Carroll-Ann W. Goldsmith

Analysis of air pollution particulate-mediated oxidant stress in alveolar macrophages

Adverse health effects of urban air pollution particulates may be attributable to particle-mediated oxidant stress and inflammation. Intracellular oxidant production in normal hamster alveolar macrophages (AMs) was measured upon exposure to concentrated ambient particulates (CAPs), residual oil fly ash (ROFA), and their water-soluble and particulate fractions. ROFA and CAPs caused increases in dichlorofluorescin (DCFH) oxidation, a fluorescent measure of intracellular reactive oxygen species (ROS) production, comparable to the positive control, phorbol myristate acetate (PMA). The water-soluble component of both CAPs and ROFA (CAPs, S and ROFA, S) significantly increased AM oxidant production over negative control. CAPs samples and components showed substantial day-to-day variability in their oxidant effects. Metal chelation by desferrioxamine (DF, 1 mM) caused significant inhibition of particulate-induced AM oxidant production. ROFA exposure resulted in increased macrophage inflammatory protein-2 (MIP-2) message in AMs and in increased tumor necrosis factor alpha (TNF-alpha) production by the monocyte-macrophage cell line, RAW 264.7. TNF-alpha production was inhibitable by the antioxidant N-acetylcysteine (NAC). The data suggest that metal components adsorbed to urban air pollution particulates can significantly contribute to particulate ability to cause oxidant stress and cytokine production in AMs.

Alveolar macrophage cytokine production in response to air particles in vitro : Role of endotoxin

The interaction of air particles and alveolar macrophages (AMs) may result in the release of proinflammatory cytokines. Normal mouse AMs were treated with concentrated air particle (CAPs) suspensions in vitro. After 5 h, cytokine release [macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor- a (TNF-a)] and phagocytosis of ambient air particles were measured. CAPs samples collected from urban air (Boston) on different days were used. The CAPs samples and their soluble and solid components caused significant MIP-2 and TNF- a production. Variability in the potency of samples collected on different days was observed. Trace endotoxin was measured in CAPs samples (EU/mg: 2.3 +/- 0.7, mean +/- SE, n = 10). A majority of biologic activity (cytokine induction) and endotoxin content was associated with the solid components. Neutralization of endotoxin by polymyxin B abrogated >80% of TNF- a induction by CAPs samples, but inhibited MIP-2 production by only 40%. The trace endotoxin present in CAPs caused much more MIP-2 production than predicted by concentration alone (28 +/- 8-fold increase, n = 9), indicating synergistic interaction with other AM-activating components of the particles. Data suggest that low levels of endotoxin may interact with air particles to activate lung macrophages.The interaction of air particles and alveolar macrophages (AMs) may result in the release of proinflammatory cytokines. Normal mouse AMs were treated with concentrated air particle (CAPs) suspensions in vitro. After 5 h, cytokine release [macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-alpha (TNF-alpha)] and phagocytosis of ambient air particles were measured. CAPs samples collected from urban air (Boston) on different days were used. The CAPs samples and their soluble and solid components caused significant MIP-2 and TNF-alpha production. Variability in the potency of samples collected on different days was observed. Trace endotoxin was measured in CAPs samples (EU/mg: 2.3 +/- 0.7, mean +/- SE, n = 10). A majority of biologic activity (cytokine induction) and endotoxin content was associated with the solid components. Neutralization of endotoxin by polymyxin B abrogated >80% of TNF-alpha induction by CAPs samples, but inhibited MIP-2 production by only approximately 40%. The trace endotoxin present in CAPs caused much more MIP-2 production than predicted by concentration alone (28 +/- 8-fold increase, n = 9), indicating synergistic interaction with other AM-activating components of the particles. Data suggest that low levels of endotoxin may interact with air particles to activate lung macrophages.

The Case for Autoimmunity in the Etiology of Schizophrenia

The treatment of schizophrenia has frustrated clinicians for over 50 years. Despite advances in neurotransmitter identification and the development of drugs targeting these transmitters, total remission of the disease is not always achieved. Potential etiologies other than neurotransmitter dysfunction merit consideration. One intriguing concept is the possible contribution of autoimmunity in patients with the disease. This breakdown of self‐tolerance has been implicated in patients with other chronic diseases, such as type 1 diabetes mellitus and myasthenia gravis. The literature on autoimmunity as a possible mechanism in the pathogenesis of schizophrenia can be conflicting, but there is a substantial amount of circumstantial, although not conclusive, evidence of immune dysfunction in patients with schizophrenia.

