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Abstract Background Madagascar has been known for having bio-geo-ecological diversity which is reflected by a complex malaria epidemiology ranging from hyperendemic to malaria-free areas. Malaria-related attacks and infection are frequently recorded both in children and adults living in areas of low malaria transmission. To integrate this variability in the national malaria control policy, extensive epidemiological studies are required to up-date previous records and adjust strategies. Methods A longitudinal malaria survey was conducted from July 1996 to June 2005 among an average cohort of 214 villagers in Saharevo, located at 900 m above the sea. Saharevo is a typical eastern foothill site at the junction between a costal wet tropical area (equatorial malaria pattern) and a drier high-altitude area (low malaria transmission). Results Passive and active malaria detection revealed that malaria transmission in Saharevo follows an abrupt seasonal variation. Interestingly, malaria was confirmed in 45% (1,271/2,794) of malaria-presumed fevers seen at the health centre. All four Plasmodia that infect humans were also found: Plasmodium falciparum; Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. Half of the malaria-presumed fevers could be confirmed over the season with the highest malaria transmission level, although less than a quarter in lower transmission time, highlighting the importance of diagnosis prior to treatment intake. P. falciparum malaria has been predominant (98%). The high prevalence of P. falciparum malaria affects more particularly under 10 years old children in both symptomatic and asymptomatic contexts. Children between two and four years of age experienced an average of 2.6 malaria attacks with P. falciparum per annum. Moreover, estimated incidence of P. falciparum malaria tends to show that half of the attacks (15 attacks) risk to occur during the first 10 years of life for a 60-year-old adult who would have experienced 32 malaria attacks. Conclusion The incidence of malaria decreased slightly with age but remained important among children and adults in Saharevo. These results support that a premunition against malaria is slowly acquired until adolescence. However, this claims for a weak premunition among villagers in Saharevo and by extension in the whole eastern foothill area of Madagascar. While the Malagasy government turns towards malaria elimination plans nowadays, choices and expectations to up-date and adapt malaria control strategies in the foothill areas are discussed in this paper.

Abstract The Atelier Paludisme (Malaria Workshop) is an international training course organized by the Institut Pasteur de Madagascar, which has been held annually for the past five years. The course was designed for both young and experienced researchers, as well as for healthcare professionals, mostly from malaria-endemic countries. Its objective is to provide participants with a broad knowledge of all features of malaria, to improve their skills in project management, to break geographical isolation by using the Internet as a source of documentary information. This six-week course makes use of concepts of andragogy and problem-based learning, i.e. a relationship between participants and tutors, which promotes a process of exchange rather than the simple transmission of knowledge, where participants have to search actively for information. This approach to training, combined with the wide background and experience of those involved, creates positive dynamics and enables participants to acquire new skills, develop their critical and analytical abilities. This paper describes the course and the lessons learned from its evaluation.

Abstract Background In order to improve the monitoring of the antimalarial drug resistance in Madagascar, a new national network based on eight sentinel sites was set up. In 2006/2007, a multi-site randomized clinical trial was designed to assess the therapeutic efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP), amodiaquine (AQ) and artesunate plus amodiaquine combination (ASAQ), the antimalarial therapies recommended by the National Malaria Control Programme (NMCP). Methods Children between six months and 15 years of age, with uncomplicated falciparum malaria, were enrolled. Primary endpoints were the day-14 and day-28 risks of parasitological failure, either unadjusted or adjusted by genotyping. Risks of clinical and parasitological treatment failure after adjustment by genotyping were estimated using Kaplan-Meier survival analysis. Secondary outcomes included fever clearance, parasite clearance, change in haemoglobin levels between Day 0 and the last day of follow-up, and the incidence of adverse events. Results A total of 1,347 of 1,434 patients (93.9%) completed treatment and follow-up to day 28. All treatment regimens, except for the chloroquine (CQ) treatment group, resulted in clinical cure rates above 97.6% by day-14 and 96.7% by day-28 (adjusted by genotyping). Parasite and fever clearance was more rapid with artesunate plus amodiaquine, but the extent of haematological recovery on day-28 did not differ significantly between the four groups. No severe side-effects were observed during the follow-up period. Conclusion These findings (i) constitute an up-dated baseline data on the efficacy of antimalarial drugs recommended by the NMCP, (ii) show that antimalarial drug resistance remains low in Madagascar, except for CQ, compared to the bordering countries in the Indian Ocean region such as the Comoros Archipelago and (iii) support the current policy of ASAQ as the first-line treatment in uncomplicated falciparum malaria.

