGF in liver have been extensively investigated in cultured hepatocytes. We studied the effects of EGF, insulin, and other growth regulators on the expression, interaction, and signaling of ErbB receptors in primary cultures of adult rat hepatocytes. Using immunological methods and ErbB tyrosine kinase inhibitors, we analyzed the expression and signaling patterns of the ErbB kinases over 120 h of culture. Basal and EGF-stimulated protein tyrosine phosphorylation increased as cells adapted in vitro. EGF receptor (EGFr) expression declined in the first 24 h, whereas ErbB3 expression rose. Although ErbB2 was not present in freshly isolated hepatocytes, EGF and insulin independently induced ErbB2 while suppressing ErbB3 expression. Low concentrations of EGF and insulin synergistically stimulated ErbB2 expression and DNA synthesis. The greatest increase in ErbB2, which is normally expressed by fetal and neonatal hepatocytes, occurred shortly before the onset of DNA synthesis (> 40 h). EGF promoted EGFr and ErbB2 coassociation, stimulating tyrosine phosphorylation of both proteins. In contrast, heregulin beta1 (HRG-beta1) did not promote ErbB2 and ErbB3 coassociation. A selective tyrphostin inhibitor of ErbB2 suppressed EGF-stimulated DNA synthesis, but maximum suppression required the blockade of the EGFr kinase as well. Maximal EGF stimulation of DNA synthesis in vitro depends on the induction of ErbB2 and involves an EGFr-ErbB2 heterodimer. The ability of insulin to induce ErbB2 suggests both a mechanism for the synergy between insulin and EGF and a possible metabolic control of ErbB2 in vivo.

Mesoscale metallic pyramids with nanoscale tips.

We report a simple procedure that can generate free-standing mesoscale metallic pyramids composed of one or more materials and having nanoscale tips (radii of curvature of less than 2 nm). Mesoscale holes (100-300 nm) in a chromium film are used as an etch mask to fabricate pyramidal pits and then as a deposition mask to form the metallic pyramids. We have fabricated two- and three-layered pyramids with control over their materials and chemical functionality.

Optical properties of surface-patterned nanostructures.

This concepts article describes our developments in nanopatterning related to photonics. We have a nanopatterning toolkit that can generate functional, nanostructured surfaces at nm-length scales and over cm(2)-areas in a single (or small number of) step(s). This paper will focus on three examples of surface-patterned nanostructures and their optical properties: (i) one-dimensional arrays of metallic nanoparticles; (ii) arrays of small-diameter ZnO nanowires; (iii) mesoscale structures of CdSe/ZnS nanocrystals. The potential for advances in nanopatterning to contribute to a broad range of light-based applications will be discussed.

Surface plasmon standing waves in large-area subwavelength hole arrays.

A flexible and parallel procedure to generate large-area, free-standing films of subwavelength hole arrays has been demonstrated. This method is materials-general, and multilayered films of different materials were constructed. The optical quality of these films was tested using a near-field scanning optical microscope, which revealed the formation of surface plasmon standing wave patterns that were consistent with numerical simulations. Because the properties of the holes and the film materials can be easily tailored, new types of plasmonic and photonic devices can be envisioned and tested.

Gold nanoparticles as spectroscopic enhancers for in vitro studies on single viruses.

Gold particles with diameters between 2.5 and 4.5 nm have been introduced in the inner cavity of an icosahedral brome mosaic virus. The optical properties of single gold-marked virions have been tested in-vitro with respect to the characteristic plasmon polariton resonance. The shift in the plasmon polariton resonance of a single Au particle encapsulated in a virus with respect to a free particle in solution indicates a close interaction between the basic residues on the inner wall of the capsid and the negative surface charge of the particle. Incorporation of a pair of Au particles, approximately 4 nm diameter, is shown to be a frequent event. In this case, the dependence of the two-particle surface plasmon spectrum on the interparticle distance and the strong particle/capsid wall interaction suggest that, in the future, it will be possible to use encapsulated Au particles to track changes in the viral capsid volume in real-time and in a physiological environment.