The London School of Hygiene and Tropical Medicine: a new century of malaria research

The global malaria situation has scarcely improved in the last 100 years, despite major advances in our knowledge of the basic biology, epidemiology and clinical basis of the disease. Effective malaria control, leading to a significant decrease in the morbidity and mortality attributable to malaria, will require a multidisciplinary approach. New tools - drugs, vaccine and insecticides - are needed but there is also much to be gained by better use of existing tools: using drugs in combination in order to slow the development of drug resistance; targeting resources to areas of greatest need; using geographic information systems to map the populations at risk and more sophisticated marketing techniques to distribute bed nets and insecticides. Sustainable malaria control may require the deployment of a highly effective vaccine, but there is much that can be done in the meantime to reduce the burden of disease.

Overview of some biomedical research projects in tropical medicine conducted at the Instituto Venezolano de Investigaciones Cientificas

The Instituto Venezolano de Investigaciones Cientificas (IVIC) is a government-funded multidisciplinary academic institution dedicated to research, development and technology in many areas of knowledge. Biomedical projects and publications comprise about 40% of the total at IVIC. In this article, we present an overview of some selected research and development projects conducted at IVIC which we believe contain new and important aspects related to malaria, ancylostomiasis, dengue fever, leishmaniasis and tuberculosis. Other projects considered of interest in the general area of tropical medicine are briefly described. This article was prepared as a small contribution to honor and commemorate the centenary of the Instituto Oswaldo Cruz.

Essential diagnostics - the role of the Department of Biomedical Research of the Royal Tropical Institute in the 21st century

In the light of emerging and overlooked infectious diseases and widespread drug resistance, diagnostics have become increasingly important in supporting surveillance, disease control and outbreak management programs. In many low-income countries the diagnostic service has been a neglected part of health care, often lacking quantity and quality or even non-existing at all. High-income countries have exploited few of their advanced technical abilities for the much-needed development of low-cost, rapid diagnostic tests to improve the accuracy of diagnosis and accelerate the start of appropriate treatment. As is now also recognized by World Healt Organization, investment in the development of affordable diagnostic tools is urgently needed to further our ability to control a variety of diseases that form a major threat to humanity. The Royal Tropical Institute's Department of Biomedical Research aims to contribute to the health of people living in the tropics. To this end, its multidisciplinary group of experts focuses on the diagnosis of diseases that are major health problems in low-income countries. In partnership we develop, improve and evaluate simple and cheap diagnostic tests, and perform epidemiological studies. Moreover, we advice and support others - especially those in developing countries - in their efforts to diagnose infectious diseases.

Current millennium biotechniques for biomedical research on parasites and host-parasite interactions

The development of biotechnology in the last three decades has generated the feeling that the newest scientific achievements will deliver high standard quality of life through abundance of food and means for successfully combating diseases. Where the new biotechnologies give access to genetic information, there is a common belief that physiological and pathological processes result from subtle modifications of gene expression. Trustfully, modern genetics has produced genetic maps, physical maps and complete nucleotide sequences from 141 viruses, 51 organelles, two eubacteria, one archeon and one eukaryote (Saccharomices cerevisiae). In addition, during the Centennial Commemoration of the Oswaldo Cruz Institute the nearly complete human genome map was proudly announced, whereas the latest Brazilian key stone contribution to science was the publication of the Shillela fastidiosa genomic sequence highlythed on a Nature cover issue. There exists a belief among the populace that further scientific accomplishments will rapidly lead to new drugs and methodological approaches to cure genetic diseases and other incurable ailments. Yet, much evidence has been accumulated, showing that a large information gap exists between the knowledge of genome sequence and our knowledge of genome function. Now that many genome maps are available, people wish to know what are we going to do with them. Certainly, all these scientific accomplishments will shed light on many more secrets of life. Nevertheless, parsimony in the weekly announcements of promising scientific achievements is necessary. We also need many more creative experimental biologists to discover new, as yet un-envisaged biotechnological approaches, and the basic resource needed for carrying out mile stone research necessary for leading us to that "promised land"often proclaimed by the mass media.