Abstract Background Antananarivo, the capital of Madagascar, is located at an altitude of over 1,200 m. The environment at this altitude is not particularly favourable to malaria transmission, but malaria nonetheless remains a major public health problem. The aim of this study was to evaluate exposure to malaria in the urban population of Antananarivo, by measuring the specific seroprevalence of Plasmodium falciparum. Methods Serological studies specific for P. falciparum were carried out with an indirect fluorescent antibody test (IFAT). In a representative population of Antananarivo, 1,059 healthy volunteers were interviewed and serum samples were taken. Results The seroprevalence of IgG+IgA+IgM was 56.1% and that of IgM was 5.9%. The major risk factor associated with a positive IgG+IgA+IgM IFAT was travel outside Antananarivo, whether in the central highlands or on the coast. The abundance of rice fields in certain urban districts was not associated with a higher seroprevalence. Conclusion Malaria transmission levels are low in Antananarivo, but seroprevalence is high. Humans come into contact with the parasite primarily when travelling outside the city. Further studies are required to identify indigenous risk factors and intra-city variations more clearly.

Abstract The protozoan Plasmodium falciparum has a complex life cycle in which asexual multiplication in the vertebrate host alternates with an obligate sexual reproduction in the anopheline mosquito. Apart from the apparent recombination advantages conferred by sex, P. falciparum has evolved a remarkable biology and adaptive phenotypes to insure its transmission despite the dangers of sex. This review mainly focuses on the current knowledge on commitment to sexual development, gametocytogenesis and the evolutionary significance of various aspects of gametocyte biology. It goes further than pure biology to look at the strategies used to improve successful transmission. Although gametocytes are inevitable stages for transmission and provide a potential target to fight malaria, they have received less attention than the pathogenic asexual stages. There is a need for research on gametocytes, which are a fascinating stage, responsible to a large extent for the success of P. falciparum.

Intermittent preventive treatment (IPT) of pregnant women with sulfadoxine–pyrimethamine (SP) is being considered as a routine practice in Madagascar, mainly to decrease the risks of malaria-associated severe anaemia in the women, and of low birthweight in their babies. There is, however, relatively little information available on the efficacy of SP when used, in Madagascar, to treat cases of Plasmodium falciparum malaria. In a preliminary study, carried out in 2003 in the village of Saharevo, 36 uncomplicated cases were each treated with a standard dose of SP and with paracetamol and then followed up for 28 days. No case of therapeutic failure occurred and all the asexual parasitaemias cleared by day 3. It therefore appears that SP is effective against P. falciparum in Saharevo (and probably in the whole, rural district of Moramanga in which the village lies). This is an encouraging observation to make before IPT is initiated throughout the country. [ABSTRACT FROM AUTHOR]

Malaria remains a major public health problem in Madagascar, as it is the first cause of morbidity in health care facilities. Its transmission remains poorly documented. An entomological study was carried out over 1 year (October 2003-September 2004) in Saharevo, a village located at an altitude of 900m on the eastern edge of the Malagasy central highlands. Mosquitoes were sampled weekly upon landing on human volunteers and in various resting-places. Out of 5515 mosquitoes collected on humans, 3219 (58.4%) were anophelines. Eleven anopheline species were represented, among which Anopheles funestus, Anopheles gambiae, Anopheles arabiensis and Anopheles mascarensis. Out of 677 mosquitoes collected in bedrooms by pyrethrum spray catches and in Muirhead-Thomson pits, 656 (96.9%) were anopheline belonging to these four latter species. The proportion of mosquitoes that fed on human varied according to the resting-places and the mosquito species: 86% of An. funestus resting in bedrooms fed on humans, whereas only 16% of An. funestus and 0% of An. mascarensis resting in pits fed on humans. The proportion of anopheline mosquitoes infected with human Plasmodium was measured by circumsporozoite protein-ELISA: 10/633 An. funestus (1.58%), 1/211 An. gambiae s.l. (0.48%) and 2/268 An. mascarensis (0.75%). The annual entomological inoculation rate (number of bites of infected anophelines per adult) was estimated at 2.78. The transmission was mainly due to An. funestus and only observed in the second half of the rainy season, from February to May. These results are discussed in the context of the current malaria vector control policy in Madagascar., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Malaria therapy, experimental, and epidemiological studies have shown that erythrocyte Duffy blood group-negative people, largely of African ancestry, are resistant to erythrocyte Plasmodium vivax infection. These findings established a paradigm that the Duffy antigen is required for P. vivax erythrocyte invasion. P. vivax is endemic in Madagascar, where admixture of Duffy-negative and Duffy-positive populations of diverse ethnic backgrounds has occurred over 2 millennia. There, we investigated susceptibility to P. vivax blood-stage infection and disease in association with Duffy blood group polymorphism. Duffy blood group genotyping identified 72% Duffy-negative individuals (FY*B(ES)/*B(ES)) in community surveys conducted at eight sentinel sites. Flow cytometry and adsorption-elution results confirmed the absence of Duffy antigen expression on Duffy-negative erythrocytes. P. vivax PCR positivity was observed in 8.8% (42/476) of asymptomatic Duffy-negative people. Clinical vivax malaria was identified in Duffy-negative subjects with nine P. vivax monoinfections and eight mixed Plasmodium species infections that included P. vivax (4.9 and 4.4% of 183 participants, respectively). Microscopy examination of blood smears confirmed blood-stage development of P. vivax, including gametocytes. Genotyping of polymorphic surface and microsatellite markers suggested that multiple P. vivax strains were infecting Duffy-negative people. In Madagascar, P. vivax has broken through its dependence on the Duffy antigen for establishing human blood-stage infection and disease. Further studies are necessary to identify the parasite and host molecules that enable this Duffy-independent P. vivax invasion of human erythrocytes.

