Fish, epibenthos and macroinfauna were collected in a
Zostera marina bed and nearby unvegetated sediments in the estuary of the Damariscotta River, on the mid-coast of Maine. Samples of epibenthic ...fauna and fish were collected at low tides both during day and night, and samples of infauna at low tides during the day. The mean density of
Zostera shoots in the study area was 335 m
−2. Abundance and species number of fish were greater at night than during the day and greater in eelgrass beds (
Z. marina) than in unvegetated habitats. Daytime fish collections were dominated by Atlantic silversides (
Medinia medinia), while juvenile winter flounder (
Pseudopleuronectes americanus) dominated night collections. Also
Zostera-associated epifaunal abundances and number of species were significantly higher at night than during the day.
Mysis stenolepis,
Idotea balthica and
Littorina obtusata were dominant species in the epifauna samples. Of the total of 37 invertebrate species encountered, only five occurred both in the infaunal and epifaunal samples. Nineteen different taxa were collected from the benthic core samples. The most abundant invertebrate infaunal taxa were sipunculids, the polychaete
Nereis virens, and oligochaetes. Infaunal invertebrate abundances and species diversity were significantly higher in eelgrass beds than in unvegetated sediments. The abundance and number of species of benthic invertebrates were also positively correlated to seagrass biomass. Community diversity values (
H′) were relatively low but fit well in the general pattern of decreasing diversity towards northern latitudes.
CsI(Tl), CsI(Na), and YAP light yield nonproportionality has been characterized using the Compton Coincidence Technique. Measured electron responses were used to calculate photon responses of the ...scintillators studied. These calculated photon responses were then compared with measured photon responses. In addition results from electron response measurements and photon response calculations were compared with previously reported results. While the CsI(Na) electron response was observed to have the largest deviation from proportionality (about 40%), YAP was observed to have a nearly proportional response. The CsI(Tl) calculated photon response was observed to agree to within 1% with measured photon response in this study for all measured photon energies. While the CsI(Na) calculated photon response agreed to within 1% of measured data for photon energies above 60 keV, deviations up to 4% were observed below 60 keV.
FTY720 (Fingolimod™), a synthetic analogue of sphingosine 1-phosphate (S1P), activates four of the five EDG-family S1P receptors and is in a phase-III clinical study for the treatment of multiple ...sclerosis. (S)-FTY720-phosphate (FTY720-P) causes S1P1 receptor internalization and targeting to the proteasomal degradative pathway, and thus functions as an antagonist of S1P1 by depleting the functional S1P1 receptor from the plasma membrane. Here we describe the pharmacological characterization of two unsaturated phosphonate enantiomers of FTY720, (R)- and (S)-FTY720-vinylphosphonate. (R)-FTY720-vinylphosphonate was a full agonist of S1P1 (EC50 20±3nM). In contrast, the (S) enantiomer failed to activate any of the five S1P GPCRs and was a full antagonist of S1P1,3,4 (Ki 384nM, 39nM, and 1190nM, respectively) and a partial antagonist of S1P2, and S1P5. Both enantiomers dose-dependently inhibited lysophospholipase D (recombinant autotaxin) with Ki values in the low micromolar range, although with different enzyme kinetic mechanisms. When injected into mice, both enantiomers caused transient peripheral lymphopenia. (R)- and (S)-FTY720-vinylphosphonates activated ERK1/2, AKT, and exerted an antiapoptotic effect in camptothecin-treated IEC-6 intestinal epithelial cells, which primarily express S1P2 transcripts and traces of S1P5. (S)-FTY720-vinylphosphonate is the first pan-antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. The biological effects of the (R)- and (S)-FTY720-vinylphosphonate analogues underscore the complexity of FTY720 cellular targets.
Abstract Objective To estimate the long-term cost-effectiveness of adding pioglitazone versus placebo to standard treatment in high-risk patients with type 2 diabetes. Methods The validated CORE ...Diabetes Model was modified to project long-term clinical and cost outcomes associated with pioglitazone versus placebo, based on results from PROactive. The model retained basic structure and functionality, with interdependent Markov submodels, Monte Carlo simulation and user interface. Adjustments to submodels were made to accommodate the PROactive primary end points. The analysis was from the perspective of a third party US health-care payer perspective, projected over a lifetime horizon using a 3% annual discount. Results Over a lifetime horizon, addition of pioglitazone was associated with increased life expectancy (0.237 life-years) and quality-adjusted life expectancy (QALE) 0.166 quality-adjusted life-years (QALYs) versus placebo. Estimated long-term complication rates showed that pioglitazone reduced the number of events versus placebo for most outcomes. Lifetime total direct costs were marginally higher with pioglitazone versus placebo ($272,694 vs. $265,390, difference $7,305). The incremental cost-effectiveness ratio for pioglitazone versus placebo was $44,105 per QALY gained. Probabilistic sensitivity analysis indicated a 55% likelihood that pioglitazone would be considered cost-effective in the United States, with a willingness to pay of $50,000 per QALY gained. Conclusions The addition of pioglitazone to existing therapy in high-risk patients with type 2 diabetes was projected to improve life expectancy, QALE and complication rates compared with placebo. Addition of pioglitazone was in the range generally considered acceptable.
