Biomedical subjects
M Cot
Publications and source records attributed to M Cot.
[First results from the ANRS-VESPA survey of persons living with HIV/AIDS].
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[Clinical research on malaria: what for the future?].
Malaria still remains one of the main public health problems in the world. In spite of early and numerous clinical trials, the situation seems to have been worsening in the last ten years. Malaria clinical research involves several levels: Several meta-analyses have been performed on this topic (in particular, the Cochrane Database Library has published studies on malaria prevention during pregnancy, management of clinical malaria attacks, vaccine trials or impregnated bed net trials). All these studies show the uneven quality of trials (only 10% to 50% can be kept in the analysis for methodological reasons), which seldom lead to similar conclusions. Besides, as resistances of both parasites and vectors to drugs or insecticides are regularly increasing, trials have to be repeated and new molecules have to be found and evaluated. Finally, practical application of such interventions may be difficult, due to the heterogeneity of epidemiological situations and the poverty of target populations. Various initiatives aiming to develop malaria clinical research have recently been launched. Donators are public or international (Global Fund, Roll Back Malaria Initiative, NIH, EDCTP programme), as well as private (Bill & Melinda Gates Foundation). These substantial funds should enhance the research of new antimalarial drugs and large-scale, adequately designed trials. However, to make sure these trials really benefit to populations exposed to the disease, ethical principles should be co-elaborated with developing countries, within collaborative networks between laboratories from industrialized and developing countries.
[Anopheles and malaria transmission in Ambohimena, a village in the Occidental fringe of Madagascar Highlands].
The anopheline vectors and malaria transmission were investigated in the Middle West of Madagascar, in the village of Ambohimena (at the altitude of 940 meters) during two years (August 1996 to July 1998). This village is located outside the vector control area, where yearly DDT house spraying campaigns have been conducted between 1993 and 1998. Collection of mosquitoes was mainly based on all night man billing collections (650 man-nights), pyrethrum spray catches (224 bedrooms) and direct collections in outdoor resting places (140 toilets, 61 pigsties, 33 holes, 19 sheds, 79 sisal hedges, 70 cart shelters). Blood fed anophelines allowed analysis of the origin of blood with an ELISA method. Presence of circum-sporozoite protein was assessed with another ELISA method. The total number of collected anophelines was 14,280. Two malaria vectors were identified: Anopheles funestus Giles, 1900 and An. arabiensis Patton, 1902. An. funestus was the most abundant mosquito, especially during the hot rainy season. Two peaks of abundance were observed (in December and April). Endophagic rate (for mosquitoes aggressive for man) of 35.3%, an endophilic rate (for resting mosquitoes) of 78.0% and an anthropophilic rate (for indoor resting mosquitoes) of 64.0% were calculated. The average parity rate was relatively low (61.2%). The Plasmodium falciparum immunological sporozoite rate was 0.20%. An. funestus presented a higher vectorial capacity during the first round of rice cultivation (January) than during the second round (April-May). An. arabiensis was mostly abundant in December and January at the beginning of the rainy season. This species was exophagic (endophagic rate = 27.5%) and zoophilic (anthropophilic rate = 7.8%). The sporozoitic index was determined as zero (number of examined mosquitoes = 871). In this village, An. arabiensis presented only marginal importance for malaria transmission. Malaria transmission occurred from December to April. Annual entomological inoculation rate, only due to An. funestus, was 8.96 during the first year, and 3.17 during the second year. In this area where transmission is moderately stable, we suggest an extension of vector imagocidal control activities up to the western fringes of the Highlands.
Malaria prevention strategies.
Acute and severe consequences of pregnancy-associated malaria (PAM), such as materno-fetal death or cerebral malaria, seem limited to unstable malaria areas. In areas of stable endemicity, the main consequences are maternal anaemia and low birth weight (LBW) babies, particularly in primigravidae. Placental malaria seems more frequent and its consequences more severe in HIV-infected women. Since 1964, several chemoprophylaxis controlled trials have been undertaken, mainly in Tropical Africa where malaria is stable. Most showed an increase in mean birth weight in the prophylaxis group, especially among primigravidae. Similar findings were made with anaemia. Prophylaxis seems less effective in the case of HIV-malaria co-infection, which may require an increase in the number of doses. At present, intermittent treatment with sulfadoxine-pyrimethamine given twice or thrice during pregnancy in antenatal clinics seems the best policy for preventing PAM. Such effective prophylaxis should be integrated with other antenatal clinic services. Recently identified molecular receptors involved in cytoadherence of parasitized erythrocytes to placenta could yield new therapeutic or vaccine approaches, specifically targeted to pregnant women.
