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EHP Library Malaria Bulletin No. 19:  August 10-23, 2001

Social Sciences and Malaria

British Medical Journal21 JUL 2001, 323/7305 (152-154)

A global health fund: A leap of faith?
Brugha R.; Walt G.R. Brugha, Health Policy Unit, Department of Public Health, London Sch.of Hyg. and Trop. Med., London WC1E 7HT United Kingdom
[email protected]

Tropical Medicine and International Health  2001, 6/7 (545-553)

Hypothetical and actual willingness to pay for insecticide-treated nets in five Nigerian communities
Onwujekwe O.; Chima R.; Shu E.; Nwagbo D.; Okonkwo P.
[email protected]

Objectives: To determine the hypothetical and actual willingness of households to pay (WTP) for insecticide-treated nets (ITNs), and compare these in areas with and without previous exposure to free ITNs.

Methodology: The contingent valuation method was used to determine the willingness of the heads of 1908 randomly selected households from five communities in southeast Nigeria to pay for two sizes of ITNs. Two communities previously had free access to ITNs. Validity was assessed using multiple regression analyses, and by offering ITNs for sale to 200 randomly selected people drawn from the original sample. The data was collected between March and September 1998. Findings: Most respondents were willing to pay for ITNs: Mbano (93.26%), Ugwogo (97.69%), Orba (83.24%), Alor-uno (95.37%), and Ibagwa-ani (87.34%). In multivariate analyses, WTP was significantly associated with the number of people living in a household, sex of the respondent, average yearly expenditure on gifts and the type of savings scheme (P < 0.05). Some of the residences were also statistically significant in the two models used, and those with prior exposure to free ITNs were negatively related to WTP. Seventy-six percent of those who were hypothetically willing to pay actually purchased them, and the WTP technique correctly predicted the choices of 80% of the respondents.

Conclusion: There was good evidence that stated WTP could be translated into actual WTP. However, peoples' perception of affordability of the nets and its link to their WTP needs further exploration. The WTP technique is a potentially valid tool for market research in healthcare, as it was able to predict the direction of actual WTP for the ITNs. The hypothetical WTP amounts could be used as guide to know either the optimal price to charge for the ITNs or the level of subsidy to introduce.

Tropical Medicine and International Health 2001, 6/7 (496-504)

Improving adherence to malaria treatment for children: The use of pre-packed chloroquine tablets vs. chloroquine syrup
Ansah E.K.; Gyapong J.O.; Agyepong I.A.; Evans D.B.
[email protected]

Malaria is a major cause of morbidity and mortality among children under five in sub-Saharan Africa. Prompt diagnosis and adequate treatment of acute clinical episodes are essential to reduce morbidity and prevent complications and mortality. In many countries, chloroquine syrup is the mainstay of malaria treatment for children under five. Not only is syrup more expensive than tablets, adherence to the prescribed dose at home is a problem because mothers use wrongly sized measuring devices or have difficulty with the instructions. We investigated the impact of introducing pre-packed tablets for children on adherence to treatment and compared the total cost of the tablets with that of syrup. Children aged 0-5 years diagnosed with malaria at the clinic over a 6-week period received either pre-packed tablets or syrup by random assignment. The principal caregivers were interviewed at home on day 4 after attending the clinic. Of the 155 caregivers given pre-packed tablets, 91% (n = 141) adhered to the recommended dosage, while only 42% (n = 61) of 144 who were provided syrup did. Only 20% of caregivers who received syrup used an accurate 5 ml measure. The cost of treatment with tablets was about one-quarter that of syrup and 62% (n = 96) of caregivers preferred tablets. Pre-packed chloroquine tablets are a viable alternative to syrup.

Cad Saude Publica 2001 Jul-Aug;17(4):897-907

Control of malaria transmission in a gold-mining area in Amapa State, Brazil, with participation by private enterprise

Couto AA A, Calvosa VS, Lacerda R, Castro F, Santa Rosa E, Nascimento JM.

Programa de Malaria, Instituto Evandro Chagas, Fundacao Nacional de Saude, Belem, PA, 66090-000, Brasil.

This paper reports on the epidemiological characterization of malaria following implementation of a program to control the endemic in a gold-mining area in northern Amapa State. The study focuses on total malaria cases in Amapa and the impact of the disease on the population, as represented by the Mineracao Novo Astro S/A company and its employees as well as the community of Vila de Lourenco in the municipality of Calcoene, and adjacent gold miners. The effect of control measures in the program area is indicated by a significant reduction in malaria incidence and malaria-related morbidity and mortality. The importance of participation by private enterprise is emphasized, particularly in large projects for the control of endemic diseases (notably malaria) in the Amazon Region.


J Infect Dis 2001 Sep 15;184(6):770-6

Chloroquine-resistant malaria.

Wellems TE, Plowe CV.

Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. 
[email protected]

The development of chloroquine as an antimalarial drug and the subsequent evolution of drug-resistant Plasmodium strains had major impacts on global public health in the 20th century. In P. falciparum, the cause of the most lethal human malaria, chloroquine resistance is linked to multiple mutations in PfCRT, a protein that likely functions as a transporter in the parasite's digestive vacuole membrane. Rapid diagnostic assays for PfCRT mutations are already employed as surveillance tools for drug resistance. Here, we review recent field studies that support the central role of PfCRT mutations in chloroquine resistance. These studies suggest chloroquine resistance arose in >/=4 distinct geographic foci and substantiate an important role of immunity in the outcomes of resistant infections after chloroquine treatment. P. vivax, which also causes human malaria, appears to differ from P. falciparum in its mechanism of chloroquine resistance. Investigation of the resistance mechanisms and of the role of immunity in therapeutic outcomes will support new approaches to drugs that can take the place of chloroquine or augment its efficiency.

Genetics 2001 Aug;158(4):1505-12
Strong Diversifying Selection on Domains of the Plasmodium falciparum Apical Membrane Antigen 1 Gene.

Polley SD, Conway DJ.

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.

The surface-accessible ectodomain region of the Plasmodium falciparum apical membrane antigen 1 (AMA1) is a malaria vaccine candidate. The amino acid sequence may be under selection from naturally acquired immune responses, and previous analyses with a small number of allele sequences indicate a non-neutral pattern of nucleotide variation. To investigate whether there is selection to maintain polymorphism within a population, and to identify the parts of the ectodomain under strongest selection, a sample of 51 alleles from a single endemic population was studied. Analyses using Fu and Li's D and F tests, Tajima's D test, and the McDonald-Kreitman test (with the chimpanzee parasite P. reichenowi as outgroup) show significant departure from neutrality and indicate the selective maintenance of alleles within the population. There is also evidence of a very high recombination rate throughout the sequence, as estimated by the recombination parameter, C, and by the rapid decline in linkage disequilibrium with increasing nucleotide distance. Of the three domains (I-III) encoding structures determined by disulfide bonds, the evidence of selection is strongest for Domains I and III. We predict that these domains in particular are targets of naturally acquired protective immune responses in humans.

 Int J Parasitol 2001 Sep;31(11):1275-7
Malaria: a vaccine concept based on sickle haemoglobin's augmentation of an innate autoimmune process to band 3.

Kennedy JR.

1414 59th Street West, 34209, Bradenton, FL, USA

The protection from malaria afforded by sickle haemoglobin (and certain other haemoglobinopathies) suggests that it may be possible to utilise a common property that their erythrocytes share with both malaria-infected erythrocytes and senescent erythrocytes to develop a vaccine. All three conditions cause clustering of a specific protein molecule, band 3, on their erythrocyte's surface and this protein, when present on senescent erythrocytes at least, results in the immune recognition and removal of these by naturally occurring antibodies. It is hypothesised that if an up-regulated immune response to this protein on sickle cells is responsible for the benefit afforded to malaria patients then a vaccine using antigenic band 3 peptides may provide similar protection.

Int J Parasitol 2001 Sep;31(11):1246-52

Identification of an MCM4 homologue expressed specifically in the sexual stage of Plasmodium falciparum.

Li J, Cox LS.

Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU, Oxford, UK

Mini-chromosome maintenance (MCM) proteins play an essential role in DNA replication initiation. We have isolated a novel gene encoding an MCM-like protein from the human malaria parasite Plasmodium falciparum using the vectorette technique. The gene has no introns and comprises an open reading frame encoding 1005 amino acid residues with a predicted Mr of 115 kDa. The encoded protein, termed PfMCM4, contains all conserved sequences in the MCM family and displays the highest homology to the Cdc54 (MCM4) of Saccharomyces cerevisiae. However, PfMCM4 possesses five unique amino acid inserts with sizes ranging from seven to 75 residues. Southern blotting of genomic DNA digests and chromosomal separations showed that the Pfmcm4 gene is present as a single copy per haploid genome and is located on chromosome 13. A 4000-nucleotide transcript of this gene is expressed specifically in the sexual erythrocytic stage, indicating that PfMCM4 may be involved in gametogenesis in which DNA is quickly replicated.

Parasitol Res 2001 Aug;87(8):605-8

Superoxide-dependent and -independent pathways are involved in the transmission blocking of malaria.

Harada M, Owhashi M, Suguri S, Kumatori A, Nakamura M, Kanbara H, Matsuoka H, Ishii A.

Department of Medical Zoology, Kagawa Medical University, Japan. [email protected]

Superoxide plays a crucial role in innate immunity to various pathogens. We examined the role of superoxides in the transmission of malaria using gp91phox knockout (X-CGD) mice that lack the ability to produce superoxide. Mosquitoes that fed on X-CGD mice infected intraperitoneally with Plasmodium berghei NK65 ANKA formed more oocysts than did those that fed on control mice at any day after infection. The number of oocysts peaked on day 5 post-infection in X-CGD and control mice and then decreased significantly after day 5 post-infection. However, on day 7 post-infection, the infectivity of gametocytes in X-CGD mice was significantly higher than that in control mice. These results show that two pathways, superoxide-dependent and -independent, are involved in the host systems regulating the transmission of malaria and inhibiting gametocyte development.

Parasitology 2001 Aug;123(Pt 2):125-31
Phagocytosis of malarial pigment haemozoin by human monocytes: a confocal microscopy study.

Schwarzer E, Bellomo G, Giribaldi G, Ulliers D, Arese P.