On the basis of nonproportionality data obtained for several scintillators, we have developed a model to describe the carrier dynamics to fit the light yield versus electron energy. The theory of ...Onsager was adapted to explain how the carriers form excitons or sequentially arrive at the activators to promote the ion to an excited state, and the theory of Birks was employed to allow for exciton-exciton annihilation. We then developed a second model to deduce the degradation in resolution that results from nonproportionality by evoking Landau fluctuations, which are essentially variations in the deposited energy density that occur as the high energy electron travels along its trajectory. In general there is agreement with the data, in terms of fitting the nonproportionality curves and reproducing the literature values of nonproportionality's contribution to the scintillator resolution.
The aim of the present study was to evaluate the cost effectiveness of rapid-acting analog insulin relative to regular human insulin in adults with type 1 diabetes mellitus in Germany.
The PRIME ...Diabetes Model, a patient-level, discrete event simulation model, was used to project long-term clinical and cost outcomes for patients with type 1 diabetes from the perspective of a German healthcare payer. Simulated patients had a mean age of 21.5 years, duration of diabetes of 8.6 years, and baseline glycosylated hemoglobin of 7.39%. Regular human insulin and rapid-acting analog insulin regimens reduced glycosylated hemoglobin by 0.312 and 0.402%, respectively. Compared with human insulin, hypoglycemia rate ratios with rapid-acting analog insulin were 0.51 (non-severe nocturnal) and 0.80 (severe). No differences in non-severe diurnal hypoglycemia were modeled. Discount rates of 3% were applied to future costs and clinical benefits accrued over the 50-year time horizon.
In the base-case analysis, rapid-acting analog insulin was associated with an improvement in quality-adjusted life expectancy of 1.01 quality-adjusted life-years per patient (12.54 vs. 11.53 quality-adjusted life-years). Rapid-acting analog insulin was also associated with an increase in direct costs of €4490, resulting in an incremental cost-effectiveness ratio of €4427 per quality-adjusted life-year gained vs. human insulin. Sensitivity analyses showed that the base case was driven predominantly by differences in hypoglycemia; abolishing these differences reduced incremental quality-adjusted life expectancy to 0.07 quality-adjusted life-years, yielding an incremental cost-effectiveness ratio of €74,622 per quality-adjusted life-year gained.
Rapid-acting analog insulin is associated with beneficial outcomes in patients with type 1 diabetes and is likely to be considered cost effective in the German setting vs. regular human insulin.
Yeast lacking mitochondrial superoxide dismutase (MnSOD) display shortened stationary-phase survival and provide a good model system for studying mitochondrial oxidative damage. We observed a marked ...decrease in respiratory function preceding stationary-phase death of yeast lacking MnSOD (sod2Δ). Agents (mitochondrial inhibitors) that are known to increase or decrease superoxide production in submitochondrial particles affected stationary-phase survival in a manner inversely correlated with their effects on superoxide production, implicating superoxide in this mitochondrial disfunction. Similar but less-dramatic effects were observed in wild-type yeast. The activities of certain mitochondrial enzymes were particularly affected. Insod2Δyeast the activity of aconitase, a 4Fe–4S-cluster-containing enzyme located in the matrix, was greatly and progressively decreased as the cells established stationary phase. Succinate dehydrogenase activity also decreased in MnSOD mutants; cytochrome oxidase and ATPase activities did not. Aconitase could be reactivated by addition of materials required for cluster assembly (Fe3+and a sulfur source), both in extracts andin vivo,indicating that inactivation of the enzyme was by disassembly of the cluster. Our results support the conclusion that superoxide is generated in the mitochondriain vivoand under physiological conditions and that MnSOD is the primary defense against this toxicity. When the balance between superoxide generation and MnSOD activity is disrupted, superoxide mediates iron release from mitochondrial iron–sulfur clusters, leading first to loss of mitochondrial function and then to death, independently of mtDNA damage. These results raise the possibility that similar processes may occur in higher eukaryotes.
PDF
