EHP LIBRARY MALARIA BULLETIN 48: OCT 28-NOV 10, 2002

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Social Sciences and Malaria 

Soc Sci Med 2002 Dec;55(11):2061-72

Afghan refugees and the temporal and spatial distribution of malaria in Pakistan.

Rowland M, Rab MA, Freeman T, Durrani N, Rehman N.

HealthNet International, University Town, Peshawar, Pakistan

Influx of refugees and establishment of camps or settlements in malaria endemic areas can affect the distribution and burden of malaria in the host country. Within a decade of the Soviet invasion of Afghanistan and the arrival of 2.3 million Afghan refugees in Pakistan’s North West Frontier Province, the annual burden of malaria among refugees had risen ten fold from 11,200 cases in 1981 to 118,000 cases in 1991, a burden greater than the one reported by the Pakistan Ministry of Health for the entire Pakistani population. Political developments in the 1990s led to over half the refugee population repatriating to Afghanistan, and the Afghan Refugee Health Programme (ARHP) was scaled down proportionately. Districts in which the ARHP recorded a reduced incidence of malaria began to show an increased incidence in the statistics of the Pakistan government health programme. This and other evidence pointed to a change in health seeking practices of the refugees who remained in Pakistan, with many turning from ARHP to Pakistani health services as aid declined. Comparison of the two sources of data produced no evidence for the spatial distribution of malaria in NWFP having changed during the 1990s. Nor was there any evidence for the presence of refugees having increased the malaria burden in the Pakistani population, as is sometimes alleged. This highlights the risk of misinterpreting health trends when parallel health services are operating. Over the decade incidence in the refugee camps decreased by 25% as a result of control activities, and by 1997 the burden among remaining refugees had fallen to 26,856 cases per annum. These trends indicate that the burden would continue to fall if political conditions in Afghanistan were to improve and more refugees returned to their homeland.

Soc Sci Med 2002 Dec;55(12):2215-26 

Strategies to improve adherence to recommended chloroquine treatment regimes: a quasi-experiment in the context of integrated primary health care delivery in Ghana.

Agyepong IA, Ansah E, Gyapong M, Adjei S, Barnish G, Evans D.

District Health Administration, P.O. Box 1, Dodowa, Ghana

This paper presents the results of an intervention study carried out as part of the activities of a District Health Management Team responsible for integrated primary health care delivery in a rural district in Ghana. The aim was to test the impact of a combination of improved information provision to patients and drug labeling on adherence to recommended anti-malarial treatment regimens

focusing on oral chloroquine, for the outpatient management of acute uncomplicated malaria. The study had a quasi-experimental pre-test post-test control group design with partly random allocation by clinic. The results show that the intervention resulted in an improved flow of information to clients prescribed chloroquine, and better labeling of drugs for the home treatment of acute clinical episodes of malaria in the intervention area. Improvements in adherence occurred in all clinics. However, improvements in adherence were most marked in the clinic that was worst performing at the start of the intervention. Implications of the results for improving adherence to chloroquine therapy on an outpatient basis are discussed.

Health Policy Plan  2002 Dec;17(4):402-411 

Willingness to pay for treated mosquito nets in Surat, India: the design and descriptive analysis of a household survey.

Bhatia M, Fox-Rushby J.

Department of Social Policy, London School of Economics and Political Science, and. Department of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, UK.

For willingness to pay (WTP) studies to have an appropriate impact on policy making, it is essential that the design and analysis are undertaken carefully. This paper aims to describe and justify the design of the survey tool used to assess hypothetical WTP for treated mosquito nets (TMN) in rural Surat, India and report its findings. Results from qualitative work were used as an input for developing the WTP questionnaire. A total of 1200 households belonging to 80 villages in rural Surat were selected for the study. A bidding format was used to elicit WTP values, using three different starting bids. The scenario was constructed in a way to reduce the possibility of respondents acting strategically. The response rate was 100%. About 79% of the respondents were willing to buy TMNs and the mean WTP was Rs57. Descriptive results of economic and other taste and preference variables are also presented, which include preventive measures used by households and treatment seeking behaviour for malaria. It is observed that WTP as well as demographic variables and prevention methods differ significantly across arms of the trial. This paper suggests that policy-makers could use the evidence following further analysis, along with information on costs of implementation, to ascertain the levels of subsidy that may be needed at different levels of coverage.  

Health Policy Plan 2002 Dec;17(4):333-344 

Self-treatment for malaria: the evidence and methodological issues.

McCombie S.

Department of Anthropology and Geography, Georgia State University, Atlanta, GA,

USA.