[Limits and weaknesses of intermittent treatment in malaria prevention].
WHO proposal of a new strategy for the control of malaria, intermittent treatment using sulfadoxine-pyrimethamine, encounters various conceptual and logistic problems. First, the treatment is dedicated only to a very small part of the population which is not representative of the population at risk. Secondly, it largely underestimates the risks of this type of drugs. At last, the difficulties of its management should lead to hamper this strategy. It would be preferable to study the real causes of the current strategy failure and to take it into account for a new strategy.
[Should clinical research in developing countries be supported?].
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[Malaria during pregnancy: consequences and interventional perspectives].
The impact of malaria during pregnancy varies greatly according to the intensity of transmission. Severe acute complications including cerebral malaria or materno-fetal death seem to be confined to areas of unstable transmission where malaria is uncommon except during epidemics. In areas of stable endemicity, the main consequences are maternal anemia and intra-uterine growth retardation resulting in low birthweight (LBW) particularly after first pregnancies. Recent studies have demonstrated that frequency and severity of placental malaria are greater in pregnant women with concurrent HIV infection. Since 1964 several controlled trials have been conducted to evaluate chemoprophylaxis in pregnant women mainly in tropical Africa where malaria transmission is stable. Findings have usually demonstrated an increase in mean birthweight after prophylaxis especially among primigravidae. Prophylaxis also had beneficial effects on anemia. Another finding of these trials was that prevention is less effective for women with HIV co-infection and that higher doses may therefore be required in such cases. In our opinion prophylaxis should be actively promoted as a routine public health measure for pregnant women in endemic areas. Current recommendations call for the use of a sulfadoxine-pyrimethamine twice or three times during pregnancy in antenatal clinics. This combination is more effective as a result of strong resistance of parasites to chloroquine. High cost and possible adverse effects in pregnant women prohibit routine use of mefloquine in developing countries. Integration of malaria prophylaxis into antenatal care services with nutrition and immunization measures should enhance the overall efficacy of prevention in outlying clinical facilities. Recent identification of molecular receptors involved in the cytoadherence of parasitized red blood cells to the placenta may lead to the development of new therapeutic or vaccinal approaches for pregnant women.
Malaria prevention during pregnancy in unstable transmission areas: the highlands of Madagascar.
Malaria transmission in Madagascar is highly variable from one region to the next, and the consequences of the disease on pregnant women and their foetuses are not fully documented. In midwestern Madagascar, the high-transmission lowlands in the west of the country meet the central plateaux, where malaria is unstable because of the high altitude and annual indoor spraying of DDT since 1993. We studied five of the region's main maternity clinics. We began by interviewing sample groups of women of childbearing age living within the vicinity of each clinic. This enabled us to determine the extent to which they had accessed and made use of available maternal health services during pregnancy and delivery, and, hence, to estimate the feasibility of boosting the prophylaxis. We then spent a whole year (from June 1996 to May 1997) observing deliveries at the five clinics in order to gauge the prevalence of placental infection and its consequences on birthweight in various transmission situations. Although only between 2 and 15% of the women said that they had taken prophylaxis during their previous pregnancy, the vast majority had benefited from preventive care: 97% had attended an antenatal visit on at least one occasion and 84% had had the assistance of medical or paramedical staff during delivery, even when their homes were situated relatively far away from the clinic (76%). In total, we observed 1637 deliveries with a mean placental malaria prevalence rate of 8.1%. Individual prevalence rates, however, were found to differ significantly between the maternity clinics situated in the east (minimum 2.1%) and west (maximum 26.2%) of the region. There were also marked variations in line with the seasonal fluctuations in entomological transmission. On the whole, a greater percentage of low birthweights (LBWs) was recorded at the lowland clinics than at the highland ones (17.1% vs. 9.7%), possibly because of the higher malaria infection rate in low altitude areas. On the other hand, the relative risk of LBW linked to placental infection was far greater in the highlands [4.9 (3.3-7.3)] than in the lowlands [1.9 (1.2-3.0)]. Although the rate of placental malaria among women inhabiting the country's central plateaux may be low, it means that transmission--and, hence, the risk of LBW because of placental infection--still persists in spite of the indoor DDT spraying programme. For maximum efficacy, we recommend a combination of vector control (extended to lower altitude areas outside the current OPID zone) and preventive care--i.e. individual chemoprophylaxis--for all highland women during pregnancy.
