Rodent models of cardiopulmonary disease: their potential applicability in studies of air pollutant susceptibility.

The mechanisms by which increased mortality and morbidity occur in individuals with preexistent cardiopulmonary disease following acute episodes of air pollution are unknown. Studies involving air pollution effects on animal models of human cardiopulmonary diseases are both infrequent and difficult to interpret. Such models are, however, extensively used in studies of disease pathogenesis. Primarily they comprise those developed by genetic, pharmacologic, or surgical manipulations of the cardiopulmonary system. This review attempts a comprehensive description of rodent cardiopulmonary disease models in the context of their potential application to susceptibility studies of air pollutants regardless of whether the models have been previously used for such studies. The pulmonary disease models include bronchitis, emphysema, asthma/allergy, chronic obstructive pulmonary disease, interstitial fibrosis, and infection. The models of systemic hypertension and congestive heart failure include: those derived by genetics (spontaneously hypertensive, Dahl S. renin transgenic, and other rodent models); congestive heart failure models derived by surgical manipulations; viral myocarditis; and cardiomyopathy induced by adriamycin. The characteristic pathogenic features critical to understanding the susceptibility to inhaled toxicants are described. It is anticipated that this review will provide a ready reference for the selection of appropriate rodent models of cardiopulmonary diseases and identify not only their pathobiologic similarities and/or differences to humans but also their potential usefulness in susceptibility studies

Efficient Transfer of Genes into Murine Cardiac Grafts by Starburst Polyamidoamine Dendrimers

Overview summary Plasmid-mediated gene therapy has been used to deliver immunosuppressive molecules into allografts to prolong graft survival. However, direct injection of naked plasmid DNA is inefficient because transgene expression is low and transient. This study investigated the ability of Starburst dendrimers to augment plasmid-mediated gene transfer efficiency in a murine cardiac transplantation model. The results demonstrate that dendrimers increased the efficiency of transfer and expression of exogenous DNA in cardiac grafts. Improved expression of an immunosuppressive cytokine viral interleukin-10 (vIL-10) by dendrimers significantly prolonged allograft survival. The dose of DNA, the charge ratio of DNA to dendrimer, and the size generation of the dendrimers were all critical for prolongation of allograft survival. Thus, the use of the Starburst dendrimer as a carrier molecule for plasmid-mediated gene transfer improved the efficiency of transfer and expression, providing further therapeutic value for treatment of cardiac allograft rejection.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63156/1/hum.1998.9.4-553.pd

fMRI of reward processing in a community-based longitudinal study

Up to 40% of youth with autism spectrum disorder (ASD) also suffer from anxiety, and this comorbidity is linked with significant functional impairment. However, the mechanisms of this overlap are poorly understood. We investigated the interplay between ASD traits and anxiety during reward processing, known to be affected in ASD, in a community sample of 1472 adolescents (mean age=14.4 years) who performed a modified monetary incentive delay task as part of the Imagen project. Blood-oxygen-level dependent (BOLD) responses to reward anticipation and feedback were compared using a 2x2 analysis of variance test (ASD traits: low/high; anxiety symptoms: low/high), controlling for plausible covariates. In addition, we used a longitudinal design to assess whether neural responses during reward processing predicted anxiety at 2-year follow-up. High ASD traits were associated with reduced BOLD responses in dorsal prefrontal regions during reward anticipation and negative feedback. Participants with high anxiety symptoms showed increased lateral prefrontal responses during anticipation, but decreased responses following feedback. Interaction effects revealed that youth with combined ASD traits and anxiety, relative to other youth, showed high right insula activation when anticipating reward, and low right-sided caudate, putamen, medial and lateral prefrontal activations during negative feedback (all clusters PFWE<0.05). BOLD activation patterns in the right dorsal cingulate and right medial frontal gyrus predicted new-onset anxiety in participants with high but not low ASD traits. Our results reveal both quantitatively enhanced and qualitatively distinct neural correlates underlying the comorbidity between ASD traits and anxiety. Specific neural responses during reward processing may represent a risk factor for developing anxiety in ASD youth