Malaria remains an important cause of death, especially in sub-Saharan Africa. Self-treatment with antimalarial drugs is a common practice that raises important issues for policy-makers. A number of important questions concerning factors related to self-treatment, adequacy of self-treatment and the role of self-treatment in malaria mortality remain unanswered. Although there are some common patterns, there is considerable diversity in treatment practices, even within a single country. Social science research on malaria treatment needs to move beyond description to evaluation of interventions. This will require a greater degree of methodological rigour and more attention to the generation of data that can be compared across time periods and studies. Definitions of malaria cases and the role of local disease categories in identifying cases need to be made more explicit. Illnesses should be classified by severity, using measures of perceived severity as well as biomedical signs of severity. Each treatment step should be considered in terms of four levels of analysis: who provided the treatment or advice, what the treatment was, where it was obtained and when it was taken in relationship to onset of illness.

Public Health  2002 Nov;116(6):374-8 

Improvement in malaria services in an urban setting: role of staff motivation.

Raghuvanshi VS.

Urban health centres and the private clinics (PCs) providing malaria services in an urban setting were compared on seven utilization-determining factors to assess why people preferred one over the other. On the other hand, motivation level of the technical staff of the corporation in the malaria services was studied to find out the extent to which the motivation level of the staff was responsible for the observed mean scores of the factors studied. It was found that PCs fared better on all of them. However, the two differed mostly on wait-in period at the outlet, distance from residence, ambience of the outlet, and getting relief. The study further showed that for the doctors and the primary health workers, the opportunity of influencing people was the strongest motivation to work in the corporation and for the subsanitary inspectors, it was affiliation. Based on this, a model is suggested to introduce changes based on motivation mix of the malaria staff.

Trop Doct  2002 Oct;32(4):206-9 

Treatment of malaria in Ethiopian folk medicine.

Gedif T, Hahn HJ.

Institute of Pharmacoepidemiology and Pharmacoeconomics, School of Pharmacy, Martin-Luther University, Halle(Saale), Germany. Email: [email protected]

Key informant interviews of herbalists were conducted to document the traditional management of malaria in Ethiopia. The perceptions of the cause and symptoms of malaria, the use of plants, their preparation and administration were recorded. Interviews were performed in rural Butajira and Addis Ababa (the main city). The result showed that 33 (75%) of the interviewed healers treat malaria using herbal drugs. Sixteen plants were reported to have been used of which eight were used as a single remedy and the rest as composite remedies with other plants. The ethnopharmacological data generated in this study on antimalarial plants is useful for further evaluations of the traditional claims of antimalarial plants in Ethiopia.

PubMed

Genes Immun 2002 Nov;3(7):414-418 

A promoter polymorphism in the gene encoding interleukin-12 p40 (IL12B) is associated with mortality from cerebral malaria and with reduced nitric oxide production.

Morahan G, Boutlis CS, Huang D, Pain A, Saunders JR, Hobbs MR, Granger DL, Weinberg JB, Peshu N, Mwaikambo ED, Marsh K, Roberts DJ, Anstey NM.

The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.

Interleukin-12 (IL-12) is an important regulatory cytokine in infection and immunity. Administration of IL-12 may reduce complications of severe malaria in rodents. Polymorphisms in IL12B, the gene encoding the IL-12 p40 subunit, influence the secretion of IL-12 and susceptibility to Type 1 diabetes. We therefore investigated whether IL12B polymorphisms may affect the outcome of severe malaria. Homozygosity for a polymorphism in the IL12B promoter was associated with increased mortality in Tanzanian children having cerebral

malaria but not in Kenyan children with severe malaria. Furthermore, homozygotes for the IL12B promotor polymorphism had decreased production of nitric oxide, which is in part regulated by IL-12 activity. These studies suggest that IL12B polymorphisms, via regulation of IL-12 production, may influence the outcome of malaria infection in at least one African population. doi:10.1038/sj.gene.6363909

J Membr Biol 2002 Nov;190(1):1-8 

A novel transporter, pfcrt, confers antimalarial drug resistance.

Howard EM, Zhang H, Roepe PD.

Dept. of Chemistry, Dept. of Biochemistry and Molecular Biology, and Program in Tumor Biology, Lombardi Cancer Center Georgetown University, 37th and O Streets, Washington, DC 20057-1227, USA.