Plasmodium falciparum induces a Th1/Th2 disequilibrium, favoring the Th1-type pathway, in the human placenta.
During pregnancy, a local and systemic Th2 bias of maternal immunity favors Th1-dependent infections such as malaria. This study measured cytokines secreted in cultures of chorionic villi, placental blood cells (PBC), and serum in term placentas from 88 malaria-infected and -noninfected Cameroon women. Interleukin (IL)--2 and --4 were consistently low; IL-1 beta, IL-6, granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)--beta 2 were highest in villi cultures. Tumor necrosis factor (TNF)--alpha, interferon (IFN)--gamma, and IL-10 were highest in PBC cultures. Malaria placental infection increased Th1-type cytokines, whereas Th2-type cytokines and TGF-beta 2 were unchanged. Addition of lipopolysaccharide or infected erythrocytes to cultures increased TNF-alpha, IL-1 beta, IL-6, and IL-10 secretions but not those of IFN-gamma and IL-4. Overall, Plasmodium falciparum induced a placental immune response involving both Th1- and Th2-type cell activation. Although the Th1 pathway was favored, IL-10 secretion was also increased, and this increase should be effective in protecting the placenta by controlling the negative effects of Th1 cytokines on pregnancy.
[The campaign against malaria in central western Madagascar: comparison of the efficacy of lambda-cyhalothrin and DDT house spraying. I--Entomological study].
For malaria vector control in Madagascar, the efficacy of lambda-cyhalothrin 10% wettable powder (ICON 10 WP) was compared with DDT 75% WP for house-spraying. This evaluation was conducted from November 1997 to September 1998 in highland villages of Vakinankaratra Region, at the fringe of the malaria epidemic zone, outside the zone covered by routine DDT house-spraying (Opération de pulvérisation intro-domiciliaire de DDT: OPID zone). Treatments were compared by house-spraying in four areas: 1) application of DDT 2g ai/m2 and 2) lambda-cyhalothrin 30 mg ai/m2 in previously unsprayed villages; 3) no intervention (control); 4) OPID 5th cycle of DDT 2g ai/m2. The prevalent vector Anopheles funestus almost disappeared from both the DDT and ICON sprayed areas, whereas in the unsprayed (control) area An. funeslus density went up to 60 females per room in April and there were two seasonal peaks of malaria transmission in January and March (see following paper). In the area sprayed with ICON, the parous rate of An. funestus decreased from 47% pre-spray to 39% six months post-spraying, while the parous rate increased in DDT-sprayed area (from 57% pre-spray to 64% six months post-spray). Bioassays of An. funestus on treated walls, six months post-spray, gave mortality rates of 100% on DDT and 90% on ICON. Conversely, ICON appeared to be more effective than DDT on thatched roofs (66% versus 100%, respectively, six months post-spray). In areas sprayed with DDT or ICON the density of An. arabiensis were little affected. This study demonstrated that, under equivalent conditions, both DDT and lambda-cyhalothrin were effective in reducing malaria transmission on the western fringes of the malaria epidemic zone of the malagasy highlands, with a residual effect lasting at least for six months. Lambda-cyhalothrin appeared to be more effective than DDT in reducing the longevity of malaria vectors. In addition to efficacy, the choice of insecticide for malaria vector control should take into account their acceptability by human populations and their toxicity and persistence in the environment.
[The campaign against malaria in central western Madagascar: comparison of lambda-cyhalothrin and DDT house spraying. II--Parasitological and clinical study].