The impact of Chagas disease control in Latin America: a review

Discovered in 1909, Chagas disease was progressively shown to be widespread throughout Latin America, affecting millions of rural people with a high impact on morbidity and mortality. With no vaccine or specific treatment available for large-scale public health interventions, the main control strategy relies on prevention of transmission, principally by eliminating the domestic insect vectors and control of transmission by blood transfusion. Vector control activities began in the 1940s, initially by means of housing improvement and then through insecticide spraying following successful field trials in Brazil (Bambui Research Centre), with similar results soon reproduced in São Paulo, Argentina, Venezuela and Chile. But national control programmes only began to be implemented after the 1970s, when technical questions were overcome and the scientific demonstration of the high social impact of Chagas disease was used to encourage political determination in favour of national campaigns (mainly in Brazil). Similarly, large-scale screening of infected blood donors in Latin America only began in the 1980s following the emergence of AIDS. By the end of the last century it became clear that continuous control in contiguous endemic areas could lead to the elimination of the most highly domestic vector populations - especially Triatoma infestans and Rhodnius prolixus - as well as substantial reductions of other widespread species such as T. brasiliensis, T. sordida, and T. dimidiata, leading in turn to interruption of disease transmission to rural people. The social impact of Chagas disease control can now be readily demonstrated by the disappearance of acute cases and of new infections in younger age groups, as well as progressive reductions of mortality and morbidity rates in controlled areas. In economic terms, the cost-benefit relationship between intervention (insecticide spraying, serology in blood banks) and the reduction of Chagas disease (in terms of medical and social care and improved productivity) is highly positive. Effective control of Chagas disease is now seen as an attainable goal that depends primarily on maintaining political will, so that the major constraints involve problems associated with the decentralisation of public health services and the progressive political disinterest in Chagas disease. Counterbalancing this are the political and technical cooperation strategies such as the "Southern Cone Initiative" launched in 1991. This international approach, coordinated by PAHO, has been highly successful, already reaching elimination of Chagas disease transmission in Uruguay, Chile, and large parts of Brazil and Argentina. The Southern Cone Initiative also helped to stimulate control campaigns in other countries of the region (Paraguay, Bolivia, Peru) which have also reached tangible regional successes. This model of international activity has been shown to be feasible and effective, with similar initiatives developed since 1997 in the Andean Region and in Central America. At present, Mexico and the Amazon Region remain as the next major challenges. With consolidation of operational programmes in all endemic countries, the future focus will be on epidemiological surveillance and care of those people already infected. In political terms, the control of Chagas disease in Latin America can be considered, so far, as a victory for international scientific cooperation, but will require continuing political commitment for sustained success.

Laboratory diagnosis of Schistosomiasis in areas of low transmission: a review of a line of research

After 57 years of successful control of schistosomiasis in Venezuela, the prevalence and intensity of infection have declined. Approximately 80% of the individuals eliminate less than 100 eggs/g of stools, therefore morbidity is mild and the majority are asymptomatic. The sensitivity of Kato-Katz decreases to approximately 60%. Available serological methods for the detection of circulating antigens only reach a 70% of sensitivity. Tests based on the detection of antibodies by immunoenzymatic assays have been improved. The circumoval precipitine test has shown a high sensitivity (97%), specificity (100%), and correlation with oviposition, being considered the best confirmatory diagnostic test. Additionally to the classical immunoenzymatic assays, the development of the alkaline phosphatase immunoassay, allowed to reach a 100% specificity with an 89% sensitivity. Recently, we have developed a modified ELISA in which the soluble egg antigen is treated with sodium metaperiodate (SMP-ELISA) in order to eliminate the glycosilated epitopes responsible for the false positive reactions. The specificity and sensitivity reaches 97% and 99%, respectively. Synthetic peptides from the excretory-secretory enzymes, cathepsin B (Sm31) legumain (Sm32) and cathepsin D (Sm45), have been synthesized. The combination of two peptides derived from the Sm31 have been evaluated, reaching a sensitivity of 96% when analyzed independently and with a 100% specificity. Antibodies raised in rabbits against peptides derived from the Sm31 and Sm32 are currently evaluated in two different antigen-capture-based assays. The development of a simple, cheap and reliable test that correlates with parasite activity is a major goal.

