Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels.
Cardiac arrest victims may experience transient brain hypoperfusion leading to delayed death of hippocampal CA1 neurons and cognitive impairment. We prevented this in adult rats by inhibiting the expression of transient receptor potential melastatin 7 (TRPM7), a transient receptor potential channel that is essential for embryonic development, is necessary for cell survival and trace ion homeostasis in vitro, and whose global deletion in mice is lethal. TRPM7 was suppressed in CA1 neurons by intrahippocampal injections of viral vectors bearing shRNA specific for TRPM7. This had no ill effect on animal survival, neuronal and dendritic morphology, neuronal excitability, or synaptic plasticity, as exemplified by robust long-term potentiation (LTP). However, TRPM7 suppression made neurons resistant to ischemic death after brain ischemia and preserved neuronal morphology and function. Also, it prevented ischemia-induced deficits in LTP and preserved performance in fear-associated and spatial-navigational memory tasks. Thus, regional suppression of TRPM7 is feasible, well tolerated and inhibits delayed neuronal death in vivo.
We measured fractional exhaled nitric oxide (FENO), spirometry, blood pressure, oxygen saturation of the blood (SaO2), and pulse rate in 16 older subjects with asthma or chronic obstructive pulmonary disease (COPD) in Seattle, Washington. Data were collected daily for 12 days. We simultaneously collected PM10 and PM2.5 (particulate matter ≤10 μm or ≤2.5 μm, respectively) filter samples at a central outdoor site, as well as outside and inside the subjects’ homes. Personal PM10 filter samples were also collected. All filters were analyzed for mass and light absorbance. We analyzed within-subject associations between health outcomes and air pollution metrics using a linear mixed-effects model with random intercept, controlling for age, ambient relative humidity, and ambient temperature. For the 7 subjects with asthma, a 10 μg/m3 increase in 24-hr average outdoor PM10 and PM2.5 was associated with a 5.9 [95% confidence interval (CI), 2.9–8.9] and 4.2 ppb (95% CI, 1.3–7.1) increase in FENO, respectively. A 1 μg/m3 increase in outdoor, indoor, and personal black carbon (BC) was associated with increases in FENO of 2.3 ppb (95% CI, 1.1–3.6), 4.0 ppb (95% CI, 2.0–5.9), and 1.2 ppb (95% CI, 0.2–2.2), respectively. No significant association was found between PM or BC measures and changes in spirometry, blood pressure, pulse rate, or SaO2 in these subjects. Results from this study indicate that FENO may be a more sensitive marker of PM exposure than traditional health outcomes and that particle-associated BC is useful for examining associations between primary combustion constituents of PM and health outcomes.
A temporal review of the fit literature highlights that most person-environment fit research is contemporaneous. Drawing on narrative theory from various disciplines, we propose a model that explains how individuals craft and recraft stories of fit in medias res, "in the middle of things." These fit narratives demonstrate how individuals understand and react to their fit experiences over time through the effects of two temporal mechanisms and time-related individual and situational influences that strengthen or weaken these mechanisms.
Most particulate matter (PM) health effects studies use outdoor (ambient) PM as a surrogate for personal exposure. However, people spend most of their time indoors exposed to a combination of indoor-generated particles and ambient particles that have infiltrated. Thus, it is important to investigate the differential health effects of indoor- and ambient-generated particles. We combined our recently adapted recursive model and a predictive model for estimating infiltration efficiency to separate personal exposure (E) to PM2.5 (PM with aerodynamic diameter ≤2.5 μm) into its indoor-generated (Eig) and ambient-generated (Eag) components for 19 children with asthma. We then compared Eig and Eag to changes in exhaled nitric oxide (eNO), a marker of airway inflammation. Based on the recursive model with a sample size of eight children, Eag was marginally associated with increases in eNO [5.6 ppb per 10-μg/m3 increase in PM2.5; 95% confidence interval (CI), −0.6 to 11.9; p = 0.08]. Eig was not associated with eNO (−0.19 ppb change per 10μg/m3). Our predictive model allowed us to estimate Eag and Eig for all 19 children. For those combined estimates, only Eag was significantly associated with an increase in eNO (Eag: 5.0 ppb per 10-μg/m3 increase in PM2.5; 95% CI, 0.3 to 9.7; p = 0.04; Eig: 3.3 ppb per 10-μg/m3 increase in PM2.5; 95% CI, −1.1 to 7.7; p = 0.15). Effects were seen only in children who were not using corticosteroid therapy. We conclude that the ambient-generated component of PM2.5 exposure is consistently associated with increases in eNO and the indoor-generated component is less strongly associated with eNO.
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