Phagocytosis as a Biomarker of Immunotoxicity in Wildlife Species Exposed to Environmental Xenobiotics

In the present paper, we are reviewing experimental evidencedemonstrating that phagocytic cells, such as macrophages, maybe used as a biomarker of immunotoxicity in wildlife studies.We will first present data obtained after exposure in vitrowith selected chemicals showing the comparative sensitivityof phagocytic cells from different species. These results demonstratethat, at least for metals, each species produce a similar shapeddose-response curve, although considerate interspecies sensitivityis evident. These results also demonstrate the sensitivity ofthe phagocytic activity, suggesting indeed that this functioncould be used to monitor exposure to chemicals. The similarshaped dose-response curves imply that mechanisms of actionmay also be similar. Furthermore, based on the relative speicessensitivity, sentinel species could be selected for field monitoring.Such an approach may also be useful to establish correctionfactors required to extrapolate results between species. Thissensitivity of the phagocytic activity of macrophages will befurther under controlled conditions in laboratory animal models.Finally, the reliability of this approach will be demonstratedusing case studies with wildlife species.     

The effect of prenatal exposure to the n-butylester of 2,4-dichlorophenoxyacetic acid (2,4-D) on the immune response in mice

Pregnant CD-1 mice were administered the n-butylester of 2,4-dichlorophenoxyacetic acid (2,4-D) by gastric intubation on day 11 of gestation at dosages ranging from 0 to 200 mg/kg (2,4-D content). The immune response in the female offspring was elevated at 6 weeks of age. The humoral immune response, antibody production against sheep red blood cells, was not altered by 2,4-D ester exposure during gestation. The mitogen responses of lymphocytes induced by concanavalin A, a T-lymphocyte mitogen, or by Escherichia coli lipopolysaccharide, a B-lymphocyte mitogen, were reduced in the highest exposure group (200 mg/kg), although the T-lymphocyte suppression was not statistically significant. A similar response pattern was observed in the background nonstimulated lymphocyte cultures, suggesting that the suppression was a generalized lymphocyte abnormality. Evaluation of the mitogen responses using stimulation indices to correct for the variable background responses demonstrated that 2,4-D produced no net suppressive effect in any of the treatment groups. Since in utero 2,4-D ester exposure produced no alterations in humoral immunity and only subtle effects on lymphocyte blastogenesis, it is unlikely to be of any immunotoxicological or immunoteratological significance. Further studies investigating commercial-grade 2,4-D formulations are necessary since these formulations contain other components that may potentially induce alterations in the immune system.     

Biotic unpredictability and sexual reproduction: Do aphid genotype-host genotype interactions favor aphid sexuality?

Summary The possibility that genetic variation among host plants favors sexuality in aphids is explored in the context of Williams and Mitton's (1973) aphid-rotifer model of sib competition. A survey of studies concerning plant resistance to aphids suggests that conditions favoring sexuality can occur where different aphid genotypes are adapted to different host plant species, or where major plant resistance genes differentially affect colonizing success of aphid genotypes. These phenomena are apparently uncommon, however. Thus it is unlikely that genetic heterogeneity among host plants is of major importance for the retention of sexuality in aphid life cycles.     

Polarity of microtubules nucleated by centrosomes and chromosomes of Chinese hamster ovary cells in vitro

The structural and growth polarities of centrosomal and chromosomal microtubules were studied by analyzing the kinetics of growth of these microtubules and those initiated by flagellar seeds. By comparing rates of elongation of centrosomal and flagellar-seeded microtubules, we determined whether the centrosomal microtubules were free to grow at their plus ends only, minus ends ony, or at both ends. Our results show that centrosomal microtubules elongate at a rate corresponding to the addition of subunits at the plus end only. The depolymerization rate was also equivalent to that for the plus end only. Chromosomal microtubule elongation was similar to the centrosome-initiated growth. Since the data do not support the hypothesis that both ends of these spindle microtubules are able to interact with monomer in solution, then growth must occur only distal or only proximal to the organizing centers, implying tha the opposite ends in unavailable for exchange of subunits. Experiments with flagellar-seeded microtubules serving as internal controls indicated that the inactivity of the minus end could not be accounted for by a diffusible inhibitor, suggesting a structural explanation. Since there is no apparent way in which the distal ends may be capped, whereas the proximal ends are embedded in the pericentriolar cloud, we conclude that centrosomal microtubules are oriented with their plus ends distal to the site of nucleation. A similar analysis for chromosomal microtubules suggests that they too must be oriented with their plus ends distal to the site of initiation.     

