A comparison of nicotine dose estimates in smokers between filter analysis, salivary cotinine, and urinary excretion of nicotine metabolites

RATIONALE: Nicotine uptake during smoking was estimated by either analyzing the metabolites of nicotine in various body fluids or by analyzing filters from smoked cigarettes. However, no comparison of the filter analysis method with body fluid analysis methods has been published. OBJECTIVES: Correlate nicotine uptake estimates between filter analysis, salivary cotinine, and urinary excretion of selected nicotine metabolites to determine the suitability of these methods in estimating nicotine absorption in smokers of filtered cigarettes. MATERIALS AND METHODS: A 5-day clinical study was conducted with 74 smokers who smoked 1–19 mg Federal Trade Commission tar cigarettes, using their own brands ad libitum. Filters were analyzed to estimate the daily mouth exposure of nicotine. Twenty-four-hour urine samples were collected and analyzed for nicotine, cotinine, and 3′-hydroxycotinine plus their glucuronide conjugates. Saliva samples were collected daily for cotinine analysis. RESULTS: Each method correlated significantly (p < 0.01) with the other two. The best correlation was between the mouth exposure of nicotine, as estimated by filter analysis, and urinary nicotine plus metabolites. Multiple regression analysis implies that saliva cotinine and urinary output are dependent on nicotine mouth exposure for multiple days. Creatinine normalization of the urinary metabolites degrades the correlation with mouth exposure. CONCLUSIONS: The filter analysis method was shown to correlate with more traditional methods of estimating nicotine uptake. However, because filter analysis is less complicated and intrusive, subjects can collect samples easily and unsupervised. This should enable improvements in study compliance and future study designs

There Is No Safe Dose of Prions

Understanding the circumstances under which exposure to transmissible spongiform encephalopathies (TSEs) leads to infection is important for managing risks to public health. Based upon ideas in toxicology and radiology, it is plausible that exposure to harmful agents, including TSEs, is completely safe if the dose is low enough. However, the existence of a threshold, below which infection probability is zero has never been demonstrated experimentally. Here we explore this question by combining data and mathematical models that describe scrapie infections in mice following experimental challenge over a broad range of doses. We analyse data from 4338 mice inoculated at doses ranging over ten orders of magnitude. These data are compared to results from a within-host model in which prions accumulate according to a stochastic birth-death process. Crucially, this model assumes no threshold on the dose required for infection. Our data reveal that infection is possible at the very low dose of a 1000 fold dilution of the dose that infects half the challenged animals (ID50). Furthermore, the dose response curve closely matches that predicted by the model. These findings imply that there is no safe dose of prions and that assessments of the risk from low dose exposure are right to assume a linear relationship between dose and probability of infection. We also refine two common perceptions about TSE incubation periods: that their mean values decrease linearly with logarithmic decreases in dose and that they are highly reproducible between hosts. The model and data both show that the linear decrease in incubation period holds only for doses above the ID50. Furthermore, variability in incubation periods is greater than predicted by the model, not smaller. This result poses new questions about the sources of variability in prion incubation periods. It also provides insight into the limitations of the incubation period assay

Assessing the cost of global biodiversity and conservation knowledge

Knowledge products comprise assessments of authoritative information supported by standards, governance, quality control, data, tools, and capacity building mechanisms. Considerable resources are dedicated to developing and maintaining knowledge products for biodiversity conservation, and they are widely used to inform policy and advise decision makers and practitioners. However, the financial cost of delivering this information is largely undocumented. We evaluated the costs and funding sources for developing and maintaining four global biodiversity and conservation knowledge products: The IUCN Red List of Threatened Species, the IUCN Red List of Ecosystems, Protected Planet, and the World Database of Key Biodiversity Areas. These are secondary data sets, built on primary data collected by extensive networks of expert contributors worldwide. We estimate that US$160 million (range: US$116-204 million), plus 293 person-years of volunteer time (range: 278-308 person-years) valued at US$14 million (range US$12-16 million), were invested in these four knowledge products between 1979 and 2013. More than half of this financing was provided through philanthropy, and nearly three-quarters was spent on personnel costs. The estimated annual cost of maintaining data and platforms for three of these knowledge products (excluding the IUCN Red List of Ecosystems for which annual costs were not possible to estimate for 2013 ) is US$6.5 million in total (range: US$6.2-6.7 million). We estimated that an additional US$114 million will be needed to reach pre-defined baselines of data coverage for all the four knowledge products, and that once achieved, annual maintenance costs will be approximately US$12 million. These costs are much lower than those to maintain many other, similarly important, global knowledge products. Ensuring that biodiversity and conservation knowledge products are sufficiently up to date, comprehensive and accurate is fundamental to inform decision-making for biodiversity conservation and sustainable development. Thus, the development and implementation of plans for sustainable long-term financing for them is critical

Transplacental Transmission of Leishmania infantum as a Means for Continued Disease Incidence in North America