Background: Madagascar has been known for having bio-geo-ecological diversity which is reflected by a complex malaria epidemiology ranging from hyperendemic to malaria-free areas. Malaria-related attacks and infection are frequently recorded both in children and adults living in areas of low malaria transmission. To integrate this variability in the national malaria control policy, extensive epidemiological studies are required to up-date previous records and adjust strategies., Methods: A longitudinal malaria survey was conducted from July 1996 to June 2005 among an average cohort of 214 villagers in Saharevo, located at 900 m above the sea. Saharevo is a typical eastern foothill site at the junction between a costal wet tropical area (equatorial malaria pattern) and a drier high-altitude area (low malaria transmission)., Results: Passive and active malaria detection revealed that malaria transmission in Saharevo follows an abrupt seasonal variation. Interestingly, malaria was confirmed in 45% (1,271/2,794) of malaria-presumed fevers seen at the health centre. All four Plasmodia that infect humans were also found: Plasmodium falciparum; Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. Half of the malaria-presumed fevers could be confirmed over the season with the highest malaria transmission level, although less than a quarter in lower transmission time, highlighting the importance of diagnosis prior to treatment intake. P. falciparum malaria has been predominant (98%). The high prevalence of P. falciparum malaria affects more particularly under 10 years old children in both symptomatic and asymptomatic contexts. Children between two and four years of age experienced an average of 2.6 malaria attacks with P. falciparum per annum. Moreover, estimated incidence of P. falciparum malaria tends to show that half of the attacks (15 attacks) risk to occur during the first 10 years of life for a 60-year-old adult who would have experienced 32 malaria attacks., Conclusion: The incidence of malaria decreased slightly with age but remained important among children and adults in Saharevo. These results support that a premunition against malaria is slowly acquired until adolescence. However, this claims for a weak premunition among villagers in Saharevo and by extension in the whole eastern foothill area of Madagascar. While the Malagasy government turns towards malaria elimination plans nowadays, choices and expectations to up-date and adapt malaria control strategies in the foothill areas are discussed in this paper.

The aim of this study was to provide baseline information of the epidemiological situation of malaria in Madagascar using serological markers. We carried out cross-sectional studies in schoolchildren from eight sites in the four different malarious epidemiological strata of Madagascar. We studied the prevalence of anti-MSP1 antibodies to assess the burden, and anti-CSP antibodies to estimate the transmission intensity, of malaria. The overall prevalence of each antibody tested was 46.1% for anti-PfMSP-1, 15.2% for anti-PvMSP-1, 14.9% for anti-PfCSP, 4.9% for anti-PvCSP and 2.4% for anti-PmCSP. The prevalence of the five antibodies varied significantly between the sites (P<10(-6)). We also found significant effects of ethnic origin on the prevalence of anti-PfMSP1 antibodies. With regular testing in the same target populations, this data will be particularly useful for managing the elimination strategy supported by the Malagasy Government.

