Sickness In Africa Research Articles

Cooperativity of catalytic and lectin-like domain of Trypanosoma congolense trans-sialidase modulates its catalytic activity.

Trans-sialidases (TS) represent a multi-gene family of unusual enzymes, which catalyse the transfer of terminal sialic acids (Sia) from sialoglycoconjugates to terminal galactose or N-acetylgalactosamine residues of oligosaccharides without the requirement of CMP-Neu5Ac, the activated Sia used by typical sialyltransferases. Enzymes comprise a N-terminal catalytic domain (CD) followed by a lectin-like domain (LD). Most work on trypanosomal TS has been done on enzymatic activities focusing on the CD of TS from Trypanosoma cruzi (causing Chagas disease in Latin America), subspecies of Trypanosoma brucei, (causing human sleeping sickness in Africa) and Trypanosoma congolense (causing African Animal Trypanosomosis in livestock). Previously, we demonstrated that T. congolense TS (TconTS)-LD binds to several carbohydrates, such as 1,4-β-mannotriose. In this study we investigated the influence of TconTS3-LD on Sia transfer efficiency of TconTS1a-CD by swapping domains. in silico analysis on structure models of TconTS enzymes revealed the potential of domain swaps between TconTS1a and TconTS3 without structural disruptions of the enzymes overall topologies. Recombinant domain swapped TconTS1a/TS3 showed clear Sia transfer activity, when using fetuin and lactose as Sia donor and acceptor substrates, respectively. While Sia transfer activity remained unchanged from the level of TconTS1a, hydrolytic release of free Neu5Ac as a side product was suppressed resulting in increased transfer efficiency. Presence of 1,4-β-mannotriose during TS reactions modulates enzyme activities enhancing transfer efficiency possibly due to occupation of the binding site in TconTS1a-LD. Interestingly this effect was in the same range as that observed when swapping TconTS1a-CD and TconTS3-LD. In summary, this study demonstrate the proof-of-principle for swapping CDs and LDs of TconTS and that TconTS3-LD influences enzymatic activity of TconTS1a-CD providing evidence that LDs play pivotal roles in modulating activities and biological functions of TconTS and possibly other TS.

Spatio-temporal survey of small mammal-borne Trypanosoma lewisi in Cotonou, Benin, and the potential risk of human infection

Human trypanosomoses are the sleeping sickness in Africa and Chagas disease in Latin America. However, atypical human infections by animal trypanosomes have been described, but poorly investigated. Among them, the supposed rat-specific T. lewisi was shown to be responsible for a few severe cases. In Africa, the scarcity of data and the null awareness about the atypical human trypanosomoses suggest that the number of cases may be higher that currently thought. Furthermore, T. lewisi is resistant to normal human serum and therefore a potential human pathogen. In order to document T. lewisi distribution and ecology, a qPCR- and 16DNA sequencing-based survey was conducted in 369 rodents from three urban districts of Cotonou city, Benin, during three different periods of the same year. Our study demonstrated very high prevalence (57.2%) even when considering only individuals identified as positive through DNA sequencing (39.2%). Black rats represented the most dominant as well as the most T. lewisi-parasitized species. No difference was retrieved neither between seasons nor districts, suggesting a large infestation of rodents by trypanosomes throughout the year and the city. Our results suggest that conditions are gathered for rat to human transmission of T. lewisi in these socio-environmentally degraded urban areas, thus pointing towards the rapidly urbanizing Abidjan-Lagos corridor as a region at particular risk.

Adenylate Cyclases of Trypanosoma brucei, Environmental Sensors and Controllers of Host Innate Immune Response.

Trypanosoma brucei, etiological agent of Sleeping Sickness in Africa, is the prototype of African trypanosomes, protozoan extracellular flagellate parasites transmitted by saliva (Salivaria). In these parasites the molecular controls of the cell cycle and environmental sensing are elaborate and concentrated at the flagellum. Genomic analyses suggest that these parasites appear to differ considerably from the host in signaling mechanisms, with the exception of receptor-type adenylate cyclases (AC) that are topologically similar to receptor-type guanylate cyclase (GC) of higher eukaryotes but control a new class of cAMP targets of unknown function, the cAMP response proteins (CARPs), rather than the classical protein kinase A cAMP effector (PKA). T. brucei possesses a large polymorphic family of ACs, mainly associated with the flagellar membrane, and these are involved in inhibition of the innate immune response of the host prior to the massive release of immunomodulatory factors at the first peak of parasitemia. Recent evidence suggests that in T. brucei several insect-specific AC isoforms are involved in social motility, whereas only a few AC isoforms are involved in cytokinesis control of bloodstream forms, attesting that a complex signaling pathway is required for environmental sensing. In this review, after a general update on cAMP signaling pathway and the multiple roles of cAMP, I summarize the existing knowledge of the mechanisms by which pathogenic microorganisms modulate cAMP levels to escape immune defense.