Department of Genetics, Biology and Biochemistry, University of Torino, Italy.

Haem from host erythrocyte (RBC) haemoglobin is polymerized in the digestive organelle of Plasmodium falciparum to haemozoin (HZ), a crystaLline, insoluble substance. Human monocytes avidly ingest HZ that persists undigested for long periods of time, and generates potent bioactive lipid peroxide derivatives. Protein kinase C, an effector of signal transduction, phagolysosome formation and acidification, is inhibited in HZ-fed monocytes. Inability to digest HZ might derive from impairment in phagolysosome formation or acidification. Time-course and extent of HZ phagocytosis and acidification of phagolysosomes were studied by quantitative confocal microscopy. From 180 min until 72 h after the start of phagocytosis approximately 75-79% of the monocytes contained massive amounts of HZ. Coincidence between red (HZ) and green (acidic organelles) fluorescent compartments was very high. Confocal images showed that at 30-60 min after the start of phagocytosis, HZ was preferentially present as separated particles, with full co-localization of red and green fluorescence. Later on HZ-laden phagolysosomes tended to fuse together. In conclusion, phagolysosome formation and acidification were normal in HZ-fed monocytes during the 72-h observation time. The presence of HZ in the phagolysosome, the site of antigen processing, may offer a physical link with immunodepression in malaria.
Parasitology 2001 Aug;123(Pt 2):113-23
Novel Plasmodium falciparum clones and rising clone multiplicities are associated with the increase in malaria morbidity in Ghanaian children during the transition into the high transmission season.

Ofosu-Okyere A, Mackinnon MJ, Sowa MP, Koram KA, Nkrumah F, Osei YD, Hill WG, Wilson MD, Arnot DE.

Noguchi Memorial Institute for Medical Research, University of Ghana, Legon.

A survey of Plasmodium falciparum infection and clone multiplicity in Ghanaian children was carried out to study the effect of the onset of the malaria transmission season on disease incidence. Fortnightly blood samples were collected from 40 children living in the rural town of Dodowa, between February and August 1998. P. falciparum parasite densities were calculated and PCR genotyping was carried out using the polymorphic MSP-1 and MSP-2 genes as target loci for the estimation of the number of parasite clones in each sample. The average clone number was estimated using maximum likelihood techniques and the minimum number of clones per patient was analysed for the effects of age, sex, season, minimum number of clones per child, level of parasitaemia and parasite genotype. The statistical analysis indicated that the more clones a child carried, the more likely they were to have a clinical malaria episode. This was true after adjusting for age and season effects and for the measured circulating parasitaemia. The probability of clinical disease also increased if the MSP-1 MAD 20 and the MSP-2 FC 27 alleles were present. This longitudinal analysis thus indicates that the probability of a Ghanaian child having a symptomatic malaria episode is positively associated with both increasing numbers and novel types of P. falciparum clones.

Am J Trop Med Hyg 2001 Aug;65(2):138-42
Effect of malaria on soluble transferrin receptor levels in Tanzanian infants.

Menendez C, Quinto LL, Kahigwa E, Alvarez L, Fernandez R, Gimenez N, Schellenberg D, Aponte JJ, Tanner M, Alonso PL.

Departamento de Bioquimica Clinica, Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic, Barcelona, Spain.

The diagnosis of iron deficiency anemia in malaria endemic areas is complicated by the influence of the infection on the laboratory tests conventionally used to assess iron status. Determination of soluble transferrin receptor (sTfR) levels has been shown to be a sensitive indicator of iron deficiency in adults and is not affected by a range of infectious and inflammatory conditions. The utility of sTfR levels in the diagnosis of iron deficiency in malaria endemic areas remains unresolved. Three hundred and fourteen infants in a rural area of southern Tanzania living under conditions of intense and perennial malaria transmission were studied to determine the utility of sTfR plasma levels in the assessment of iron deficiency anemia. Independent of the presence of anemia, malaria parasitemia was associated with a significant increase in sTfR plasma levels that were even higher than those found in iron deficiency anemia. We conclude that the measurement of sTfR levels does not have a role in the diagnosis of iron deficiency anemia in young children exposed to malaria infection.

Am J Trop Med Hyg 2001 Aug;65(2):136-7
Short report: Hookworm infection is associated with decreased body temperature during mild Plasmodium falciparum malaria.

Nacher M, Singhasivanon P, Traore B, Dejvorakul S, Phumratanaprapin W, Looareesuwan S, Gay F.

Unite INSERM 511, Immunobiologie Cellulaire et Moleculaire des Infections Parasitaires, Faculte de medecine Pitie-Salpetriere, Paris, France. [email protected]

Malaria's pyrogenic threshold seems to depend on factors such as age and transmission patterns. We studied the temperature at admission of 200 patients with mild malaria and observed that after adjusting for body mass index, the presence of other helminths, and other confounders, only hookworm-infected patients had lower fever at admission that those without hookworm infection (37.5 +/- 0.9 and 38 +/- 0.8, respectively; P < 0.001). Thus, we suggest the age dependence of the pyrogenic threshold could have been confounded by the epidemiology of iron deficiency.

