Severity of imported falciparum malaria: effect of taking antimalarial prophylaxis.

OBJECTIVE--To investigate the effects of antimalarial chemoprophylaxis and other variables on the severity of falciparum malaria. DESIGN--Review of consecutive malaria cases between 1987 and 1991. SETTING--The Hospital for Tropical Diseases, London. SUBJECTS--250 consecutive cases of mild and 51 consecutive cases of severe falciparum malaria. RESULTS--Prophylaxis was taken in 52.4% (131/250) of the cases of mild malaria and 21.6% (11/51) of cases of severe malaria. Severe malaria was more common in white patients than in those of African origin and was also seen more commonly in people returning from central, southern, and east Africa than in those returning from west Africa. Patients with severe malaria presented sooner than patients with mild malaria. CONCLUSIONS--Prior chemoprophylaxis led to a reduction in the severity of falciparum malaria. Ethnic origin, time to presentation, and sex were also associated with the severity of malaria.     

Association analyses of NCR3 polymorphisms with P. falciparum mild malaria

Plasmodium falciparum malaria is a major cause of morbidity and mortality in many developing countries especially in sub-Saharan Africa. A susceptibility locus for mild malaria has been mapped to the MHC region, and TNF polymorphisms have been associated with mild malaria. The Natural Cytotoxicity-triggering Receptor 3 (NCR3) gene is located in the peak region of linkage, and is 15kb distal to TNF. In this study, we considered NCR3 as a candidate gene, and we genotyped ten NCR3 single nucleotide polymorphisms (SNPs). Here, we report evidence of an association between mild malaria and NCR3 -412G>C polymorphism located within the promoter. Population-based association analysis showed that NCR3 -412C carriers had more frequent mild malaria attacks than NCR3 -412GG individuals (P=0.001). Using the family-based association test (FBAT) program and its phenotype (PBAT) option, we further found that NCR3 -412C (P=0.0009) and a haplotype containing NCR3 -412C (P=0.008) were significantly associated with increased risk of mild malaria, and that the association was not due to the association of TNF with mild malaria. These observations suggest that there are at least two genes located on the central region of MHC involved in genetic control of human malaria. The association of NCR3 with malaria should provide new insights into the role of Natural Killer cells in this common disease.     

Advantages and disadvantages of the animal models v. in vitro studies in iron metabolism: a review

Iron deficiency is the most common nutritional deficiency in the world. Special molecules have evolved for iron acquisition, transport and storage in soluble, nontoxic forms. Studies about the effects of iron on health are focused on iron metabolism or nutrition to prevent or treat iron deficiency and anemia. These studies are focused in two main aspects: (1) basic studies to elucidate iron metabolism and (2) nutritional studies to evaluate the efficacy of iron supplementation to prevent or treat iron deficiency and anemia. This paper reviews the advantages and disadvantages of the experimental models commonly used as well as the methods that are more used in studies related to iron. In vitro studies have used different parts of the gut. In vivo studies are done in humans and animals such as mice, rats, pigs and monkeys. Iron metabolism is a complex process that includes interactions at the systemic level. In vitro studies, despite physiological differences to humans, are useful to increase knowledge related to this essential micronutrient. Isotopic techniques are the most recommended in studies related to iron, but their high cost and required logistic, making them difficult to use. The depletion–-repletion of hemoglobin is a method commonly used in animal studies. Three depletion–-repletion techniques are mostly used: hemoglobin regeneration efficiency, relative biological values (RBV) and metabolic balance, which are official methods of the association of official analytical chemists. These techniques are well-validated to be used as studies related to iron and their results can be extrapolated to humans. Knowledge about the main advantages and disadvantages of the in vitro and animal models, and methods used in these studies, could increase confidence of researchers in the experimental results with less costs.     

Cerebral malaria: the contribution of studies in animal models to our understanding of immunopathogenesis

Cerebral malaria is a serious and often fatal complication of Plasmodium falciparum infections. The precise mechanisms involved in the onset of neuropathology remain unknown, but parasite sequestration in the brain, metabolic disturbances and host immune responses are all thought to be involved. This review outlines the current state of knowledge of cerebral disease in humans, and discusses the contribution of studies of animal models to elucidation of the underlying mechanisms.     

Herpesvirus-associated lymphomas: Investigations in humans and animal models

Lymphomas are solid tumors consisting of lymphoid cells; they form a heterogeneous group of less or more malignant disorders. A portion of lymphomas develop due to latent herpesvirus infections established in B and/or T-lymphocytes. The basis for latency is a lifelong presence of the circularized covalently linked viral genome within nuclei of carrier lymphocytes. In certain cases, however, the essential event leading to tumor formation is the integration of a portion(s) of viral DNA into the host cell DNA. This leads to rearrangements within the host cell genome on one hand, and, on other hand, to unregulated expression of oncoproteins encoded by the integrated fragment. Our review deals with mechanisms of lymphoma formation regarding to the role of non-structural herpesvirus oncoproteins interfering with the regulation of cell division and/or exerting anti-apoptotic effects. In addition, the authors wish to highlight the common procedures, which allowed isolation and/or identification of lymphoma-associated viruses in cell cultures derived from tumors and/or proliferating lymphatic tissues.     