Dogs are a favored feeding source for sand flies that transmit human L. infantum infection. Zoonotic visceral leishmaniasis (ZVL) is an emerging problem in some U.S. dog breeds, with over 20% of at-risk Foxhounds infected. Although classically Leishmania is transmitted by infected sand flies which exist in the United States, no role has yet been determined for vector-borne transmission. Means of ongoing L. infantum transmission in U.S. dogs is unknown. Possibilities include transplacental and horizontal/venereal transmission. Aims for this study were to establish whether transplacental transmission occurred in Leishmania-infected U.S. dogs and determine the effect of this transmission on immune recognition of Leishmania. This novel report describes wide-spread infection as identified by kqPCR in 8 day-old pups born to a naturally-infected, seropositive U.S. dog with no travel history. This is the first report of transplacental transmission of L. infantum in naturally-infected dogs in North America. Evidence that mom-to-pup transmission of ZVL may continue disease in an otherwise non-endemic region has significant implications on current control strategies for ZVL. Determining frequency of vertical transmission and incorporating canine sterilization with vector control may have a more significant impact on ZVL transmission to people in endemic areas than current control efforts

Differential Disclosure Across Social Network Ties Among Women Living with HIV

Women’s disclosure of their HIV serostatus across social network ties was examined in a sample of women living in Los Angeles (n = 234), using multivariate random intercept logistic regressions. Women with disclosure-averse attitudes were less likely to disclose, while women with higher CD4+ counts were significantly more likely to disclose, regardless of relationship type. Relative to all other types of relationships, spouses/romantic partners were greater than four times more likely to be the targets of disclosure. Women were more than 2.5 times more likely to disclose to a given network member if that target provided the woman with social support. Social network members whom women believed to be HIV-positive were more than 10 times more likely to be the targets of disclosure. The implications for how social roles and social identities are manifest in these results are discussed, including the implications such an interpretation has for future prevention research

Acute Regulation of Cardiac Metabolism by the Hexosamine Biosynthesis Pathway and Protein O-GlcNAcylation

OBJECTIVE: The hexosamine biosynthesis pathway (HBP) flux and protein O-linked N-acetyl-glucosamine (O-GlcNAc) levels have been implicated in mediating the adverse effects of diabetes in the cardiovascular system. Activation of these pathways with glucosamine has been shown to mimic some of the diabetes-induced functional and structural changes in the heart; however, the effect on cardiac metabolism is not known. Therefore, the primary goal of this study was to determine the effects of glucosamine on cardiac substrate utilization. METHODS: Isolated rat hearts were perfused with glucosamine (0-10 mM) to increase HBP flux under normoxic conditions. Metabolic fluxes were determined by (13)C-NMR isotopomer analysis; UDP-GlcNAc a precursor of O-GlcNAc synthesis was assessed by HPLC and immunoblot analysis was used to determine O-GlcNAc levels, phospho- and total levels of AMPK and ACC, and membrane levels of FAT/CD36. RESULTS: Glucosamine caused a dose dependent increase in both UDP-GlcNAc and O-GlcNAc levels, which was associated with a significant increase in palmitate oxidation with a concomitant decrease in lactate and pyruvate oxidation. There was no effect of glucosamine on AMPK or ACC phosphorylation; however, membrane levels of the fatty acid transport protein FAT/CD36 were increased and preliminary studies suggest that FAT/CD36 is a potential target for O-GlcNAcylation. CONCLUSION/INTERPRETATION: These data demonstrate that acute modulation of HBP and protein O-GlcNAcylation in the heart stimulates fatty acid oxidation, possibly by increasing plasma membrane levels of FAT/CD36, raising the intriguing possibility that the HBP and O-GlcNAc turnover represent a novel, glucose dependent mechanism for regulating cardiac metabolism

Variation in RNA Virus Mutation Rates across Host Cells

It is well established that RNA viruses exhibit higher rates of spontaneous mutation than DNA viruses and microorganisms. However, their mutation rates vary amply, from 10−6 to 10−4 substitutions per nucleotide per round of copying (s/n/r) and the causes of this variability remain poorly understood. In addition to differences in intrinsic fidelity or error correction capability, viral mutation rates may be dependent on host factors. Here, we assessed the effect of the cellular environment on the rate of spontaneous mutation of the vesicular stomatitis virus (VSV), which has a broad host range and cell tropism. Luria-Delbrück fluctuation tests and sequencing showed that VSV mutated similarly in baby hamster kidney, murine embryonic fibroblasts, colon cancer, and neuroblastoma cells (approx. 10−5 s/n/r). Cell immortalization through p53 inactivation and oxygen levels (1–21%) did not have a significant impact on viral replication fidelity. This shows that previously published mutation rates can be considered reliable despite being based on a narrow and artificial set of laboratory conditions. Interestingly, we also found that VSV mutated approximately four times more slowly in various insect cells compared with mammalian cells. This may contribute to explaining the relatively slow evolution of VSV and other arthropod-borne viruses in nature