Am J Trop Med Hyg 2001 Aug;65(2):115-9
Antioxidant status and acute malaria in children in Kampala, Uganda.

Metzger A, Mukasa G, Shankar AH, Ndeezi G, Melikian G, Semba RD.

Department of International Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.

Although antioxidant status has been implicated in the pathogenesis of malaria, these factors need further characterization. A longitudinal study was conducted involving 273 children 1-10 years of age with acute, uncomplicated malaria in Kampala, Uganda. Plasma vitamin A, carotenoids, and vitamin E were measured at enrollment and on day 7. Malaria parasitemia was measured at enrollment, on day 3, and on day 7. Malaria parasitemia had completely cleared in 57.1% and 85.3% of children by day 3 and day 7, respectively. Plasma vitamin A, alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin, and vitamin E were depressed at enrollment and increased by day 7. Multivariate analyses showed that higher plasma lycopene concentrations at enrollment were associated with clearance of parasitemia between enrollment and day 3 (odds ratio = 1.46, 95% confidence interval = 1.07-2.06, per 0.10 micromol/L of lycopene). This study suggests that children with acute malaria have depressed plasma concentrations of antioxidants, and that higher plasma lycopene is associated with more rapid clearance of malaria parasitemia.

Am J Trop Med Hyg 2001 Aug;65(2):100-7
Longitudinal study of natural immune responses to the Plasmodium falciparum apical membrane antigen (AMA-1) in a holoendemic region of malaria in western Kenya: Asembo Bay Cohort Project VIII.

Udhayakumar V, Kariuki S, Kolczack M, Girma M, Roberts JM, Oloo AJ, Nahlen BL, Lal AA.

Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health and Human Services, Atlanta, Georgia, USA. 
[email protected]

We investigated the development and maintenance of proliferative and antibody responses to apical membrane antigen-1 (AMA-1) epitopes in a holoendemic area of western Kenya. Young children (< 10 years), older children (10-17 years), and adults (> or = 18 years) were followed longitudinally for antibody and T-cell responses at 3 time points with an interval of 3-4 months. The proliferative responses against the AMA-1 T epitopes (PL171, PL172, PL173, PL186, PL191, and PL192) were not stable during follow-up; however, response to mycobacterial antigen PPD was highly stable. The responder frequencies were similar in all 3 time points except for epitope PL192. The younger and older children responded more frequently to T-cell epitopes, but the differences were not significant. A positive proliferative response to PL191 was associated with a significantly lower risk of parasitemia at subsequent follow-up (relative risk, 0.5; P = 0.03). The presence of antibody response to B epitopes PL169, PL170, PL173, PL187, and PL192 in one time point was associated with a subsequent response (P = 0.0001-0.008) suggesting a stable response. Younger (P = 0.046) and older children (P = 0.017) more frequently responded to epitope PL169 than did adults, and adults responded more frequently to PL187 than did younger children (P = 0.009). Responses to AMA-1 T-cell epitopes were short lived, and antibody responses were relatively stable.

West Afr J Med 2001 Jan-Mar;20(1):42-5

Serum ferritin and other haematological measurements in apparently healthy children with malaria parasitaemia in Lagos, Nigeria.

Odunukwe NN, Salako LA, Okanny C, Ahmed OA, Mafe AG, Efinemokwu C, Raheem TY.

Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria.

One hundred apparently normal nursery and primary school children aged between 2 to 12 years from private schools, in Lagos Nigeria were studied. From this study the mean ferritin levels for children aged 2-5 years, and 6-12 years were 112 +/- 48 micrograms/l, and 119 +/- 38 micrograms/l respectively. Mean haematocrit values were 37.6 +/- 2.2%, and 37.5 +/- 2.6%, while mean haemoglobin levels were 126 +/- 9 g/l 127 +/- 7.9 g/l (2-5 years and 6-12 years respectively). The mean values for MCV, MCH, MCHC were 92 +/- 8.6 fl, 27.6 +/- 3.0 pg, 338.0 +/- 15.0 g/l and 93.5 +/- 9.0 fl, 28.7 +/- 2.5 pg, 332.0 +/- 17.0 g/l (2-5 years and 6-12 years respectively). All haematological parameters measured were similar in both malaria parasitaemia positive and negative subjects, except ferritin level which was significantly higher in subjects with malaria parasitaemia (p < 0.05). There was positive correlation between ferritin concentration and malaria density (r = 0.85, p < 0.05). From the above findings, it would be concluded that, ferritin estimation without examination for malaria parasitaemia in a malarious region like Nigeria is not reliable. It is also concluded that with the high mean ferritin level obtained in this study for normal children on balanced diet, routine iron supplementation may not be necessary for this group of children in Nigeria.

Am J Trop Med Hyg 2001 Jul;65(1):21-6
Plasmodium falciparum dihydrofolate reductase alleles and pyrimethamine use in pregnant Ghanaian women.

Mockenhaupt FP, Eggelte TA, Bohme T, Thompson WN, Bienzle U.

Institut fur Tropenmedizin, Medizinische Fakultat Charite, Humboldt Universitat zu Berlin, Germany.