The elucidation of the molecular details of drug resistance phenomena is a very active area of research that crosses many disciplinary boundaries. Drug resistance is due to altered drug-target interaction, and/or dysregulated signaling related to cell growth and death. Since many drugs need to rapidly diffuse into and within cells in order to find their targets, and since transmembrane ion transport is an important facet of cellular signaling, it is not surprising that membrane transport phenomena have been implicated in the evolution of drug resistance in tumor cells, bacteria, and intracellular parasites such as Plasmodium falciparum, the causative agent of the most lethal form of human malaria. The most infamous membrane transport protein involved in drug resistance is “MDR protein” or “P-glycoprotein” (Pgp),1 which was found to be overexpressed in drug-resistant tumor cells over 15 years ago, and which is representative of the ATP-binding cassette (ABC) superfamily that also includes the important cystic fibrosis transmembrane conductance regulator (CFTR) and sulfonyl urea receptor (SUR) ion channels. Availability of mouse and human Pgp cDNA rather quickly led to the identification of homologues in many species, including P. falciparum, and these were de facto assumed to be the ultimate determinants of drug resistance in these systems as well. However, research over the past 10 years has taught us that this assumption likely is wrong and that the situation is more complex. We now know that human Pgp plays a relatively minor role in clinically relevant tumor drug resistance, and that an integral membrane protein with no homology to the ABC superfamily, Pfcrt, ultimately confers chloroquine resistance in P. falciparum. Thus, the general hypothesis that membrane transport and membrane transport proteins are important in drug resistance phenomena remains correct, but at a genetic, biochemical, and physiological level we have recently witnessed a few very interesting surprises.

Trends Mol Med 2002 Nov;8(11):531-7 

Human complement receptor type 1 (CR1) binds to a major malarial adhesin.

Krych-Goldberg M, Moulds JM, Atkinson JP.

Division of Rheumatology, Washington University School of Medicine, 63110, St. Louis, MO, USA

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a major adhesin molecule expressed on Plasmodium-falciparum-infected erythrocytes, interacts with several receptors on endothelial cells and uninfected erythrocytes. This ‘stickiness’, known as rosetting, is a strategy used by the parasite to remain sequestered in the microvasculature to avoid destruction in the spleen and liver. Erythrocyte rosetting causes obstruction of the blood flow in microcapillaries. Recent data suggest a direct interaction between PfEMP1 and a functional site of complement receptor type 1 (CR1; CD35) on uninfected erythrocytes. Consistent with the hypothesis that CR1 is important in malaria pathogenesis is a 40-70-fold increase in the frequency of two CR1 blood-group antigens (at least one of which might rosette less efficiently) in malaria-exposed African populations. Furthermore, structural differences in erythrocyte CR1 between human and non-human primates are probably explained by the selective pressure of malaria.

Parasitol Int 2002 Dec;51(4):343-52 

Differential localization of processed fragments of Plasmodium falciparum  serine repeat antigen and further processing of its N-terminal 47 kDa fragment.

Li J, Mitamura T, Fox BA, Bzik DJ, Horii T.

Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, 565-0871, Osaka, Japan

The serine repeat antigen (SERA) of Plasmodium falciparum is a blood stage malaria vaccine candidate. It has been shown that 120 kDa SERA was proteolytically processed into N-terminal 47 kDa fragment (P47), central 56 kDa fragment (P56) that was further converted to 50 kDa (P50), and C-terminal 18 kDa fragment (P18). Here, we have examined the processing of SERA and the localization of its processed fragments by using mouse antibodies directed against recombinant proteins corresponding to different domains of SERA. Western blot analysis showed that all the processing events occurred inside parasitized erythrocytes at the stage just prior to the schizont rupture, that P47 was further processed into two 25 kDa fragments and that the two fragments, which were linked to P18 through disulfide bonds, were associated with the merozoite. In contrast, P50 was completely shed into culture medium and absent from the merozoite. This observation was further supported by the results of indirect immunofluorescence assay. These results could account for the findings that antibodies against P47 were inhibitory to the parasite growth in vitro but those against P50 were not. Finally, we demonstrated that the further processing of P47 is allelic type-dependent. The results of the present study would help in vaccine designing based on SERA.

Insect Mol Biol 2002 Dec;11(6):517-25 

Genomic organization and regulation of three Cecropin genes in Anopheles gambiae.

Zheng XL, Zheng AL.

The First Military Medical University, Department of Parasitology, Guangzhou, The People’s Republic of China; and Yale University School of Medicine, Department of Epidemiology and Public Health, New Haven, CT, USA.

Three cecropin genes (AgCecA-C) were identified from Anopheles gambiae, a major vector for malaria in sub-Saharan Africa. These genes form a cluster with AgCecA and AgCecB positioned in opposite orientation, while AgCecC is downstream of AgCecA in the same direction. One intron is present in each of these three genes. Motif searches of promoter regions revealed elements that could be regulated by the NF-kappaB family of transcriptional regulators. The divergent promoter (1186 nucleotides in length) between CecA and CecB and the promoter for CecC were analysed by transfection in An. gambiae cell lines. Results showed that these promoters were up-regulated by lipopolysaccharide. The activity was further elevated when heat-inactivated microbes were used to challenge the cell line. At least one NF-kappaB site was required for inducible expression of both CecA and CecB.

