Neglected Tropical Diseases outside the Tropics

Background

The neglected tropical diseases (NTDs) cause significant morbidity and mortality worldwide. Due to the growth in international travel and immigration, NTDs may be diagnosed in countries of the western world, but there has been no specific focus in the literature on imported NTDs.

Methods

Retrospective study of a cohort of immigrants and travelers diagnosed with one of the 13 core NTDs at a Tropical Medicine Referral Unit in Spain during the period April 1989-December 2007. Area of origin or travel was recorded and analyzed.

Results

There were 6168 patients (2634 immigrants, 3277 travelers and 257 VFR travelers) in the cohort. NTDs occurred more frequently in immigrants, followed by VFR travelers and then by other travelers (p<0.001 for trend). The main NTDs diagnosed in immigrants were onchocerciasis (n = 240, 9.1%) acquired mainly in sub-Saharan Africa, Chagas disease (n = 95, 3.6%) in immigrants from South America, and ascariasis (n = 86, 3.3%) found mainly in immigrants from sub-Saharan Africa. Most frequent NTDs in travelers were: schistosomiasis (n = 43, 1.3%), onchocerciasis (n = 17, 0.5%) and ascariasis (n = 16, 0.5%), and all were mainly acquired in sub-Saharan Africa. The main NTDs diagnosed in VFR travelers were onchocerciasis (n = 14, 5.4%), and schistosomiasis (n = 2, 0.8%).

Conclusions

The concept of imported NTDs is emerging as these infections acquire a more public profile. Specific issues such as the possibility of non-vectorial transmission outside endemic areas and how some eradication programmes in endemic countries may have an impact even in non-tropical western countries are addressed. Recognising NTDs even outside tropical settings would allow specific prevention and control measures to be implemented and may create unique opportunities for research in future.     

Role of alveolar macrophage and migrating neutrophils in hemorrhage-induced priming for ALI subsequent to septic challenge

Acute lung injury (ALI) is identified with the targeting/sequestration of polymorphonuclear leukocytes (PMN) to the lung. Instrumental to PMN targeting are chemokines [e.g., macrophage inflammatory protein-2 (MIP-2), keratinocyte-derived chemokine (KC), etc.] produced by macrophage, PMN, and other resident pulmonary cells. However, the relative contribution of resident pulmonary macrophages as opposed to PMN in inducing ALI is poorly understood. We therefore hypothesize that depletion of peripheral blood PMN and/or the oblation of a macrophage-mediated PMN chemokine signal (via macrophage deficiency) will reduce the inflammation and ALI observed in mice following hemorrhage (Hem) and subsequent sepsis (CLP) in our murine model of ALI. To examine this we pretreated mice with either 500 microg anti-mouse Gr1 antibody/animal (to deplete PMN) or subjected mice deficient in mature macrophage (B6C3Fe-a/a-CsF1op) to Hem (90 min at 35 +/- 5 mmHg) followed by resuscitation. Twenty-four hours post-Hem, mice were subjected to CLP and killed 24 h later, and lung tissue samples were collected. Our data showed that in the absence of either peripheral blood PMN or mature tissue macrophages there was a suppression of IL-6, KC, and MIP-2 levels in lung tissue from Hem/CLP mice as well as a reduction in PMN influx to the lung and lung injury (bronchoalveolar lavage fluid protein). In contrast, lung tissue IL-10 and TNF-alpha levels were suppressed in the macrophage-deficient Hem/CLP mice compared with PMN-depleted Hem/CLP mice. Together, these data suggest that both the PMN and the macrophage are required to induce inflammation seen here, however, macrophage not PMN regulate the release of IL-10, independent of local changes in TNF.     

Evolution of Plasmodium and the recent origin of the world populations of Plasmodium falciparum

We have investigated the evolution of Plasmodium parasites by analyzing DNA sequences of several genes. We reach the following conclusions: (1) The four human parasites, P. falciparum, P. malariae, P. ovale, and P. vivax are very remotely related to each other, so that their evolutionary divergence predates the origin of the hominids; several of these parasites became associated with the human lineage by lateral transfer from other hosts. (2) P. falciparum diverged from P. reichenowi about 8 million years ago, consistently with the time of divergence of the human lineage from the apes; a parsimonious inference is that falciparum has been associated with humans since the origin of the hominids. (3) P. malariae is genetically indistinguishable from P. brasilianum, a parasite of New World monkeys; and, similarly. (4) P. vivax is genetically indistinguishable from the New World monkey parasite P. simium. We infer in each of these two cases a very recent lateral transfer between the human and monkey hosts, and explore alternative hypotheses about the direction of the transfer. We have also investigated the population structure of P. falciparum by analyzing 10 genes and conclude that the extant world populations of this parasite have evolved from a single strain within the last several thousand years. The extensive polymorphisms observed in the highly repetitive central region of the Csp gene, as well as the apparently very divergent two classes of alleles at the Msa-1 gene, are consistent with this conclusion.     