Drug resistance in Plasmodium falciparum affects prevention of malaria in pregnancy. In a cross-sectional study of 530 pregnant Ghanaian women, P. falciparum dihydrofolate reductase (DHFR) gene mutations linked with pyrimethamine resistance were assessed and associations with pyrimethamine intake were analyzed. P. falciparum infected 69% of women without pyrimethamine use, 59% of those who had a history of pyrimethamine consumption but a negative urine test, and 53% of individuals with a positive urine test. Eighty-one percent, 43%, and 74% of the isolates contained the mutations Asn-108, Ile-51, and Arg-59, respectively. Thr-108 occurred in 8%. Pyrimethamine use was associated with increased frequencies of Asn-108 and Arg-59 but not of Ile-51 or Thr-108. In women with prophylaxis, wild-type parasites were absent and anemia tended to be more common with an increasing number of DHFR gene mutations. Pyrimethamine appears to be not adequately effective in this part of Ghana, most likely due to the predominance of resistant parasites. Selection for resistance following insufficient prophylaxis could possibly affect the efficacy of future intermittent sulfadoxine-pyrimethamine treatment.

J Health Popul Nutr 2001 Jun;19(2):59-65
Influence of placental malaria infection and maternal hypergammaglobulinaemia on materno-foetal transfer of measles and tetanus antibodies in a rural west African population.

Okoko BJ, Wesuperuma LH, Ota MO, Banya WA, Pinder M, Gomez FS, Osinusi K, Hart AC.

Medical Research Council Laboratories, PO Box 273, Banjul, The Gambia, West Africa. 
[email protected]

Placental malaria infection jeopardizes pregnancy outcome, and its influence may also impair the transplacental transfer of some antibodies. Two hundred and thirteen Gambian mother-baby pairs were studied to determine the influence of placental malaria infection and maternal hypergammaglobulinaemia on transplacental transfer of measles and tetanus antibodies in Gambian population. Placental blood and tissue were collected for placental malaria diagnosis. Cord and maternal sera were tested for total IgG concentration by laser nephelometry and for IgG antibody to tetanus toxoid and measles by ELISA. The prevalence of placental malaria infection was 51.1%. Mothers whose placentae were parasitized had a significantly higher mean total serum IgG (22.0 g/L vs 11.3 g/L, p < 0.001) and measles antibody level (4.02 IU/mL vs 1.21 IU/mL, p < 0.01), but not tetanus antibody, than mothers with non-parasitized placentae. Results of multiple regression analysis showed that placental malaria infection and maternal hypergammaglobulinaemia were associated with the reduction of 72% (95% CI 67.84) and 86% (95% CI 76.91) in transplacental transfer of measles antibody respectively but did not influence the transfer of tetanus antibody. It is concluded that the combined influence of placental malaria infection and maternal hypergammaglobulinaemia is significantly associated with the transfer of impaired measles antibody in this population.

Lancet 2001 Aug 4;358(9279):368-74
Amodiaquine, sulfadoxine/pyrimethamine, and combination therapy for treatment of uncomplicated falciparum malaria in Kampala, Uganda: a randomised trial.

Staedke SG, Kamya MR, Dorsey G, Gasasira A, Ndeezi G, Charlebois ED, Rosenthal PJ.

Department of Medicine, San Francisco General Hospital, University of California, Box 0811, 3rd and Parnassus Avenue, San Francisco, CA 94143, USA. 
[email protected]

BACKGROUND: Increasing Plasmodium falciparum resistance to chloroquine in sub-Saharan Africa necessitates use of alternative antimalarial agents. Affordable alternative treatments include sulfadoxine/pyrimethamine and amodiaquine. Combination of antimalarial agents can increase therapeutic efficacy and delay emergence of drug resistance. We compared the efficacy of sulfadoxine/pyrimethamine, amodiaquine, and an amodiaquine/sulfadoxine/pyrimethamine combination for treatment of uncomplicated malaria in a region of high chloroquine resistance. METHODS: Patients with symptoms of uncomplicated falciparum malaria and confirmed disease in Kampala, Uganda, were randomly assigned to receive sulfadoxine/pyrimethamine (25 mg/kg sulfadoxine, and 1.25 mg/kg pyrimethamine) plus placebo; amodiaquine (25 mg/kg) plus placebo; or amodiaquine plus sulfadoxine/pyrimethamine. Patients were followed up for 14 days, and clinical and parasitological outcomes were assessed. FINDINGS: 90% (400/445) of patients enrolled in the study successfully completed 14 days of follow-up. Treatment failure based on clinical criteria occurred in 13 of 131 (10%) patients on sulfadoxine/ pyrimethamine, nine of 131 (7%) on amodiaquine, and four of 138 (3%) on amodiaquine/sulfadoxine/pyrimethamine. Based on parasitological criteria, treatment failed in 26%, 16%, and 10% of these patients, respectively. Amodiaquine/sulfadoxine/pyrimethamine was significantly more effective than sulfadoxine/pyrimethamine alone in children aged younger than 5 years (clinical failure in 3.5% vs 13.9%, respectively, risk difference 10.4% [95% CI, 1.6-19.3] p=0.021; parasitological failure in 12.8% vs 26.4%, risk difference 13.6% [1.2-26.0] p=0.041). INTERPRETATION: Sulfadoxine/pyrimethamine, amodiaquine, and amodiaquine/sulfadoxine/pyrimethamine were all effective for treatment of uncomplicated falciparum malaria in Uganda. The amodiaquine/sulfadoxine/pyrimethamine combination was the most effective, and could be the optimum low-cost alternative to chloroquine in Africa.

