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EHP Library Malaria Bulletin No. 28: -Jan 4-17, 2002


Social Sciences and Malaria

  • Partnership for Social Sciences in Malaria Control - TDR News January 2002

Social Science and Medicine 2002, 54/3 (377-386)

Health care switching behaviour of malaria patients in a Kenyan rural community

Nyamongo I.K. Institute of African Studies, University of Nairobi, P.O. Box 30197, Nairobi Kenya  [email protected]

Patients ordinarily use multiple sources of health care. This study reveals the transitions patients in a rural region of Gusii, Kenya are likely to make beyond the homestead in their search for alternatives to combat malaria. Malaria is a very common health problem in the region resulting in enormous human and economic losses. Data on health care seeking behaviour were collected over a 10-month period. The primary data for this paper is from malaria-focused ethnographic interviews with 35 adults (18 women and 17 men). Results show that patients are more likely to start with self-treatment at home as they wait for a time during which they observe their progress. This allows them to minimise expenditure incurred as a result of the sickness. They are more likely to choose treatments available outside the home during subsequent decisions. The decisions include visiting a private health care practitioner, a government health centre or going to a hospital when the situation gets desperate. Knowledge and duration of sickness, the anticipated cost of treatment, and a patient's judgement of the intensity of sickness determine their choice of treatment. reserved.

Am J Trop Med Hyg 2001 Dec;65(6):883-6

Economic advantage of a community-based malaria management program in the Brazilian Amazon.

Pang LW, Piovesan-Alves F.

Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. [email protected]

In the Brazilian Amazon, travel costs to centralized malaria clinics for diagnosis and treatment can approach 20% of one's monthly salary. A program was established in a mining town for community-based dipstick test diagnosis and treatment. An economic analysis was performed that compared expected costs under the old program to the observed costs of the new one. Data were obtained through interviews, government reports, clinic and hospital records, and community records. There was a 53% reduction (by 1,219 visits) of clinic visits but a doubling of malaria hospitalization admissions (to 191). The new program had an overall annual savings of $60,900 ($11.8K-$160K, sensitivity limits), a 77% reduction of the old program's cost. The benefit-to-cost ratio was 9:1, where benefits were patients' savings from travel and lost wages and costs were government drug, diagnostic, training, and monitoring expenses. A community-based program incorporating dipstick tests for malaria management can have economic advantages.

Am J Trop Med Hyg 2001 Dec;65(6):877-82

Factors influencing the use of bed nets in Mbarara municipality of Uganda.

Nuwaha F.

Health Services Sector, Bushenyi Local Government, Uganda.

In order to identify independent predictors for bed net use, respondents from 643 households selected randomly from 21 clusters were interviewed in Mbarara municipality, Uganda. Respondents answered questions about demographic characteristics, social economic conditions, causes and transmission of malaria, beliefs about severity and complications of malaria, malaria morbidity and health care-seeking behavior, perceived control of malaria prevention, beliefs about utility of bed nets, perceived susceptibility to malaria, and whether they use bed nets or not. Univariate and multivariate logistic regression analyses were used to identify predictors for bed net use. Fifty-five percent (356 of 643) of the households had bed net users. The independent factors that favored bed net use were as follows: 1) age < 30 years, 2) ownership of a television, 3) having mosquito nets in ventilators of the house, 4) being a skilled worker or a professional, or owning a major business, 5) living in a permanent house, 6) believing that bed nets prevent malaria, 7) believing that bed nets are worth their cost, 8) not believing that convulsions cannot be cured by modern medicine, and 9) believing that bed nets are not expensive. The strongest predictors of bed net use are living in a permanent house and agreeing that bed nets are worth their cost, with adjusted odds ratios of 4.29 (95% confidence interval, 2.76-6.71) and 3.93 (95% confidence interval, 2.5-26.13), respectively. These data suggest that in order to increase the use of bed nets, the price of bed nets needs to be reduced and educational messages that stress the favorable use of bed nets need to be increased.

Am J Trop Med Hyg 2001 Dec;65(6):872-6

Community-based program for malaria case management in the Brazilian Amazon.

Cunha ML, Piovesan-Alves F, Pang LW.

Health Sciences Department, Federal University of Brasilia, Brazil.

In areas of drug-resistant malaria, control programs may restrict chemotherapy until malaria has been confirmed via microscopy to contain costs and toxicity. In Brazil, patients travel to centralized laboratory posts (FNS) at great cost for diagnosis and treatment. A program was established through the bars of a mining town offering free dipstick diagnosis and mefloquine treatment on a 24-hr basis; falciparum malaria dipstick tests are accurate and easy to use. Outcomes were compared with historical data and results of a neighboring non-intervention village. Guidelines for dipstick use and treatment were followed for 98% of visits. The number of FNS visits was reduced from 2,316 (expected) to 1,097 (observed) with 626 dipstick tests applied. Ninety-five percent of those who visited the FNS experienced onset of malaria symptoms in the town where the FNS was located. There was an unexpected doubling of the malaria hospital admission rate. We demonstrate that dipstick testing can be used in a sustainable, community-based program that should be applicable in a wide variety of settings.


Proc Natl Acad Sci U S A 2002 Jan 15; http://www.pnas.org

Visual arrestins in olfactory pathways of Drosophila and the malaria vector mosquito Anophelesgambiae.

Merrill CE, Riesgo-Escovar J, Pitts RJ, Kafatos FC, Carlson JR, Zwiebel LJ.

Department of Biological Sciences, Program in Developmental Biology and Center for Molecular Neuroscience, VU Station B35-1812, Vanderbilt University, Nashville, TN 37235-1812; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; Department of Developmental Neurobiology, Centro de Neurobiologia, Apdo. Postal 1-1141, Queretaro, Qro 76001, Mexico; and European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.

Arrestins are important components for desensitization of G protein-coupled receptor cascades that mediate neurotransmission as well as olfactory and visual sensory reception. We have isolated AgArr1, an arrestin-encoding cDNA from the malaria vector mosquito, Anopheles gambiae, where olfaction is critical for vectorial capacity. Analysis of AgArr1 expression revealed an overlap between chemosensory and photoreceptor neurons. Furthermore, an examination of previously identified arrestins from Drosophila melanogaster exposed similar bimodal expression, and Drosophila arrestin mutants demonstrate impaired electrophysiological responses to olfactory stimuli. Thus, we show that arrestins in Drosophila are required for normal olfactory physiology in addition to their previously described role in visual signaling. These findings suggest that individual arrestins function in both olfactory and visual pathways in Dipteran insects; these genes may prove useful in the design of control strategies that target olfactory-dependent behaviors of insect disease vectors.

 J Biol Chem 2002 Jan 15; http://www.jbc.org

Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl ACP reductase.

Perozzo R, Kuo M, bir Singh Sidhu A, Valiyaveettil JT, Bittman R, Jacobs WR Jr, Fidock DA, Sacchettini JC.

Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128.

The human malaria parasite Plasmodium falciparum synthesizes fatty acids using a type II pathway that is absent in humans. The final step in fatty acid elongation is catalyzed by enoyl acyl carrier protein reductase, a validated antimicrobial drug target. Here, we report the cloning and expression of the P. falciparum enoyl acyl carrier protein reductase gene, which encodes a 50 kDa protein (PfENR) predicted to target to the unique parasite apicoplast. Purified PfENR was crystallized and its structure resolved as a binary complex with NADH, a ternary complex with triclosan and NAD+, and as ternary complexes bound to the triclosan analogs 1 and 2 with NADH. Novel structural features were identified in the PfENR binding loop region that most closely resembled bacterial homologs; elsewhere the protein was similar to ENR from the plant Brassica napus (RMS 0.30 ). Triclosan and its analogs 1 and 2 killed multi-drug resistant strains of intra-erythrocytic P. falciparum parasites at sub to low micromolar concentrations in vitro. These data define the structural basis of triclosan binding to PfENR and will facilitate structure-based optimization of PfENR inhibitors.

Clin Med 2001 Nov-Dec;1(6):495-500

Cell-cell interaction in the pathogenesis of severe falciparum malaria.

Pasvol G.

Wellcome Centre for Clinical Tropical Medicine, Faculty of Medicine, Imperial College, London. [email protected]

One of the major unresolved questions in malaria is why some patients with Plasmodium falciparum infection become so sick and die. Cell-cell interactions between the parasite and the host involving adherence/invasion appear generally, but not exclusively, to correlate with severity. The most important of these interactions in the asexual blood cycle are: (i) the invasion of red cells by merozoites, (ii) the binding of parasitised red blood cells (PRBC) to uninfected red cells (rosetting), (iii) the binding of PRBC to endothelial cells in critical organs (cytoadherence) and (iv) the induction of pro-inflammatory cytokines by PRBC, notably tumour necrosis factor (TNFalpha). The resulting clinical manifestations are protean. Analysis of these cellular interactions has revealed marked heterogeneity in molecular specificity which highlights the complexity of pathogenesis, but also opens the way to new modalities for treating this deadly infection.

