The strong reduction in the incidence of disease and infections observed in our study opens up the possibility that protection against malaria could at least have contributed to the heterozygote advantage of SAO in PNG. It is now well established that both and are associated with severe disease and death in Melanesian populations [9],[10],[29],[52]. by PCR (95% CI 22C71, parasitaemia in children 3C21 months (1,111/l versus 636/l, infections in children 15C21 months (odds ratio [OR]?=?0.39, 95% CI 0.23C0.67, or mixed malaria (OR?=?0, 95% CI 0C1.56, malaria (OR?=?0.38, 95% CI 0.15C0.87, Duffy binding proteinCspecific binding inhibitory antibodies were observed significantly more often in sera from SAO than non-SAO children (SAO, 22.2%; non-SAO, 6.7%; malaria by a mechanism that is independent of the Duffy antigen. malaria may have contributed to shaping the unique host genetic adaptations to malaria in Asian and Oceanic populations. deletion is usually lethal in the homozygous state [4], prevalence of heterozygosity reaches 35% in some PNG coastal populations [3]. Therefore, the deletion is usually thought to be associated with improved survival against malaria in these populations. Indeed, SAO has been associated with complete protection against cerebral but not other forms of severe malaria in previous epidemiological studies in PNG [5]. SAO was, however, found Olesoxime to have little or no association with reduced prevalence, parasitaemia, or uncomplicated malaria [6]C[8]. Although non-parasites are often considered to cause only moderate disease, recent data from the island of New Guinea [9]C[11], Brazil [12], and India [13] show that infections are associated with severe disease and mortality. In addition, mortality rates of 5% to 15% were regularly observed in patients challenged with for therapy of tertiary syphilis [14]C[18]. Thus, may be responsible for, or contribute to, natural selection of erythrocyte polymorphisms. This selective pressure is usually suggested by the emergence of the unique, non-African Duffy-negative allele (blood-stage contamination [19]. The proposed Austronesian origin of malaria could have contributed to selection of this genetic polymorphism. An early cross-sectional [21] and a case-control study [6] indicated that Melanesians with hereditary ovalocytosis experienced lower parasitaemia and frequency of contamination with and/or and prevalence of blood-stage contamination, no significant relationship with susceptibility to contamination was observed [7],[22],[23]. However, these were small cross-sectional studies with insufficient statistical power to unmask an association. In vitro studies have shown that SAO red cells are relatively resistant to invasion by some isolates [24],[25], with the degree of resistance influenced by the receptor preferences of the isolate [26] and deformability of the red cell membrane [25]. Ovalocytes exhibit reduced susceptibility to invasion by in Olesoxime vitro, with the suggestion that this is usually mediated by diminished adherence [27]. Olesoxime These observations indicate that SAO may protect against contamination with malaria in vivo. In order to assess the relationship between SAO (i.e., species [30]. Methods Description of Field Studies Infant cohort Between July 2006 and June 2009, a total of 1 1,121 infants 3 mo of age were enrolled in a randomized, placebo-control trial of intermittent preventive treatment for the prevention of malaria and anemia [28]. After screening, consent, and enrolment children were randomized to receive a full treatment course of either amodiaquine+sulphadoxine/pyramethamine (SP), artesunate+SP, or placebo at 3, 6, 9, and 12 mo. A total of 1 1,079 children completed follow-up until 15 mo of age, with an additional 857 followed to 21 mo. Olesoxime At each treatment/follow-up time point, bednet usage was assessed, recent antimalarial treatment documented, and a 250-l finger-prick blood sample was collected from all children for later Mouse monoclonal to ACTA2 detection of contamination (by light microscopy [LM] and post-PCR ligase detection reaction-fluorescent microsphere assay [LDR-FMA] [31]). A full clinical examination was only conducted on children spontaneously reporting signs of clinical illness. A passive case detection system was maintained at the local health centre, three associated aid posts, and a system of monthly study clinics for the entire study period. All children presenting with self-reported signs of a febrile illness were promptly assessed for presence of malaria contamination by rapid diagnostic test (RDT) (ICT Combo test), and only RDT positive children treated with arthemeter-lumefantrine (Coartem, Novartis). A finger-prick sample was collected from all febrile cases for confirmation of malarial infections by LM and PCR. Olesoxime For clinical management and analysis purposes, malarial illness was defined as axillary temperature 37.5C, or history of fever in preceding 48 h, plus an infection of any density by LM and/or a positive RDT with speciation subsequently confirmed by PCR. A more detailed description of the study and its primary outcomes is usually given elsewhere [28]. Pediatric severe malaria case-control study Between October 2006 and December 2009, a total of 318 children of Madang or Sepik parentage aged 0.5C10 y.