Chagas disease: current epidemiological trends after the interruption of vectorial and transfusional transmission in the Southern Cone countries

Chagas disease, named after Carlos Chagas who first described it in 1909, exists only on the American Continent. It is caused by a parasite, Trypanosoma cruzi, transmitted to humans by blood-sucking triatomine bugs and by blood transfusion. Chagas disease has two successive phases, acute and chronic. The acute phase lasts 6 to 8 weeks. After several years of starting the chronic phase, 20% to 35% of the infected individuals, depending on the geographical area will develop irreversible lesions of the autonomous nervous system in the heart, esophagus, colon and the peripheral nervous system. Data on the prevalence and distribution of Chagas disease improved in quality during the 1980's as a result of the demographically representative cross-sectional studies carried out in countries where accurate information was not available. A group of experts met in Brasília in 1979 and devised standard protocols to carry out countrywide prevalence studies on human T. cruzi infection and triatomine house infestation. Thanks to a coordinated multi-country program in the Southern Cone countries the transmission of Chagas disease by vectors and by blood transfusion has been interrupted in Uruguay in1997, in Chile in 1999, and in 8 of the 12 endemic states of Brazil in 2000 and so the incidence of new infections by T. cruzi in the whole continent has decreased by 70%. Similar control multi-country initiatives have been launched in the Andean countries and in Central America and rapid progress has been recorded to ensure the interruption of the transmission of Chagas disease by 2005 as requested by a Resolution of the World Health Assembly approved in 1998. The cost-benefit analysis of the investments of the vector control program in Brazil indicate that there are savings of US$17 in medical care and disabilities for each dollar spent on prevention, showing that the program is a health investment with good return. Since the inception in 1979 of the Steering Committee on Chagas Disease of the Special Program for Research and Training in Tropical Diseases of the World Health Organization (TDR), the objective was set to promote and finance research aimed at the development of new methods and tools to control this disease. The well known research institutions in Latin America were the key elements of a world wide network of laboratories that received - on a competitive basis - financial support for projects in line with the priorities established. It is presented the time line of the different milestones that were answering successively and logically the outstanding scientific questions identified by the Scientific Working Group in 1978 and that influenced the development and industrial production of practical solutions for diagnosis of the infection and disease control.

The state of the art of paleoparasitological research in the old world

Paleoparasitology in the Old World has mainly concerned the study of latrine sediments and coprolites collected from mummified bodies or archaeological strata, mostly preserved by natural conditions. Human parasites recovered include cestodes, trematodes, and nematodes. The well preserved conditions of helminth eggs allowed paleoepidemiological approaches taking into account the number of eggs found by archaeological stratum. Tentatively, sanitation conditions were assessed for each archaeological period.

Biologic data of Macaca mulatta, Macaca fascicularis, and Saimiri sciureusused for research at the fiocruz primate center

Physiological parameters of laboratory animals used for biomedical research is crucial for following several experimental procedures. With the intent to establish baseline biologic parameters for non-human primates held in closed colonies, hematological and morphometric data of captive monkeys were determined. Data of clinically healthy rhesus macaques (Macaca mulatta), cynomolgus monkeys (Macaca fascicularis), and squirrel monkeys (Saimiri sciureus) were collected over a period of five years. Animals were separated according to sex and divided into five age groups. Hematological data were compared with those in the literature by Student's t test. Discrepancies with significance levels of 0.1, 1 or 5% were found in the hematological studies. Growth curves showed that the sexual dimorphism of rhesus monkeys appeared at an age of four years. In earlier ages, the differences between sexes could not be distinguished (p < 0.05). Sexual dimorphism in both squirrel monkeys and cynomolgus monkeys occurred at an age of about 32 months. Data presented in this paper could be useful for comparative studies using primates under similar conditions.

The role of the scientific research in the control of schistosomiasis in endemic areas

The way the researches established the lines of direction for considering fight against schistosomiasis on the double aspect of transmission and morbidity control is outstanding. Chemotherapy in the morbidity control is emphasized. The research priorities for schistosomiasis control are mentioned.

The human immunodeficiency virus preventive vaccine research at the French National Agency for acquired immunodeficiency syndrome research

The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic is of unprecedented gravity and is spreading rapidly, notably in the most disadvantaged regions of the world. The search for a preventive vaccine is thus an absolute priority. For over 10 years the French National Agency for AIDS research (ANRS) has been committed to an original program combining basic science and clinical research. The HIV preventive vaccine research program run by the ANRS covers upstream research for the definition of immunogens, animal models, and clinical research to evaluate candidate vaccines. Most researchers in 2004 believe that it should be possible to obtain partial vaccine protection through the induction of a strong and multiepitopic cellular response. Since 1992, the ANRS has set up 15 phases I and II clinical trials in order to evaluate the safety and the capacity of the candidate vaccines for inducing cellular immune responses. The tested candidate vaccines were increasingly complex recombinant canarypox viruses (Alvac) containing sequences coding for certain viral proteins, utilized alone or combined with other immunogens (whole or truncated envelope proteins). ANRS has also been developing an original strategy based on the utilization of lipopeptides. These comprise synthetic fragments of viral proteins associated with lipids that facilitate the induction of a cellular immune response. These approaches promptly allowed the assessment of a prime-boost strategy combining a viral vector and lipopeptides.

