The MAREDAT global database of high performance liquid chromatography marine pigment measurements

A global pigment database consisting of 35 634 pigment suites measured by high performance liquid chromatography was assembled in support of the MARine Ecosytem DATa (MAREDAT) initiative. These data originate from 136 field surveys within the global ocean, were solicited from investigators and databases, compiled, and then quality controlled. Nearly one quarter of the data originates from the Laboratoire d\u27Oceanographie de Villefranche (LOV), with an additional 17% and 19% stemming from the US JGOFS and LTER programs, respectively. The MAREDAT pigment database provides high quality measurements of the major taxonomic pigments including chlorophylls a and b, 19\u27-butanoyloxyfucoxanthin, 19\u27-hexanoyloxyfucoxanthin, alloxanthin, divinyl chlorophyll a, fucoxanthin, lutein, peridinin, prasinoxanthin, violaxanthin and zeaxanthin, which may be used in varying combinations to estimate phytoplankton community composition. Quality control measures consisted of flagging samples that had a total chlorophyll a concentration of zero, had fewer than four reported accessory pigments, or exceeded two standard deviations of the log-linear regression of total chlorophyll a with total accessory pigment concentrations. We anticipate the MAREDAT pigment database to be of use in the marine ecology, remote sensing and ecological modeling communities, where it will support model validation and advance our global perspective on marine biodiversity. The original dataset together with quality control flags as well as the gridded MAREDAT pigment data may be downloaded from PANGAEA: http://doi.pangaea.de/10.1594/PANGAEA.793246

Rethinking America's Illegal Drug Policy

This paper provides a critical review of the empirical and theoretical literatures on illegal drug policy, including cross-country comparisons, in order to evaluate three drug policy regimes: criminalization, legalization and “depenalization.” Drawing on the experiences of various states, as well as countries such as Portugal and the Netherlands, the paper attempts to identify cost-minimizing policies for marijuana and cocaine by assessing the differing ways in which the various drug regimes would likely change the magnitude and composition of the social costs of each drug. The paper updates and evaluates Jeffrey Miron’s 1999 national time series analysis of drug prohibition spending and the homicide rate, which underscores the lack of a solid empirical base for assessing the theoretically anticipated crime drop that would come from drug legalization. Nonetheless, the authors conclude that given the number of arrests for marijuana possession, and the costs of incarceration and crime systemic to cocaine criminalization, the current regime is unlikely to be cost-minimizing for either marijuana or cocaine.

Therapeutic Drug Monitoring for Slow Response to Tuberculosis Treatment in a State Control Program, Virginia, USA

TOC summary: Diabetes was associated with increased risk for slow response and low rifampin levels

Linezolid Clearance During Continuous Venovenous Hemodiafiltration: A Case Report

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90207/1/phco.23.8.1071.32874.pd

Pharmacokinetic Modeling, Simulation, and Development of a Limited Sampling Strategy of Cycloserine in Patients with Multidrug-/Extensively Drug-Resistant Tuberculosis

BACKGROUND AND OBJECTIVE: Multidrug-resistant tuberculosis has much poorer treatment outcomes compared with drug-susceptible tuberculosis because second-line drugs for treating multidrug resistant tuberculosis are less effective and are frequently associated with side effects. Optimization of drug treatment is urgently needed. Cycloserine is a second-line tuberculosis drug with variable pharmacokinetics and thus variable exposure when programmatic doses are used. The objective of this study was to develop a population pharmacokinetic model of cycloserine to assess drug exposure and to develop a limited sampling strategy for cycloserine exposure monitoring. MATERIAL AND METHODS: Patients with multidrug-/extensively drug-resistant tuberculosis who were treated for > 7 days with cycloserine were eligible for inclusion. Patients received cycloserine 500 mg (body weight ≤ 50 kg) or 750 mg (body weight > 50 kg) once daily. MW/Pharm 3.83 (Mediware, Groningen, The Netherlands) was used to parameterize the population pharmacokinetic model. The model was compared with pharmacokinetic values from the literature and evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset. Monte Carlo simulations were used to develop a limited sampling strategy. RESULTS: Cycloserine plasma concentration vs time curves were obtained from 15 hospitalized patients (nine male, six female, median age 35 years). Mean dose/kg body weight was 11.5 mg/kg (standard deviation 2.04 mg/kg). Median area under the concentration-time curve over 24 h (AUC0-24 h) of cycloserine was 888 h mg/L (interquartile range 728-1252 h mg/L) and median maximum concentration of cycloserine was 23.31 mg/L (interquartile range 20.14-33.30 mg/L). The final population pharmacokinetic model consisted of the following pharmacokinetic parameters [mean (standard deviation)]: absorption constant Ka_po of 0.39 (0.31) h-1, distribution over the central compartment (Vd) of 0.54 (0.26) L/kg LBM, renal clearance as fraction of the estimated glomerular filtration rate of 0.092 (0.038), and metabolic clearance of 1.05 (0.75) L/h. The population pharmacokinetic model was successfully evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset of Chinese patients (difference of 14.6% and 19.5% in measured and calculated concentrations and AUC0-24 h, respectively). Root-mean-squared-errors found in predicting the AUC0-24 h using a one- (4 h) and a two- (2 h and 7 h) limited sampling strategy were 1.60% and 0.14%, respectively. CONCLUSIONS: This developed population pharmacokinetic model can be used to calculate cycloserine concentrations and exposure in patients with multidrug-/extensively drug-resistant tuberculosis. This model was successfully validated by internal and external validation methods. This study showed that the AUC0-24 h of cycloserine can be estimated in patients with multidrug-/extensively drug-resistant tuberculosis using a 1- or 2-point limited sampling strategy in combination with the developed population pharmacokinetic model. This strategy can be used in studies to correlate drug exposure with clinical outcome. This study also showed that good target attainment rates, expressed by time above the minimal inhibitory concentration, were obtained for cycloserine with a minimal inhibitory concentration of 5 and 10 mg/L, but low rates with a minimal inhibitory concentration of 20 and 32.5 mg/L