Int J Gynaecol Obstet 2001 Aug;74(2):133-8
Malaria prophylaxis and the reduction of anemia at childbirth.

Geelhoed DW, Visser LE, Addae V, Asare K, Schagen van Leeuwen JH, van Roosmalen J.

Holy Family Hospital, Berekum, Ghana

Objectives: To assess the effect of introducing chloroquine prophylaxis during pregnancy on prevalence of anemia (<10.9 g/dl) at childbirth and perinatal outcome. Methods: Observational study in a rural district hospital in Ghana, which compared 2803 women who received chloroquine prophylaxis during pregnancy with 3084 historical controls, who had not received prophylaxis during pregnancy. Main outcome measures were hemoglobin level at childbirth, perinatal mortality and birth weight. Results: Mean hemoglobin level before childbirth increased from 10.7 g/dl (S.D.=1.0 g/dl) to 11.0 g/dl (S.D.=0.9 g/dl). Prevalence of anemia decreased from 29.4 to 13.3% (OR=0.4 and 95% CI=0.3-0.4). Prevalence of moderately severe anemia (<9.0 g/dl) decreased from 4.4 to 3.3% (OR=0.7, 95% CI=0.6-0.97). Perinatal mortality and low birth weight (<2500 g) remained unchanged. Conclusions: Routine chloroquine prophylaxis in pregnancy is useful in reducing anemia at childbirth in malaria-endemic regions. Fetal outcome did not improve with chloroquine prophylaxis in this study.

Mem Inst Oswaldo Cruz 2001 Jul;96(5):709-12
Variants of the Plasmodium vivax circumsporozoite protein (VK210 and VK247) in Colombian isolates.

Gonzalez J, Hurtado S, Arevalo-Herrera M, Herrera S.

Instituto de Inmunologia del Valle, Universidad del Valle, Cali, Colombia.

Phenotypic diversity has been described in the central repeated region of the circumsporozoite protein (CSP) from Plasmodium vivax. Two sequences VK210 (common) and VK247 (variant) have been found widely distributed in P. vivax isolates from several malaria endemic areas around the world. A third protein variant called P. vivax-like showing a sequence similar to the simian parasite P. simio-ovale has also been described. Here, using an immunofluorescent test and specific monoclonal antibodies, we assessed the presence of two of these protein variants (VK210 and VK247) in laboratory produced sporozoite. Both sequences were found in parasite isolates coming from different geographic regions of Colombia. Interestingly, sporozoites carrying the VK247 sequence were more frequently produced in Anopheles albimanus than sporozoites with the VK210 sequence. This difference in sporozoites production was statistically significant (p <0.05, Kruskal-Wallis); not correlation was found with parameters as the total number of parasites or gametocytes in blood from human donors used to feed mosquitoes. Previous studies in the same region have shown a higher prevalence of anti-VK210 antibodies which in theory may suggest their role in blocking the development of sporozoites carrying the CSP VK210 sequence.

Mem Inst Oswaldo Cruz 2001 Jul;96(5):683-6
Diagnostic performance characteristics of rapid dipstick test for Plasmodium vivax malaria.

Aslan G, Ulukanligil M, Seyrek A, Erel O.

Research Hospital, Department of Microbiology and Parasitology, Medical Faculty, Mersin University, Mersin, 33070, Turkey.

We compared the diagnostic performance characteristics of newly developed method, the rapid dipstick test, which provides colorimetric determination by developing antibody to the lactate dehydrogenase enzyme of parasites, with conventional standard thick-blood film examination. For the rapid test, OptiMAL commercial kits were used. The results were also evaluated with clinical findings from patients. The parasites were determined by microscopic examination of thick-blood films from 81 patients with vivax malaria from southeastern Anatolia, Turkey. The OptiMAL test results were found to be negative in five patients who were diagnosed clinically and through thick-film testing as having vivax malaria. There was no false positivity observed with the OptiMAL test. We concluded that this rapid malaria test has a lower level of sensitivity than the classical thick-blood-film test for malaria, but that these methods have equal specificity.

Infect Immun 2001 Sep;69(9):5849-56
Fresh Isolates from Children with Severe Plasmodium falciparum Malaria Bind to Multiple Receptors.

Heddini A, Pettersson F, Kai O, Shafi J, Obiero J, Chen Q, Barragan A, Wahlgren M, Marsh K.

Microbiology and Tumor Biology Center (MTC), Karolinska Institutet, and Swedish Institute for Infectious Disease Control, Stockholm, Sweden.