Microsomal lipid peroxidation: mechanisms of initiation. The role of iron and iron chelators

The role of iron and iron chelators in the initiation of microsomal lipid peroxidation has been investigated. It is shown that an Fe3+ chelate in order to be able to initiate enzymically induced lipid peroxidation in rat liver microsomes has to fulfill three criteria: (a) reducibility by NADPH; (b) reactivity of the Fe2+ chelate with rat liver microsomes has to fulfill three criteria: (a) reducibility by NADPH; (b) reactivity of the Fe2+ chelate with O2; and (c) formation of a relatively stable perferryl radical. NADH can support lipid peroxidation in the presence of ADP-Fe3+ or oxalate-Fe3+ at rates comparable to those obtained with NADPH but requires 10 to 15 times higher concentrations of the Fe3+ chelates for maximal activity. The results are discussed in relation to earlier proposed mechanisms of microsomal lipid peroxidation.     

The effect of synthetic iron chelators on bacterial growth in human serum

Abstract The effect of synthetic iron chelators of the 1-alkyl-3-hydroxy-2-methylpyrid-4-one class (the L1 series) and 1-hydroxypyrid-2-one (L4) on bacterial growth in human serum was compared with those of the plant iron chelators mimosine and maltol and of the microbial siderophore desferrioxamine. None of the synthetic chelators enhanced growth of 3 Gram-negative organisms ( Yersinia enterocolitica, Escherichia coli and Pseudomonas aeruginosa ); in some cases they were even inhibitory. L4 strongly stimulated growth of Staphylococcus epidermidis , but the L1 series had only a marginal effect. Maltol was mildly inhibitory to all 4 bacterial species, while mimosine enhanced the growth of S. epidermidis and Y. enterocolitica but had little effect on E. coli or P. aeruginosa . Desferrioxamine enhanced the growth chelators of synthetic or plant origin may carry less risk of increasing susceptibility to bacterial infection in patients undergiong chelation therapy for iron overload than does desferrioxamine, the drug currently in clinical use.     

The relevance of non-human primate and rodent malaria models for humans

At the 2010 Keystone Symposium on "Malaria: new approaches to understanding Host-Parasite interactions", an extra scientific session to discuss animal models in malaria research was convened at the request of participants. This was prompted by the concern of investigators that skepticism in the malaria community about the use and relevance of animal models, particularly rodent models of severe malaria, has impacted on funding decisions and publication of research using animal models. Several speakers took the opportunity to demonstrate the similarities between findings in rodent models and human severe disease, as well as points of difference. The variety of malaria presentations in the different experimental models parallels the wide diversity of human malaria disease and, therefore, might be viewed as a strength. Many of the key features of human malaria can be replicated in a variety of nonhuman primate models, which are very under-utilized. The importance of animal models in the discovery of new anti-malarial drugs was emphasized. The major conclusions of the session were that experimental and human studies should be more closely linked so that they inform each other, and that there should be wider access to relevant clinical material.     

The effect of synthetic iron chelators on bacterial growth in human serum

The effect of synthetic iron chelators of the 1-alkyl-3-hydroxy-2-methylpyrid-4-one class (the L1 series) and 1-hydroxypyrid-2-one (L4) on bacterial growth in human serum was compared with those of the plant iron chelators mimosine and maltol and of the microbial siderophore desferrioxamine. None of the synthetic chelators enhanced growth of 3 Gram-negative organisms (Yersinia enterocolitica, Escherichia coli and Pseudomonas aeruginosa); in some cases they were even inhibitory. L4 strongly stimulated growth of Staphylococcus epidermidis, but the L1 series had only a marginal effect. Maltol was mildly inhibitory to all 4 bacterial species, while mimosine enhanced the growth of S. epidermidis and Y. enterocolitica but had little effect on E. coli or P. aeruginosa. Desferrioxamine enhanced the growth of all except E. coli. These results suggest that the chelators of synthetic or plant origin may carry less risk of increasing susceptibility to bacterial infection in patients undergoing chelation therapy for iron overload than does desferrioxamine, the drug currently in clinical use.     

Respiratory muscle injury in animal models and humans

Respiratory muscle injury may result from excessive loading due to a decrease in respiratory muscle strength, an increase in the work of breathing, or an increase in the rate of ventilation. Other conditions such as hypoxemia, hypercapnia, aging, decreased nutrition, and immobilization may potentiate respiratory muscle injury. Respiratory muscle injury has been shown in animal models using direct muscle or phrenic nerve stimulation, acute inspiratory resistive loading, tracheal banding, corticosteroids, phrenic nerve section, and the mdx mouse. Although numerous examples of diaphragm injury have been shown in animal models, evidence in humans is sparse. Potential mechanisms which may contribute to respiratory muscle injury include high levels of intracellular calcium-activated degradative enzymes, non-uniformity of stresses and strains, plasma membrane disruptions, and activation of the inflammatory process.     