Hypoxemia in the absence of blood loss upregulates iNOS expression and activity in macrophages

Regional hypoxia,associated with hemorrhage, is thought to induce a variety ofalterations in immune cell function, including upregulation ofmacrophage-inducible nitric oxide synthase (iNOS) expression andactivity (NO production). Furthermore, NO may cause immune celldysfunction similar to that associated with hemorrhagic shock. However,it remains unknown whether hypoxia per se in the absence of any bloodloss is a sufficient stimulus to cause iNOS expression and NOproduction by macrophages. To study this, male Sprague-Dawley rats(275-325 g) were placed in a plastic box flushed with a gasmixture containing 5% O₂-95%N₂ for 60 min. Peritoneal andsplenic macrophages were isolated 0-5.5 h thereafter, and bloodsamples were obtained. Nitrite and nitrate (stable degradation productsof NO) production by splenic and peritoneal macrophages cultured for 48 h was significantly increased 3 and 5.5 h after hypoxemia. The increasein NO production by macrophages was preceded by elevated expression ofiNOS mRNA at 1.5 h after hypoxia. Additionally, interferon-(IFN-) levels in plasma from rats subjected to hypoxemia weresignificantly elevated soon after the insult (0-1.5 hposthypoxemia), suggesting a causal relationship between IFN-production and upregulation of iNOS activity. We propose that ahypoxemia-induced increase in macrophage iNOS activity followinghemorrhage may in part be responsible for the observed immunedysfunction. Thus attempts to suppress macrophage iNOS activity afterthis form of trauma may be helpful in improving immune function underthose conditions.     

Adaptation and novelty: teleological explanations in evolutionary biology

Knives, birds' wings, and mountain slopes are used for certain purposes: cutting, flying, and climbing. A bird's wings have in common with knives that they have been 'designed' for the purpose they serve, which purpose accounts for their existence, whereas mountain slopes have come about by geological processes independently of their uses for climbing. A bird's wings differ from a knife in that they have not been designed or produced by any conscious agent; rather, the wings, like the slopes, are outcomes of natural processes without any intentional causation. Evolutionary biologists use teleological language and teleological explanations. I propose that this use is appropriate, because teleological explanations are hypotheses that can be subject to empirical testing. The distinctiveness of teleological hypotheses is that they account for the existence of a feature in terms of the function it serves; for example, wings have evolved and persist because flying is beneficial to birds by increasing their chances of surviving and reproducing. Features of organisms that are explained with teleological hypotheses include structures, such as wings; processes, such as development from egg to adult; and behaviours, such as nest building. A proximate explanation of these features is the function they serve; an ultimate explanation that they all share is their contribution to the reproductive fitness of the organisms. I distinguish several kinds of teleological explanations, such as natural and artificial, as well as bounded and unbounded, some of which but not others apply to biological explanations.     

The Echinococcus granulosus antigen B shows a high degree of genetic variability

Echinococcus granulosus larvae secret a polymeric lipoprotein known as antigen B (AgB) into the metacestode hydatid fluid. Three similar AgB subunits have been previously identified (AgB1, AgB2, and AgB3), and their respective genes isolated, but the actual number of genes encoding AgB subunits remains uncertain. In this study, we characterize the variability of genes encoding the AgB2 subunit, using PCR and RT-PCR followed by cloning and sequencing. We have analyzed 32 cDNA and 34 genomic sequences from a single metacestode, showing a high degree of sequence polymorphism. In addition, we have identified a possibly new AgB subunit, which we call AgB4. Additionally, we describe an AgB2 genomic clone lacking (i) a segment corresponding to the intron and (ii) a short, 45 bp sequence within exon II. The 45 bp segment encompasses the conserved splicing signals and corresponds to a highly conserved insect promoter motif.     

