Pharmacokinetic evaluation of oral dantrolene in the dog

The pharmacokinetics of dantrolene and its active metabolite, 5‐hydroxydantrolene, after a single oral dose of either 5 or 10 mg/kg of dantrolene was determined. The effects of exposure to dantrolene and 5‐hydroxydantrolene on activated whole‐blood gene expression of the cytokines interleukin‐2 (IL‐2) and interferon‐γ (IFN‐γ) were also investigated. When dantrolene was administered at a 5 mg/kg dose, peak plasma concentration (C_max) was 0.43 μg/mL, terminal half‐life (t_1/2) was 1.26 h, and area under the time–concentration curve (AUC) was 3.87 μg·h/mL. For the 10 mg/kg dose, C_max was 0.65 μg/mL, t_1/2 was 1.21 h, and AUC was 5.94 μg·h/mL. For all calculated parameters, however, there were large standard deviations and wide ranges noted between and within individual dogs: t_1/2, for example, ranged from 0.43 to 6.93 h, C_max ratios ranged from 1.05 to 3.39, and relative bioavailability (rF) values ranged from 0.02 to 1.56. While activated whole‐blood expression of IL‐2 and IFN‐γ as measured by qRT‐PCR was markedly suppressed following exposure to very high concentrations (30 and 50 μg/mL, respectively) of both dantrolene and 5‐hydroxydantrolene, biologically and therapeutically relevant suppression of cytokine expression did not occur at the much lower drug concentrations achieved with oral dantrolene dosing.     

Governing the landscape: potential and challenges of integrated approaches to landscape sustainability in Indonesia

Landscape Ecology - In recent years, landscape sustainability, the maintenance and improvement of biodiversity, ecosystem services, and human well-being in landscapes, has become a core objective...     

500,000-year stable carbon isotopic record from devils hole, nevada

The record of carbon-13 (delta(13)C) variations in DH-11 vein calcite core from Devils Hole, Nevada, shows four prominent minima near glacial terminations (glacial-interglacial transitions) V to II. The delta(13)C time series is inversely correlated with the DH-11 oxygen isotope ratio time series and leads it by as much as 7000 years. The delta(13)C variations likely record fluctuations in the delta(13)C of dissolved inorganic carbon of water recharging the aquifer. How such variations are transported 80 kilometers to Devils Hole without obliteration by water-rock reaction remains an enigma. The record may reflect (i) global variations in the delta(13)C of atmospheric CO(2) and, hence, the delta(13)C of continental biomass or (ii) variations in extent and density of vegetation in the southern Great Basin. In the latter case, delta(13)C minima at 414, 334, 246, and 133 thousand years ago mark times of maximum vegetation.     

A 250,000-year climatic record from great basin vein calcite: implications for milankovitch theory

A continuous record of oxygen-18 (delta(18)O) variations in the continental hydrosphere during the middle-to-late Pleistocene has been obtained from a uranium-series dated calcitic vein in the southern Great Basin. The vein was deposited from ground water that moved through Devils Hole-an open fault zone at Ash Meadows, Nevada-between 50 and 310 ka (thousand years ago). The configuration of the delta(18)O versus time curve closely resembles the marine and Antarctic ice core (Vostok) delta(18)O curves; however, the U-Th dates indicate that the last interglacial stage (marine oxygen isotope stage 5) began before 147 +/- 3 ka, at least 17,000 years earlier than indicated by the marine delta(18)O record and 7,000 years earlier than indicated by the less well dated Antarctic delta(18)O record. This discrepancy and other differences in the timing of key climatic events suggest that the indirectly dated marine delta(18)O chronology may need revision and that orbital forcing may not be the principal cause of the Pleistocene ice ages.     

Genomic sequencing and methylation analysis by ligation mediated PCR

Genomic sequencing permits studies of in vivo DNA methylation and protein-DNA interactions, but its use has been limited because of the complexity of the mammalian genome. A newly developed genomic sequencing procedure in which a ligation mediated polymerase chain reaction (PCR) is used generates high quality, reproducible sequence ladders starting with only 1 microgram of uncloned mammalian DNA per reaction. Different sequence ladders can be created simultaneously by inclusion of multiple primers and visualized separately by rehybridization. Relatively little radioactivity is needed for hybridization and exposure times are short. Methylation patterns in genomic DNA are readily detectable; for example, 17 CpG dinucleotides in the 5' region of human X-linked PGK-1 (phosphoglycerate kinase 1) were found to be methylated on an inactive human X chromosome, but unmethylated on an active X chromosome.     

The structure of arthropod hemocyanins

Hemocyanins are large multi-subunit copper proteins that transport oxygen in many arthropods and molluscs. Comparison of the amino acid sequence data for seven different subunits of arthropod hemocyanins from crustaceans and chelicerates shows many highly conserved residues and extensive regions of near identity. This correspondence can be matched closely with the three domain structure established by x-ray crystallography for spiny lobster hemocyanin. The degree of identity is particularly striking in the second domain of the subunit that contains the six histidines which ligate the two oxygen-binding copper atoms. The polypeptide architecture of spiny lobster hemocyanin appears to be the same in all arthropods. This structure must therefore be at least as old as the estimated time of divergence of crustaceans and chelicerates, about 540 to 600 million years ago.     

Mass-Spectrometric 230Th-234U-238U Dating of the Devils Hole Calcite Vein

The Devils Hole calcite vein contains a long-term climatic record, but requires accurate chronologic control for its interpretation. Mass-spectrometric U-series ages for samples from core DH-11 yielded (230)Th ages with precisions ranging from less than 1,000 years (2sigma) for samples younger than approximately 140 ka (thousands of years ago) to less than 50,000 years for the oldest samples ( approximately 566 ka). The (234)U/(238)U ages could be determined to a precision of approximately 20,000 years for all ages. Calcite accumulated continuously from 566 ka until approximately 60 ka at an average rate of 0.7 millimeter per 10(3) years. The precise agreement between replicte analyses and the concordance of the (230)Th/(238)U (234)U/(238)U ages for the oldest samples indicate that the DH-11 samples were closed systems and validate the dating technique in general.