Barcoding in trypanosomes.

Trypanosomes (genus Trypanosoma) are parasites of humans, and wild and domestic mammals, in which they cause several economically and socially important diseases, including sleeping sickness in Africa and Chagas disease in the Americas. Despite the development of numerous molecular diagnostics and increasing awareness of the importance of these neglected parasites, there is currently no universal genetic barcoding marker available for trypanosomes. In this review we provide an overview of the methods used for trypanosome detection and identification, discuss the potential application of different barcoding techniques and examine the requirements of the 'ideal' trypanosome genetic barcode. In addition, we explore potential alternative genetic markers for barcoding Trypanosoma species, including an analysis of phylogenetically informative nucleotide changes along the length of the 18S rRNA gene.

Chronic kidney disease in African Americans: Puzzle pieces are falling into place.

Recent decades have seen great advances in the understanding of chronic kidney disease, spurred by standardizing disease definitions and large-scale patient surveillance. African Americans are disproportionately affected by the disease, and recently discovered genetic variants in APOL1 that protect against sleeping sickness in Africa provide an important explanation for the increased burden. Studies are now under way to determine if genetic testing of African American transplant donors and recipients is advisable.

Zoonotic trypanosomes in South East Asia: Attempts to control Trypanosoma lewisi using human and animal trypanocidal drugs

Beside typical human trypanosomes responsible of sleeping sickness in Africa and Chagas disease in Latin America, there is a growing number of reported atypical human infections due to Trypanosoma evansi, a livestock parasite, or Trypanosoma lewisi, a rat parasite, especially in Asia. Drugs available for the treatment of T. brucei ssp. in humans are obviously of choice for the control of T. evansi because it is derived from T. brucei. However, concerning T. lewisi, there is an urgent need to determine the efficacy of trypanocidal drugs for the treatment in humans. In a recent study, pentamidine and fexinidazole were shown to have the best efficacy against one stock of T. lewisi in rats.In the present study suramin, pentamidine, eflornitine, nifurtimox, benznidazole and fexinidazole, were evaluated at low and high doses, in single day administration to normal rats experimentally infected with a stock of T. lewisi recently isolated in Thailand. Because none of these treatments was efficient, a trial was made with the most promising trypanocide identified in a previous study, fexinidazole 100mg/kg, in 5 daily administrations. Results observed were unclear. To confirm the efficacy of fexinidazole, a mixed infection protocol was set up in cyclophosphamide immunosuppressed rats. Animals were infected successively by T. lewisi and T. evansi, and received 10 daily PO administrations of 200mg/kg fexinidazole. Drastic effects were observed against T. evansi which was cleared from the rat's blood within 24 to 48h; however, the treatment did not affect T. lewisi which remained in high number in the blood until the end of the experiment. This mixed infection/treatment protocol clearly demonstrated the efficacy of fexinidazole against T. evansi and its inefficacy against T. lewisi. Since animal trypanocides were also recently shown to be inefficient, other protocols as well as other T. lewisi stocks should be investigated in further studies.

Structural and Biochemical Analyses of the Eukaryotic Heat Shock Locus V (HslV) from Trypanosoma brucei

