Incorporating Scale Dependence in Disease Burden Estimates: The Case of Human African Trypanosomiasis in Uganda

Background

The WHO has established the disability-adjusted life year (DALY) as a metric for measuring the burden of human disease and injury globally. However, most DALY estimates have been calculated as national totals. We mapped spatial variation in the burden of human African trypanosomiasis (HAT) in Uganda for the years 2000–2009. This represents the first geographically delimited estimation of HAT disease burden at the sub-country scale.

Methodology/Principal Findings

Disability-adjusted life-year (DALY) totals for HAT were estimated based on modelled age and mortality distributions, mapped using Geographic Information Systems (GIS) software, and summarised by parish and district. While the national total burden of HAT is low relative to other conditions, high-impact districts in Uganda had DALY rates comparable to the national burden rates for major infectious diseases. The calculated average national DALY rate for 2000–2009 was 486.3 DALYs/100 000 persons/year, whereas three districts afflicted by rhodesiense HAT in southeastern Uganda had burden rates above 5000 DALYs/100 000 persons/year, comparable to national GBD 2004 average burden rates for malaria and HIV/AIDS.

Conclusions/Significance

These results provide updated and improved estimates of HAT burden across Uganda, taking into account sensitivity to under-reporting. Our results highlight the critical importance of spatial scale in disease burden analyses. National aggregations of disease burden have resulted in an implied bias against highly focal diseases for which geographically targeted interventions may be feasible and cost-effective. This has significant implications for the use of DALY estimates to prioritize disease interventions and inform cost-benefit analyses.     

Emergence of new variants of antibiotic resistance genomic islands among multidrug-resistant Salmonella enterica in poultry

Non-typhoidal Salmonella enterica (NTS) are diverse and important bacterial pathogens consisting of more than 2600 different serovars, with varying host-specificity. Here, we characterized the poultry-associated serovars in Israel, analysed their resistome and illuminated the molecular mechanisms underlying common multidrug resistance (MDR) patterns. We show that at least four serovars including Infantis, Muenchen, Newport and Virchow present a strong epidemiological association between their temporal trends in poultry and humans. Worrisomely, 60% from all of the poultry isolates tested (n = 188) were multidrug resistant, mediated by chromosomal SNPs and different mobile genetics elements. A novel streptomycin-azithromycin resistance island and previously uncharacterized versions of the mobilized Salmonella genomic island 1 (SGI1) were identified and characterized in S. Blockley and S. Kentucky isolates respectively. Moreover, we demonstrate that the acquisition of SGI1 does not impose fitness cost during growth under nutrient-limited conditions or in the context of Salmonella infection in the mouse model. Overall, our data emphasize the role of the poultry production as a pool of specific epidemic MDR strains and autonomous genetic elements, which confer resistance to heavy metals and medically relevant antibiotics. These are likely to disseminate to humans via the food chain and fuel the increasing global antibiotic resistance crisis.     

Cyclic AMP-dependent protein kinase type I mediates the inhibitory effects of 3',5'-cyclic adenosine monophosphate on cell replication in human T lymphocytes.

Human T lymphocytes were used as a model system to study the expression and roles of cAMP-dependent protein kinase isozymes (cAKI and cAKII) in cAMP-induced inhibition of cell replication. Human peripheral blood T lymphocytes expressed mRNA for the alpha-subforms (RI alpha and RII alpha) of the regulatory subunits of cAKI and cAKII and for the alpha- and beta-subforms (C alpha and C beta) of the catalytic subunits of cAK. At the protein level, RI alpha represented approximately 75% of the total R subunit activity, whereas RII alpha (phospho and dephospho forms) accounted for the remaining 25%. RII beta was not detected at either the mRNA or the protein level. The RI alpha protein was mainly (greater than 75%) cytosolic, whereas RII alpha was almost exclusively (greater than 90%) particulate associated. Treatment of proliferating T lymphocytes (activated through the CD3 cell surface marker) with 10 different cAMP analogs demonstrated that all inhibited cell replication in a concentration-dependent manner. The potency (as measured by the concentration giving 50% inhibition, IC50) of the cAMP analogs ranged from 30 microM for 8-chlorophenylthio-cAMP to 1100 microM for 8-piperidino-cAMP. A cAMP analog pair directed to activate cAKI (8-aminohexylamino-cAMP and 8-piperidino-cAMP) synergized in the inhibition of T lymphocyte proliferation, whereas a cAKII-directed cAMP analog pair (8-chlorophenylthio-cAMP and N6-benzoyl-cAMP) did not. We conclude that activation of cAKI is sufficient to inhibit T lymphocyte proliferation. The membrane-bound cAKII may mediate cAMP actions not related to cell replication.     

Notes on the behaviour of lumpfish in sea pens with and without Atlantic salmon present

The behaviour of lumpfish, Cyclopterus lumpus L., in sea pens, with and without Atlantic salmon, Salmo salar L., present, was assessed by underwater camera technology. Behaviour was classified by recording the principal activity of individual fish for 30-s intervals. The majority of daylight time was spent actively foraging for food. Antagonistic behaviour between Atlantic salmon and lumpfish was not observed during the whole experimental period and no mortality was seen in either species. Cleaning behaviour, but at low frequency, was observed as lumpfish cleaned sea lice off Atlantic salmon. Significantly lower sea lice infection levels were seen on Atlantic salmon when reared together with lumpfish compared to the control group without lumpfish. Feeding behaviour can be classified as strongly opportunistic.     