Am J Trop Med Hyg 2001 Dec;65(6):918-23

Contribution of humoral immunity to the therapeutic response in falciparum malaria.

Mayxay M, Chotivanich K, Pukrittayakamee S, Newton P, Looareesuwan S, White NJ.

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

The contribution of humoral immunity to the therapeutic response in acute falciparum malaria was assessed in a case-control study. Forty adult Thai patients with acute falciparum malaria who had subsequent recrudescent infections and 40 patients matched for age, therapeutic regimen, and disease severity who were cured by Day 28 were studied. All cured patients had positive immunoglobulin (Ig) G to ring-infected erythrocyte surface antigen (RESA) in their admission plasma, compared with only 60% of patients who failed to respond to treatment (P < 0.001). The proportion of IgM-positive cases at admission was also higher in the successfully treated group than in the group with failure (70% versus 30%) (P < 0.001). The geometric mean (95% confidence interval) reciprocal IgG titer at admission was significantly higher in cured patients (187.0 [83.5-418.3]) compared with those who experienced treatment failure (11.6 [5.1-26.5]) (P < 0.001). The patients with uncomplicated malaria who were both IgG and IgM positive at admission had significantly shorter fever clearance times and lower admission parasitemia levels compared with those who were negative (P = 0.01 and P = 0.02, respectively). The median (range) in vitro parasite multiplication rate was significantly lower in cultures containing positive anti-RESA antibody plasma compared with those containing normal plasma (0.7 [0.1-3.5] versus 2.6 [0.1-12.1]; P < 0.001). These results suggest that antimalarial antibodies may play an important supportive role in the therapeutic response to antimalarial drugs during acute falciparum malaria.

Am J Trop Med Hyg 2001 Dec;65(6):912-7

Natural human immunoglobulin G subclass responses to Plasmodium falciparum serine repeat antigen in Uganda.

Okech BA, Nalunkuma A, Okello D, Pang XL, Suzue K, Li J, Horii T, Egwang TG.

Division of Medical Parasitology and Tropical Medicine, Med Biotech Laboratories, Kampala, Uganda.

Serum samples from Ugandan residents of a malaria-hyperendemic region were tested by enzyme-linked immunosorbent assay for reactivity against recombinant constructs of the 47 (SE47')- and 50 (SE50A)-kDa fragments of Plasmodium falciparum serine repeat antigen (SERA). Immunoglobulin (Ig) G3 and IgG1 were the predominant subclass responses to SE47' and SE50A, respectively. The geometric mean optical density (OD) for IgG3 anti-SE47' was significantly lower in children < 15 years compared with adults > or = 15 years (P < 0.0001). By contrast, the geometric mean IgG1 anti-SE50A was slightly higher in children compared with adults (P < 0.01). The proportion of high responders (ODs > 0.5) to SE47' was significantly lower in children compared with adults (P < 0.001), whereas the proportion of high responders to SE50A was comparable in children and adults (P = 0.07). This first detailed study of SERA in a malaria-hyperendemic region suggests that natural human IgG3 anti-SE47' might be associated with immunity to malaria.

Am J Trop Med Hyg 2001 Dec;65(6):834-6

Helminth infections are associated with protection from malaria-related acute renal failure and jaundice in Thailand.

Nacher M, Singhasivanon P, Silachamroon U, Treeprasertsuk S, Vannaphan S, Traore B, Gay F, Looareesuwan S.

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

Following studies showing an association between helminth infections and protection from cerebral malaria, we compared 22 patients with malaria-associated acute renal failure with 157 patients with moderately severe malaria. Helminths were associated with protection from renal failure (adjusted odds ratio [AOR], 0.16 [0.03-0.85], P = 0.03). Helminth-infected controls were less likely to have jaundice (AOR, 0.39 [0.16-0.96], P = 0.04) or to have peripheral mature schizonts (AOR, 0.2 [0.07-0.62], P = 0.005) than controls without helminths. This suggested that preexisting helminth infections may have been protective by influencing sequestration and obstructive jaundice, 2 possible determinants of acute tubular necrosis.

Am J Trop Med Hyg 2001 Dec;65(6):822-7

Malaria in the first 6 months of life in urban African infants with anemia.

Afolabi BM, Salako LA, Mafe AG, Ovwigho UB, Rabiu KA, Sanyaolu NO, Ibrahim MM.

Nigerian Institute of Medical Research, Yaba, Lagos. [email protected]

A total of 446 infants in the first 6 months of life who presented at an urban children's hospital with complaints of any illness whatsoever were recruited into a study with the aim of determining the contribution of malaria to infant morbidity in a malaria-endemic urban area in Nigeria. Sixty-eight of the infants were in their first month of life and 79, 77, 61, 97, and 64 were in their second, third, fourth, fifth and sixth month of life, respectively. Overall, 107 (24.0%) infants were clinically diagnosed as having malaria. This included 3 who were in the first month of life, 12 in the second, 15 in the third, 17 in the fourth, 33 in the fifth, and 27 in the sixth months of life (4.4, 15.2, 19.5, 27.9, 34.0, and 42.1%, respectively). Laboratory investigations confirmed 35 (32.7%) of those clinically diagnosed and 86 (25.4%) of those not clinically diagnosed (n = 339) as having malaria parasitemia, giving an overall malaria parasite rate of 27.1% among the infants. Acute respiratory infection was the major diagnosis (41.3%) among those that were not initially diagnosed as malaria but turned out to have malaria parasitemia followed by gastroenteritis (11.8%) and failure to growth (1.5%). Overall geometric mean parasite density was 202.5 parasites/microL of blood (range, 12-65,317 parasites/microL of blood). The mean hematocrit of infants with parasites (33.0%) was significantly lower (P < 0.005) than that of infants without parasites (35.1%). The mean hematocrit of infants with malaria parasites in each age group was lower than that of infants without malaria parasites in the corresponding age group. Among the infants with malaria parasites, those aged 2 to 2.9 months recorded the lowest mean hematocrit (30.1%), and those aged < 1 month recorded the highest mean hematocrit (42.7%). Axillary temperature increased and hematocrit decreased with increase in parasite density. The percentage of infants with anemia likewise increased as the parasite density increased. Plasmodium falciparum was present in all infected infants, but mixed infection with P. malariae was present in only 2.5% of infections. Analysis of our data suggests an urgent need for health education of caretakers and for training of clinicians for increased awareness of malaria as an important cause of illness and anemia in infants aged < 6 months so as to reduce children's wasting due to an easily preventable and treatable disease.

Am J Trop Med Hyg 2001 Dec;65(6):798-803

Molecular epidemiology of malaria in Yaounde, Cameroon. VIII. Multiple Plasmodium falciparum infections in symptomatic patients.

Basco LK, Ringwald P.

Unite de Recherche Paludologie afro-Tropicale, Institut de Recherche pour le Developpement and Laboratoire de Recherche sur le Paludisme, Organisation de Coordination pour la lutte contre les Endemies en Afrique Centrale, Yaounde, Cameroon.

The extent of genetically distinct parasite populations coinfecting individual human hosts (i.e., multiplicity) was studied by polymerase chain reaction amplification of 3 polymorphic genetic markers, circumsporozoite protein and merozoite surface antigens (MSA) 1 and 2, in symptomatic children and adults and analyzed in relation with age and initial parasitemia. Of the total of 177 DNA samples analyzed (of which 115 were paired pre- and posttreatment samples), 101 (57%) were composed of multiclonal infections, with up to 7 distinguishable parasite populations. Among the 3 polymorphic markers, msa-2 yielded the highest proportion of clinical isolates with multiclonal populations. Patients with multiclonal infections before treatment had, on average, 2.9 genetically distinct parasite populations. The extent of multiplicity decreased significantly (P < 0.05) in recrudescent parasites, but not with reinfections, as compared with the pretreatment samples. Neither age (5-60 years) nor initial parasitemia was correlated with multiplicity. Further studies in different epidemiological settings are required to understand the role of multiclonal Plasmodium falciparum infections in influencing malaria transmission.

Am J Trop Med Hyg 2001 Dec;65(6):736-7

Short report: codon 125 polymorphism of CD31 and susceptibility to malaria.

Casals-Pascual C, Allen S, Allen A, Kai O, Lowe B, Pain A, Roberts DJ.

Nuffield Department of Clinical Laboratory Sciences and National Blood Service, John Radcliffe Hospital, Headington, Oxford, United Kingdom.