In many bacteria, heat shock locus V (HslV) functions as a protease, which is activated by heat shock locus U (HslU). The primary sequence and structure of HslV are well conserved with those of the β-subunit of the 20 S proteasome core particle in eukaryotes. To date, the HslVU complex has only been characterized in the prokaryotic system. Recently, however, the coexistence of a 20 S proteasome with HslV protease in the same living organism has been reported. In Trypanosoma brucei, a protozoan parasite that causes human sleeping sickness in Africa, HslV is localized in the mitochondria, where it has a novel function in regulating mitochondrial DNA replication. Although the prokaryotic HslVU system has been studied extensively, little is known regarding its eukaryotic counterpart. Here, we report the biochemical characteristics of an HslVU complex from T. brucei. In contrast to the prokaryotic system, T. brucei possesses two potential HslU molecules, and we found that only one of them activates HslV. A key activating residue, Tyr(494), was identified in HslU2 by biochemical and mutational studies. Furthermore, to our knowledge, this study is the first to report the crystal structure of a eukaryotic HslV, determined at 2.4 Å resolution. Drawing on our comparison of the biochemical and structural data, we discuss herein the differences and similarities between eukaryotic and prokaryotic HslVs.

The concept of <i>shalōm</i> as a constructive bereavement healing framework within a pluralist health seeking context of Africa

Absence of health, that is, sickness in Africa is viewed in personalistic terms. A disease is explained as effected by ‘the active purposeful intervention of an agent, who may be human’, non-human (a ghost, an ancestor, an ‘evil spirit), or supernatural (a deity or other very powerful being)’ (Foster). Illness is thus attributed to breaking of taboos, offending God and/ or ancestral spirits; witchcraft, sorcery, the evil eye, passion by an evil spirit and a curse from parents or from an offended neighbour. In view of these personalistic theories of ill health, treatment is through ritual purification, exorcism or sacrifices. For an appropriate diagnosis and intervention, it is imperative to determine ‘who’ caused the illness and then ‘why’ it was caused, to which answers are offered through divination by a healer. This interpretive framework, is applicable to all types of sickness, facilitates co-existence of African traditional healing and biomedical treatment, that is, plurality of health seeking practices. The approach fails to offer a constructive approach and contradicts the biblical healing framework whereby one may not have explanatory causes to a situation of ill health. This article engaged the biblical concept of shalōm as a relevant constructive framework. The Hebrew concept of shalōm, though distinctly salvific, is inclusive of holistic and personalistic healing aspects. The concept encompasses constructive aspects of completeness, wholeness, health, peace, welfare, safety, soundness, tranquillity, prosperity, perfectness, fullness, rest, harmony and the absence of agitation or discord, which provides a useful holistic healing theological framework. It therefore provides a health and well-being framework that is relational, sensitive and applicable to healing patterns in Africa. Using the case study of the Abaluyia people of East Africa, this article discussed bereavement as a state that requires healing and how the biblical framework of shalōm could be applied in fostering bereavement healing.

Neglected tropical diseases: operational research for elimination and control.