Balloon-Expandable Stent Treatment of Experimental Coarctation of the Aorta: Early Hemodynamic and Pathological Evaluation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72292/1/j.1540-8183.1993.tb00843.x.pd

Multiwavelength Observations of the Gamma-Ray Blazar PKS 0528+134 in Quiescence

We present multiwavelength observations of the ultraluminous blazar-type radio loud quasar PKS 0528+134 in quiescence during the period July to December 2009. Significant flux variability on a time scale of several hours was found in the optical regime, accompanied by a weak trend of spectral softening with increasing flux. We suggest that this might be the signature of a contribution from the accretion disk at the blue end of the optical spectrum. The optical flux is weakly polarized with rapid variations of the degree and direction of polarization, while the polarization of the 43 GHz radio core remains steady. Optical spectropolarimetry suggests a trend of increasing degree of polarization with increasing wavelength, providing additional evidence for an accretion disc contribution towards the blue end of the optical spectrum. We constructed four SEDs indicating that even in the quiescent state, the bolometric luminosity of PKS 0528+134 is dominated by its gamma-ray emission. A leptonic single-zone jet model produced acceptable fits to the SEDs with contributions to the high-energy emission from synchrotron self-Compton radiation and Comptonization of direct accretion disk emission. Fit parameters close to equipartition were obtained. The moderate variability on long time scales implies the existence of on-going particle acceleration, while the observed optical polarization variability seems to point towards a turbulent acceleration process. Turbulent particle acceleration at stationary features along the jet therefore appears to be a viable possibility for the quiescent state of PKS 0528+134.Comment: Accepted for Publication in The Astrophysical Journal. - Acknowledgement adde

Evidence for Exotic J^{PC}=1^{-+} Meson Production in the Reaction pi- p --> eta pi- p at 18 GeV/c

Details of the analysis of the eta pi- system studied in the reaction pi^{-} p --> eta pi^{-} p at 18 GeV/c are given. Separate analyses for the 2 gamma and pi+ pi- pi0 decay modes of the eta are presented. An amplitude analysis of the data indicates the presence of interference between the a(2)(1320)- and a J^{PC}=1^{-+} wave between 1.2 and 1.6 GeV/c^2. The phase difference between these waves shows phase motion not attributable solely to the a(2)(1320)-. The data can be fitted by interference between the a(2)(1320)- and an exotic 1^{-+} resonance with M = 1370 +-16 +50 -30} MeV/c^2 and Gamma = 385 +- 40 +65 -105 MeV/c^2. Our results are compared with those of other experiments.Comment: 50 pages of text and 34 figure

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group

Background: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. Patients and methods: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m2 over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. Results: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. Conclusions: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administratio

Identifying the Location in the Host Galaxy of the Short GRB 111117A with the Chandra Sub-arcsecond Position

We present our successful Chandra program designed to identify, with sub-arcsecond accuracy, the X-ray afterglow of the short GRB 111117A, which was discovered by Swift and Fermi. Thanks to our rapid target of opportunity request, Chandra clearly detected the X-ray afterglow, though no optical afterglow was found in deep optical observations. The host galaxy was clearly detected in the optical and near-infrared band, with the best photometric redshift of z=1.31_{-0.23}^{+0.46} (90% confidence), making it one of the highest known short GRB redshifts. Furthermore, we see an offset of 1.0 +- 0.2 arcseconds, which corresponds to 8.4 +- 1.7 kpc, between the host and the afterglow position. We discuss the importance of using Chandra for obtaining sub-arcsecond X-ray localizations of short GRB afterglows to study GRB environments.Comment: 17 pages, 11 figures, accepted for publication in Ap

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.Fil: Hutchison, M. A.. National Institutes of Health; Estados UnidosFil: Gu, X.. National Institutes of Health; Estados UnidosFil: Adrover, Martín Federico. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Lee, M. R.. National Institutes of Health; Estados UnidosFil: Hnasko, T. S.. University of California at San Diego; Estados UnidosFil: Alvarez, V. A.. National Institutes of Health; Estados UnidosFil: Lu, W.. National Institutes of Health; Estados Unido