MMWR Surveill Summ 2002 Mar 29;51(1):15-28 

Malaria surveillance–United States, 1999.

Newman RD, Barber AM, Roberts J, Holtz T, Steketee RW, Parise ME.

Epidemic Intelligence Service, Epidemiology Program Office, USA.

PROBLEM/CONDITION: Malaria is caused by four species of intraerythrocytic protozoa of the genus Plasmodium (i.e., P. falciparum, P. vivax, P. ovale, or P. malariae). Malaria is transmitted by the bite of an infective female Anopheles sp. mosquito. The majority of malaria infections in the United States occur in persons who have traveled to areas with ongoing transmission. In the United States, cases can occur through exposure to infected blood products, by congenital transmission, or locally through mosquitoborne transmission. Malaria surveillance is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers. PERIOD 

COVERED: Cases with onset of illness during 1999. DESCRIPTION OF SYSTEM: Malaria cases confirmed by blood films are reported to local and state health departments by health-care providers or laboratory staff. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS). Data from NMSS serve as the basis for this report. RESULTS: CDC received reports of 1,540 cases of malaria with an onset of symptoms during 1999 among persons in the United States or one of its territories. This number represents an increase of 25.5% from the 1,227 cases reported for 1998. P. falciparum, P. vivax, P. malariae, and P. ovale were identified in 46.0%, 30.7%, 4.6%, and 3.6% of cases, respectively. More than one species was present in 12 patients (0.8% of total). The infecting species was unreported or undetermined in 223 (14.5%) cases. The number of reported malaria cases acquired in Africa increased 27.6% (n = 901), compared with 1998, and an increase of 2.9% (n = 246) occurred in cases acquired in Asia, compared with 1998. Cases from the Americas increased by 19.7% (n = 274) from 1998. Of 831 U.S. civilians who acquired malaria abroad, 159 (19.1%) reported that they had followed a chemoprophylactic drug regimen recommended by CDC for the area to which they had traveled. Three patients became infected in the United States, all through probable local mosquitoborne transmission. Five deaths were attributed to malaria, all caused by P. falciparum. 

INTERPRETATION: The 25.5% increase in malaria cases in 1999, compared with 1998, resulted primarily from increases in cases acquired in Africa and the Americas. This increase is possibly related to a change in the system by which states report to CDC, but it could also have resulted from local changes in disease transmission, increased travel to these regions, improved reporting to state and local health departments, or a decreased use of effective antimalarial chemoprophylaxis. In the majority of reported cases, U.S. civilians who acquired infection abroad were not on an appropriate chemoprophylaxis regimen for the country where they acquired malaria. 

PUBLIC HEALTH ACTIONS: Additional information was obtained concerning the five fatal cases and the three infections acquired in the United States. The NMSS surveillance form was modified to gather more detailed information regarding compliance with prescribed chemoprophylaxis regimens. Persons traveling to a malarious area should take one of the recommended chemoprophylaxis regimens appropriate to the region of travel, and travelers should use personal protection measures to prevent mosquito bites. Any person who has been to a malarious area and who subsequently develops a fever or influenza-like symptoms should seek medical care immediately; investigation should include a blood-film test for malaria. Malaria infections can be fatal if not diagnosed and treated promptly. Recommendations concerning prevention of malaria can be obtained from CDC.

J Am Chem Soc 2002 Nov 13;124(45):13434-6 

Rapid synthesis of a glycosylphosphatidylinositol-based malaria vaccine  using automated solid-phase oligosaccharide synthesis.

Hewitt MC, Snyder DA, Seeberger PH.

Contribution from the Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.

Described is an automated synthesis of hexasaccharide malarial toxin 1, currently under development as a malaria vaccine candidate. Using a combination of automated solid-phase methods and solution-phase fragment coupling, the target glycosylphosphatidylinositol was assembled in a matter of days, compared with several weeks for a comparable solution-phase synthesis.

P N G Med J 2001 Mar-Jun;44(1-2):17-23 

Towards a malaria vaccine for Papua New Guinea.

Reeder JC.