Treatment of schizophrenia in the 21st Century : beyond the neurotransmitter hypothesis

Over the last six decades, the treatment of schizophrenia has focused primarily on interactions at monoamine neurotransmitter receptor sites, including those for dopamine and serotonin. While first-generation antipsychotics demonstrate antagonism at the dopamine 2 receptor, newer atypical agents involve multiple receptors at various neurotransmitter sites. Despite the advent of these newer agents, the treatment of schizophrenia continues to elude clinicians, perhaps owing to a lack of information about the factors contributing to the development of the disease. While the etiology is complex and not yet fully delineated, we suggest that treating clinicians be willing to look beyond neurotransmitters and entertain other potential factors involved in the pathogenesis of schizophrenia. One such factor that is often overlooked is the possible contribution of autoimmunity to disease development in at least a subset of patients. In this article we make an argument for consideration of immune dysfunction in the development of schizophrenia and suggest future directions for the field.

Airway hyperresponsiveness caused by aerosol exposure to residual oil fly ash leachate in mice.

Particulate air pollution is associated with exacerbation of asthma and other respiratory disorders. This study sought to further characterize the pulmonary effects of residual oil fly ash (ROFA), an experimentally useful surrogate for combustion-derived particulates in ambient air. Mice were exposed to aerosols of the soluble leachate of residual oil fly ash (ROFA-s). Physiologic testing of airway function (non invasive plethysmography) showed increased Penh, an index of airway hyperresponsiveness (AHR), in a time- and dose-dependent manner after exposure to ROFA-s. BAL analysis showed a minor influx of neutrophils, which was maximal at 12 h after exposure and essentially resolved by the time point of maximal AHR (48 h after exposure). The AHR caused by ROFA-s was reproduced by a mixture of its major metal components (Ni, V, Zn, Co, Mn, Cu) but not by any individual metal alone. Systemic pretreatment of mice with the antioxidant dimethylthiourea abrogated ROFA-s-mediated AHR. Analysis of mice of varying ages showed that ROFA-s had no marked effect on airway responsiveness of 2-wk-old mice, in contrast to the AHR seen in 3- and 8-wk old mice. ROFA-s-mediated AHR was unchanged in neurokinin 1 receptor knockout mice and in mice treated with an neurokinin antagonist, arguing against a role for this mediator in ROFA-s-mediated effects. Data indicate that ROFA-s mediates AHR in mice through antioxidant-sensitive mechanisms that require multiple metal constituents. Maturational differences in susceptibility to ROFA-induced AHR may be useful for further studies of mechanisms of particle effects.

Nonprescription medication use and literacy among New Hampshire eighth graders

OBJECTIVES To assess whether New Hampshire (NH) eighth graders were self-medicating with over-the-counter (OTC) medications, had literacy skills necessary to safely and accurately interpret OTC medication labels, and showed improvement in OTC medication safe use and literacy skills after student pharmacist-led education. DESIGN Cross-sectional repeated-measures study. SETTING NH, five separate sessions, in 2010 and 2011. PARTICIPANTS 101 NH eighth grade students. INTERVENTION Participants answered questions derived from OTC drug facts labels that assessed OTC medication safe use and literacy before and after a student pharmacist-led presentation describing each section of the labels. MAIN OUTCOME MEASURES Participant use of OTC medications, whether participants interpreted OTC drug facts labels correctly, and whether participants were able to identify safe use of OTC medications before and after instruction about OTC drug facts labels. RESULTS 57% of participants reported taking OTC medications in the previous month, 22% reported taking OTC medications autonomously, and 43% reported checking with a trusted adult before self-administration. After student pharmacist-led education, significant improvements were seen in identifying product indications, calculating adult doses, interpreting adverse effects, knowing when to call a medical provider, understanding proper medication storage, identifying expiration dates, and identifying duplicate medications in products. CONCLUSION NH eighth graders were self-medicating with OTC medications. Significant improvements in OTC medication label literacy were seen after student pharmacist-led education. These results provide evidence of the need for, and positive effects of, OTC medication education among U.S. adolescents.

The Effects of Synchronized Distance Education on Academic Achievement in a Physician Assistant Program

Purpose: This pilot study examined differences in academic achievement between two cohorts of physician assistant (PA) students; one cohort received the majority (>80%) of class content via synchronous distance education (SDE), while the other received the majority (>80%) of class content onsite via traditional delivery (TD). Methods: Course grades and practical exam grades were used to measure student achievement and compare the performances of the SDE and traditional students. At the end of the spring (May 2008), summer (August 2008), and fall (December 2008) terms, grades were recorded and compared across delivery models. Nondirectional independent samples t‐tests were conducted to test for difference in academic achievement between the groups. Results: Academic achievement was not statistically significantly different between the SDE and traditional cohorts on any of the 13 course grades or 8 practical/lab grades measured. Conclusions: These results suggest that academic achievement of PA students was not dependent upon whether they received their curricular content via SDE or TD.