Platelet-endothelial cell adhesion molecule 1 (PECAM-1/CD31) has been identified as an endothelial cell receptor of Plasmodium falciparum-infected erythrocytes. The significance of adhesion of infected erythrocytes to this receptor in malaria infection has not been determined. We have therefore studied the association of the functional mutation CTG-->GTG (Leu-->Val) in codon 125 of the Cd31 gene with severe disease in 2 case-control studies of malaria in Madang Hospital, Papua New Guinea, and in Kilifi District Hospital, Kenya. We analyzed data from 442 cases and controls from Papua New Guinea and data from 396 cases and controls from Kenya. The codon 125 polymorphism was not associated with severe malaria in either study. We conclude that the presence of CTG-->GTG (Leu-->Val) substitution in codon 125 in CD31 is not associated with protection from severe malaria, and we suggest that selective forces other than malaria may maintain this high-frequency polymorphism.

Am J Trop Med Hyg 2001 Dec;65(6):729-32

Confirmation of Anopheles varuna in vietnam, previously misidentified and mistargeted as the malaria vector Anopheles minimus.

Van Bortel W, Harbach RE, Trung HD, Roelants P, Backeljau T, Coosemans M.

Department of Parasitology, Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium. [email protected]

Malaria control programs in Southeast Asia are faced with several questions concerning vector behavior and species identification, which need to be answered to consolidate and further improve the results of control practices. The vector system in Southeast Asia is complex because of the number of species potentially involved in malaria transmission. Additionally, the follow-up and evaluation of preventive control measures are hampered by the misidentification of vectors due to overlapping morphological characters of the female mosquitoes. In central Vietnam, control practices are aimed at 2 main species, Anopheles dirus s.l. and Anopheles minimus s.l. These reputed vectors were studied in an area of Binh Thuan Province of south-central Vietnam. Different collection methods were used to capture mosquitoes quarterly during a 1-year period. Mosquitoes were identified in the field and later subjected to detailed morphological examination and polymerase chain reaction-restriction fragment length polymorphism analysis. What was thought to be an unusual morphotype of An. minimus was shown to be Anopheles varuna, and most specimens identified as the former species in the field proved to be the latter species. Very few An. minimus individuals were found during the study period. The population of An. varuna was found to be highly zoophilic, and based on this behavior, it cannot be considered a vector in Vietnam. Because this species was previously being misidentified as An. minimus, a nonvector was mistargeted as a malaria vector in Binh Thuan Province. Anopheles dirus, which was found positive for Plasmodium falciparum circumsporozoite via enzyme-linked immunosorbent assay, is clearly the main vector in this area. Despite the fact that several potential secondary vectors were found during the study, the primary target for vector control in the region should be An. dirus.

Am J Trop Med Hyg 2001 Dec;65(6):711-6

Cardiac effects of amodiaquine and sulfadoxine-pyrimethamine in malaria-infected African patients.

Ngouesse B, Basco LK, Ringwald P, Keundjian A, Blackett KN.

Centre Hospitalo-Universitaire de Yaounde, Faculte de Medecine, Universite de Yaounde I, Cameroon.

The cardiac effect of amodiaquine and sulfadoxine-pyrimethamine was studied in adult Cameroonian patients with acute uncomplicated Plasmodium falciparum malaria by electrocardiographic monitoring over the course of 7 days. Clinical and parasitological responses were monitored until Day 14. Bradycardia was observed in 16 of 20 amodiaquine-treated patients on Day 2, which corresponds to the time when maximal cumulative plasma concentration is reached, and in 12 of 20 patients on Day 7. A bradycardic effect lasting several days was not noted in patients treated with sulfadoxine-pyrimethamine. Significantly prolonged P, PQ, QRS, and QTc intervals were recorded on Day 2 after both 30 and 35 mg of amodiaquine base per kilogram of body weight had been administered, but these intervals were not correlated with the plasma monodesethylamodiaquine (main human active metabolite of amodiaquine) level. Electrocardiographic changes after therapy with sulfadoxine-pyrimethamine were minor and transient. All patients had fever and parasite clearance on or before Day 3 and remained free of fever and parasites until Day 14. None of the patients complained of cardiovascular adverse effects during the follow-up. These results suggest the absence of significant cardiac effects of amodiaquine and sulfadoxine-pyrimethamine at usual therapeutic doses, but they should draw the attention of clinicians treating malaria-infected patients who have taken other antimalarial drugs with cardiovascular side effects or those who are under treatment with cardiovascular drugs.

Am J Trop Med Hyg 2001 Dec;65(6):696-9

In vivo-in vitro model for the assessment of clinically relevant antimalarial cross-resistance.

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

Department of Specific Prophylaxis and Tropical Medicine, Institute of Pathophysiology, University of Vienna, Austria.

Cross-resistance may be considered one of the most important factors leading to decreased drug susceptibility of Plasmodium falciparum. The study aimed to determine whether clinically relevant cross-sensitivity of P. falciparum existed between artemisinin and mefloquine. Seventy-six patients with falciparum malaria were admitted and treated with artemisinin derivatives. Treatment response parameters were assessed and in vitro drug sensitivity tests were performed with artemisinin, mefloquine, quinine, and chloroquine. Distinct in vitro cross-sensitivity between artemisinin and mefloquine was observed (p = 0.604; P < 0.001). To assess the relevance of this finding for clinical cross-resistance, we used an analytical model based on the relation of in vivo treatment response parameters (fever, parasite and symptom clearance) to a single reference drug with in vitro drug sensitivity data of several other drugs. Artemisinin (R = 0.554; P = 0.009) and mefloquine (R = 0.615; P = 0.002) in vitro drug sensitivities were equally well reflected in the in vivo treatment response to artemisinin, thereby suggesting the clinical relevance of in vitro cross-sensitivity.

Am J Trop Med Hyg 2001 Dec;65(6):679-84

Efficacy of mefloquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum infection in Machinga District, Malawi, 1998.

MacArthur J, Stennies GM, Macheso A, Kolczak MS, Green MD, Ali D, Barat LM, Kazembe PN, Ruebush TK 2nd.

Malaria Epidemiology Branch, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30341-3717, USA. [email protected]

In response to the spread of chloroquine-resistant Plasmodium falciparum, Malawi changed its first-line antimalarial drug in 1993 from chloroquine to sulfadoxine-pyrimethamine (SP). Surveillance data has suggested that resistance to SP may be increasing. We compared the efficacy of SP with a potential successor, mefloquine (MQ). By use of a modified World Health Organization in vivo protocol, children infected with P. falciparum were randomized to receive SP (sulfadoxine 25 mg/kg) or MQ (15 mg/kg). We observed combined RII and RIII parasitologic failures of 20.0 and 22.0% in the SP and MQ arms, respectively. Among those in the MQ arm, the relative hazard of failing with a Day 2 drug level < 500 ng/mL was 10.6 times higher than those with levels > or = 500 ng/mL. Given the decreased efficacy of the first-line antimalarial drug and the high failure rates of MQ at this lower dosage, Malawi should consider assessing the efficacy and feasibility of alternative drugs to treat uncomplicated falciparum malaria.

Science 2002 Jan 11;295(5553):342-5

Stage-specific transcription of distinct repertoires of a multigene family during Plasmodium life cycle.

Preiser PR, Khan S, Costa FT, Jarra W, Belnoue E, Ogun S, Holder AA, Voza T, Landau I, Snounou G, Renia L.

Division of Parasitology, National Institute for Medical Research, The Ridgeway, London, NW7 1AA, UK. [email protected]

Members of a multigene family in the rodent malaria parasite Plasmodium yoelii yoelii code for 235-kilodalton proteins (Py235) that are located in the merozoite apical complex, are implicated in virulence, and may determine red blood cell specificity. We show that distinct subsets of py235 genes are expressed in sporozoites and hepatic and erythrocytic stages. Antibodies to Py235 inhibited sporozoite invasion of hepatocytes. The switch in expression profile occurred immediately after transition from one stage to another. The results suggest that this differential expression is driven by strong biological requirements and provide evidence that hepatic and erythrocytic merozoites differ.

J Biol Chem 2002 Jan 10; http://www.jbc.org

Structure and Mechanism of 2-C-Methyl-D-Erythritol 2,4-Cyclodiphosphate Synthase. An enzyme in the mevalonate independent isoprenoid biosynthetic pathway.

Richard SB, Ferrer JL, Bowman ME, Lillo AM, Tetzlaff CN, Cane DE, Noel JP.

Structural Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.