Malaria is a major problem in Papua New Guinea, where it accounts for a high proportion of sickness and death. In addition to the human suffering, malaria also puts severe stress on the health services, and may directly hinder economic growth. A malaria vaccine would be the best, most cost-effective and safest public health measure to reduce the burden of malaria. Though considerable technical challenges are present, much natural and scientific evidence suggests a vaccine is achievable. Through the malaria vaccine program at the Papua New Guinea Institute of Medical Research, Papua New Guinea is playing a significant role in the global effort to develop a malaria vaccine, and ensuring that the malaria patterns of the Asia-Pacific region figure strongly in vaccine development strategies. Discussed here are some of the major issues to be considered as we work towards a malaria vaccine for Papua New Guinea.

Biochem Biophys Res Commun 2002 Nov 1;298(3):371-6 

Molecular characterization and expression of an alternate proliferating cell nuclear antigen homologue, PfPCNA2, in Plasmodium falciparum.

Patterson S, Whittle C, Robert C, Chakrabarti D.

Department of Molecular Biology and Microbiology, University of Central Florida, 32826, Orlando, FL, USA

The malaria parasite Plasmodium falciparum genome sequencing has revealed the existence of a second gene for proliferating cell nuclear antigen (PCNA), a key factor in a variety of DNA metabolic events. The alternate copy of PCNA (PfPCNA2) shows only 23% identity to an earlier reported P. falciparum PCNA homologue (PfPCNA1). Our analysis indicated structural conservation of PfPCNA2 compared to eukaryotic PCNAs. PfPCNA1 and 2 polypeptides showed differential expression in the intraerythrocytic cell cycle of the malaria parasite. PfPCNA1 expression slowly increases about threefold from the ring to the late schizont stage. In contrast PfPCNA2 showed robust expression in trophozoites and early schizonts with a sudden drop in expression in the late schizont stage, suggesting that the two PfPCNAs may function under different physiological conditions. Chemical cross-linking indicated the presence of a trimeric PfPCNA2 protein, indicating the possible existence of a functional ring-like PfPCNA2 structure.

Blood 2002 Oct 31; [epub ahead of print] 

T cell activation and cytokine production via a bispecific single-chain 

antibody fragment targeted to blood-stage malaria parasites.

Yoshida S, Kobayashi T, Matsuoka H, Seki C, Gosnell WL, Chang SP, Ishii A.

A novel bispecific single-chain antibody fragment (biscFv) has been constructed to address the possibility of a new approach to malaria therapeutic drug development. The biscFv consists of two different single-chain antibody fragments linked by a flexible peptide linker (Gly4-Ser)3. One of the two scFv fragments is directed against a conserved epitope of the 19 kDa C-terminal fragment of the major surface protein of human malignant malaria parasite, Plasmodium falciparum, and the other is directed against the CD3 antigen of human T cells. The biscFv expressed by a recombinant baculovirus retained the antigen-binding properties of the corresponding univalent single-chain antibody fragments and formed a bridge between P. falciparum and T cells. In cooperation with T cells, the biscFv specifically induced not only IFN-gamma and TNF-alpha, but also a significant increase of merozoite phagocytosis and growth inhibition of P. falciparum in vitro. Thus, the biscFv possesses highly selective malaria targeting properties and stimulates T cells to induce cytokines, presumably resulting in activation of macrophages, neutrophils and NK cells and parasite killing in vivo.

Zhonghua Yu Fang Yi Xue Za Zhi 2002 Mar;36(2):103-105 

GIS prediction model of malaria transmission in Jiangsu province.

Yang G, Zhou X, Malone J, McCarroll J, Wang T, Liu J, Gao Q, Zhang X, Hong Q,

Sun L.

Jiangsu Institute of Parasitic Diseases, Wuxi 214064, China.

OBJECTIVES: To perform GIS spatial analysis on malaria transmission patterns in Jiangsu after setting up a malaria database and developing GIS model of malaria transmission in Jiangsu province. METHODS: The epidemiological GIS database of malaria in Jiangsu province was established using ArcView 3.0a software. The climate data covering Jiangsu province and its peripheral area were extracted from the FAOCLIM database, the total growing degree days (TGDD) for Plasmodium vivax were calculated, and spatial distribution for TGDD was analyzed by ArcVeiw 3.0a. RESULTS: The predicted malaria distribution map based on TGDD was created, which showed that the transmission of malaria decreased gradually from west to east, which can be divided into three belts according to the degree of transmission. The 14-year mean morbidity distribution map of malaria in Jiangsu showed that the middle and west parts of Jiangsu is the most serious endemic area. The morbidity in the areas along the Taihu valley, such as Suzhou, Wuxi and Changzhou, as well as Nantong and a few of northern counties are the lowest. The morbidity of other places is at the middle level. The 14-year mean morbidity distribution map of malaria is correlated with predicted malaria distribution map for TGDD. CONCLUSION: It is possible to monitor the malaria transmission by GIS predicted model based on TGDD.