Current epidemiological trends for Chagas disease in Latin America and future challenges in epidemiology, surveillance and health policy

Chagas disease, named after Carlos Chagas, who first described it in 1909, exists only on the American Continent. It is caused by a parasite, Trypanosoma cruzi, which is transmitted to humans by blood-sucking triatomine bugs and via blood transfusion. Chagas disease has two successive phases: acute and chronic. The acute phase lasts six-eight weeks. Several years after entering the chronic phase, 20-35% of infected individuals, depending on the geographical area, will develop irreversible lesions of the autonomous nervous system in the heart, oesophagus and colon, and of the peripheral nervous system. Data on the prevalence and distribution of Chagas disease improved in quality during the 1980s as a result of the demographically representative cross-sectional studies in countries where accurate information was not previously available. A group of experts met in Brasilia in 1979 and devised standard protocols to carry out countrywide prevalence studies on human T. cruzi infection and triatomine house infestation. Thanks to a coordinated multi-country programme in the Southern Cone countries, the transmission of Chagas disease by vectors and via blood transfusion was interrupted in Uruguay in 1997, in Chile in 1999 and in Brazil in 2006; thus, the incidence of new infections by T. cruzi across the South American continent has decreased by 70%. Similar multi-country initiatives have been launched in the Andean countries and in Central America and rapid progress has been reported towards the goal of interrupting the transmission of Chagas disease, as requested by a 1998 Resolution of the World Health Assembly. The cost-benefit analysis of investment in the vector control programme in Brazil indicates that there are savings of US$17 in medical care and disabilities for each dollar spent on prevention, showing that the programme is a health investment with very high return. Many well-known research institutions in Latin America were key elements of a worldwide network of laboratories that carried out basic and applied research supporting the planning and evaluation of national Chagas disease control programmes. The present article reviews the current epidemiological trends for Chagas disease in Latin America and the future challenges in terms of epidemiology, surveillance and health policy.

A century of research: what have we learned about the interaction of Trypanosoma cruzi with host cells?

Since the discovery of Trypanosoma cruzi and the brilliant description of the then-referred to "new tripanosomiasis" by Carlos Chagas 100 years ago, a great deal of scientific effort and curiosity has been devoted to understanding how this parasite invades and colonises mammalian host cells. This is a key step in the survival of the parasite within the vertebrate host, and although much has been learned over this century, differences in strains or isolates used by different laboratories may have led to conclusions that are not as universal as originally interpreted. Molecular genotyping of the CL-Brener clone confirmed a genetic heterogeneity in the parasite that had been detected previously by other techniques, including zymodeme or schizodeme (kDNA) analysis. T. cruzi can be grouped into at least two major phylogenetic lineages: T. cruzi I, mostly associated with the sylvatic cycle and T. cruzi II, linked to human disease; however, a third lineage, T. cruziIII, has also been proposed. Hybrid isolates, such as the CL-Brener clone, which was chosen for sequencing the genome of the parasite (Elias et al. 2005, El Sayed et al. 2005a), have also been identified. The parasite must be able to invade cells in the mammalian host, and many studies have implicated the flagellated trypomastigotes as the main actor in this process. Several surface components of parasites and some of the host cell receptors with which they interact have been described. Herein, we have attempted to identify milestones in the history of understanding T. cruzi- host cell interactions. Different infective forms of T. cruzi have displayed unexpected requirements for the parasite to attach to the host cell, enter it, and translocate between the parasitophorous vacuole to its final cytoplasmic destination. It is noteworthy that some of the mechanisms originally proposed to be broad in function turned out not to be universal, and multiple interactions involving different repertoires of molecules seem to act in concert to give rise to a rather complex interplay of signalling cascades involving both parasite and cellular components.