The enzyme 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MECDP)1 synthase catalyses the conversion of 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDP-ME2P) to MECDP. This biosynthetic step in the mevalonate-independent pathway for isoprenoid biosynthesis involves the formation of a highly unusual cyclodiphosphate-containing intermediate on the pathway to isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) biosynthesis. Notably, the mevalonate independent or deoxyxylulose / 2-C-methyl D-erythritol 4-phosphate (DXP/MEP) pathway occurs in a number of bacteria, as well as in algae, the plastids of plant cells, and the apicoplast of the malaria parasite. Since vertebrates synthesize isoprenoid precursors using a mevalonate-dependent pathway, MECDP synthase and other enzymes of the mevalonate-independent pathway for isoprenoid production represent attractive targets for the structure-based design of selective antibacterial, herbicidal, and antimalarial drugs. We now report two x-ray crystal structures of MECDP synthase refined to 2.8 resolution. The first structure contains a bound Mn2+ cation, and the second structure contains CMP, MECDP, and Mn2+. The protein adopts a homotrimeric quaternary structure built around a central hydrophobic cavity and three externally facing active sites. Each of these active sites is located between two adjacent monomers. A tetrahedrally arranged transition metal binding site, potentially occupied by Mn2+ sits at the base of the active site cleft. A phosphate oxygen of MECDP, and the side chains of Asp8, His10, and His42 occupy the metal ion coordination sphere. Analyses of the structures of the Mn2+-bound form and the CMP-MECDP-Mn2+ complex reveal the complete active site architecture. Moreover, these two structures reveal for the first time the structural determinants underlying substrate, product, and Mn2+ recognition, and the likely catalytic mechanism accompanying the biosynthesis of the cyclodiphosphate-containing isoprenoid precursor, MECDP.

Mem Inst Oswaldo Cruz 2001 Nov;96(8):1081-4

The distribution of two major malaria vectors, Anopheles gambiae and Anopheles arabiensis, in Nigeria.

Onyabe DY, Conn JE.

Department of Biology, University of Vermont, Burlington, USA.

The distribution of Anopheles gambiae and An. arabiensis across the ecological zones of Nigeria (arid savanna in the north gradually turns into humid forest in the south) was investigated. Results of the present study were compared to the distributions determined from samples of indoor-resting females reported by an earlier study over 20 years ago. Larvae were sampled in the rainy seasons of 1997 and 1999 from 24 localities, 10 of which were sampled in both years. Specimens were identified by the polymerase chain reaction method. Results showed that species composition changed significantly among the 10 localities in both years (chi2=13.62, P = 0.0002), but this change was significant in only four of the 10 localities. The identity of the prevalent (more abundant) species changed between 1997 and 1999 in only three of 10 localities. An. arabiensis was prevalent in several localities in the southern Guinea savanna, an area where it was virtually absent over 20 years ago. The data suggest that An. arabiensis has extend its range, although differences in sampling technique (larval sampling versus adult collection) can not be ruled out as a possible explanation.

Mem Inst Oswaldo Cruz 2001 Nov;96(8):1055-9

Plasmodium/intestinal helminth co-infections among pregnant Nigerian women.

Egwunyenga A, Ajayi J, Nmorsi O, Duhlinska-Popova D.

Applied Parasitology Research Laboratory, Department of Zoology, University of Jos, Jos, Nigeria.

Hospital based studies were conducted to investigate the occurrence of Plasmodium/intestinal helminth co-infections among pregnant Nigerian women, and their effects on birthweights, anaemia and spleen size. From 2,104 near-term pregnant women examined, 816 (38.8%) were found to be infected with malaria parasites. Among the 816 parasitaemic subjects, 394 (48.3%) were also infected with intestinal helminths, 102 (12.5%) having mixed helminth infections. The prevalence of the helminth species found in stool samples of parasitaemic subjects examined was, Ascaris lumbricoides (19.1%), hookworm (14.2%), Trichuris trichiura (7%) Schistosoma mansoni (3.4%), Enterobius vermicularis (2%), Hymenolepis sp. (1.6%) and Taenia sp. (1%). Mothers with Plasmodium infection but without intestinal helminth infection had neonates of higher mean birthweights than those presenting both Plasmodium and intestinal helminth infections and this effect was more pronounced in primigravids. The mean haemoglobin values of malarial mothers with intestinal helminth infections were lower than those with Plasmodium infection but without intestinal helminth infections but these were not statistically significant. Severe splenomegaly was predominant among parasitaemic gravidae who also harboured S. mansoni infection in two of the hospitals studied.

Mem Inst Oswaldo Cruz 2001 Nov;96(8):1033-42

The search for new antimalarial drugs from plants used to treat fever and malaria or plants randomly selected: a review.

Krettli AU, Andrade-Neto VF, Brandao Md MG, Ferrari WM.

Centro de Pesquisas Rene Rachou, Fiocruz, Belo Horizonte, MG, 30190-002, Brasil.

In this review we discuss the ongoing situation of human malaria in the Brazilian Amazon, where it is endemic causing over 610,000 new acute cases yearly, a number which is on the increase. This is partly a result of drug resistant parasites and new antimalarial drugs are urgently needed. The approaches we have used in the search of new drugs during decades are now reviewed and include ethnopharmocology, plants randomly selected, extracts or isolated substances from plants shown to be active against the blood stage parasites in our previous studies. Emphasis is given on the medicinal plant Bidens pilosa, proven to be active against the parasite blood stages in tests using freshly prepared plant extracts. The anti-sporozoite activity of one plant used in the Brazilian endemic area to prevent malaria is also described, the so called "Indian beer" (Ampelozizyphus amazonicus, Rhamnaceae). Freshly prepared extracts from the roots of this plant were totally inactive against blood stage parasites, but active against sporozoites of Plasmodium gallinaceum or the primary exoerythrocytic stages reducing tissue parasitism in inoculated chickens. This result will be of practical importance if confirmed in mammalian malaria. Problems and perspectives in the search for antimalarial drugs are discussed as well as the toxicological and clinical trials to validate some of the active plants for public health use in Brazil.

Ann Trop Med Parasitol 2001 Dec;95(8):789-96

Malaria-attributable morbidity in Assam, north-eastern India.

Dev V, Hira CR, Rajkhowa MK.

Malaria Research Centre (ICMR), Sonapur, Assam - 782 402, India.

Malaria is endemic in the Indian state of Assam and transmission of the causative parasites is perennial and persistent. The available data on malaria-related morbidity and mortality in the state for the years 1991-1999 have been reviewed. Over this period, Plasmodium falciparum was the predominant parasite, causing 58%-68% of the malaria cases; all other cases were attributed to P. vivax. All malaria-related deaths were attributed to P. falciparum infection, and the numbers of such deaths were correlated with the numbers of cases of P. falciparum malaria. The deaths occurred mostly in the rainy season (April-September) and among all age-groups of both sexes. The factors responsible for focal outbreaks of malaria across the state are discussed in relation to the existing health infrastructure.

Ann Trop Med Parasitol 2001 Dec;95(8):781-8

Molecular markers for chloroquine-resistant Plasmodium falciparum malaria in Thailand and Laos.

Labbe AC, Bualombai P, Pillai DR, Zhong KJ, Vanisaveth V, Hongvanthong B, Looareesuwan S, Kain KC.

Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Canada.

Chloroquine-resistant Plasmodium falciparum is well documented in Thailand. Laos, however, continues to use chloroquine (CQ) as the first-line therapy for the treatment of P. falciparum malaria. The objective of the present study was to determine the prevalence, in these two areas, of the cg2, pfmdr1 and pfcrt allelic types that have previously been associated with CQ resistance. Isolates of P. falciparum were collected from participants in ongoing treatment studies conducted in Thailand (near the Thai-Cambodian border) and in Laos (Vang Vieng district). The pfmdr1 and pfcrt alleles were characterized by PCR-RFLP and mutations in cg2 were characterized by PCR and single-stranded-conformation-polymorphism (SSCP) electrophoresis. Eight (32%) of the 25 Laotian isolates but only one (4%) of the 25 Thai isolates were found to contain the pfmdr1 mutation N86Y (P = 0.02). In contrast, the cg2 polymorphisms previously associated with CQ resistance were present in only 10 of the isolates from Laos but 24 of those from Thailand (40% v. 96%; P < 0.001). All the samples from both countries contained the pfcrt K76T mutant allele reported to confer resistance to CQ. The results may indicate that drug pressure for the maintenance of the pfmdr1 and cg2 alleles varies in intensity in the Thai and Laotian study areas, probably reflecting differences in the national malaria-treatment policies of Thailand and Laos.

Ann Trop Med Parasitol 2001 Dec;95(8):741-54

Malaria epidemiology and control in refugee camps and complex emergencies.

Rowland M, Nosten F.

HealthNet International, Peshawar, Pakistan, and London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, U.K.

Owing to the breakdown of health systems, mass population displacements, and resettlement of vulnerable refugees in camps or locations prone to vector breeding, malaria is often a major health problem during war and the aftermath of war. During the initial acute phase of the emergency, before health services become properly established, mortality rates may rise to alarming levels. Establishing good case management and effective malaria prevention are important priorities for international agencies responsible for emergency health services. The operational strategies and control methods used in peacetime must be adapted to emergency conditions, and should be regularly re-assessed as social, political and epidemiological conditions evolve. During the last decade, research on malaria in refugee camps on the Pakistan-Afghanistan and Thailand-Burma borders has led to new methods and strategies for malaria prevention and case management, and these are now being taken up by international health agencies. This experience has shown that integration of research within control programmes is an efficient and dynamic mode of working that can lead to innovation and hopefully sustainable malaria control. United Nations' humanitarian and non-governmental agencies can play a significant part in resolving the outstanding research issues in malaria control.

