The tragedy caused by fake antimalarial drugs.

Counterfeit antimalarials (mainly artemisinin derivatives) is a crucial health problem in developing countries, particularly in Africa. The illegal production, sale and distribution of fake drugs is a huge market evaluated to several billion of dollars and represents more than 50% of the pharmaceutical market in several African countries. Fake drugs have led to a very great number of deaths from untreated malaria or fatality provoked by toxic ingredients. These fake medicines increase the risk of artemisinin resistance developed by the use of sub therapeutic dosages of antimalarials. Tackling this criminal traffic is the objective of an international program created by WHO and involves the international police and custom organizations like INTERPOL. Several very important and encouraging results have been obtained, but the problem will be completely solved if genuine antimalarials, free-of-charge, are handed-over to populations in sub Sahara African countries.

[Predicting and controlling trends for rational nationwide distribution of healthcare services]. / La démographie médicale Prévoir et maîtriser son evolution. Assurer une meilleure répartition de l'offre de soins sur l'ensemble du territoire national.

The uneven geographic distribution of healthcare services in France is an increasingly important problem. Commission XVI of the National Academy of Medicine had updated its previous reports on this subject, focusing on general practitioners, who form the backbone of the French healthcare system. The Commission calls for a more precise estimate of medical demographics, and particularly for regular prospective studies that take into account the increasing feminization of the medical profession. To permit rational adjustment of yearly medical school intake, prospective surveys must look at least 10 years in advance. Coercive measures must be abandoned in favor of incitements to relocate. For example, the obligation placed on newly graduated GPs to spend their last two years of training in medically underserved regions can only encourage them to settle in local practices.

Intracellular oxidative response of human monocytes and granulocytes to different strains of Aspergillus fumigatus.

Aspergillus fumigatus is one of the most prevalent airborne fungal pathogens, causing severe and often fatal infections. Its fungal virulence factors have not been clearly identified. Reactive oxygen species produced by phagocytic cells are potent fungicides for A. fumigatus. The aim of this study was to examine the influence of conidia pigmentation, fungal development stage and genotype strain on human leucocytes oxidative response. Various A. fumigatus strains were used and the oxidative response was analysed by flow cytometry. A significant difference was observed between live- and killed-conidia. A pigmentless strain gave an important intracellular oxidative response compared with pigmented strains. But no difference was observed between strains isolated from patients with invasive aspergillosis (IA) and bronchial colonisation. The modification of healthy phagocytes' oxidative response caused by A. fumigatus components is not sufficient to explain the virulence of fungus and to predict an evolution of patients with IA.

Human cytomegalovirus downregulates complement receptors (CR3, CR4) and decreases phagocytosis by macrophages.

Human cytomegalovirus (HCMV) infection is associated with an increased susceptibility to opportunistic infections. Although the subversion of adaptive immune responses has been extensively studied, the consequences of HCMV infection on natural immune responses are not well documented. A striking selective downmodulation of CD11b/CD18 (CR3) or CD11c/CD18 (CR4) was found upon HCMV infection, on two models, the monocytic THP-1 cell line and monocyte- derived macrophages. HCMV-infected macrophages have an altered adhesion/phagocytic capacity to Candida albicans, a pathogen responsible for some opportunistic infections in immunocompromised patients. These results suggest a new mechanism implicated in the augmentation of opportunistic infections in HCMV patients.

[Recommendations of the National Academy of Medicine for improvement of the clinical training of medical students]. / Recommandations de l'Académie nationale de médecine pour la formation clinique initiale des etudiants en médecine.

Young medical students' initiation into clinical activity and clinical responsabilities could be improved by developing theoretical courses and clinical activities under the strict control of senior medical staff. Such teaching activities should be taken into account in career advancement.

Infection of human astrocytes and glioblastoma cells with Toxoplasma gondii: monocyte chemotactic protein-1 secretion and chemokine expression in vitro.

In immunocompromised hosts, disruption of toxoplasmic cysts and conversion from bradyzoites to tachyzoites occur in brain. In these areas, infiltrates of mononuclear cells are observed. In the murine toxoplasmosis model, recent data suggest that chemokines may play a role in leukocyte recruitment in the central nervous system (CNS). This study analyzed the monocyte chemotactic protein-1 (MCP-1) secretion and chemokine expression after Toxoplasma gondii infection of human astrocytes, glioblastoma cells (U373) and fibroblasts (MRC5) in vitro. T. gondii infection of these CNS cells, astrocytes and glioblastoma cells significantly increased MCP-1 secretion, particularly for astrocytes. In our cellular models, the pattern of chemokine gene expression is dominated by MCP-1 expression. MCP-1 mRNAs were also quantified by real-time-PCR (LightCycler). The behavior of cells studied after T. gondii infection was different (invasion and growth) and the cell mechanisms of chemokine regulation could be dependent on the type of cells infected, while MCP-1 may contribute to the cell recruitment during human cerebral reactivation of T. gondii.

[Malaria: from genetic and molecular biology to disease control]. / Paludisme: de la génétique et de la biologie moléculaire au contrôle de la maladie.