Clin Infect Dis 2002 Nov 15;35(10):1147-54 

Efficacy of atovaquone/proguanil for malaria prophylaxis in children and its effect on the immunogenicity of live oral typhoid and cholera vaccines.

Faucher JF, Binder R, Missinou MA, Matsiegui PB, Gruss H, Neubauer R, Lell B, Que JU, Miller GB, Kremsner PG.

Medical Research Unit, Albert Schweitzer Hospital, Lambarene, Gabon.

A double-blind, placebo-controlled study was conducted to measure the impact of malaria prophylaxis with atovaquone/proguanil (A-P) on the immunogenicity of vaccines against typhoid fever and cholera, Salmonella serotype Typhi Ty21a and Vibrio cholerae CVD103-HgR, respectively. A total of 330 Gabonese schoolchildren were assigned to receive either A-P or placebo for 12 weeks. Vaccination occurred 3 weeks after the start of prophylaxis, and immunogenicity was assessed 4 weeks after vaccination. The protective efficacy of A-P against Plasmodium falciparum malaria was of 97% (95% confidence interval, 79%-100%). The 2 treatment groups did not differ significantly with regard to changes in antibody titers after vaccination (P=.96 for anti-S. Typhi IgG antibodies, P=.07 for anti-S. Typhi IgA antibodies, and P=.64 for vibriocidal antibodies). The A-P combination was highly effective for malaria prophylaxis, without interfering with the in vivo immunogenicity of CVD103-HgR and Ty21a vaccines, and it could therefore be simultaneously administered with these vaccines.

Nucleic Acids Res 2002 Nov 1;30(21):4607-17 

The malaria parasite Plasmodium falciparum encodes members of the Puf RNA-binding protein family with conserved RNA binding activity.

Cui L, Fan Q, Li J.

Department of Entomology, The Pennsylvania State University, 501 ASI Building, University Park, PA 16802, USA.

A novel class of RNA-binding proteins, Puf, regulates translation and RNA stability by binding to specific sequences in the 3′-untranslated region of target mRNAs. Members of this protein family share a conserved Puf domain consisting of eight 36 amino acid imperfect repeats. Here we report two Puf family member genes, PfPuf1 and PfPuf2, from the human malaria parasite Plasmodium falciparum. Both genes are spliced with four and three introns clustered within or near the Puf domains, respectively. Northern and RT-PCR analysis indicated that both genes were differentially expressed in gametocytes during erythrocytic development of the parasite. Except for similarities in the Puf domain and expression profile, the deduced PfPuf1 and PfPuf2 proteins differ considerably in size and structure. PfPuf1 has 1894 amino acids and a central Puf domain, whereas PfPuf2 is much smaller with a C-terminal Puf domain. The presence of at least two Puf members in other Plasmodium species suggests that these proteins play evolutionarily similar roles during parasite development. Both in vivo studies using the yeast three-hybrid system and in vitro binding assays using the recombinant Puf domain of PfPuf1 expressed in bacteria demonstrated intrinsic binding activity of the PfPuf1 Puf domain to the NRE sequences in the hunchback RNA, the target sequence for Drosophila Pumilio protein. Altogether, these results suggest that PfPufs might function during sexual differentiation and development in Plasmodium through a conserved mechanism of translational regulation of their target mRNAs.

Am J Trop Med Hyg 2002 Sep;67(3):230-2 

Cerebral involvement in benign tertian malaria.

Beg MA, Khan R, Baig SM, Gulzar Z, Hussain R, Smego RA Jr.

Department of Microbiology, The Aga Khan University Medical College, Karachi, Pakistan. Email: [email protected]

Although Plasmodium vivax usually causes benign uncomplicated malaria, it can occasionally result in severe disease with life threatening, end-organ involvement generally seen with falciparum malaria. We report a case of cerebral malaria caused by P. vivax and review the literature on this subject.

Am J Trop Med Hyg 2002 Sep;67(3):225-9 

Pyrimethamine/sulfadoxine combination in the treatment of uncomplicated falciparum malaria: relation between dihydropteroate synthase/dihydrofolate reductase genotypes, sulfadoxine plasma levels, and treatment outcome.

Khalil I, Alifrangis M, Ronn AM, Gabar HA, Jelinek T, Satti GM, Bygbjerg IC.