Background: In order to improve the monitoring of the antimalarial drug resistance in Madagascar, a new national network based on eight sentinel sites was set up. In 2006/2007, a multi-site randomized clinical trial was designed to assess the therapeutic efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP), amodiaquine (AQ) and artesunate plus amodiaquine combination (ASAQ), the antimalarial therapies recommended by the National Malaria Control Programme (NMCP)., Methods: Children between six months and 15 years of age, with uncomplicated falciparum malaria, were enrolled. Primary endpoints were the day-14 and day-28 risks of parasitological failure, either unadjusted or adjusted by genotyping. Risks of clinical and parasitological treatment failure after adjustment by genotyping were estimated using Kaplan-Meier survival analysis. Secondary outcomes included fever clearance, parasite clearance, change in haemoglobin levels between Day 0 and the last day of follow-up, and the incidence of adverse events., Results: A total of 1,347 of 1,434 patients (93.9%) completed treatment and follow-up to day 28. All treatment regimens, except for the chloroquine (CQ) treatment group, resulted in clinical cure rates above 97.6% by day-14 and 96.7% by day-28 (adjusted by genotyping). Parasite and fever clearance was more rapid with artesunate plus amodiaquine, but the extent of haematological recovery on day-28 did not differ significantly between the four groups. No severe side-effects were observed during the follow-up period., Conclusion: These findings (i) constitute an up-dated baseline data on the efficacy of antimalarial drugs recommended by the NMCP, (ii) show that antimalarial drug resistance remains low in Madagascar, except for CQ, compared to the bordering countries in the Indian Ocean region such as the Comoros Archipelago and (iii) support the current policy of ASAQ as the first-line treatment in uncomplicated falciparum malaria.

The Malaria Workshop organized by Institut Pasteur de Madagascar is an original course that applies innovative concepts to training of health professionals involved in malaria control in endemic countries. Course objectives are to enhance the skills needed to fight malaria (transversal competencies, critical approach, and position statement), to reinforce project cycle management proficiency, and to demonstrate how the Internet can be used as a source of documentation to compensate for geographical isolation. The Malaria Workshop is a six-consecutive-week full-day course that has been presented once a year since 2003. Seventy-six researchers, physicians or health ministry officials have already benefited from this training. Teaching methods emphasize andragogy that facilitates a learner/mentor relationship promoting exchange rather than transmission of knowledge and problem-based learning that engages learners to take an active part in gathering information. These methods in combination with the diverse backgrounds and experience of course participants foster a positive dynamic environment for learning that is monitored by weekly progress evaluation. Follow-up surveys have confirmed the positive effect of this training on the professional performance of former participants who become more involved in program development and fund-raising efforts. A professional network is growing and learners are starting to their experience. In this report workshop organizers describe the course's origins and concepts and present the conclusions drawn based on the first five yearly sessions.

We assessed the status of point mutations associated with chloroquine resistance in pfcrt codon 76 and in pfmdr1 codon 86 among Plasmodium falciparum isolates from symptomatic patients in 3 sites in Madagascar. The in vitro susceptibility of P. falciparum isolates to quinoline-containing drugs was also determined. All isolates (N = 117) successfully typed were pfcrt wild-type, except one from Tsiroanomandidy (1 of 27). However, 67.5% (95% CI: 58.2-75.9%) of these isolates contained mutant pfmdr1 86Y. The pfmdr1 N86Y mutation is associated with higher mefloquine susceptibility, but it did not affect the sensitivity of parasites to chloroquine or quinine. Our findings demonstrate that pfmdr1 mutant P. falciparum are prevalent in Madagascar and confirm the low prevalence of pfcrt mutant P. falciparum after 60 years of chloroquine use. They provide additional field-based evidence for increased mefloquine susceptibility in pfmdr1 mutant P. falciparum and are suggestive of the intrahost selection of pfmdr1 mutant parasites.