Neglected tropical diseases (NTDs) are the common denominator for infectious diseases that occur almost exclusively in poor populations in developing countries. The main NTDs include schistosomiasis, filariasis, intestinal helminth infections, leprosy, Buruli ulcer and protozoan infections such as trypanosomiasis (causing sleeping sickness in Africa or Chagas disease in South America) and leishmaniasis.1 While biologically diverse, they share a number of characteristics: all are strongly associated with poverty and flourish best in tropical areas, where they often coexist. Taken together, they are a leading cause of disability, comparable to tuberculosis and malaria, with over a billion people affected.1 Many predominantly target children, compromising physical growth and cognitive development. These ancient ‘companions of poverty’ undermine the wellbeing and productivity of already destitute populations, and severely impede meeting the United Nations 2015 Millennium Development Goals. By definition, NTDs have not ranked high on the national and international political agendas. For most, there are no or few adequate diagnostics, tools or vaccines, the local health systems are deficient and overburdened and financial resources scarce. In terms of research and development, these diseases are also truly neglected; less than 1% of new therapeutic developments over the past decades have concerned tropical diseases.2 The treatment of Chagas disease and African trypanosomiasis still relies on drugs that were developed more than 40–60 years ago. NTDs have fortunately received increased attention more recently from funders, global philanthropists, policy makers and researchers. A number of new global international networks have been established, and several ambitious initiatives have been launched, including some directed at the elimination of a range of NTDs.3 A major new initiative aims for the integrated control and elimination of lymphatic filiariasis, onchocerciasis, schistosomiasis, intestinal helminthiases and trachoma through the use of mass drug treatment (preventive chemotherapy) with a combination of drugs.4 However, huge knowledge gaps currently exist on how to widely implement this strategy in the most acceptable, (cost-) effective and sustainable way. Its global health impact and its interaction with and effect on already overburdened health systems remain to be better defined.5 Issues such as safety and the emergence of drug resistance also need to be carefully assessed. For other diseases, early diagnosis and treatment constitute key control measures. Although improved diagnostic tools and drugs have been developed, for example for visceral leishmaniasis, their large-scale implementation has proved challenging. While India, Nepal and Bangladesh have committed to eliminating visceral leishmaniasis by 2015, they struggle to make timely diagnosis and treatment widely accessible.6 Monitoring and surveillance systems are suboptimal. Additional operational research will need to be conducted to enhance the effectiveness of current strategies and to evaluate novel approaches. The same applies to East Africa, where treatment for visceral leishmaniasis is still predominantly provided by non-governmental organisations.6 For diseases such as African trypanosomiasis and Chagas disease, there are no easy to use, reliable tests for diagnosis and/or test of cure. Therapy is lengthy, complicated and/or often poorly tolerated. Efforts of not-for-profit research and development organisations such as the Drugs for Neglected Diseases initiative (DNDi) and the Foundation for Innovative New Diagnostics (FIND) will hopefully help fill this gap. As most NTDS are vector-borne or zoonotic in nature, efforts directed towards the control of the vector, intermediate host or animal reservoir will also be key.1 Successful control of NTDs will ultimately hinge on the concerted efforts of all stakeholders, within a multi-disciplinary approach. How to maximise the impact of these efforts will have to be carefully assessed, and innovative strategies will have to be explored. Operational research will have its role to play.7 Research findings will need to be easibly accessible, widely disseminated and able to reach decision makers and programme managers. Public Health Action is a new, open-access journal ‘disseminating new knowledge on health systems and health services for vulnerable groups’, and aiming to provide a ‘voice for operational research’. Hopefully, we can expect many operational research studies on NTDs from the field in the years to come, including in this journal.

Jamot through Bado's eyes

The author reviews a biography published in 2011 of Dr. Eugene Jamot (1879-1937), a colonial army physician who devoted 25 years of his life to the fight against sleeping sickness in Africa. In this book, which includes previously unpublished information, the Burkinabe author describes the breakthroughs that tropical medicine has made against human African trypanosomiasis, particularly in Cameroon. He also highlights the interpersonal conflicts with the colonial administration that punctuated Jamot's life in Africa. This article describes the circumstances of the discovery of Dr. Jamot's private papers in 1999 and the insight that these documents provide into the personality of this illustrious army doctor.

ChemInform Abstract: The Chemistry and Biology of Trypanosomal trans‐Sialidases: Virulence Factors in Chagas Disease and Sleeping Sickness

AbstractReview: 181 refs.

The Chemistry and Biology of Trypanosomal trans‐Sialidases: Virulence Factors in Chagas Disease and Sleeping Sickness

trans-Sialidases constitute a special group of the sialidase family. They occur in some trypanosome species and, in a unique reversible reaction, transfer sialic acids from one glycosidic linkage with galactose (donor) to another galactose (acceptor), to form (α2-3)-sialyl linkages. Trypanosomes cause such devastating human diseases as Chagas disease in South America (Trypanosoma cruzi) or sleeping sickness in Africa (Trypanosoma brucei). The trans-sialidases strongly contribute to the pathogenicity of the trypanosomes by scavenging sialic acids from the host or blood meal to coat the parasite surface; this aids their survival strategy in the insect's intestine, and in the blood circulation or cells of the host, and serves to compromise the immune system of the human or animal host. American and African trypanosomes express trans-sialidases at different stages of their vector/host development. They are transmitted to humans by insect vectors (tsetse fly or other insect "bug" species). trans-Sialidase activity with varying linkage specificity has also been found in a few bacteria species and in human serum. trans-Sialidases are of increasing practical importance for the chemo-enzymatic synthesis of sialylated glycans. The search for appropriate inhibitors of trans-sialidases and vaccination strategies is intensifying, as less toxic medicaments for the treatment of these widespread and often chronic tropical diseases are required.