For malaria vector control in Madagascar, 10 WP (lambda-cyhalothrin 10% wettable powder) was compared with DDT 75% WP for house-spraying, from November 1997 to September 1998. This study was implemented at the fringe of the malaria epidemic zone, in villages on western slopes of the central highlands, outside the area covered for the past five years by routine DDT house-spraying (OPID). Four types of treatment were compared in different areas: 1) DDT 2 g ai/m2 and 2) lambda-cyhalothrin 30 mg ai/m2 in previously unsprayed villages, 3) no intervention (control); 4) yearly DDT spraying (OPID fifth cycle). To investigate the malariological impact of spraying, cross-sectional surveys of the village populations were performed in each study area at intervals of two months, before and after spraying. In the newly sprayed areas, from December to June, malaria indices decreased by 62% in the ICON area and 44% in the DDT area, whereas in the unsprayed village malaria increased by 32% during the same season. There was a similar decrease in the number of gametocyte carriers in the newly sprayed areas. Active malaria case detection among febrile individuals was performed fortnightly in each village outside the OPID area. Results showed decreased malaria incidence from February (two months post-spraying) in the sprayed villages, despite the rainy season, whereas in the unsprayed area the decline occurred only after the main transmission season. This study demonstrated that, parasitologically as well as entomologically, house-spraying with residual insecticide (DDT or ICON) was an effective method for controlling malaria on the western fringes of the Madagascar highlands epidemic zone. Both products were effective, but ICON had slightly better impact than DDT, i.e. more reduction of malaria indices and of vector longevity, less irritancy of mosquitoes. For best results in this area of transition between stable and unstable malaria, we recommend earlier annual spraying (as soon as November) and extension of the OPID barrier towards western and northern slopes of the Plateau.
[Resp-informations].
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Genetic epidemiology of host predisposition microfilaraemia in human loiasis.
Evidence is accumulating from experimental and human studies that genetic factors are involved both in the control of infectious diseases and in the regulation of infection levels and clinical presentation. So far few studies have investigated the role of these genetic factors in human infection by the filarial parasite Loa loa. We present a segregation analysis on 74 nuclear families who live in the tropical rainforest of southern Cameroun and are exposed to homogeneous loiasis transmission. The results indicate that there is a genetic predisposition to be microfilaraemic and that predisposed subjects might be genetically unable to mount an efficient immune response against loiasis antigens. This individual susceptibility could explain at least in part why the prevalence of infection (microfilaraemic individuals) does not usually exceed 30% of the exposed population in hyperendemic regions. Further genetic studies, based on linkage analysis using both familial information and genetic markers, will help to identify the nature of the genetic factors predisposing to microfilaraemia.
Longitudinal study of Plasmodium falciparum infection and immune responses in infants with or without the sickle cell trait.
BACKGROUND: Individuals may be homozygous (SS) or heterozygous (AS) sickle cell gene carriers or have normal adult haemoglobin (AA). Haemoglobin S could have a protective role against malaria but evidence is sparse and the operating mechanisms are poorly known. METHODS: We followed two cohorts of children. The first was enrolled at birth (156 newborn babies) and the second at 24-36 months old (84 children). Both cohorts were followed for 30 months; monthly for parasitological data and half yearly for immunological data. RESULTS: In the first cohort, 22%, and in the second 13% of children were AS. Whatever their age parasite prevalence rates were similar in AA and AS individuals. Mean parasite densities increased less rapidly with age in AS than in AA children, and were significantly lower in AS than in AA children >48 months old. The AA children tended to be more often admitted to hospital than AS children (22% versus 11%, NS). Both anti-Plasmodium falciparum and anti-Pfl55/RESA antibody rates increased more rapidly in AA than in AS children. Conversely, the prevalence rate of cellular responders to the Pfl55/RESA antigen was similar in AA and AS children during the first 2 years of life, then it was higher in AS than in AA children. CONCLUSIONS: Sickle cell trait related antimalarial protection varies with age. The role of the modifications of the specific immune response to P. falciparum in explaining the protection of AS children against malaria is discussed.
Development of antibodies against chondroitin sulfate A-adherent Plasmodium falciparum in pregnant women.
