California Wildfires of 2008: Coarse and Fine Particulate Matter Toxicity

BackgroundDuring the last week of June 2008, central and northern California experienced thousands of forest and brush fires, giving rise to a week of severe fire-related particulate air pollution throughout the region. California experienced PM(10-2.5) (particulate matter with mass median aerodynamic diameter > 2.5 mum to < 10 mum; coarse ) and PM(2.5) (particulate matter with mass median aerodynamic diameter < 2.5 mum; fine) concentrations greatly in excess of the air quality standards and among the highest values reported at these stations since data have been collected.ObjectivesThese observations prompt a number of questions about the health impact of exposure to elevated levels of PM(10-2.5) and PM(2.5) and about the specific toxicity of PM arising from wildfires in this region.MethodsToxicity of PM(10-2.5) and PM(2.5) obtained during the time of peak concentrations of smoke in the air was determined with a mouse bioassay and compared with PM samples collected under normal conditions from the region during the month of June 2007.ResultsConcentrations of PM were not only higher during the wildfire episodes, but the PM was much more toxic to the lung on an equal weight basis than was PM collected from normal ambient air in the region. Toxicity was manifested as increased neutrophils and protein in lung lavage and by histologic indicators of increased cell influx and edema in the lung.ConclusionsWe conclude that the wildfire PM contains chemical components toxic to the lung, especially to alveolar macrophages, and they are more toxic to the lung than equal doses of PM collected from ambient air from the same region during a comparable season

Solid polymeric microparticles enhance the delivery of siRNA to macrophages in vivo

Therapeutics based on small interfering RNA (siRNA) have a great clinical potential; however, delivery problems have limited their clinical efficacy, and new siRNA delivery vehicles are greatly needed. In this report, we demonstrate that submicron particles (800–900 nm) composed of the polyketal PK3 and chloroquine, termed as the PKCNs, can deliver tumor necrosis factor-α (TNF-α) siRNA in vivo to Kupffer cells efficiently and inhibit gene expression in the liver at concentrations as low as 3.5 μg/kg. The high delivery efficiency of the PKCNs arises from the unique properties of PK3, which can protect siRNA from serum nucleases, stimulate cell uptake and trigger a colloid osmotic disruption of the phagosome and release encapsulated siRNA into the cell cytoplasm. We anticipate numerous applications of the PKCNs for siRNA delivery to macrophages, given their high delivery efficiency, and the central role of macrophages in causing diseases such as hepatitis, liver cirrhosis and chronic renal disease

PET/CT Imaging of c-Myc Transgenic Mice Identifies the Genotoxic N-Nitroso-Diethylamine as Carcinogen in a Short-Term Cancer Bioassay

Background: More than 100,000 chemicals are in use but have not been tested for their safety. To overcome limitations in the cancer bioassay several alternative testing strategies are explored. The inability to monitor non-invasively onset and progression of disease limits, however, the value of current testing strategies. Here, we report the application of in vivo imaging to a c-Myc transgenic mouse model of liver cancer for the development of a short-term cancer bioassay. Methodology/Principal Findings: mCT and 18 F-FDG mPET were used to detect and quantify tumor lesions after treatment with the genotoxic carcinogen NDEA, the tumor promoting agent BHT or the hepatotoxin paracetamol. Tumor growth was investigated between the ages of 4 to 8.5 months and contrast-enhanced mCT imaging detected liver lesions as well as metastatic spread with high sensitivity and accuracy as confirmed by histopathology. Significant differences in the onset of tumor growth, tumor load and glucose metabolism were observed when the NDEA treatment group was compared with any of the other treatment groups. NDEA treatment of c-Myc transgenic mice significantly accelerated tumor growth and caused metastatic spread of HCC in to lung but this treatment also induced primary lung cancer growth. In contrast, BHT and paracetamol did not promote hepatocarcinogenesis. Conclusions/Significance: The present study evidences the accuracy of in vivo imaging in defining tumor growth, tumor load, lesion number and metastatic spread. Consequently, the application of in vivo imaging techniques to transgeni

Antihyperalgesia by α2-GABAA Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites

Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABAA receptors (GABAARs) containing α2 subunits (α2-GABAARs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal α2-GABAARs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABAAR-mutated mice, which either lack α2-GABAARs specifically from the spinal cord, or, which express only benzodiazepine-insensitive α2-GABAARs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all α2-GABAARs were benzodiazepine insensitive. The major (α2-dependent) component of GABAAR-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal α2-GABAARs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target α2-GABAARs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions

Contributions on the development of the reproductive system in Sternotherus odoratus (latreille)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47667/1/441_2004_Article_BF00572100.pd

Effects of dietary carotenoids on mouse lung genomic profiles and their modulatory effects on short-term cigarette smoke exposures

Male C57BL/6 mice were fed diets supplemented with either β-carotene (BC) or lycopene (LY) that were formulated for human consumption. Four weeks of dietary supplementations results in plasma and lung carotenoid (CAR) concentrations that approximated the levels detected in humans. Bioactivity of the CARs was determined by assaying their effects on the activity of the lung transcriptome (~8,500 mRNAs). Both CARs activated the cytochrome P450 1A1 gene but only BC induced the retinol dehydrogenase gene. The contrasting effects of the two CARs on the lung transcriptome were further uncovered in mice exposed to cigarette smoke (CS) for 3 days; only LY activated ~50 genes detected in the lungs of CS-exposed mice. These genes encoded inflammatory-immune proteins. Our data suggest that mice offer a viable in vivo model for studying bioactivities of dietary CARs and their modulatory effects on lung genomic expression in both health and after exposure to CS toxicants

THE PRESENT STATUS OF THE GERM-CELL PROBLEM IN VERTEBRATES

(i) Morphological studies relating to the origin and differentiation of the definitive germ cells in vertebrates have, as indicated, resulted in conflicting views. In many instances two or more competent investigators who have studied the same form have reached different conclusions. (2) Some contend that the germ cells are set aside from the soma during the early stages of embryonic development, and that these alone serve as the progenitors of the functional sex cells. (3) Others recognize an early differentiation of sex cells but hold that these are supplemented by others produced from the somatic epithelium of the gonad in late embryonic or post-embryonic stages. (4) Another group recognizes the early differentiated cells as germ cells but contend that these all degenerate and that the definitive ones are formed from the germinal epithelium. These degenerating germ cells are believed by certain authors to be a phylogenetic recapitulation of the condition in lower forms. (5) Finally, yet another group contends that the so-called primordial germ cells are not germ cells at all but are enlarged cells in some stage of mitosis or in some specific metabolic phase. This group believes that all germ cells are derived from the somatic cells of the germinal epithelium. (6) Experimental work supports the view that the primordial germ cells, which are recognized early, are the progenitors of the definitive sex cells. When these primordial germ cells are prevented from reaching the site of the developing gonad the individual fails to develop sex cells, although a sterile gonad and its associated structures may develop. (7) I suggest that the observed proliferation of germ cells from the germinal epithelium, reported by numerous investigators, can be interpreted in another way by a thorough study of the enlarged germ cells in relation to the epithelium. It seems probable that the cells of the epithelium, which form functional sex elements, are not and never were a part of the mesothelial covering, but are cells which were segregated early, and are merely stored in the epithelium.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74677/1/j.1469-185X.1945.tb00313.x.pd

Antioxidant intervention of smoking-induced lung tumor in mice by vitamin E and quercetin

<p>Abstract</p> <p>Background</p> <p>Epidemiological and in vitro studies suggest that antioxidants such as quercetin and vitamin E (VE) can prevent lung tumor caused by smoking; however, there is limited evidence from animal studies.</p> <p>Methods</p> <p>In the present study, Swiss mouse was used to examine the potential of quercetin and VE for prevention lung tumor induced by smoking.</p> <p>Results</p> <p>Our results suggest that the incidence of lung tumor and tumor multiplicity were 43.5% and 1.00 ± 0.29 in smoking group; Quercetin has limited effects on lung tumor prevention in this in vivo model, as measured by assays for free radical scavenging, reduction of smoke-induced DNA damage and inhibition of apoptosis. On the other hand, vitamin E drastically decreased the incidence of lung tumor and tumor multiplicity which were 17.0% and 0.32 ± 0.16, respectively (p < 0.05); and demonstrated prominent antioxidant effects, reduction of DNA damage and decreased cell apoptosis (p < 0.05). Combined treatment with quercetin and VE in this animal model did not demonstrate any effect greater than that due to vitamin E alone. In addition, gender differences in the occurrence of smoke induced-lung tumor and antioxidant intervention were also observed.</p> <p>Conclusion</p> <p>We conclude that VE might prevent lung tumor induced by smoking in Swiss mice.</p