13C NMR evidence of the slow exchange of tryptophans in dihydrofolate reductase between stable conformations.

¹³C NMR spectra are reported for dihydrofolate reductase of $\text{Streptococcus}\text{faecium}$ labeled with [γ-¹³C]tryptophan. Two of the four tryptophans generate unusual resonances indicating slow exchange of the residues between alternative stable conformations. Since 3′, 5′-dichloromethotrexate sharpens two of the resonances, it apparently locks the corresponding residues into one conformation.     

Recolonization history and large-scale dispersal in the open sea: the case study of the North Atlantic cod, Gadus morhua L.

Most studies of the genetic structure of Atlantic cod have focused on small geographical scales. In the present study, the genetic structure of cod sampled on spawning grounds in the North Atlantic was examined using eight microsatellite loci and the Pan I locus. A total of 954 cod was collected from nine different regions: the Baltic Sea, the North Sea, the Celtic Sea, the Irish Sea and Icelandic waters during spring 2002 and spring 2003, from Norwegian waters and the Faroe Islands (North and West spawning grounds) in spring 2003, and from Canadian waters in 1998. Temporal stability among spawning grounds was observed in Icelandic waters and the Celtic Sea, and no significant difference was observed between the samples from the Baltic Sea and between the samples from Faroese waters. F -statistics showed significant differences between most populations and a pattern of isolation-by-distance was described with microsatellite loci. The Pan I locus revealed the presence of two genetically distinguishable basins, the North-west Atlantic composed of the Icelandic and Canadian samples and the North-east Atlantic composed of all other samples. Permutation of allele sizes at each microsatellite locus among allelic states supported a mutational component to the genetic differentiation, indicating a historical origin of the observed variation. Estimation of the time of divergence was approximately 3000 generations, which places the origin of current genetic pattern of cod in the North Atlantic in the late Weichselian (Wisconsinian period), at last glacial maximum.  © 2008 The Linnean Society of London, Biological Journal of the Linnean Society , 2008, 94 , 315–329.     

Long-term costs and health impact of continued global fund support for antiretroviral therapy

Background

By the end of 2011 Global Fund investments will be supporting 3.5 million people on antiretroviral therapy (ART) in 104 low- and middle-income countries. We estimated the cost and health impact of continuing treatment for these patients through 2020.

Methods and Findings

Survival on first-line and second-line ART regimens is estimated based on annual retention rates reported by national AIDS programs. Costs per patient-year were calculated from country-reported ARV procurement prices, and expenditures on laboratory tests, health care utilization and end-of-life care from in-depth costing studies. Of the 3.5 million ART patients in 2011, 2.3 million will still need treatment in 2020. The annual cost of maintaining ART falls from $1.9 billion in 2011 to $1.7 billion in 2020, as a result of a declining number of surviving patients partially offset by increasing costs as more patients migrate to second-line therapy. The Global Fund is expected to continue being a major contributor to meeting this financial need, alongside other international funders and domestic resources. Costs would be $150 million less in 2020 with an annual 5% decline in first-line ARV prices and $150–370 million less with a 5%–12% annual decline in second-line prices, but $200 million higher in 2020 with phase out of stavudine (d4T), or $200 million higher with increased migration to second-line regimens expected if all countries routinely adopted viral load monitoring. Deaths postponed by ART correspond to 830,000 life-years saved in 2011, increasing to around 2.3 million life-years every year between 2015 and 2020.

Conclusions

Annual patient-level direct costs of supporting a patient cohort remain fairly stable over 2011–2020, if current antiretroviral prices and delivery costs are maintained. Second-line antiretroviral prices are a major cost driver, underscoring the importance of investing in treatment quality to improve retention on first-line regimens.