Lateralization of Simulated Sources and Echoes Differing in Frequency Based on Interaural Temporal Differences

This study examined listeners’ ability to process interaural temporal differences (ITDs) in one of two sequential sounds when the two differed in spectral content. A correlational analysis assessed weights given to ITDs of simulated source and echo pulses for echo delays of 8–128ms for conditions in which responses were based on the source or echo, a 3000-Hz Gaussian (target) pulse. The other (distractor) pulse was spectrally centered at 1500, 2000, 3000, 4000, or 5000 Hz. Also measured were proportion correct and proportion of responses predicted from the weights. Regardless of whether the echo or source pulse served as the target, target weight, and proportion correct increased with increasing distractor frequency, consistent with low-frequency dominance [Divenyi, J. Acoust. Soc. Am. 91, 1078–1084 (1992)]. Effects of distractor frequency were observed at echo delays out to 128 ms when the source served as the target, but only out to 64 ms when the echo served as the target. At echo delays beyond 8 ms, recency effects were exhibited with higher proportions correct obtained for judgments based on the echo pulse than the source pulse

Exposure to environmentally persistent free radicals during gestation lowers energy expenditure and impairs skeletal muscle mitochondrial function in adult mice

© 2016 the American Physiological Society. We have investigated the effects of in utero exposure to environmentally persistent free radicals (EPFRs) on growth, metabolism, energy utilization, and skeletal muscle mitochondria in a mouse model of diet-induced obesity. Pregnant mice were treated with laboratory-generated, combustion derived particular matter (MCP230). The adult offspring were placed on a high-fat diet for 12 wk, after which we observed a 9.8% increase in their body weight. The increase in body size observed in the MCP230-exposed mice was not associated with increases in food intake but was associated with a reduction in physical activity and lower energy expenditure. The reduced energy expenditure in mice indirectly exposed to MCP230 was associated with reductions in skeletal muscle mitochondrial DNA copy number, lower mRNA levels of electron transport genes, and reduced citrate synthase activity. Upregulation of key genes involved in ameliorating oxidative stress was also observed in the muscle of MCP230-exposed mice. These findings suggest that gestational exposure to MCP230 leads to a reduction in energy expenditure at least in part through alterations to mitochondrial metabolism in the skeletal muscle

Kinetics and Determining Factors of the Virologic Response to Antiretrovirals during Pregnancy

HIV-infected pregnant women with undetectable plasma HIV RNA concentrations at delivery pose a minimal risk of vertical transmission. We studied the kinetics and the determinants of the virologic response to antiretroviral therapy in 117 consecutive pregnancies. Patients who initiated therapy during pregnancy had a VL decrease of 2 and 2.5 log10 after 4 and 24 weeks, respectively. Therapeutic drug monitoring (TDM) of the protease inhibitors administered in doses recommended for nonpregnant adults resulted in below-target concentrations in 29%, 35%, and 44% of 1st, 2nd, and 3rd trimester measurements, respectively, but low drug concentrations did not correlate with virologic failure. Demographic characteristics, antiretroviral experience prior to pregnancy, baseline VL, or use of specific antiretrovirals did not affect the virologic response. Adherence to ≥95% of prescribed doses and utilization of psychosocial services were associated with undetectable plasma HIV RNA at delivery. In conclusion, the virologic responses of pregnant and nonpregnant adults share similar charactersitics

Characterization of candidate genes in inflammatory bowel disease-associated risk loci

GWAS have linked SNPs to risk of inflammatory bowel disease (IBD), but a systematic characterization of disease-associated genes has been lacking. Prior studies utilized microarrays that did not capture many genes encoded within risk loci or defined expression quantitative trait loci (eQTLs) using peripheral blood, which is not the target tissue in IBD. To address these gaps, we sought to characterize the expression of IBD-associated risk genes in disease-relevant tissues and in the setting of active IBD. Terminal ileal (TI) and colonic mucosal tissues were obtained from patients with Crohn\u27s disease or ulcerative colitis and from healthy controls. We developed a NanoString code set to profile 678 genes within IBD risk loci. A subset of patients and controls were genotyped for IBD-associated risk SNPs. Analyses included differential expression and variance analysis, weighted gene coexpression network analysis, and eQTL analysis. We identified 116 genes that discriminate between healthy TI and colon samples and uncovered patterns in variance of gene expression that highlight heterogeneity of disease. We identified 107 coexpressed gene pairs for which transcriptional regulation is either conserved or reversed in an inflammation-independent or -dependent manner. We demonstrate that on average approximately 60% of disease-associated genes are differentially expressed in inflamed tissue. Last, we identified eQTLs with either genotype-only effects on expression or an interaction effect between genotype and inflammation. Our data reinforce tissue specificity of expression in disease-associated candidate genes, highlight genes and gene pairs that are regulated in disease-relevant tissue and inflammation, and provide a foundation to advance the understanding of IBD pathogenesis