Center for Medical Parasitology, Institute of Medical Microbiology and Immunology, University of Copenhagen, Denmark. Email: [email protected]

Several in vitro studies have shown the correlation between mutations in dhfr and dhps genes and resistance to pyrimethamine/sulfadoxine (PYR/SDX) combination, but the in vivo correlates of these mutations with PYR/ SDX efficacy have not been investigated fully. We assessed PYR/SDX efficacy in relation to the frequency of dhfr and dhps mutations in 37 Plasmodium falciparum isolates sampled before treatment. Plasma levels of SDX measured at days 0, 3, 7, and 14 ascertained drug absorption. Point mutations were detected only at codons 51 and 108 of dhfr and codon 436 of dhps. The frequency of dhfr 51/108 and dhps 436 mutations was 79% and 8%. The plasma levels of SDX indicated adequate drug absorption by all patients. The presence of Ile 51 and Asn 108 mutations among parasites that cleared after treatment indicates that these mutations alone are insufficient to cause in vivo resistance. In all recrudescent parasites, however, the presence of Ile 51/Asn 108 dhfr mutations was coupled with the dhps Ala 436. The findings suggest that the presence of Ile 51/Asn 108 dhfr mutations and Ala 436 dhps confers decreased susceptibility of P. falciparum to PYR/SDX in areas of low endemicity.

J Hered 2002 Jul-Aug;93(4):249-53 

Genetic Differentiation of Anopheles gambiae s.s. Populations in Mali, West Africa, Using Microsatellite Loci.

Carnahan J, Zheng L, Taylor CE, Toure YT, Norris DE, Dolo G, Diuk-Wasser M, Lanzaro GC.

Department of Organismic Biology, Ecology and Evolution, University of California, Los Angeles, CA 90095-1606 (Carnahan, Taylor, and Diuk-Wasser).

Anopheles gambiae sensu stricto is a principal vector of malaria through much of sub-Saharan Africa, where this disease is a major cause of morbidity and mortality in human populations. Accordingly, population sizes and gene flow in this species have received special attention, as these parameters are important in attempts to control malaria by impacting its mosquito vector. Past measures of genetic differentiation have sometimes yielded conflicting results, in some cases suggesting that gene flow is extensive over vast distances (6000 km) and is disrupted only by major geological disturbances and/or barriers. Using microsatellite DNA loci from populations in Mali, West Africa, we measured genetic differentiation over uniform habitats favorable to the species across distances ranging from 62 to 536 km. Gene flow was strongly correlated with distance (r(2) = 0.77), with no major differences among chromosomes. We conclude that in this part of Africa, at least, genetic differentiation for microsatellite DNA loci is consistent with traditional models of isolation by distance.

Parasite Immunol 2002 Aug;24(8):395-9 

Relationship between reactive nitrogen intermediates and total immunoglobulin E, soluble CD21 and soluble CD23: comparison between cerebral malaria and nonsevere malaria.

Nacher M, Singhasivanon P, Kaewkungwal J, Silachamroon U, Treeprasertsuk S, Tosukhowong T, Vannaphan S, Looareesuwan S.

Unite INSERM 511, Immunobiologie Cellulaire et Moleculaire des Infections Parasitaires, Faculte de Medecine Pitie-Salpetriere, Paris, France and Faculty of Tropical Medicine, Mahidol University, Hospital for Tropical Diseases, Bangkok, Thailand.

To search for evidence of a protective role of the CD23/NO pathway against cerebral malaria, concentrations of reactive nitrogen intermediates (RNI) and sCD21, total immunoglobulin (Ig)E and sCD23 were compared between 17 cases of cerebral malaria and 33 controls. The geometric mean of sCD23 concentration was higher among cerebral malaria cases than among controls (optical density 2643/1495, P = 0.01). The ratio between sCD21 and sCD23 was significantly lower in cerebral malaria cases than in controls (0.67 +/- 0.02 versus 0.77 +/- 0.02, respectively, P = 0.009). Multiple linear regression analysis showed that, among cerebral malaria cases, there was a clear correlation between RNI and both IgE (P = 0.007) and sCD21 (P < 0.0001). Among controls, there was a strong negative correlation between RNI and sCD23 concentrations (r = -0.61, P < 0.0001). However, multivariate analysis unmasked the fact that, in controls, there was also a positive correlation between RNI and IgE (P = 0.045). Logistic regression showed that increased RNI concentrations were associated with a cerebral malaria adjusted odds ratio of 1.05 per unit increase [95% confidence interval (CI) 1.006-1.1, P = 0.02] and that an increased ratio between sCD21 and sCD23 was associated with protection from cerebral malaria (adjusted OR = 0.00001 per unit increase (95% CI 0-0.03, P = 0.005). These different immunological profiles suggest that, among controls, the CD23/NO pathway was chronically stimulated whereas, in cerebral malaria, its stimulation was acute, which could explain why some patients developed cerebral malaria and others did not.

Parassitologia 2001 Dec;43(4):179-82 

Preliminary lack of evidence for simian odour preferences of savanna  populations of Anopheles gambiae and other malaria vectors.