The knowledge of the genomic structure of Plasmodium falciparum and of its main vector, Anopheles gambiae, may offer new perspectives for malaria therapy, vaccines or control of mosquito-borne transmission. New targets for future antimalarial drugs were identified, mainly apicoplast (a vestige of a vegetal structure incorporated by the parasite) and several enzymes, particularly proteases. The practical difficulty is now to select a few number of these "promising molecules", probably no more than 3 or 4, for a preclinical and clinical pharmaceutical development. Indeed, several other antimalarial drugs are already under development, and the industrial possibilities for developing new drugs are evidently limited. Many new vaccination targets and antigenic proteins were also identified. According to scientific and industrial limitations, a complete evaluation of these antigens is absolutely necessary to select a few of them for clinical development. For anti-malarial vaccinations, DNA vaccines may offer the most interesting perspectives, with the possibility of simultaneous immunisation against different Plasmodium stages and of an adjuvant effect by adding a gene encoding certain cytokines. In Anopheles gambiae genome, several genes encoding key-proteins (particularly odorant receptors necessary for blood feeding) were identified, as other genes encoding for proteins limiting the sexual development of Plasmodium inside its vector. From a theoretical viewpoint, genetically modified non biting or non transmitting mosquitoes offer new perspectives for the control of malaria transmission, but until now, the preliminary practical attempts gave rather poor results. On the whole, the genomic and proteomic of Plasmodium falciparum and Anopheles gambiae yielded exciting scientific results, but it is still too early and very speculative to imagine their practical applications for the control of malaria.

Detection of circulating Aspergillus fumigatus galactomannan: value and limits of the Platelia test for diagnosing invasive aspergillosis.

The effectiveness of galactomannan detection with the Platelia test was evaluated in a prospective study of 3,327 sera from 807 patients. The specificity was 99.6% (748 of 751 cases). For the groups of patients with proven and probable invasive aspergillosis, the sensitivity was 50.0% (17 of 34 cases). The disappointing sensitivity associated with the presence of rare false-positive cases underlines the limits of this test.

Monocyte chemotactic protein-1 secretion and expression after Toxoplasma gondii infection in vitro depend on the stage of the parasite.

Infection of human fibroblasts with tachyzoites of RH and Prugniaud strains, two different strains of Toxoplasma gondii, significantly increased monocyte chemotactic protein (MCP)-1 secretion contrary to what happened with bradyzoites of the cystogenetic strain. Quantification of MCP-1 mRNA by RT-PCR showed that this phenomenon is regulated at the transcriptional level. Thus, the stage of parasite can be deciding in MCP-1 induction since only tachyzoites induced MCP-1 expression and secretion. MCP-1 induced by tachyzoites could be involved in cell recruitment, as shown by the quantification of MCP1 ARNm by real-time PCR (LightCycler, Roche Diagnostics), in the pathogenesis of T. gondii infection.

Toxoplasma gondii infection can regulate the expression of tumour necrosis factor-alpha receptors on human cells in vitro.

The in vitro regulation of tumour necrosis factor (TNF)-alpha receptors during Toxoplasma gondii infection of human MRC5 fibroblasts and human myelomonocytic THP-1 cells was investigated. Cells were infected with the virulent RH of T. gondii. TNFR membrane receptors were analysed by flow cytometry with biotinylated TNF-alpha. Shedding of the soluble form of TNFR1 and TNFR2 in cell culture supernatants was measured by enzyme-linked immunosorbent assay, and expression of mRNA production of TNFR1 and TNFR2 was analysed by quantitative real-time polymerase chain reaction, 1 h after infection. In the MRC5 cell line, T. gondii infection did not induce any up- or down-regulation of membrane TNFRs, soluble TNFRs or mRNA of TNFRs. However, THP-1 cell infection with living parasites induced a significant soluble TNFR1 release by THP-1 cells after 1 h. We detected an approximately 50% up-regulation (P < 0.01) of soluble TNFR1 in infected THP-1 cells compared to controls. No change in soluble TNFR2 levels was observed in the same conditions. Moreover, infection decreased the level of TNF membrane receptors, but had no effect on TNFR1 and TNFR2 mRNA levels. TNFR modulation by T. gondii infection, in vitro, depends on the cell type. Furthermore, our data suggest that living parasites control the shedding of the soluble form of TNFR1. This mechanism may influence the role of TNF-alpha in toxoplasmosis.

[Role, mission, and expectations of general physicians]. / Réflexions sur le rôle, les missions et les attentes des médecins généralistes.

Considering the importance of the general medicine in the French public health sector, National Academy of Medicine has created a workgroup specifically devoted to this problem (the role, the missions and the expectations of the general practitioners (GP). Several hearings of GP and of members of patients associations were organized and all the medical unions were also asked by letter. The conclusions of the workgroup mainly concern: 1) the need of better GP-patients relationships 2) the need of a more appropriate professional education 3) better Hospital-GP or health insurance-GP relationships 4) improvement of the GP "status" with the possibility of a better participation to national health campaigns. Among several proposals, the members of the workgroup suggest the organisation of a national meeting devoted to the place and attempts of GP in the French public health. They consider their report as a preliminary one and they have announced that they will continue trying to make more specific suggestions.

Inmunoparasitologia: origem, estado actual y perspectivas / Immunoparasitology: origin, current status and perspectives

Se hace un repaso de los principales adelantos logrados por la inmunoparasitología en su corta existencia. Luego de señalar los obstáculos que deben superarse para obtener antígenos adecuados, se explican brevemente las principales aplicaciones práticas de la nueva disciplina, a saber: inmunodiagnóstico de parasitosis, encuestas epidemiológicas, evaluación de la curación de las parasitosis despúes del tratamiento, inmunopatología de enfermedades parasitarias y perspectivas de la elaboración de vacunas antiparasitarias, principalmente contra el paludismo causado por P. falciparum. La descripción de estos adelantos está basada en la experiencia del autor y en una revisión bibliográfica. Se destaca la rapidez del avance de la inmunoparasitología en años recientes y la orientación práctica de muchas investigaciones en este campo