Ann Trop Med Parasitol 2001 Oct;95(7):671-7

The performance and utility of rapid diagnostic assays for Plasmodium falciparum malaria in a field setting in the Lao People's Democratic Republic.

Labbe AC, Pillai DR, Hongvangthong B, Vanisaveth V, Pomphida S, Inkathone S, Hay Burgess DC, Kain KC.

Tropical Disease Unit, Department of Medicine, Division of Infectious Diseases, University of Toronto, Toronto, Ontario, M5G 2C4, Canada.

Rapid diagnostic assays for malaria have the potential to improve the management and control of the disease in developing countries. The objectives of the present study were to evaluate, in a field setting, the performance of several such assays for Plasmodium falciparum infection and to examine the usefulness of these assays in identifying subjects for treatment trials in rural field sites. Residents of 12 villages in Laos who presented with fever were eligible for inclusion. Blood was collected by fingerprick for a dipstick assay, developed by the Program for Appropriate Technology in Health (PATH), performed and interpreted in the field by local healthcare workers. Compared with 'blinded' reference microscopy (N =196), the sensitivity and specificity of the PATH assay were 96.2% and 93.0%, respectively. Two rapid diagnostic assays (PATH and OptiMAL) were also performed on the subset of subjects eligible to participate in an in-vivo treatment trial (N = 97), and the results again compared with those of 'blinded' reference microscopy. In this subset, a subject was considered a 'true positive' if found positive by microscopy or the alternate rapid assay. Using this modified reference standard, the sensitivity and specificity of the PATH assay were 96.7% and 94.4%, and those of the OptiMAL assay were 91.8% and 100%, respectively. Both of the rapid assays tested therefore appear suitable for use in rural field settings by local healthcare providers and can accurately identify participants for treatment trials.

Ann Trop Med Parasitol 2001 Oct;95(7):661-9

Plasmodium falciparum in Kenya: high prevalence of drug-resistance-associated polymorphisms in hospital admissions with severe malaria in an epidemic area.

Omar SA, Adagu IS, Gump DW, Ndaru NP, Warhurst DC.

Centre for Biotechnology Research Development, Kenya Medical Research Institute, P.O. Box 54840, Mbagathi Road, Nairobi, Kenya.

During an epidemic of Plasmodium falciparum malaria in Chogoria, Kenya, P. falciparum DNA was collected from 24 cases of severe malaria admitted to hospital for parenteral quinine treatment. These patients had all failed first- (chloroquine) and second-line (sulfadoxine-pyrimethamine or amodiaquine) drug treatments. Twenty-two (92%) of the 24 patients sampled carried parasites with the (Asn)86(Tyr) point mutation in the pfmdr1 gene (chromosome 5), 20 (83%) had an (Asp)1246(Tyr) mutation and 18 (82%) had both of these mutations. These alleles are both reported to be associated with chloroquine-resistance. Polymorphisms in the cg2 gene (chromosome 7) are also associated with chloroquine resistance, and 18 (75%) of the 24 parasite samples each had the cg2 and pfmdr1 polymorphisms. These 18 samples also had the mutations associated with resistance to pyrimethamine and sulfadoxine: (Asn)51(Ile), (Cys)59(Arg) and (Ser)108(Asn) of gene dhfr (chromosome 4) and (Ala)437(Gly) and (Lys)540(Glu) of dhps (chromosome 8), respectively. Genotyping of the parasites from all 24 patients revealed extensive diversity in the sequences for the merozoite surface antigens (MSA-1 and MSA-2) and the glutamate-rich protein (GLURP) and indicated that each sample contained more than one parasite clone. Although samples from non-admitted malaria cases were not available, it appears that drug resistance may have played an important role in the development of severe malaria in this epidemic.

Ann Trop Med Parasitol 2001 Oct;95(7):655-9

Plasmodium vivax relapses after 5 days of primaquine treatment, in some industrial complexes of India.

Dua VK, Sharma VP.

Malaria Research Centre, Industrial Malaria Unit, BHEL, Sect. III, Hardwar 249 403, India.

In an investigation of relapse patterns, 5541 cases of Plasmodium vivax malaria, from four major industrial complexes, each received at least one, 5-day course of primaquine (at 15 mg/day). Any subject relapsing was retreated with the same course. Overall, 511 (9.2%) of the P. vivax cases relapsed after the first course and 99 (1.78%), 25 (0.45) and three (0.05%) cases relapsed two, three and four times, respectively. Most cases of relapse occurred within 1 year of treatment. Clearly, a 5-day primaquine regimen is inadequate to control relapses among P. vivax cases and there is therefore an urgent need to review the treatment strategy. It may now be appropriate to implement the 14-day regimen recommended by the World Health Organization, although this is much less feasible under field conditions.

Ann Trop Med Parasitol 2001 Oct;95(7):645-53

Comparative clinical characteristics and responses to oral 4-aminoquinoline therapy of malarious children who did and did not develop 4-aminoquinoline-induced pruritus.

Sowunmi A, Falade AG, Adedeji AA, Falade CO.

Department of Pharmacology and Therapeutics and Postgraduate Institute for Medical Research & Training, University of Ibadan, Ibadan, Nigeria.

The clinical characteristics and the responses to oral 4-aminoquinoline therapy of 150 malarious children presenting consecutively were investigated in an endemic area. At presentation, the 75 children who subsequently developed pruritus were significantly older and had significantly higher body temperatures than the 75 children who did not develop pruritus. There were no other significant differences in clinical presentation between the two groups. In children with pruritus, there was no correlation between age, weight, presenting body temperature, duration of illness or presenting peripheral parasite density and duration of pruritus. Responses to oral antimalarial drugs were similar in both groups. There was no correlation between indices of therapeutic response and the duration of pruritus. Analysis of the disposition kinetics of parasitaemia and of the hepatomegaly associated with malaria, using a non-compartmental model similar to that used in characterizing drug disposition, showed that the two groups had similar half-lives of parasitaemia (t((1/2)pd)), volumes of blood completely cleared of parasites per unit time (CL(Bpd)) and ratios of parasite-clearance time to t((1/2)pd), and similar values for the corresponding parameters derived from hepatomegaly resolution. There was no apparent relationship between the indices of parasite- or hepatomegaly-disposition kinetics and the duration of pruritus.

J Med Chem 2002 Jan 17;45(2):292-303

Structure-Activity Relationships of the Antimalarial Agent Artemisinin. 6. The Development of Predictive In Vitro Potency Models Using CoMFA and HQSAR Methodologies.

Avery MA, Alvim-Gaston M, Rodrigues CR, Barreiro EJ, Cohen FE, Sabnis YA, Woolfrey JR.

Department of Medicinal Chemistry, School of Pharmacy, Thad Cochran National Center for Natural Products Research, and Department of Chemistry, University of Mississippi, University, Mississippi 38677, Laboratorio de Avaliacao e Sintese de Substancias Bioativas (LASSBio), Departamento de Farmacos, Faculdade de Farmacia, UFRJ, RJ, Brazil, 21944-910, and Department of Cellular Molecular Pharmacology, University of California, San Francisco, California 94143-0446.

Artemisinin (1) is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua L. Because of the effectiveness of Artemisinin in the treatment of drug-resistant Plasmodium falciparum and its rapid clearance of cerebral malaria, development of clinically useful semisynthetic drugs for severe and complicated malaria (artemether, artesunate) was prompt. However, recent reports of fatal neurotoxicity in animals with dihydroartemisinin derivatives such as artemether have spawned a renewed effort to develop nontoxic analogues of artemisinin. In our effort to develop more potent, less neurotoxic agents for the oral treatment of drug-resistant malaria, we utilized comparative molecular field analysis (CoMFA) and hologram QSAR (HQSAR), beginning with a series of 211 artemisinin analogues with known in vitro antimalarial activity. CoMFA models were based on two conformational hypotheses: (a) that the X-ray structure of artemisinin represents the bioactive shape of the molecule or (b) that the hemin-docked conformation is the bioactive form of the drug. In addition, we examined the effect of inclusion or exclusion of racemates in the partial least squares (pls) analysis. Databases derived from the original 211 were split into chiral (n = 157), achiral (n = 34), and mixed databases (n = 191) after leaving out a test set of 20 compounds. HQSAR and CoMFA models were compared in terms of their potential to generate robust QSAR models. The r(2) and q(2) (cross-validated r(2)) were used to assess the statistical quality of our models. Another statistical parameter, the ratio of the standard error to the activity range (s/AR), was also generated. CoMFA and HQSAR models were developed having statistically excellent properties, which also possessed good predictive ability for test set compounds. The best model was obtained when racemates were excluded from QSAR analysis. Thus, CoMFA of the n = 157 database gave excellent predictions with outstanding statistical properties. HQSAR did an outstanding job in statistical analysis and also handled predictions well.