Costantini C, Diallo M.

Istituto Pasteur-Fondazione Cenci Bolognetti, Sezione di Parassitologia, Dipartimento di Scienze di Sanita Pubblica, Universita di Roma La Sapienza, Italy. Email: [email protected]

The behavioural response to several culicine and anopheline mosquitoes to the odour of alternative hosts (human vs monkey) arranged in a choice set-up using odour-baited entry traps (OBETs) was assessed in a field experiment in south-eastern Senegal. The experimental protocol followed procedures analogous to those adopted in olfactometer laboratory tests. Two adult Cercopithecus aethiops and a child of similar mass slept inside separate tents and their odours were drawn to each one of two paired OBETs so that approaching mosquitoes could experience both odour-laden streams before “choosing” to fly against one of the two air currents and into the trap. The traps were set up in a riverine forest clearing near the town of Kedougou, where primates (Papio papio, Cercopithecus aethiops, and Erythrocebus patas) are common. A total of 192 mosquitoes belonging to 4 genera was captured during 8 trap nights. All major human malaria vectors including Anopheles gambiae sensu lato, An. funestus, and An. nili, which constituted the bulk of the trap catch (N = 153), clearly expressed a preference for human odour, with > 90% of captured mosquitoes  caught in the human-baited trap. A sub-sample of specimens belonging to the An. Gambiae complex caught in both traps was identified by rDNA-PCR and RFLP as An. Gambiae sensu stricto molecular form S (7/10), and An. arabiensis (3/10). The only species that did not show a preference for the alternative odour-laden air streams, among those caught in significant numbers, were mosquitoes of the genus Mansonia, with both Ma. uniformis and Ma. africana weakly preferring human odour, but not at a statistically significant level. These results are in accordance with the hypothesis that the strongly anthropophilic feeding preferences of An. gambiae did not evolve from an ancestral association with non-human primates.

J Infect Dis 2002 Nov 1;186(9):1371-1375 

Immunity to Placental Malaria. IV. Placental Malaria Is Associated with Up-Regulation of Macrophage Migration Inhibitory Factor in Intervillous Blood.

Chaisavaneeyakorn S, Moore JM, Othoro C, Otieno J, Chaiyaroj SC, Shi YP, Nahlen BL, Lal AA, Udhayakumar V.

Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, United States Department of Health and Human Services, Atlanta, and Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand.

Macrophage migration inhibitory factor (MIF) may play a role in immune responses to malaria during pregnancy by virtue of its ability to activate macrophages and to overcome the immunosuppressive effect of glucocorticoids. The present study investigated whether plasma MIF levels are altered in pregnant women with placental malaria (PM) and/or human immunodeficiency virus (HIV) infection. For the first time it is demonstrated that MIF levels in the intervillous blood (IVB) plasma were significantly elevated, compared with that in both peripheral plasma ( approximately 500-fold) and cord plasma (4.6-fold; P<.01). IVB mononuclear cells also produced significantly higher levels of MIF, compared with that of peripheral blood mononuclear cells. PM was associated with increased levels of MIF in the IVB plasma (P<.02). Primigravid and secundigravid women had significantly higher levels of MIF in their IVB plasma than did multigravid women (P<.05). HIV infection did not significantly alter MIF levels in any site examined.

J Infect Dis 2002 Nov 1;186(9):1321-9 

Opsonin-Independent Phagocytosis: An Effector Mechanism against Acute Blood-Stage Plasmodium chabaudi AS Infection.

Su Z, Fortin A, Gros P, Stevenson MM.

Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal General Hospital, Montreal, Quebec, Canada. Email: [email protected]

Opsonin-independent macrophage phagocytosis was investigated as a possible mechanism of controlling early blood-stage Plasmodium chabaudi AS infection. Early during infection, peritoneal macrophages from resistant C57BL/6 (B6) mice exhibited increased phagocytosis of parasitized red blood cells (pRBCs) and free merozoites, which was absent in mice with deficient interferon (IFN)-gamma production during infection, including susceptible A/J, interleukin (IL)-12 p40, and IFN-gamma gene knockout mice. IFN-gamma treatment of macrophages collected from B6 and A/J mice early during infection enhanced phagocytosis of pRBCs, but IL-10 treatment inhibited this function. In vitro and in vivo studies in which type I and II class A scavenger receptor-deficient mice and inhibitors of scavenger and mannose receptors were used revealed that scavenger receptors other than class A type I and II and mannose receptors may play a role in malaria parasite uptake. These results indicate that opsonin-independent phagocytosis contributes to the IFN-gamma-dependent control of acute blood-stage malaria infection.

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