Towards an Optimal Design of Target for Tsetse Control: Comparisons of Novel Targets for the Control of Palpalis Group Tsetse in West Africa

BackgroundTsetse flies of the Palpalis group are the main vectors of sleeping sickness in Africa. Insecticide impregnated targets are one of the most effective tools for control. However, the cost of these devices still represents a constraint to their wider use. The objective was therefore to improve the cost effectiveness of currently used devices.Methodology/Principal FindingsExperiments were performed on three tsetse species, namely Glossina palpalis gambiensis and G. tachinoides in Burkina Faso and G. p. palpalis in Côte d'Ivoire. The 1×1 m2 black blue black target commonly used in W. Africa was used as the standard, and effects of changes in target size, shape, and the use of netting instead of black cloth were measured. Regarding overall target shape, we observed that horizontal targets (i.e. wider than they were high) killed 1.6-5x more G. p. gambiensis and G. tachinoides than vertical ones (i.e. higher than they were wide) (P<0.001). For the three tsetse species including G. p. palpalis, catches were highly correlated with the size of the target. However, beyond the size of 0.75 m, there was no increase in catches. Replacing the black cloth of the target by netting was the most cost efficient for all three species.Conclusion/SignificanceReducing the size of the current 1*1 m black-blue-black target to horizontal designs of around 50 cm and replacing black cloth by netting will improve cost effectiveness six-fold for both G. p. gambiensis and G. tachinoides. Studying the visual responses of tsetse to different designs of target has allowed us to design more cost-effective devices for the effective control of sleeping sickness and animal trypanosomiasis in Africa.

Prevention and control of malaria and sleeping sickness in Africa: Where are we and where are we going?

The International Symposium on Malaria and Human African Trypanosomiasis: New Strategies for their Prevention & Control was held 7-8 October, 2010 in Cotonou, Benin with about 250 participants from 20 countries. This scientific event aimed at identifying the gaps and research priorities in the prevention and control of malaria and sleeping sickness in Africa and to promote exchange between North and South in the fields of medical entomology, epidemiology, immunology and parasitology. A broad range of influential partners from academia (scientists), stakeholders, public health workers and industry attempted the meeting and about 40 oral communications and 20 posters were presented by phD students and internationally-recognized scientists from the North and the South. Finally, a special award ceremony was held to recognize efforts in pioneer work conducted by staff involved in the diagnostic of the Sleeping illness in West Africa with partnership and assistance from WHO and Sanofi-Aventis group.

Molecular epidemiology of African sleeping sickness

Human sleeping sickness in Africa, caused by Trypanosoma brucei spp. raises a number of questions. Despite the widespread distribution of the tsetse vectors and animal trypanosomiasis, human disease is only found in discrete foci which periodically give rise to epidemics followed by periods of endemicity A key to unravelling this puzzle is a detailed knowledge of the aetiological agents responsible for different patterns of disease--knowledge that is difficult to achieve using traditional microscopy. The science of molecular epidemiology has developed a range of tools which have enabled us to accurately identify taxonomic groups at all levels (species, subspecies, populations, strains and isolates). Using these tools, we can now investigate the genetic interactions within and between populations of Trypanosoma brucei and gain an understanding of the distinction between human- and nonhuman-infective subspecies. In this review, we discuss the development of these tools, their advantages and disadvantages and describe how they have been used to understand parasite genetic diversity, the origin of epidemics, the role of reservoir hosts and the population structure. Using the specific case of T.b. rhodesiense in Uganda, we illustrate how molecular epidemiology has enabled us to construct a more detailed understanding of the origins, generation and dynamics of sleeping sickness epidemics.

Trypanosoma brucei homologous recombination is dependent on substrate length and homology, though displays a differential dependence on mismatch repair as substrate length decreases

Homologous recombination functions universally in the maintenance of genome stability through the repair of DNA breaks and in ensuring the completion of replication. In some organisms, homologous recombination can perform more specific functions. One example of this is in antigenic variation, a widely conserved mechanism for the evasion of host immunity. Trypanosoma brucei, the causative agent of sleeping sickness in Africa, undergoes antigenic variation by periodic changes in its variant surface glycoprotein (VSG) coat. VSG switches involve the activation of VSG genes, from an enormous silent archive, by recombination into specialized expression sites. These reactions involve homologous recombination, though they are characterized by an unusually high rate of switching and by atypical substrate requirements. Here, we have examined the substrate parameters of T. brucei homologous recombination. We show, first, that the reaction is strictly dependent on substrate length and that it is impeded by base mismatches, features shared by homologous recombination in all organisms characterized. Second, we identify a pathway of homologous recombination that acts preferentially on short substrates and is impeded to a lesser extent by base mismatches and the mismatch repair machinery. Finally, we show that mismatches during T. brucei recombination may be repaired by short-patch mismatch repair.

