Structural studies of the polysaccharide from Aloe plicatilis Miller

The interior part of the leaves of the succulent Aloe plicatilis Miller (Liliaceae) consists of a transparent jelly containing mainly an acetylated glucomannan. Structural studies show that glucose and mannose, which are present in the ratio 1:2.8, are (1 → 4)-linked and that there is no branching. The hexose residues are randomly and variously substituted at positions 2,3,6, 2,3, 2, and 3 with acetyl groups; a small proportion of the sugar units is unsubstituted.     

Studies on the metabolism of 2,4′-isobutylphenylpropionic acid (ibuprofen) by gas chromatography and mass spectrometry : Dialysis fluid, a convenient medium for studies on drug metabolism

2,4′-Isobutylphenylpropionic acid (ibuprofen) has previously been demonstrated to yield four urinary metabolites, formed by ω1-, ω2- and ω3-hydroxylation and by a further oxidation of the primary alcohol of the ω1-hydroxylated metabolite to a carboxyl group. By synthesis and gas chromatography—mass spectrometry the suggested structure of the ω3-hydroxylated metabolite was verified in the present study. Moreover, a new metabolite, 2,4′-carboxyphenylpropionic acid, was demonstrated to be present in substantial amounts in dialysis fluid from a nephrectomized patient. In such patients ingested drugs cannot be excreted in the urine, but are metabolized to end products. Thus, dialysis fluid may be a convenient medium for studies on drug metabolism.     

The long-term effect of current and new interventions on the new case detection of leprosy: a modeling study

Background

Although the number of newly detected leprosy cases has decreased globally, a quarter of a million new cases are detected annually and eradication remains far away. Current options for leprosy prevention are contact tracing and BCG vaccination of infants. Future options may include chemoprophylaxis and early diagnosis of subclinical infections. This study compared the predicted trends in leprosy case detection of future intervention strategies.

Methods

Seven leprosy intervention scenarios were investigated with a microsimulation model (SIMCOLEP) to predict future leprosy trends. The baseline scenario consisted of passive case detection, multidrug therapy, contact tracing, and BCG vaccination of infants. The other six scenarios were modifications of the baseline, as follows: no contact tracing; with chemoprophylaxis; with early diagnosis of subclinical infections; replacement of the BCG vaccine with a new tuberculosis vaccine ineffective against Mycobacterium leprae (“no BCG”); no BCG with chemoprophylaxis; and no BCG with early diagnosis.

Findings

Without contact tracing, the model predicted an initial drop in the new case detection rate due to a delay in detecting clinical cases among contacts. Eventually, this scenario would lead to new case detection rates higher than the baseline program. Both chemoprophylaxis and early diagnosis would prevent new cases due to a reduction of the infectious period of subclinical cases by detection and cure of these cases. Also, replacing BCG would increase the new case detection rate of leprosy, but this effect could be offset with either chemoprophylaxis or early diagnosis.

Conclusions

This study showed that the leprosy incidence would be reduced substantially by good BCG vaccine coverage and the combined strategies of contact tracing, early diagnosis, and treatment of infection and/or chemoprophylaxis among household contacts. To effectively interrupt the transmission of M. leprae, it is crucial to continue developing immuno- and chemoprophylaxis strategies and an effective test for diagnosing subclinical infections.     

Estimating past and future male loss in three Zambian lion populations

African lions (Panthera leo) are declining continent-wide, with protected area populations subject to a variety of anthropogenic effects. Zambia contains viable lion populations of considerable importance for photographic and hunting tourism, but long-term lion demographic data do not exist to guide recent management directives and population projections under different strategies. We described population size, as well as age and sex structure of lions in 3 Zambian national park populations bordering hunting areas, and found them to be male-depleted relative to other systems. We then estimated rates of adult male loss leading to male depletion in these populations and the effect of different future hunting management options on population characteristics. Predictions from matrix population models constructed within a Bayesian framework confirmed that the observed population structure was likely due to high rates of adult male loss and that instituting age limits on male harvests with quota reductions would reduce male depletion, improve tourism by providing older and more abundant males, and slightly increase population size. Reducing male mortality from wire snare poaching would also result in similar demographic impacts, and in concert with changes in hunting regulations would substantially improve the quality and quantity of adult male lions. However, model results varied depending on whether we assumed historical population stability. Predictions assuming negative historical growth rate indicated that substantially more conservative lion harvest management is warranted. We discuss the relevance of these findings for maintaining viable lion populations in and around protected areas in Zambia. © 2012 The Wildlife Society.     