In areas where Plasmodium falciparum is endemic, pregnant women are at increased risk for malaria, and this risk is greatest during the first pregnancy. The placenta sequesters parasites that are able to cytoadhere to chondroitin sulfate A (CSA), a molecule expressed by the placental syncytiotrophoblast, while parasites from a nonpregnant host do not bind to CSA. Cytoadherence is mediated by the expression of variants of the P. falciparum-erythrocyte membrane protein 1 family. Each member of this molecule family induces antibodies that specifically agglutinate infected erythrocytes and inhibit their cytoadherence ability. We investigated whether the higher susceptibility of primigravidae was related to the lack of immune response towards CSA-binding parasites. In a cross-sectional study, primigravidae delivering with a noninfected placenta were less likely to have antibodies agglutinating CSA-binding parasites than multigravidae (P < 0.01). In contrast, parasites from nonpregnant hosts were as likely to be recognized by the sera from women of various parities. In a longitudinal study, at 6 months of pregnancy, antibodies against CSA-binding parasites were present in 31.8% of primigravidae and in 76.9% of secundigravidae (P = 0.02). The antibodies against CSA-binding parasites inhibited the cytoadherence of a CSA-adherent parasite strain to the human placental trophoblast. Our data support the idea that the higher susceptibility of primiparae is related to a lack of a specific immune response to placental parasites.
[Intestinal schistosomiasis from Schistosoma mansoni in Madagascar: extent and center of the endemic].
Schistosoma mansoni and S. haematobium affect respectively 2 million and 500,000 persons in Madagascar. Over the past decade, S. mansoni has spread in the central Highlands of Madagascar, essentially throughout the mid-west and Antananarivo plain. To understand this recent change in the epidemiology of S. mansoni, we examined the relationship between its spatial distribution and several host factors, including labour migration, urbanization and water development projects. In the Highlands, the disease in distribution could be superimposed on the potential expansion areas of snail distribution defined in 1958. However, the distribution is not homogeneous, as for example the road between Betafo and Mandoto (South West of Antananarivo). This focal pattern described in other African countries is unique to the central Highlands of Madagascar. Rice cultivation is the main economic activity and is associated with intense water contact. The focal distribution may be related to an environmental adaptation of host-parasite interaction depending on behavioural patterns, water and soil chemistry and incompatibility between Biomphalaria pfeifferi and S. mansoni. It is also possible that these focal patterns precede homogeneous endemicity, as along the road Itasy-Tsiroanomandidy (west Antananarivo). Major water development carried out in this migration area led to a rapid endemization of the disease. In Befato-Mandoto, where soil management is more restricted, schistosomiasis due to S. mansoni seems to have been established in some foci where epidemiologic conditions are favourable (for example, traditional irrigation canals). In contrast, the spread of S. mansoni in the Antananarivo plain closely follows the settlement of an infected rural population. Epidemiologic surveys conducted on school children in the Antananarivo suburbs, where sanitary conditions are poor, showed a prevalence of 25%. Human migration linked to development projects and urbanization seems to be the principal factor associated with the spread of schistosomiasis in the mid-west area and Antananarivo plain. In the Highlands, the preferential exposure of adult labour migrants has contributed to the widening of the endemic area.
Effect of chloroquine prophylaxis during pregnancy on maternal haematocrit.
Two controlled trials of chloroquine prophylaxis during pregnancy were performed, one in Burkina Faso in 1987, on all pregnant women, and the other in Cameroon in 1992, on primigravidae only. Maternal haematocrit at delivery was found to be significantly higher in those women who had received chloroquine than in those who had not, both in Burkina Faso (37.4% v. 36.5%; P = 0.01) and in Cameroon (34.8% v. 32.8%; P = 0.02). Anaemia, defined as an haematocrit of < 30%, was also less common in those treated with chloroquine (6.3% v. 8.5% in Burkina Faso and 8.3% v. 18.4% in Cameroon) but this difference was not significant in either country. A slight improvement in haematological status when prophylaxis is given has also been observed in similar studies performed in other tropical countries. The present results confirm the usefulness of targeting antimalarial prophylaxis at pregnant women. Such prophylaxis during the first pregnancy also increases birthweight.