Background: Antananarivo, the capital of Madagascar, is located at an altitude of over 1,200 m. The environment at this altitude is not particularly favourable to malaria transmission, but malaria nonetheless remains a major public health problem. The aim of this study was to evaluate exposure to malaria in the urban population of Antananarivo, by measuring the specific seroprevalence of Plasmodium falciparum., Methods: Serological studies specific for P. falciparum were carried out with an indirect fluorescent antibody test (IFAT). In a representative population of Antananarivo, 1,059 healthy volunteers were interviewed and serum samples were taken., Results: The seroprevalence of IgG+IgA+IgM was 56.1% and that of IgM was 5.9%. The major risk factor associated with a positive IgG+IgA+IgM IFAT was travel outside Antananarivo, whether in the central highlands or on the coast. The abundance of rice fields in certain urban districts was not associated with a higher seroprevalence., Conclusion: Malaria transmission levels are low in Antananarivo, but seroprevalence is high. Humans come into contact with the parasite primarily when travelling outside the city. Further studies are required to identify indigenous risk factors and intra-city variations more clearly.

Malaria transmission remains poorly documented in areas of low transmission. A study has been carried out over two consecutive years in Analamiranga, a village located at an altitude of 885m on the western edge of the Malagasy highlands, with the aim of generating and updating malariometric indexes for both mosquitoes and schoolchildren. In this village, no vector control measures were performed during the study period nor during previous decades. Mosquitoes were collected monthly when landing on human volunteers and in various resting-places. Blood samples were taken every 3 months from schoolchildren aged 6-12 years and microscopically examined. Of 7,480 mosquitoes collected on human subjects, 5,790 were anophelines. Ten anopheline species were represented and three of these, Anopheles funestus, Anopheles arabiensis and Anopheles mascarensis, accounted for 59.2% of the collection. Of these three species 4,640 were also collected in resting places. The proportion of mosquitoes fed on bovids was high; conversely, the anthropophilic rate (mosquitoes fed on human beings) was especially low: 31%, 7% and 1%, respectively, for A. funestus, A. arabiensis and A. mascarensis. The only confirmed malaria vector was A. funestus with a low sporozoite index (of 6,830 A. funestus, five were positive for Plasmodium falciparum and four for Plasmodium vivax). The annual entomological inoculation rate (number of bites of infected anophelines per adult person) was estimated at 2.49 with low variation over the 2 years. Overall, 909 thick blood smears were tested from blood samples taken from schoolchildren with 30.3% being malaria-positive. The four Plasmodium species infecting human subjects were detected in the following proportions: P. falciparum 78.9%, P. vivax 19.4%, Plasmodium malariae 1.0% and Plasmodium ovale 0.7%. The proportions of children who were infected with any Plasmodium ranged from 10.7% in February to 51.0% in September. Parasitemic children with fever (axillary temperature >37.5 degrees C) accounted for 16.4% of the children sampled. This study demonstrates that there are substantial parasitological consequences of even a relatively low entomological transmission and also recommends including exterior resting-places of mosquitoes in future spraying campaigns in the highlands of Madagascar.

Plasmodium species, the etiologic agents of malaria, are obligatory sexual organisms. Gametocytes, the precursors of gametes, are responsible for parasite transmission from human to mosquito. The sex ratio of gametocytes has been shown to have consequences for the success of this shift from vertebrate host to insect vector. We attempted to document the effect of chemotherapy on the sex ratio of two different Plasmodium species: Plasmodium falciparum in children from endemic area with uncomplicated malaria treated with chloroquine (CQ) or sulfadoxine-pyrimethamine (SP), and P. vinckei petteri in mice treated with CQ or untreated. The studies involved 53 patients without gametocytes at day 0 (13 CQ and 40 SP) followed for 14 days, and 15 mice (10 CQ and 5 controls) followed for five days. During the course of infection, a positive correlation was observed between the time of the length of infection and the proportion of male gametocytes in both Plasmodium species. No effects of treatment (CQ versus SP for P. falciparum or CQ versus controls for P. vinckei petteri) on the gametocyte sex ratio were found for either Plasmodium species. This indicates that parasites do not respond to chemotherapy by altering their sex allocation strategy, even though, in the case of P. falciparum, they apparently increase their overall investment in sexual stages. This suggests that malaria parasite species respond to different environmental cues for their sex differentiation and sex determination.

Intermittent preventive treatment (IPT) of pregnant women with sulfadoxine-pyrimethamine (SP) is being considered as a routine practice in Madagascar, mainly to decrease the risks of malaria-associated severe anaemia in the women, and of low birthweight in their babies. There is, however, relatively little information available on the efficacy of SP when used, in Madagascar, to treat cases of Plasmodium falciparum malaria. In a preliminary study, carried out in 2003 in the village of Saharevo, 36 uncomplicated cases were each treated with a standard dose of SP and with paracetamol and then followed up for 28 days. No case of therapeutic failure occurred and all the asexual parasitaemias cleared by day 3. It therefore appears that SP is effective against P. falciparum in Saharevo (and probably in the whole, rural district of Moramanga in which the village lies). This is an encouraging observation to make before IPT is initiated throughout the country.