Same barcode,different biology: differential patterns of infectivity,specificity and pathogenicity in two almost identical parasite strains

Two Norwegian isolates of the monogenean Gyrodactylus salaris Malmberg, 1957 with identical cytochrome c oxidase subunit I barcodes from different hosts, show highly divergent biological and behavioural characteristics. The Lierelva parasite strain, typically infecting Atlantic salmon, Salmo salar L., grew exponentially on Atlantic salmon, but the Pålsbufjorden parasite strain, commonly infecting Arctic charr, Salvelinus alpinus L., grew slowly on both hosts and was non-pathogenic to Atlantic salmon. Both parasite strains reproduced successfully on Arctic charr, but the Atlantic salmon-infecting Lierelva strain grew faster on both hosts. Experiments with isolated worms revealed differences in reproductive rates which may account for the observed population differences. Atlantic salmon parasites consistently gave birth at an earlier age than the Arctic charr parasites, with the differential increasing from 1 day for the first birth up to 2–4 days for the third birth. Arctic charr-infecting parasites were more active on Atlantic salmon than salmon parasites on Arctic charr, a behavioural strategy leading to enhanced G. salaris mortality. Sequencing of 10 kb of nuclear genomic markers revealed only four single nucleotide polymorphisms, confirming that isolates of G. salaris with differences in fitness traits influencing establishment, fecundity and behaviour may be remarkably similar at a molecular level. The framework for reporting and control of G. salaris requires re-appraisal in light of the discovery of variants with such divergent biology.     

Immunohistochemical evidence for an endocrine/paracrine role for ghrelin in the reproductive tissues of sheep

Background  

The gut hormone, ghrelin, is involved in the neuroendocrine and metabolic responses to hunger. In monogastric species, circulating ghrelin levels show clear meal-related and body weight-related changes. The pattern of secretion and its role in ruminant species is less clear. Ghrelin acts via growth hormone secretagogue receptors (GHSR-1a) to alter food intake, fat utilization, and cellular proliferation. There is also evidence that ghrelin is involved in reproductive function. In the present study we used immunohistochemistry to investigate the presence of ghrelin and GHSR-1a in sheep reproductive tissues. In addition, we examined whether ghrelin and GHSR-1a protein expression is developmentally regulated in the adult and fetal ovine testis, and whether there is an association with markers of cellular proliferation, i.e. stem cell factor (SCF) and proliferating cell nuclear antigen (PCNA).     

Ontogenetic changes in habitat use by whitefish,Coregonus lavaretus

Synopsis The whitefish, Coregonus lavaretus, in the lake Mj?sa exhibited two niche changes during their life cycle. Juveniles (< 25 cm body length) were confined to the shallow (0–30 m) epibenthic zone. Medium sized whitefish (25–35 cm body length) expanded their habitat use to include the deep (30–90 m) epibenthic zone as well as the pelagic zone. From a body length of 35 cm, habitat use was restricted to the deep epibenthic zone. Small fish in the shallow epibenthic zone ate small and medium-sized prey (zooplankton, insect larvae and surface insects). Medium-sized fish in this zone were in addition feeding on the larger amphipod, Pallasea quadrispinosa. In the pelagic zone, the diet of medium-sized whitefish was dominated by zooplankton, although some larger prey like surface insects and age-0 smelt, Osmerus eperlanus, were also eaten. In the deep epibenthic zone, the diet of both medium-sized and large (< 35 cm) whitefish consisted mainly of the large prey P. quadrispinosa.     

Induction of antitumor immunity by CTL epitopes genetically linked to membrane-anchored beta2-microglobulin

Level and persistence of antigenic peptides presented by APCs on MHC class I (MHC-I) molecules influence the magnitude and quality of the ensuing CTL response. We recently demonstrated the unique immunological properties conferred on APCs by expressing beta2-microglobulin (beta2m) as an integral membrane protein. In this study, we explored membrane-anchored beta2m as a platform for cancer vaccines using as a model MO5, an OVA-expressing mouse B16 melanoma. We expressed in mouse RMA-S cells two H-2Kb binding peptides from MO5, OVA257-264, and TRP-2181-188, each genetically fused with the N terminus of membranal beta2m via a short linker. Specific Ab staining and T cell hybridoma activation confirmed that OVA257-264 was properly situated in the MHC-I binding groove. In vivo, transfectants expressing both peptides elicited stronger CTLs and conferred better protection against MO5 than peptide-saturated RMA-S cells. Cells expressing OVA257-264/beta2m were significantly superior to OVA257-264-charged cells in their ability to inhibit the growth of pre-established MO5 tumors. Our results highlight the immunotherapeutic potential of membranal beta2m as a universal scaffold for optimizing Ag presentation by MHC-I molecules.     

Rocky intertidal fish communities of California: temporal and spatial variation

Synopsis We examined data from our own and published collections of intertidal and shallow littoral fishes of the North American Pacific Coast with respect to temporal and spatial trends in species composition and dominance. We compared (1) recent and past intertidal collections made five and seven years apart, respectively, for two California localities, (2) intertidal collections from twelve localities in California, Oregon, and British Columbia, and (3) intertidal versus subtidal collections at one California locality. Temporal comparisons indicated substantially lower abundance of the cottid Oligocottus snyderi at two California localities during 1984, at one locality due to depressed abundance of young. Interannual differences in abundances suggested that other tidepool fish assemblages undergo significant changes as well. Geographical comparisons indicated general similarity in species composition, with cottids predominating in tidepools although several other families also were well represented (e.g., Stichaeidae, Scorpaenidae). Eel-shaped stichaeids and pholids occurred at high densities in exposed boulder fields. Both the tidepool and boulder field assemblages showed north-south changes in species abundances. Comparison of collections from the intertidal and subtidal zones at one California locality demonstrated that fishes of these habitats form two essentially distinct assemblages, with most species restricted to or concentrated in one or the other habitat.