Civil conflict and sleeping sickness in Africa in general and Uganda in particular.

Conflict and war have long been recognized as determinants of infectious disease risk. Re-emergence of epidemic sleeping sickness in sub-Saharan Africa since the 1970s has coincided with extensive civil conflict in affected regions. Sleeping sickness incidence has placed increasing pressure on the health resources of countries already burdened by malaria, HIV/AIDS, and tuberculosis. In areas of Sudan, the Democratic Republic of the Congo, and Angola, sleeping sickness occurs in epidemic proportions, and is the first or second greatest cause of mortality in some areas, ahead of HIV/AIDS. In Uganda, there is evidence of increasing spread and establishment of new foci in central districts. Conflict is an important determinant of sleeping sickness outbreaks, and has contributed to disease resurgence. This paper presents a review and characterization of the processes by which conflict has contributed to the occurrence of sleeping sickness in Africa. Conflict contributes to disease risk by affecting the transmission potential of sleeping sickness via economic impacts, degradation of health systems and services, internal displacement of populations, regional insecurity, and reduced access for humanitarian support. Particular focus is given to the case of sleeping sickness in south-eastern Uganda, where incidence increase is expected to continue. Disease intervention is constrained in regions with high insecurity; in these areas, political stabilization, localized deployment of health resources, increased administrative integration and national capacity are required to mitigate incidence. Conflict-related variables should be explicitly integrated into risk mapping and prioritization of targeted sleeping sickness research and mitigation initiatives.

Landscapes of Exposure: Knowledge and Illness in Modern Environments (review)

Reviewed by: Landscapes of Exposure: Knowledge and Illness in Modern Environments Christian Warren Gregg Mitman, Michelle Murphy, and Christopher Sellers , eds. Landscapes of Exposure: Knowledge and Illness in Modern Environments. Osiris, 2d ser., no. 19. Chicago: University of Chicago Press, 2004. 304 pp. Ill. $50.50 (cloth, 0-226-53249-6), $33.00 (paperbound, 0-226-53251-8). This informative and largely engaging collection of essays dives right into the thick of it—literally—describing a dense haze of unknown but largely anthropogenic composition blanketing much of southern Asia. This "Asian Brown Cloud," identified in 2002 by the United Nations Environmental Program, is used to introduce the book's central themes of scale, uncertainty, and materiality. The editors then make a claim for their book almost as large as the cloud itself: "By exploring the implications of recent phenomena such as the Asian Brown Cloud, this Osiris volume announces a fundamental revision in the way we understand the history of environment and health" (p. 2). Scholars of environmental or medical history, and especially those laboring at the intersection of those fields (many of whose works are referenced throughout these chapters), might disagree as to how fundamentally the field is revised here; still, it is good to have this interdisciplinary collection by some of the best and brightest scholars working at this crossroad. Considerably more than the conference proceedings that its form and origins suggest, considerably less than the foundational document that it claims to be, Landscapes of Exposure deserves to be widely read by scholars and students. The book grew out of a 2002 workshop at the University of Wisconsin entitled "Environment and Health in Global Perspective." The editors have divided the volume into four sections in a valiant attempt to lump the sixteen chapters coherently—but the chapters' expansive and overlapping themes resist any neat [End Page 850] containment. The first section, "Ecology and Infection," groups chapters by Helen Tilley, Warwick Anderson, and Nicholas B. King that together offer a multifocal study of the emergence of holism in twentieth-century biomedical sciences. The age of the microbe hunters and their search for single causes subject to specific therapies might have seemed, Anderson muses, "an arid waste of reductionism" (p. 41); on the contrary, these scholars find that throughout much of the twentieth century a number of highly influential scientists worked from a more Galenic view toward environmental factors in health. Quite in keeping with the theme of holism, their careers are presented not in terms of a chain of "begats," but as a shifting network developing organically—from British researchers studying sleeping sickness in Africa at the beginning of the twentieth century, to Theobald Smith, René Dubos, and others studying the interactions of living creatures in a complex environment. The next section, "Economy and Place," contains three striking chapters: Conevery Bolton Valencius tells the stories of people on the move in search of health in the nineteenth century; Gregg Mitman traces the history of Denver—a city built on the ironic juxtaposition of healthy climate and mining—as its health-resort industry adjusted to the shifting burdens of chronic respiratory disease; and Giovanna Di Chiro takes readers on a "toxic tour" of the U.S.-Mexican border where impoverished transnational workers and their allies fight governments and industries to ameliorate the unhealthful "nature" of environments in which they work and live. Despite obvious differences in methodology and approach, these three chapters produce a satisfactory triptych, a thought-provoking meditation on the interplay of geography, society, and health. If the title of the third section, "Material Flows and Public Health," sounds a bit jargony, the "flows" is certainly apt: in Susan D. Jones's chapter, milk from tubercular cows flows through food-industry channels from farm to fridge; Harold Platt describes attempts in two Progressive Era cities to deal with the flood of germs flowing through their water supplies; Scott Kirsch deals with fallout-borne radioiodine flowing over the American landscape; and Christopher Sellers studies two nations' relationship to fluoride, whether flowing through kitchen taps or bubbling up from natural or polluted groundwater sources. Three of these chapters employ transnational comparisons, which Jones argues can "demonstrate the generalizability of . . . factors...