Proc Natl Acad Sci U S A 2002 Jan 8; http://www.pnas.org

Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine.

Banerjee R, Liu J, Beatty W, Pelosof L, Klemba M, Goldberg DE.

Howard Hughes Medical Institute, Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8230, St. Louis, MO 63110.

Hemoglobin degradation is a metabolic process that is central to the growth and maturation of the malaria parasite Plasmodium falciparum. Two aspartic proteases that initiate degradation, plasmepsins (PMs) I and II, have been identified and extensively characterized. Eight additional PM genes are present in the P. falciparum genome. To better understand the enzymology of hemoglobin degradation, it is necessary to determine which of these genes are expressed when hemoglobin degradation is occurring, which encode active enzymes, and which gene products are found in the food vacuole where catabolism takes place. Our genome-wide analysis reveals that PM I, II, and IV and histo-aspartic protease encode hemoglobin-degrading food vacuole proteases. Despite having a histidine in place of one of the catalytic aspartic acids conserved in other aspartic proteases, histo-aspartic protease is an active hydrolase.

Clin Microbiol Rev 2002 Jan;15(1):66-78

Rapid diagnostic tests for malaria parasites.

Moody A.

Department of Clinical Parasitology, Hospital for Tropical Diseases, University Collge Hospital, London, United Kingdom. [email protected]

Malaria presents a diagnostic challenge to laboratories in most countries. Endemic malaria, population movements, and travelers all contribute to presenting the laboratory with diagnostic problems for which it may have little expertise available. Drug resistance and genetic variation has altered many accepted morphological appearances of malaria species, and new technology has given an opportunity to review available procedures. Concurrently the World Health Organization has opened a dialogue with scientists, clinicians, and manufacturers on the realistic possibilities for developing accurate, sensitive, and cost-effective rapid diagnostic tests for malaria, capable of detecting 100 parasites/microl from all species and with a semiquantitative measurement for monitoring successful drug treatment. New technology has to be compared with an accepted "gold standard" that makes comparisons of sensitivity and specificity between different methods. The majority of malaria is found in countries where cost-effectiveness is an important factor and ease of performance and training is a major consideration. Most new technology for malaria diagnosis incorporates immunochromatographic capture procedures, with conjugated monoclonal antibodies providing the indicator of infection. Preferred targeted antigens are those which are abundant in all asexual and sexual stages of the parasite and are currently centered on detection of HRP-2 from Plasmodium falciparum and parasite-specific lactate dehydrogenase or Plasmodium aldolase from the parasite glycolytic pathway found in all species. Clinical studies allow effective comparisons between different formats, and the reality of nonmicroscopic diagnoses of malaria is considered.

Genome Res 2002 Jan;12(1):57-66

A Comparative Genomic Analysis of Two Distant Diptera, the Fruit Fly, Drosophila melanogaster, and the Malaria Mosquito, Anopheles gambiae.

Bolshakov VN, Topalis P, Blass C, Kokoza E, della Torre A, Kafatos FC, Louis C.

Genome Research Laboratory, Institute of Molecular Biology and Biotechnology, FORTH, 71110 Heraklion, Crete, Greece.

Genome evolution entails changes in the DNA sequence of genes and intergenic regions, changes in gene numbers, and also changes in gene order along the chromosomes. Genes are reshuffled by chromosomal rearrangements such as deletions/insertions, inversions, translocations, and transpositions. Here we report a comparative study of genome organization in the main African malaria vector, Anopheles gambiae, relative to the recently determined sequence of the Drosophila melanogaster genome. The ancestral lines of these two dipteran insects are thought to have separated ~250 Myr, a long period that makes this genome comparison especially interesting. Sequence comparisons have identified 113 pairs of putative orthologs of the two species. Chromosomal mapping of orthologous genes reveals that each polytene chromosome arm has a homolog in the other species. Between 41% and 73% of the known orthologous genes remain linked in the respective homologous chromosomal arms, with the remainder translocated to various nonhomologous arms. Within homologous arms, gene order is extensively reshuffled, but a limited degree of conserved local synteny (microsynteny) can be recognized.

J Egypt Soc Parasitol 2001 Dec;31(3):905-14

Serum levels of some cytokines and soluble adhesion molecules in normal and patients with malignant malaria in Zambia.

Gamra MM, el-Sharkawy EM, Shinondo C.

Department of Parasitology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

The present study revealed no changes in the serum levels of IL-8 in malaria patients compared with controls. Such result however, does not exclude a role for IL-8 in falciparum malaria, as it is produced by activated endothelial cells that may be captured by receptors on the endothelial surface. This would allow local concentrations of IL-8 to be generated at the vessel wall without being shed into the circulation. The marked elevation of ICAM-1 and VCAM-1 in serum of falciparum malaria patients may support the concept that dysfunction of the endothelium is important in the pathophysiology of the disease. Increased level of IL-6 in serum of patients may contribute to endothelial damage and dysfunction by expression of endothelial adhesion molecules that in turn result in infected erythrocytes attraction to the endothelium and pathologic endothelial dysfunction.

Pediatrics 2002 Jan;109(1):E6

Vitamin A supplements ameliorate the adverse effect of HIV-1, malaria, and diarrheal infections on child growth.

Villamor E, Mbise R, Spiegelman D, Hertzmark E, Fataki M, Peterson KE, Ndossi G, Fawzi WW.

Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [email protected]

OBJECTIVE: Evidence from animal experiments and observational studies in humans suggests that vitamin A plays a fundamental role in physical growth. However, results from vitamin A supplementation trials in children are inconsistent; whereas some did not find an overall effect on growth, others found benefits only among specific groups, including children with low concentrations of serum retinol or short duration of breastfeeding. The apparent lack of an overall effect of vitamin A on growth could be attributed to context-specific distribution of conditions that affect both growth and the response to supplementation, eg, baseline vitamin A status, deficiency of other nutrients (fat, zinc), and the presence of infectious diseases. Human immunodeficiency virus (HIV) infection, malaria, and diarrheal disease adversely affect growth and are associated with increased prevalence of vitamin A deficiency. We hypothesize that vitamin A supplementation could ameliorate the adverse effect of these infections on child growth. METHODS: We conducted a randomized, clinical trial among 687 Tanzanian children who were 6 to 60 months of age and admitted to the hospital with pneumonia. Children were assigned to oral doses of 200 000 IU vitamin A (half that dose if <12 months) or placebo on the day of admission, a second dose on the following day, and third and fourth doses at 4 and 8 months after discharge from the hospital, respectively. Anthropometric measurements were obtained at baseline and at monthly visits to the study clinics during 12 months after the initial hospitalization. Surveillance on the incidence and severity of diarrhea and respiratory infections was conducted during biweekly visits, alternately at a study clinic and the child's home, using a pictorial diary that the mothers were trained to use. A blood specimen was drawn at baseline for determination of HIV status, malaria infection, and hemoglobin levels. We used mixed effects models to compare estimated total weight and height increases after 1 year of follow-up between treatment arms, overall and within levels of HIV status, malaria, and other possible baseline effect modifiers. We also assessed the potential modulating effect of vitamin A on the risk of stunting (height-for-age <-2 standard deviations of the gender-specific National Center for Health Statistics median reference) attributable to diarrheal and respiratory infections during follow-up, in the subset of children who were not stunted at baseline. A similar approach was followed for wasting (weight-for-height <-2 standard deviations of the reference median). Cox regression models were used to estimate relative risks and 95% confidence intervals (CI), treating episodes of infection as time-dependent covariates. RESULTS: A total of 554 children had at least 2 follow-up measurements of height or weight and constituted the study base. Baseline characteristics did not differ significantly by treatment arm. Seventy-three percent of the children were <2 years of age, and 37% were <12 months; 31% were stunted at baseline and 9% were wasted. Malaria (Plasmodium falciparum) and HIV infection were found in 24% and 9% of the children, respectively. Median duration of follow-up was 351 days, with 10 measurements/child, on average, irrespectively of treatment assignment. Supplementation with vitamin A among children who had HIV infection and were <18 months of age resulted in a significant length increase. Four months after the first dose, infants who were HIV positive in the vitamin A arm had gained, on average, 2.8 cm (95% CI: 1.0-4.6) more than children who received placebo, whereas no effect was observed among infants who were HIV negative (difference at 4 months: -0.2 cm; 95% CI: -0.8-0.5). Children who were <12 months of age and had malaria at enrollment experienced a 747-g (95% CI: 71-1423) higher yearly weight gain attributable to vitamin A; among children without malaria, however, the supplements did not have a significant effect (-57 g; 95% CI: -461-348). These results remained unchanged after controlling for indicators of the socioeconomic and nutritional status at baseline. Linear growth was also improved by vitamin A among children from households with poor water supply (0.8 cm/year; 95% CI: 0-1.5) but not in children with tap water in the house or compound (-1.0 cm/year; 95% CI: -1.9-0). Weight gain was greater among children with mid-upper arm circumference below the 25th percentile of the age-specific distribution at baseline (458 g/year; 95% CI: 1-905), but no benefit was evident among children with higher mid-upper arm circumference. The risk of stunting associated with episodes of persistent diarrhea (lasting 14 or more days) during follow-up was virtually eliminated by vitamin A supplements. Among children in the placebo group, the average risk of stunting associated with 1 or more episodes of persistent diarrhea between 2 consecutive visits was 5.2 times higher (95% CI: 2.4-11.2) than that of children without diarrhea or with acute episodes. In contrast, among children who received vitamin A, there was virtually no risk of stunting associated with persistent diarrhea (relative risk: 1.0; 95% CI: 0.3-1.3). This effect was slightly attenuated after controlling for the number of household possessions, gender, baseline low arm circumference, HIV infection, and presence of malaria parasites in blood. Vitamin A supplements did not modify the associations between respiratory infections and the risk of stunting or wasting. CONCLUSIONS: Vitamin A supplementation improves linear and ponderal growth in infants who are infected with HIV and malaria, respectively, and decreases the risk of stunting associated with persistent diarrhea. Supplementation could constitute a low-cost, effective intervention to decrease the burden of growth retardation in settings where infectious diseases are highly prevalent.