The sequestration of Plasmodium falciparum-infected erythrocytes (pRBC) away from the peripheral circulation is a property of all field isolates. Here we have examined the pRBC of 111 fresh clinical isolates from children with malaria for a number of adhesive features in order to study their possible coexpression and association with severity of disease. A large number of adhesion assays were performed studying rosetting, giant rosetting, and binding to CD36, intercellular adhesion molecule 1, platelet endothelial cell adhesion molecule 1, thrombospondin, heparin, blood group A, and immunoglobulins. Suspension assays were performed at the actual parasitemia of the isolate, while all the static adhesion assays were carried out at an equal adjusted parasitemia. The ability to bind to multiple receptors, as well as the ability to form rosettes and giant rosettes, was found to be more frequent among isolates from children with severe versus mild malaria (P = 0.0015). Rosettes and giant rosettes were more frequent for children with severe malaria, and the cell aggregates were larger and tighter, than for those with mild disease (P = 0.0023). Binding of immunoglobulins (97% of isolates) and of heparin (81% of isolates) to infected erythrocytes was common, and binding to heparin and blood group A was associated with severity of disease (P = 0.011 and P = 0.031, respectively). These results support the idea that isolates that bind to multiple receptors are involved in the causation of severe malaria and that several receptor-ligand interactions work synergistically in bringing about severe disease.

Infect Immun 2001 Sep;69(9):5565-72
Multistage Multiantigen Heterologous Prime Boost Vaccine for Plasmodium knowlesi Malaria Provides Partial Protection in Rhesus Macaques.

Rogers WO, Baird JK, Kumar A, Tine JA, Weiss W, Aguiar JC, Gowda K, Gwadz R, Kumar S, Gold M, Hoffman SL.

Malaria Program, Naval Medical Research Center, Silver Spring, Maryland 20910, Bethesda, Maryland 20889.

A nonhuman primate model for malaria vaccine development allowing reliable, stringent sporozoite challenge and evaluation of both cellular and antibody responses is needed. We therefore constructed a multicomponent, multistage DNA vaccine for the simian malaria species Plasmodium knowlesi including two preerythrocytic-stage antigens, the circumsporozoite protein (PkCSP) and sporozoite surface protein 2 (PkSSP2), and two blood stage antigens, apical merozoite antigen 1 (PkAMA1) and merozoite surface protein 1 (PkMSP1p42), as well as recombinant canarypox viruses encoding the four antigens (ALVAC-4). The DNA vaccine plasmids expressed the corresponding antigens in vitro and induced antiparasite antibodies in mice. Groups of four rhesus monkeys received three doses of a mixture of the four DNA vaccine plasmids and a plasmid encoding rhesus granulocyte-monocyte colony-stimulating factor, followed by boosting with a single dose of ALVAC-4. Three groups received the priming DNA doses by different routes, either by intramuscular needle injection, by intramuscular injection with a needleless injection device, the Biojector, or by a combination of intramuscular and intradermal routes by Biojector. Animals immunized by any route developed antibody responses against sporozoites and infected erythrocytes and against a recombinant PkCSP protein, as well as gamma interferon-secreting T-cell responses against peptides from PkCSP. Following challenge with 100 P. knowlesi sporozoites, 1 of 12 experimental monkeys was completely protected and the mean parasitemia in the remaining monkeys was significantly lower than that in 4 control monkeys. This model will be important in preclinical vaccine development.

Infect Immun 2001 Sep;69(9):5223-9
Selection of glutamate-rich protein long synthetic peptides for vaccine development: antigenicity and relationship with clinical protection and immunogenicity.

Theisen M, Dodoo D, Toure-Balde A, Soe S, Corradin G, Koram KK, Kurtzhals JA, Hviid L, Theander T, Akanmori B, Ndiaye M, Druilhe P.

Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen, Denmark.

Antibodies against three long synthetic peptides (LSPs) derived from the glutamate-rich protein (GLURP) of Plasmodium falciparum were analyzed in three cohorts from Liberia, Ghana, and Senegal. Two overlapping LSPs, LR67 and LR68, are derived from the relatively conserved N-terminal nonrepeat region (R0), and the third, LR70, is derived from the R2 repeat region. A high prevalence of antibody responses to each LSP was observed in all three areas of endemic infection. Levels of cytophilic immunoglobulin G (IgG) antibodies against both GLURP regions were significantly correlated with protection from clinical P. falciparum malaria. Protected children from the Ghana cohort possessed predominantly IgG1 antibodies against the nonrepeat epitope and IgG3 antibodies against the repeat epitope. T-cell proliferation responses, studied in the cohort from Senegal, revealed that T-helper-cell epitopes were confined to the nonrepeat region. When used as immunogens, the LR67 and LR68 peptides elicited strong IgG responses in outbred mice and LR67 also induced antibodies in mice of different H-2 haplotypes, confirming the presence of T-helper-cell epitopes in these constructs. Mouse antipeptide antisera recognized parasite proteins as determined by immunofluorescence and immunoblotting. This indicates that synthetic peptides derived from relatively conserved epitopes of GLURP might serve as useful immunogens for vaccination against P. falciparum malaria.

Curr Opin Microbiol 2001 Aug;4(4):415-20
Conservation of a novel vacuolar transporter in Plasmodium species and its central role in chloroquine resistance of P. falciparum.

Carlton JM, Fidock DA, Djimde A, Plowe CV, Wellems TE.