Differential antibody responses to Plasmodium falciparum glycosylphosphatidylinositol anchors in patients with cerebral and mild malaria

Glycosylphosphatidylinositol (GPI) membrane anchors of Plasmodium falciparum surface proteins are thought to be important factors contributing to malaria pathogenesis, and anti-GPI antibodies have been suggested to provide protection by neutralizing the toxic activity of GPIs. In this study, IgG responses against P. falciparum GPIs and a baculovirus recombinant MSP1p19 antigen were evaluated in two distinct groups of 70 patients each, who were hospitalized with malaria. Anti-GPI IgGs were significantly lower in patients hospitalized with confirmed cerebral malaria compared to those with mild malaria (P < 0.01) but did not discriminate for fatal outcome. In contrast, a specific marker of the anti-parasite immunity, as monitored by the anti-MSP1p19 IgG response, was similar in both cerebral and mild malaria individuals, although it was significantly lower in a subgroup with fatal outcomes. These results are consistent with a potential anti-toxin role for anti-GPI antibodies associated with protection against cerebral malaria.     

Plasmodium falciparum clinical malaria: lessons from longitudinal studies in Senegal

Development of new antimalaria strategies and particularly vaccines, needs an in-depth understanding of the relationships between transmission, infection, immunity, morbidity and mortality. The intensive and longitudinal collection of entomological, parasitological and clinical data from the Senegalese populations of Dielmo (250-300 inhabitants), exposed to a perennial and intense transmission (about 200 infective bites/person/year) and of Ndiop (300-350 inhabitants) exposed to a seasonal transmission (about 20 infective bites/person/year), allows to respond to many questions about this subject. The acquisition of an antimalaria immunity as one gets older appears to reduce parasite density, complexity of infection, risk of new patent infection after a suppressive treatment but does not reduce the prevalence (as assessed by PCR) of infection which is commonly chronic and asymptomatic. The existence of a pyrogenic threshold effect of parasitaemia allows the individual diagnosis of malaria attacks. P. falciparum genotyping suggests that successive malaria attacks are due to distinct recently inoculated parasite populations that multiply initially without restriction, a dominant population is generally responsible of the clinical manifestations and all new populations do not trigger systematically attacks. The initial intensity of clinical manifestations does not differ perceptibly among children and adults, is not related to the duration of the attacks, does not allow the distinction between several types of attacks, is not predictive of their severity, and the clearance of parasites and manifestations is longer among youngest persons. The risk of malaria attacks is lower as one gets older and among carriers of AS haemoglobin, is higher when transmission increases and during pregnancy up to three months after delivery, and vary between children. The risk of malaria attack per infective bite is negatively related to the intensity of transmission. Because of their high sensitivity in malaria case detection, this type of small community-based studies are powerful and useful for the identification of protective immunological mechanisms as well as for testing rapidly and cheaply the clinical efficacy of any intervention such as antimalarial vaccines and drug therapy or prophylaxis. As a lot of vaccine candidates and drug combinations will be screened or tested in the perspective of the 'Roll-Back Malaria' programme, more attention must be given to longitudinal studies of this type.     

Topical applications of iron chelators in photosensitization.

Generation of the reactive oxygen species (ROS) in skin by exposure to ultraviolet (UV) radiation induces a number of cutaneous pathologies such as skin cancer, photosensitization, and photoaging among others. Skin iron catalyzes UV generation of ROS. Topical application of iron chelators reduces erythema, epidermal and dermal hypertrophy, wrinkle formation, tumour appearance. It has been proposed that iron chelators can be useful agents against damaging effects of both short- and long-term UV exposure. A better understanding of the action mechanisms of iron chelators, might be useful to developing effective anticancer and antiphotoaging cosmetic products. Iron chelators may lead to accumulation of protoporphyrin IX (PpIX), a strong photosensitizer. The action of iron chelators in skin, related to PpIX increase has not yet been thoroughly studied. Therefore, we have investigated the formation of PpIX in normal mouse skin after topical application of creams containing metal chelators. The amount and distribution of porphyrins formed was determined by means of non-invasive fluorescence spectroscopy. Deferoxamine (DF), ethylenediaminetetraacetic acid (EDTA), 1,2-diethyl-3-hydroxypyridin-4-one (CP94), but not meso-2,3-dimercaptosuccinic acid (DMSA), caused increased accumulation of endogenous porphyrins in the skin. Fluorescence excitation and emission spectroscopy confirmed that PpIX was the main fluorescent species. The amount of PpIX accumulated in skin under the present conditions was not large enough to produce any significant erythema after light exposure. Further studies are needed to evaluate the role of PpIX induced by iron chelators used, against photoaging and cancer prevention.