MyD88- and Bruton's tyrosine kinase-mediated signals are essential for T cell-independent pathogen-specific IgM responses

Bacteremia is one of the leading causes of death by infectious disease. To understand the immune mechanisms required for the rapid control of bacteremia, we studied Borrelia hermsii, a bacterial pathogen that colonizes the blood stream of humans and rodents to an extremely high density. A T cell-independent IgM response is essential and sufficient for controlling B. hermsii bacteremia. Mice deficient in Bruton's tyrosine kinase (Btk), despite their known defect in BCR signaling, generated B. hermsii-specific IgM and resolved bacteremia, suggesting that an alternative activation or costimulatory pathway remained functional for T cell-independent B cells in Btk(-/-) mice. B. hermsii contains putative ligands for TLRs, and we found that mice deficient in TLR1, TLR2, or the TLR adaptor MyD88 generated anti-B. hermsii IgM with delayed kinetics and suffered more severe episodes of bacteremia. In striking contrast to the anti-B. hermsii IgM response in mice deficient only in Btk, mice deficient in both Btk and MyD88 were entirely incapable of generating B. hermsii-specific Ab or resolving bacteremia. The response to a T cell-dependent model Ag was unaffected in Btk(-/-) x MyD88(-/-) mice. These results suggest that MyD88 specifically promotes T cell-independent BCR signaling and that, in the absence of Btk, this TLR-mediated stimulation is a required component of this signal.     

TLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat

Viral infections are associated epidemiologically with the expression of type 1 diabetes in humans, but the mechanisms underlying this putative association are unknown. To investigate the role of viruses in diabetes, we used a model of viral induction of autoimmune diabetes in genetically susceptible biobreeding diabetes-resistant (BBDR) rats. BBDR rats do not develop diabetes in viral-Ab-free environments, but approximately 25% of animals infected with the parvovirus Kilham rat virus (KRV) develop autoimmune diabetes via a mechanism that does not involve beta cell infection. Using this model, we recently documented that TLR agonists synergize with KRV infection and increase disease penetrance. We now report that KRV itself activates innate immunity through TLR ligation. We show that KRV infection strongly stimulates BBDR splenocytes to produce the proinflammatory cytokines IL-6 and IL-12p40 but not TNF-alpha. KRV infection induces high levels of IL-12p40 by splenic B cells and Flt-3-ligand-induced bone marrow-derived dendritic cells (DCs) but only low levels of IL-12p40 production by thioglycolate-elicited peritoneal macrophages or GM-CSF plus IL-4-induced bone marrow-derived DCs. KRV-induced cytokine production is blocked by pharmacological inhibitors of protein kinase R and NF-kappaB. Genomic KRV DNA also induces BBDR splenocytes and Flt-3L-induced DCs from wild-type but not TLR9-deficient mice to produce IL-12p40; KRV-induced up-regulation of B lymphocytes can be blocked by TLR9 antagonists including inhibitory CpG and chloroquine. Administration of chloroquine to virus-infected BBDR rats decreases the incidence of diabetes and decreases blood levels of IL-12p40. Our data implicate the TLR9-signaling pathway in KRV-induced innate immune activation and autoimmune diabetes in the BBDR rat.     

Evidence for a trade-off between early growth and tooth wear in Svalbard reindeer

Ruminants depend on efficient physical degradation of forage through chewing to increase the surface area of the food particles presented to the microflora. Fossil evidence suggests that increased molar height is an adaptation for wear tolerance in dry ecosystems with sparse vegetation, but no study has shown selection pressure for hypsodonty in contemporary ruminants. We explored the relationships between particle size in rumen, tooth wear (scanned molar occlusal topography), age and body mass of female Svalbard reindeer living in an arctic desert at 78 degrees latitude on Svalbard. We predicted that (H1) if the rumen particle size is determined mainly by constraints due to tooth wear, and if tooth wear is mainly a function of age, average particle size in rumen should increase with age. From allometric relations it is known that larger individuals can survive on a lower-quality diet, we therefore predicted (H2) larger particle sizes with increases in (ln) body mass, irrespective of age and wear. Lastly, if there is a trade-off between growth and tooth wear in dry ecosystems (a selection pressure for hypsodonty), we predicted (H3) that teeth of heavier animals should be more worn than those of lighter animals of the same age. The proportion of small particles (<1.0 mm) decreased rapidly with increasing age (consistent with H1). Heavier females within an age class had more worn teeth (consistent with H3) than lighter ones. A close-to-isometric relationship between particle size and body mass suggested that heavier animals partly compensated for reduced tooth efficiency by chewing more. We provide the first evidence of a trade-off between fast early growth and wear (a somatic cost) of a senescence-related trait--the structure and height of the molar--in a wild ruminant inhabiting an arctic desert where selection pressure for increased tooth height is expected. This suggests that foraging conditions are more extreme than the environment in which the species originally evolved.