National Center for Biotechnology Research, National Library of Medicine, National Institutes of Health, Building 45, 45 Center Drive, 20892-6510, Bethesda, MD, USA

Chloroquine resistance in Plasmodium falciparum has recently been shown to result from mutations in the novel vacuolar transporter, PfCRT. Field studies have demonstrated the importance of these mutations in clinical resistance. Although a pfcrt ortholog has been identified in Plasmodiumvivax, there is no association between in vivo chloroquine resistance and codon mutations in the P. vivax gene. This is consistent with lines of evidence that suggest alternative mechanisms of chloroquine resistance among various malaria parasite species.
Acta Trop 2001 Sep 1;80(1):39-44
Antimalarial activity of azithromycin, artemisinin and dihydroartemisinin in fresh isolates of Plasmodium falciparum in Thailand.

Noedl H, Wernsdorfer WH, Krudsood S, Wilairatana P, Kollaritsch H, Wiedermann G, Looareesuwan S.

Department of Specific Prophylaxis and Tropical Medicine, Institute of Pathophysiology, University of Vienna, Kinderspitalgasse 15, A-1095, Vienna, Austria

Antibiotics with antimalarial activity may offer an interesting alternative for the treatment of multidrug-resistant falciparum malaria. Azithromycin, a relatively recent semisynthetic derivative of erythromycin, was tested for its in vitro activity against fresh isolates of Plasmodium falciparum. As the reportedly slow onset of action of azithromycin suggests its combination with fast-acting substances, such as artemisinin-derivatives, dihydroartemisinin (DHA) was tested parallel as a possible combination partner. The effective concentrations found for azithromycin in this study (EC(50)=29.3&mgr;mol/l, EC(90)=77.1&mgr;mol/l blood medium mixture (BMM)) are comparable to those of other antimalarials in the antibiotics class and are considerably higher than those found for mefloquine or quinine. The absence of an activity correlation between azithromycin and chloroquine, quinine and artemisinin emphasises the independence of azithromycin drug response from the sensitivity to these drugs. A weak activity correlation (rho(EC90)=0.352; p=0.028), which could point to a potential cross-sensitivity but is probably of little clinical importance, was found with mefloquine above the EC(50) level. Provided that further clinical trials support the combination of these drugs, DHA may offer an interesting combination partner for azithromycin owing to its rapid onset of action and the comparatively low effective concentrations (EC(50)=1.65nmol/l, EC(90)=7.10nmol/l BMM). This combination may serve as an interesting alternative for tetracycline and doxycycline, which cannot be used in pregnant women and children, and exhibit phototoxicity. Nevertheless, the relatively high cost of this combination, as well as the controversial reports of the clinical efficacy, may limit the usefulness of azithromycin in malaria therapy and require an adjustment of previously used treatment regimens.

Acta Trop 2001 Sep 1;80(1):1-8
The impact of indoor residual spraying with malathion on malaria in refugee camps in eastern Sudan.

Charlwood JD, Qassim M, Elnsur EI, Donnelly M, Petrarca V, Billingsley PF, Pinto J, Smith T.

Centro de Malaria e Outros Doencas Tropicais, Instituto de Higiene e Medicina Tropical, Rua da Junqueira 96, 1300, Lisboa, Portugal

An exploratory trial of the efficacy of indoor spraying with malathion on morbidity and mortality in refugee camps in eastern Sudan was conducted during the rainy season of 1997. The interior walls of houses from a randomly selected group of five camps were sprayed with malathion in mid-September and morbidity and mortality rates in the camps for the months October to December compared with rates in five controls. Pyrethrum spray collection and human landing catches were performed in two collection rounds. An exophagic but endophilic population of Anopheles arabiensis was the most common mosquito collected. The mean human blood index of 242 mosquitoes from eight camps was 0.51. Only two of 1040 mosquitoes examined harboured sporozoites. Blood samples of 83 putative malaria patients were examined for parasites by PCR. Mortality rates in the 3 months following spraying were significantly lower in sprayed camps although differences in clinical malaria incidence between sprayed and non-sprayed camps were not significant.

Indian J Exp Biol 2001 Mar;39(3):287-90
Midgut specific immune response of vector mosquito Anopheles stephensi to malaria parasite Plasmodium.

Gakhar SK, Shandilya HK.

Department of Biosciences, Maharshi Dayanand University, Rohtak, India. 
[email protected]

Innate immune-related polypeptides expression in midgut in the ageing vector mosquito A. stephensi following infection by malaria parasite, Plasmodium yoelii yoelii has been studied. Twenty polypeptides were induced by an infected blood meal during various stages of adult life. A 24 kDa polypeptide was induced generally in most of the stages. Maximum parasite induced polypeptides i.e. 22, 33, 111, 122, 127, 140, 143 and 146 kDa were found in 5 days of post blood feeding (PBF) which coincides with the presence of oocysts on the midgut. However, in addition, three polypeptides in 11 days PBF and 8 polypeptides in 20 days PBF were also induced due to parasite infection in aged mosquitoes. Quantitatively, the amount of soluble proteins in the midgut in oocyst-sporozoite-positive mosquitoes was always less as compared to their normal counterparts. The parasite evidently elicits defined immune responses by inducing specific polypeptides in the midgut of the mosquito.
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Last modified September 21, 2001