The protozoan Plasmodium falciparum has a complex life cycle in which asexual multiplication in the vertebrate host alternates with an obligate sexual reproduction in the anopheline mosquito. Apart from the apparent recombination advantages conferred by sex, P. falciparum has evolved a remarkable biology and adaptive phenotypes to insure its transmission despite the dangers of sex. This review mainly focuses on the current knowledge on commitment to sexual development, gametocytogenesis and the evolutionary significance of various aspects of gametocyte biology. It goes further than pure biology to look at the strategies used to improve successful transmission. Although gametocytes are inevitable stages for transmission and provide a potential target to fight malaria, they have received less attention than the pathogenic asexual stages. There is a need for research on gametocytes, which are a fascinating stage, responsible to a large extent for the success of P. falciparum.

Fifty children from 9 families were enrolled in a longitudinal study of 8 months to evaluate individual levels of Plasmodium falciparum density in blood during asymptomatic infections. Individual parasite densities were adjusted for age and date of blood intake. The arithmetic means of these adjusted parasite densities (MAPD) were not influenced by sickle cell trait nor by G6PD enzyme activity. On the contrary, family analysis revealed the presence of similar MAPD values according to the sibships. Moreover, sibships frequently infected with P. malariae exhibited the highest P. falciparum MAPDs. The difference in aggressiveness of malaria vectors between the northern and southern halves of the village did not explain the distribution of MAPD, nor did it explain the differences in mean frequency of P. malariae infection among the sibships. We conclude that the familial characteristic of susceptibility to both P. falciparum and P. malariae infections is more likely influenced by the host's genetic background than by differences in the levels of malaria transmission.

Objective: The mechanism of action of methotrexate (MTX) in inflammatory joint disease is still unclear. We examined the possible interactions of MTX with the oxidative metabolism of rabbit articular chondrocytes., Methods: Cell cultures of articular chondrocytes enzymatically isolated from juvenile New Zealand white rabbits were incubated 24 h with either MTX (0.22 or 1.1 microM), bacterial lipopolysaccharide (LPS, 50 microg/ml), or both. Cytofluorometry was then performed using 2',7'-dichlorofluorescein diacetate (DCFH-DA), rhodamine 123 (Rh123), or propidium iodide (PI). These fluorochromes allow evaluation of cellular production of H2O2, mitochondrial membrane potential, and cell viability, respectively. In a separate experiment, we used the Griess colorimetric technique to evaluate cellular nitric oxide (NO) production., Results: Addition of MTX alone (0.22 or 1.1 microM) inhibited spontaneous production by chondrocytes of H2O2 (p < 0.01 and p < 0.001, respectively) and NO (p < 0.01 both concentrations). The LPS induced increase in H2O2, production was inhibited by MTX at 0.22 and 1.1 microM (p < 0.01 both concentrations), whereas the LPS induced increase in NO synthesis was not influenced by MTX, even at 1.1 microM. MTX did not significantly modify mitochondrial activity or cell viability., Conclusion: MTX at therapeutic concentrations in vitro inhibits the production of H2O2 and NO by unstimulated chondrocytes, and only the H2O2 overproduction by LPS stimulated chondrocytes. These properties may contribute to the therapeutic effect of MTX in RA.

Two species of macaques, including two Macaca fascicularis from the Philippines, two M. fascicularis from Mauritius, and one Macaca mulatta, were experimentally infected with blood stages of Plasmodium coatneyi and followed during their clinical, parasitological, biological, and immunological evolution. Plasma cytokine (TNF-alpha, IL-1beta, IL-6, IFN-gamma) production peaked for all monkeys 11 days after inoculation, concomitantly with peaks of parasitemia. Only the M. fascicularis from the Philippines survived the infection. The main features, which discriminated nonfatal from fatal cases, were the observation in M. fascicularis from the Philippines of a mean CD4+/CD8+ ratio below I and of their ability, as revealed by mitogenic stimulation of whole blood, to produce increasing amounts of IFN-gamma as infection evolved. The contribution of environmental and genetic factors, which may differentiate the three groups of monkeys and therefore explain fatal or nonfatal evolution of the infection among them, is discussed.