J Clin Microbiol 2002 Jan;40(1):155-8

Evaluation of the OptiMAL rapid antigen test and species-specific PCR to detect placental Plasmodium falciparum infection at delivery.

Mankhambo L, Kanjala M, Rudman S, Lema VM, Rogerson SJ.

College of Medicine, University of Malawi, Blantyre, Malawi.

During pregnancy, Plasmodium falciparum infection of the placenta frequently occurs in the absence of parasites in peripheral blood. We investigated the abilities of the OptiMAL rapid immunochromatographic strip test for P. falciparum lactate dehydrogenase and species-specific PCR performed on peripheral blood to detect placental infection or malaria-associated low birth weight. Of 509 Malawian women screened by microscopy, 76 had malaria infection. Among these 509 women, the frequency of peripheral blood parasitemia was low. The OptiMAL test gave positive results in 37 of 171 women tested (one of whom had placental but not peripheral blood parasitemia) and had sensitivities of 71% for peripheral parasitemia and 38% for placental parasitemia compared to the microscopy values. The specificity for peripheral parasitemia was 94%. In 135 women, PCR had sensitivities of 94% for peripheral blood malaria detected by microscopy and 72% for placental infection. In samples examined by PCR, the prevalence of malaria in peripheral blood increased from 26.7% by microscopy to 51.9%. Women with placental malaria and women with malaria in peripheral blood samples by microscopy or OptiMAL testing, but not women with malaria detected only by PCR, had lower-birth-weight babies than did women without malaria by these criteria. Positive results by PCR in the absence of microscopic parasitemia were not associated with low birth weight. Neither OptiMAL nor PCR testing of peripheral blood is adequately sensitive to detect all placental malaria infection, but a positive result by OptiMAL testing identifies women with a high proportion of low-birth-weight babies.

Parasitol Res 2001 Dec;87(12):1020-3

Change in Plasmodium falciparum genotype during successive malaria episodes in Gabonese children.

Missinou MA, Kun JF, Lell B, Kremsner PG.

Department of Parasitology, Institute of Tropical Medicine, University of Tubingen, Germany.

Extensive polymorphism in the malaria parasite Plasmodium falciparum is one of the major obstacles to controlling the disease. With the aim of analysing the dynamics of P. falciparum inoculations, we investigated the parasite genotypes of successive malaria episodes. Polymerase chain reaction was performed on blood samples collected longitudinally from 31 children in Lambarene, Gabon. The polymorphic regions of the merozoite surface antigens 1 and 2 were used as genetic markers. The data show that children in this area are exposed to many different P. falciparum strains. In a few cases, the same parasite genotypic pattern was observed in samples from two consecutive clinical attacks indicating probable recrudescences after therapy. In six cases the first successive infections with a particular merozoite surface antigen (MSA)-2 strain (3D7) were followed by infections with the other MSA-2 genotype (FC27). In all other cases the genetic characteristics of the parasite were different from one infection to the next, indicating that reinfection was caused by a new parasite strain.

Parasitol Res 2001 Dec;87(12):1007-10

The analysis of Plasmodium vivax Duffy receptor binding domain gene sequence from resurgent Korea isolates.

Suh IB, Hoffman KJ, Kim SH, Song KJ, Song JW, Lee JS, Lim CS.

Department of Clinical Pathology, College of Medicine, Korea University 516, Ansan City, Kyunggi Province, Republic of Korea.

The Duffy binding domain gene structures of Plasmodium vivax facilitate the invasion of erythrocytes. Human erythrocytes that lack Duffy blood group antigens are resistant to invasion by P. vivax. We have sequenced the Duffy binding domain gene from eight P. vivax isolates collected from malaria cases in South Korea. When compared to isolates from other regions in the world, the amino acid sequences of the Korean isolates showed unique variations in region II. From 606 sequenced amino acids, 32 variations were found. Of these, three variations were regularly found in positions 424, 437 and 503 of the Sal-1 amino acid sequence. In region III, six isolates had a loss of the 30 bp (FAESTKSAE) insert. However, six isolates had 6 bp (SD) inserts at the end of region III. Two cases had a reverse pattern. Our results suggest that the P. vivax currently found in South Korea are unique when compared to other isolates and can be divided, by the analysis of their molecular structure, into two strains.

J Med Entomol 2001 Nov;38(6):822-8

Effect of passive zooprophylaxis on malaria transmission in The Gambia.

Bogh C, Clarke SE, Pinder M, Sanyang F, Lindsay SW.

Danish Bilharziasis Laboratory, Charlottenlund, Denmark. [email protected]

The effect of zooprophylaxis on malaria transmission has not been studied on the African continent despite that the World Health Organization has recommended this intervention method since 1982. The effect of passive zooprophylaxis on malaria vector abundance, mosquito feeding preferences, and infectivity was studied in an area of moderate seasonal transmission in The Gambia. A paired cohort of 204 children <7 yr of age was selected and matched in groups for presence or absence of cattle (Bos taurus) within 20 m of their bedroom. Comparisons were made between mosquitoes collected from the bedrooms of the two groups of children. Other ruminants and equines were present in both groups of compounds. Most of the anopheline mosquitoes (98.5%) collected were Anopheles gambiae sensu lato. There was no difference in the geometric mean number of An. gambiae s.l. mosquitoes caught in houses near or far from cattle. The species composition of the An. gambiae complex was similar in both groups. Blood meal analysis of specimens collected in houses without cattle showed a human blood index (HBI) of 82% for An. Arabiensis (Patton), 56% for An. gambiae sensu stricto (Giles), and 36% for Anopheles Melas (Theobald), indicating that each of these sibling species fed readily on animals. The presence of cattle reduced the HBI of An. arabiensis but did not significantly alter the HBI of An. gambiae s.s. or An. melas. There was no significant difference between the groups in the sporozoite rates of An. gambiae s.l. nor in the estimated malaria transmission risk. These findings suggest that passive zooprophylaxis using cattle does not alter the individual exposure to malaria parasites in The Gambia.

J Infect Dis 2002 Jan 1;185(1):127-31

Immunity to Placental Malaria. III. Impairment of Interleukin(IL)-12, not IL-18, and Interferon-Inducible Protein-10 Responses in the Placental Intervillous Blood of Human Immunodeficiency Virus/Malaria-Coinfected Women.

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

Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA and Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand.

Pregnant women are highly susceptible to malaria, and human immunodeficiency virus (HIV) infection increases this susceptibility. In our previous studies, placental malaria (PM), HIV infection, and HIV/PM coinfection were all associated with decreased interferon (IFN)-gamma production by maternal placental (intervillous) blood mononuclear cells (IVBMC). This study investigated whether in vitro production of the IFN-gamma regulatory cytokines interleukin (IL)-12 and IL-18 and the chemokine IFN-inducible protein (IP)-10 by IVBMC is altered in women who have been exposed to malaria and are infected with HIV. IL-12 production from IVBMC was significantly lower in HIV-positive women, regardless of PM status, in contrast to HIV-negative, PM-negative women. IL-18 and IP-10 production by IVBMC was reduced in HIV-positive, PM-negative women but elevated in HIV-positive, PM-positive women. These results reveal a substantial impairment of IL-12 production by IVBMC in HIV-positive women, implicating this cytokine as a potentially critical regulator of malaria antigen-specific IFN-gamma responses in HIV-infected and HIV/PM-coinfected women.

Trends Parasitol 2001 Dec;17(12):597-600

Parasites that cause problems in Malaysia: soil-transmitted helminths and malaria parasites.

Singh B, Cox-Singh J.

Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, 94300 Kota Samarahan, Sarawak, Malaysia

Malaysia is a developing country with a range of parasitic infections. Indeed, soil-transmitted helminths and malaria parasites continue to have a significant impact on public health in Malaysia. In this article, the prevalence and distribution of these parasites, the problems associated with parasitic infections, the control measures taken to deal with these parasites and implications for the future will be discussed.

Trends Parasitol 2001 Dec;17(12):593-7

The past, present and future of childhood malaria mortality in Africa.

Snow RW, Trape JF, Marsh K.

The Wellcome Trust/Kenya Medical Research Institute Collaborative Programme, PO Box 43640, Nairobi, Kenya

During the past few years, there has been a historic series of declarations of renewed commitment to malaria control in Africa. Whether the burden of malaria is increasing in Africa is a moot point. This article attempts to re-construct the evidence for the trends in childhood mortality as a result of Plasmodium falciparum infection over the last century in Africa.

Trends Parasitol 2001 Dec;17(12):582-8

Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next?

Sibley CH, Hyde JE, Sims PF, Plowe CV, Kublin JG, Mberu EK, Cowman AF, Winstanley PA, Watkins WM, Nzila AM.

Department of Genetics, Box 357360, University of Washington, 98195-7360, Seattle, WA, USA

Chemotherapy remains the only practicable tool to control falciparum malaria in sub-Saharan Africa, where >90% of the world's burden of malaria mortality and morbidity occurs. Resistance is rapidly eroding the efficacy of chloroquine, and the combination pyrimethamine-sulfadoxine is the most commonly chosen alternative. Resistant populations of Plasmodium falciparum were selected extremely rapidly in Southeast Asia and South America. If this happens in sub-Saharan Africa, it will be a public health disaster because no inexpensive alternative is currently available. This article reviews the molecular mechanisms of this resistance and discusses how to extend the therapeutic life of antifolate drugs.

Trends Parasitol 2001 Dec;17(12):570-1

Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next?

Sibley CH, Hyde JE, Sims PF, Plowe CV, Kublin JG, Mberu EK, Cowman AF, Winstanley PA, Watkins WM, Nzila AM.

Department of Genetics, Box 357360, University of Washington, 98195-7360, Seattle, WA, USA

Chemotherapy remains the only practicable tool to control falciparum malaria in sub-Saharan Africa, where >90% of the world's burden of malaria mortality and morbidity occurs. Resistance is rapidly eroding the efficacy of chloroquine, and the combination pyrimethamine-sulfadoxine is the most commonly chosen alternative. Resistant populations of Plasmodium falciparum were selected extremely rapidly in Southeast Asia and South America. If this happens in sub-Saharan Africa, it will be a public health disaster because no inexpensive alternative is currently available. This article reviews the molecular mechanisms of this resistance and discusses how to extend the therapeutic life of antifolate drugs.

Trends Parasitol 2001 Dec;17(12):563-5

Malaria vaccine trials in a wormy world.

Nacher M.

Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi road, 10400, Bangkok, Thailand

The promising malaria vaccine candidates that have been tested in the field have, so far, yielded disappointing and, at times, conflicting results. Considerable efforts are being made to isolate new immunogenic molecules. However, the fact that most populations in malaria endemic areas are also infected by helminths appears to be overlooked. Helminth-related hyporesponsiveness to tetanus or cholera vaccines, and the interactions between malaria parasites and helminths, raise the possibility that a potent malaria vaccine will not be identified in helminth-infected populations, thus necessitating a change in vaccine trial design.

Acta Trop 2002 Jan;81(1):33-46

Plasmodium falciparum merozoite surface protein 1 (MSP1): genotyping and humoral responses to allele-specific variants.

Ekala MT, Jouin H, Lekoulou F, Issifou S, Mercereau-Puijalon O, Ntoumi F.

Centre International de Recherches Medicales, Franceville (CIRMF) B.P. 769, Franceville, Gabon

The present study is the first to investigate Plasmodium falciparum merozoite surface protein 1 (MSP1) allele-specific humoral responses in residents of central Africa. In endemic areas, acquired immune responses to malaria are assumed to reflect the need to be infected with a large number of antigenically diverse parasite populations. In the work presented here, the relationship between antibody specificity and the infecting parasite genotype was investigated in asymptomatic subjects and patients with uncomplicated malaria in order to possibly clarify the relationship between anti-MSP1 block2 antibodies and clinical malaria. Overall isolates were typed by nested PCR using allele-specific primers of the P. falciparum MSP1 gene to identify the infecting parasite genotype. The K1 type was the predominant allelic family in both clinical groups. Polyinfection (number of isolates with more than one parasite genotype) and the complexity of infections (mean number of parasite genotype per infected subject) were higher in isolates from asymptomatic individuals. Total immunoglobulins G (IgG) responses to schizont crude extract antigens and to MSP1 variant-specific peptides were assessed by ELISA test. More than 90% of the sera reacted against schizont extract, whatever the clinical group and the K1 seroprevalence was the highest in both clinical groups. Our results showed an age-dependence in the number of different variants of MSP1 block2 recognised by serum. Indeed, isolates from older (>14 years) subjects showed lower multiplicity of infection and higher was the mean number of different MSP1 variants recognised by their serum. This corresponded to the age reported for the acquisition of anti-parasite immunity under high malaria endemicity. The contribution of variant-specific immunity in asymptomatic malaria infections is discussed.

Acta Trop 2002 Jan;81(1):13-9

Performance appraisal of rapid on-site malaria diagnosis (ICT malaria Pf/Pv test) in relation to human resources at village level in Myanmar.

Min-Naing C, Gatton ML.

Malaria Biology Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Qld 4029, Brisbane, Australia

Logistic, economic and technical factors limit rapid access to microscopic confirmation of symptomatic diagnosis of malaria in many rural areas in endemic countries such as Myanmar. A study was conducted to evaluate a rapid on-site immunochromatographic test (ICT Malaria Pf/Pv) for detection of Plasmodium falciparum and P. vivax in two villages in the Taikkyi region of Myanmar. The ICT Malaria tests were performed by a volunteer health worker (VHW) in Yae-Aye-San village and by a professionally trained midwife (MW) in Kankone village. A total of 1000 symptomatic patients participated in the study by providing blood samples for an ICT test and for microscopy. The ICT performance indices, relative to microscopy, were better for the trained MW compared with the less experienced VHW. For P. falciparum and/or P. vivax infections, the sensitivities were 82.7% for the VHW compared with 93.7% for the MW. For P. falciparum infections, the sensitivities were 82.2% for the VHW and 91.3% for the MW, while the corresponding values for P. vivax infections were 66.7 and 79%, respectively. Although the test kit appeared to perform better in more experienced hands, this study questions whether this difference is related to the use of the ICT Malaria Pf/Pv test kit, or related to other factors such as differences in the quality of blood slides prepared by the VHW and MW for microscopic examination. Overall, the results suggest that a rapid diagnostic assay such as the ICT Malaria Pf/Pv test kit can be used in rural settings by relatively inexperienced persons, such as VHWs, with a reasonable degree of sensitivity, thus providing on-site confirmation of symptomatic diagnosis of malaria.

Mol Biochem Parasitol 2002 Jan;119(1):63-73

Molecular characterization of dihydrofolate reductase in relation to antifolate resistance in Plasmodium vivax.

Leartsakulpanich U, Imwong M, Pukrittayakamee S, White NJ, Snounou G, Sirawaraporn W, Yuthavong Y.

National Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Rama 6 Road, 10400, Bangkok, Thailand

The genes encoding the wild-type and six (five single and one double) mutant dihydrofolate reductase (DHFR) domains of the human malaria parasite, Plasmodium vivax (Pv), were cloned and expressed in Escherichia coli. The catalytic activities and the kinetic parameters of the purified recombinant wild-type and the mutant PvDHFRs were determined. Generally, all the PvDHFR mutants yielded enzymes with poorer catalytic activities when compared to the wild type enzyme. The widely used antifolates, pyrimethamine and cycloguanil, were effective inhibitors of the wild-type PvDHFR, but were approximately 60 to >4000 times less active against the mutant enzymes. In contrast to the analogous S108N mutation of Plasmodium falciparum DHFR (PfDHFR), the single S117N mutation in PvDHFR conferred approximately 4000- and approximately 1600-fold increased resistance to pyrimethamine and cycloguanil, respectively, compared to the wild-type PvDHFR. The S58R+S117N double mutant PvDHFR was 10- to 25-fold less resistant than the S117N mutant to the inhibitors, but also exhibited higher k(cat)/K(m) value than the single mutant. The antifolate WR99210 was equally effective against both the wild-type and SP21 (S58R+S117N) mutant DHFRs, but was much less effective against some of the single mutants. Data on kinetic parameters and inhibitory constant suggest that the wild-type P. vivax is susceptible to antimalarial antifolates and that point mutations in the DHFR domain of P. vivax are responsible for antifolate resistance.


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