Glycosylinositolphosphate soluble variant surface glycoprotein inhibits IFN-gamma-induced nitric oxide production via reduction in STAT1 phosphorylation in African trypanosomiasis.

Macrophages are centrally involved in the host immune response to infection with Trypanosoma brucei rhodesiense, a protozoan parasite responsible for human sleeping sickness in Africa. During trypanosome infections, the host is exposed to parasite-derived molecules that mediate macrophage activation, specifically GPI anchor substituents associated with the shed variant surface glycoprotein (VSG), plus the host-activating agent IFN-gamma, which is derived from activated T cells and is essential for resistance to trypanosomes. In this study, we demonstrate that the level and timing of exposure of macrophages to IFN-gamma vs GPI ultimately determine the macrophage response at the level of induced gene expression. Treatment of macrophages with IFN-gamma followed by GIP-sVSG (the soluble form of VSG containing the glycosylinositolphosphate substituent that is released by parasites) stimulated the induction of gene expression, including transcription of TNF-alpha, IL-6, GM-CSF, and IL-12p40. In contrast, treatment of macrophages with GIP-sVSG before IFN-gamma stimulation resulted in a marked reduction of IFN-gamma-induced responses, including transcription of inducible NO synthase and secretion of NO. Additional experiments revealed that the inhibitory activity of GIP-sVSG was associated with reduction in the level of STAT1 phosphorylation, an event required for IFN-gamma-induced macrophage activation. These results suggest that modulation of specific aspects of the IFN-gamma response may be one mechanism by which trypanosomes overcome host resistance during African trypanosomiasis.

Synthesis and biological activity of nitro heterocycles analogous to megazol, a trypanocidal lead.

As part of our efforts to develop new compounds aimed at the therapy of parasitic infections, we synthesized and assayed analogues of a lead compound megazol, 5-(1-methyl-5-nitro-1H-2-imidazolyl)-1,3,4-thiadiazol-2-amine, CAS no. 19622-55-0), in vitro. We first developed a new route for the synthesis of megazol. Subsequently several structural changes were introduced, including substitutions on the two rings of the basic nucleus, replacement of the thiadiazole by an oxadiazole, replacement of the nitroimidazole part by a nitrofurane or a nitrothiophene, and substitutions on the exocyclic nitrogen atom for evaluation of an improved import by the glucose or the purine transporters. Assays of the series of compounds on the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani, as either extracellular cells or infected macrophages, indicated that megazol was more active than the derivatives. Megazol was then evaluated on primates infected with Trypanosoma brucei gambiense, including late-stage central nervous system infections in combination with suramin. Full recovery was observed in five monkeys in the study with no relapse of parasitemia within a 2 year follow-up. Because there is a lack of efficacious treatments for sleeping sickness in Africa and Chagas disease in South America, megazol is proposed as a potential alternative. The mutagenicity of this compound is at present being reevaluated, and metabolism is also under investigation prior to possible further developments.