Bone morphogenetic protein-1/Tolloid-like proteinases process dentin matrix protein-1

Bone morphogenetic protein-1 (BMP-1)/Tolloid-like metalloproteinases play key roles in formation of mammalian extracellular matrix (ECM), through the biosynthetic conversion of precursor proteins into their mature functional forms. These proteinases probably play a further role in formation of bone through activation of transforming growth factor beta-like BMPs. Dentin matrix protein-1 (DMP1), deposited into the ECM during assembly and involved in initiating mineralization of bones and teeth, is thought to undergo proteolysis in vivo to generate functional cleavage fragments found in extracts of mineralized tissues. Here, we have generated recombinant DMP1 and demonstrate that it is cleaved, to varying extents, by all four mammalian BMP-1/Tolloid-like proteinases, to generate fragments similar in size to those previously isolated from bone. Consistent with possible roles for the BMP-1/Tolloid-like proteinases in the physiological processing of DMP1, NH2-terminal sequences of products generated by BMP-1 cleavage of DMP1 match those predicted from processing at the predicted DMP1 site that shows greatest cross-species conservation of sequences. Moreover, fibroblasts derived from mouse embryos homozygous null for genes encoding three of the four mammalian BMP-1/Tolloid-like proteinases appear to be deficient in processing of DMP1. Thus, a further role for BMP-1-Tolloid-like proteinases in formation of mineralized tissues is indicated, via proteolytic processing of DMP1.     

Spatial and seasonal variation of macroalgal biomass in Laguna Ojo de Liebre, Baja California Sur, Mexico

Laguna Ojo de Liebre is part of El Vizcaíno Biosphere's Reserve, one of the largest protected natural areas in the world. The contribution of seaweeds to the lagoons' total biomass had not been previously quantified. The purpose of this study was to evaluate the spatial and temporal variations of seaweed biomass in the lagoon. Seaweed samples were taken every season during 1995 at six sampling stations distributed throughout the lagoon. Total specific biomass of seaweeds was at its peak in the summer, and minimum in spring. The highest total annual biomass was found at Isla Brosa in the lagoon's central portion, and the lowest in El Dátil at the head. The seasonal and spatial variation of biomass in the lagoon is related with species richness and environmental parameters. Potentially important species in terms of biomass, wide spatial and temporal distribution, and potential use were: Spyridia filamentosa, Entheromorpha clathrata, Dasya baillouviana, Hypnea valentiaeand Sargassum sinicola .Using PCA three groups of stations were defined: one chiefly at the lagoon's mouth, another comprised the islands in the central portion, and the last in the lagoon's head.     

Sex-specific p38 MAP kinase activation following trauma-hemorrhage: involvement of testosterone and estradiol

Although immune functions are markedly depressed in males and not in proestrous females following trauma-hemorrhage (T-H), the mechanisms responsible for the divergent responses remain unknown. Because sex steroids modulate the activation of p38, our aim was to determine whether differences in the activation of p38 by phosphorylation (p38-P) might contribute to the sex-dimorphic immune response following T-H. The effects of testosterone and estradiol on the activation of p38 were also examined. Intact male mice (C3H/HeN), castrated males treated with vehicle, 5alpha-dihydrotestosterone (DHT), or 17beta-estradiol, and proestrous females were subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (35 +/- 5 mmHg for 90 min and resuscitation) or sham operation. At 2 h thereafter, splenic (SMphi) and peritoneal macrophages (PMphi) were harvested and cultured (with 10 microg/ml LPS), and Western blot analysis was carried out for quantification of p38 and p38-P. Sex, testosterone and estradiol plasma levels, and T-H did not alter the constitutive expression of p38 in SMphi and PMphi. In contrast, the activated form of p38 (p38-P) was markedly increased in SMphi and PMphi from female shams compared with male shams. Moreover, the phosphorylation of p38-P increased in males after T-H, whereas it decreased in females under those conditions. Castration before T-H prevented the increase in p38-P in males. Castrated animals treated with DHT displayed increased p38-P following T-H, whereas 17beta-estradiol had no effect on p38-P in castrated mice. Thus 1) sex influences the activation of p38 MAP kinase, 2) DHT is responsible for the increased activation of p38 in male mice, and 3) this sex-specific activation of p38 might be responsible for the sexually dimorphic immune response following T-H.