Using Physiologically-Based Pharmacokinetic Models to Incorporate Chemical and Non-Chemical Stressors into Cumulative Risk Assessment: A Case Study of Pesticide Exposures

Cumulative risk assessment has been proposed as an approach to evaluate the health risks associated with simultaneous exposure to multiple chemical and non-chemical stressors. Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can allow for the inclusion and evaluation of multiple stressors, including non-chemical stressors, but studies have not leveraged PBPK/PD models to jointly consider these disparate exposures in a cumulative risk context. In this study, we focused on exposures to organophosphate (OP) pesticides for children in urban low-income environments, where these children would be simultaneously exposed to other pesticides (including pyrethroids) and non-chemical stressors that may modify the effects of these exposures (including diet). We developed a methodological framework to evaluate chemical and non-chemical stressor impacts on OPs, utilizing an existing PBPK/PD model for chlorpyrifos. We evaluated population-specific stressors that would influence OP doses or acetylcholinesterase (AChE) inhibition, the relevant PD outcome. We incorporated the impact of simultaneous exposure to pyrethroids and dietary factors on OP dose through the compartments of metabolism and PD outcome within the PBPK model, and simulated combinations of stressors across multiple exposure ranges and potential body weights. Our analyses demonstrated that both chemical and non-chemical stressors can influence the health implications of OP exposures, with up to 5-fold variability in AChE inhibition across combinations of stressor values for a given OP dose. We demonstrate an approach for modeling OP risks in the presence of other population-specific environmental stressors, providing insight about co-exposures and variability factors that most impact OP health risks and contribute to children’s cumulative health risk from pesticides. More generally, this framework can be used to inform cumulative risk assessment for any compound impacted by chemical and non-chemical stressors through metabolism or PD outcomes

Molecular Pathogenesis of Alzheimer’s Disease: Reductionist versus Expansionist Approaches

Alzheimer’s disease (AD) is characterized clinically by dementia and pathologically by two hallmark lesions, senile plaques and neurofibrillary tangles. About a quarter century ago these hallmark lesions were purified and their protein constituents identified, precipitating an avalanche of molecular studies as well as substantial optimism about successful therapeutic intervention. In 2009, we now have copious knowledge on the biochemical cascades that produce these proteins, the different modifications and forms in which these proteins exist, and the ability to selectively target these proteins for therapeutic intervention on an experimental basis. At the same time, there has been no discernible alteration in the natural course of AD in humans. While it may be that the complexity of AD will exceed our capacity to make significant treatment progress for decades or more, a paradigm shift from the reductionism that defines amyloid-β and tau hypotheses, to one that more accurately reflects the meaning of neuropathological changes, may be warranted. We and others have demonstrated that AD pathology is a manifestation of cellular adaptation, specifically as a defense against oxidative injury. As such, AD pathology is therefore a host response rather than a manifestation of cytotoxic protein injury, and is unlikely to be a fruitful target for therapeutic intervention. An “expansionist” view of the disease, we believe, with oxidative stress as a pleiotropic and upstream process, more aptly describes the relationship between various and numerous molecular alterations and clinical disease

Do β-Defensins and Other Antimicrobial Peptides Play a Role in Neuroimmune Function and Neurodegeneration?

It is widely accepted that the brain responds to mechanical trauma and development of most neurodegenerative diseases with an inflammatory sequelae that was once thought exclusive to systemic immunity. Mostly cationic peptides, such as the β-defensins, originally assigned an antimicrobial function are now recognized as mediators of both innate and adaptive immunity. Herein supporting evidence is presented for the hypothesis that neuropathological changes associated with chronic disease conditions of the CNS involve abnormal expression and regulatory function of specific antimicrobial peptides. It is also proposed that these alterations exacerbate proinflammatory conditions within the brain that ultimately potentiate the neurodegenerative process

A flow cytometric assay to quantify \u3ci\u3ein vivo\u3c/i\u3e bacterial uptake by alveolar macrophages

Our laboratory has developed a flow cytometric assay to quantify alveolar macrophage (MФ) phagocytosis of bacteria within a live animal. MФs collected by bronchoalveolar lavage from rats infected transtracheally with Syto 9-labeled bacteria are fluorescently labeled for identification and analyzed by flow cytometry to quantify their bacterial uptake

Symbiotic starburst-black hole AGN -- I. Isothermal hydrodynamics of the mass-loaded ISM

Compelling evidence associates the nuclei of active galaxies and massive starbursts. The symbiosis between a compact nuclear starburst stellar cluster and a massive black hole can self-consistently explain the properties of active nuclei. The young stellar cluster has a profound effect on the most important observable properties of active galaxies through its gravity, and by mass injection through stellar winds, supernovae and stellar collisions. Mass injection generates a nuclear ISM which flows under gravitational and radiative forces until it leaves the nucleus or is accreted onto the black hole or accretion disc. The radiative force exerted by the black hole--accretion disc radiation field is not spherically symmetric. This results in complex flows in which regions of inflow can coexist with high Mach number outflowing winds and hydrodynamic jets. We present two-dimensional hydrodynamic models of such nISM flows, which are highly complex and time variable. Shocked shells, jets and explosive bubbles are produced, with bipolar winds driving out from the nucleus. Our results graphically illustrate why broad emission line studies have consistently failed to identify any simple, global flow geometry. The real structure of the flows is _inevitably_ yet more complex.Comment: 51 pages, 85 postscript figures, Latex, using MNRAS macros, to be published in MNRAS. Postscript will full resolution pictures and mpeg simulations available via http://ast.leeds.ac.uk/~rjrw/agn.htm

Presentation and Outcomes After Medical and Surgical Treatment Versus Medical Treatment Alone of Spontaneous Infectious Spondylodiscitis: A Systematic Literature Review and Meta-Analysis.

Study Design: Systematic literature review. Objectives: The aims of this study were to (1) describe the clinical features, disabilities, and incidence of neurologic deficits of pyogenic spondylodiscitis prior to treatment and (2) compare the functional outcomes between patients who underwent medical treatment alone or in combination with surgery for pyogenic spondylodiscitis. Methods: A systematic literature review was performed using PubMed according to PRISMA guidelines. No year restriction was put in place. Statistical analysis of pooled data, when documented in the original report (ie, number of patients with desired variable and number of patients evaluated), was conducted to determine the most common presenting symptoms, incidence of pre- and postoperative neurologic deficits, associated comorbidities, infectious pathogens, approach for surgery when performed, and duration of hospitalization. Outcomes data, including return to work status, resolution of back pain, and functional recovery were also pooled among all studies and surgery-specific studies alone. Meta-analysis of studies with subgroup analysis of pain-free outcome in surgical and medical patients was performed. Results: Fifty of 1286 studies were included, comprising 4173 patients undergoing either medical treatment alone or in combination with surgery. Back pain was the most common presenting symptom, reported in 91% of patients. Neurologic deficit was noted in 31% of patients. Conclusion: Medical management remains first-line treatment of infectious pyogenic spondylodiscitis. Surgery may be indicated for progressive pain, persistent infection on imaging, deformity or neurologic deficits. If surgery is required, reported literature shows potential for significant pain reduction, improved neurologic function and a high number of patients returning to a normal functional/work status