Social Sciences and Malaria

EHP Library Malaria Bulletin No. 36:  April 26-May 9, 2002

Social Sciences and Malaria

Bull World Health Organ 2002;80(3):251-2

The contribution of social science research to malaria prevention and control.

Williams HA, Jones C, Alilio M, Zimicki S, Azevedo I, Nyamongo I, Sommerfeld J, Meek S, Diop S, Bloland PB, Greenwood B.

Partnership for Social Sciences in Malaria Control.

Malaria in Sri Lanka: current knowledge on transmission and control.

Editors – Konradsen, F.; Amerasinghe, F. P.; Hoek, W. van der; Amerasinghe, P. H.

xiii + 77 pp.
Publication Year: 2000
Publisher: International Water Management Institute — Colombo, Sri
Lanka
ISBN: 92-9090-406-2

This book contains 5 chapters focusing on the following topics: (1)
epidemiology of malaria in Sri Lanka, including recent trends in the
number of malaria cases, cyclical pattern of epidemics, risk factors and relapse of Plasmodium vivax malaria; (2) entomology of anopheline mosquitoes in Sri Lanka, including biting and resting behaviour of Anopheles sp. in Sri Lanka, human biting rates, breeding sites of Anopheles culicifacies, and vector resistance against insecticides; (3) disease resistance and prospects for vaccine development; (4) malaria control, including diagnosis and treatment, health information system, chemoprophylaxis, vector control and malaria control policies; and (5) economic and social impacts of malaria, and the cost of malaria control

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BMC Int Health Hum Rights 2002 Apr 30;2(1):4

Paediatric referrals in rural Tanzania: the Kilombero District Study- a case series.

Font Sierra F, Quinto L, Masanja H, Nathan R, Ascaso C, Menendez C, Tanner M, Armstrong Schellenberg J, Alonso P.

Email: [email protected]

Abstract Background Referral is a critical part of appropriate primary care and of the Integrated Management of Childhood Illness (IMCI) strategy. We set out to study referrals from the aspect both of primary level facilities and the referral hospital in Kilombero District, southern Tanzania. Through record review and a separate prospective study we estimate referral rates, report on delays in reaching referral care and summarise the appropriateness of pediatric referral cases in terms of admission to the pediatric ward at a district hospital Methods A sample of patient records from primary level government health facilities throughout 1993 were summarised by age, diagnosis, whether a new case or a reattendance, and whether or not they were referred. From August 1994 to July 1995, mothers or carers of all sick children less than five years old attending the Maternal and Child Health (MCH) clinic or outpatient department (OPD) of SFDDH were interviewed using a standard questionnaire recording age, sex, diagnosis, place of residence, whether the child was admitted to the paediatric ward, and whether the child was referred. Results From record review, only 0.6% of children from primary level government facilities were referred to a higher level of care. At the referral hospital, 7.8 cases per thousand under five catchment population had been referred annually. The hospital MCH clinic and OPD were generally used by children who lived nearby: 91% (n=7,166) of sick children and 75% (n=607) of admissions came from within 10km. Of 235 referred children, the majority (62%) had come from dispensaries. Almost half of the referrals (48%) took 2 or more days to arrive at the hospital. Severe malaria and anaemia were the leading diagnoses in referred children, together accounting for a total of 70% of all the referrals. Most referred children (167/235, 71%) were admitted to the hospital paediatric ward. Conclusions The high admission rate among referrals suggests that the decision to refer is generally appropriate, but the low referral rate suggests that too few children are referred. Our findings suggest that the IMCI strategy may need to be adapted in sparsely-populated areas with limited transport, so that more children may be managed at peripheral level and fewer children need referral.

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Med Trop (Mars) 2001;61(6):495-9

Malaria survey of 162 households in the city of Bouake, Cote d’Ivoire

[Article in French]

Dossou-Yovo J, Amalaman K, Carnevale P.

L’Unite de recherche et de lutte contre le paludisme, Institut P. Richet/OCCGE, 01 BP 1500 Bouake 01, Cote d’Ivoire. 
Email: [email protected]

This survey of 162 households in the city of Bouake, Cote d’Ivoire was undertaken to study the behavior of the population in diagnosing and treating malaria. Findings indicate that awareness of symptoms and ability to evaluate the severity of malaria is high. In most cases, mild malaria is treated at home. In case of presumptive diagnosis of malaria, 87.6% of households undertake self-treatment, 9.3% seek institutional healthcare, 1.2% go to traditional healers, and 1.9% use traditional remedies. The most frequent drug for primary treatment is chloroquine (68.3%) which is generally obtained from pharmacies (98.8%). However, proper dosages are rarely used. If primary treatment fails, behavior is complex depending on the estimated severity of disease. Although many causes of malaria are mentioned, most people implicate mosquitoes (75.6%). In 95.1% of households surveyed, chloroquine prophylaxis was used for newborns. Most households (89.5%) practice mosquito bite protection but use of mosquito nets is low (4.9%). These results showing the preference for family-based management suggest that informational campaigns are needed to promote effective and consistent home treatment. Education is also needed to increase knowledge about mosquito nets and insecticides

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.PUBMED

Proc Natl Acad Sci U S A 2002 May 7 – http://www.pnas.org

Structure of 2C-methyl-D-erythritol 2,4- cyclodiphosphate synthase: An essential enzyme for isoprenoid biosynthesis and target for antimicrobial drug development.

Kemp LE, Bond CS, Hunter WN.

Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.

The crystal structure of the zinc enzyme Escherichia coli 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase in complex with cytidine 5′-diphosphate and Mn(2+) has been determined to 1.8-A resolution. This enzyme is essential in E. coli and participates in the nonmevalonate pathway of isoprenoid biosynthesis, a critical pathway present in some bacterial and apicomplexans but distinct from that used by mammals. Our analysis reveals a homotrimer, built around a beta prism, carrying three active sites, each of which is formed in a cleft between pairs of subunits. Residues from two subunits recognize and bind the nucleotide in an active site that contains a Zn(2+) with tetrahedral coordination. A Mn(2+), with octahedral geometry, is positioned between the alpha and beta phosphates acting in concert with the Zn(2+) to align and polarize the substrate for catalysis. A high degree of sequence conservation for the enzymes from E. coli, Plasmodium falciparum, and Mycobacterium tuberculosis suggests similarities in secondary structure, subunit fold, quaternary structure, and active sites. Our model will therefore serve as a template to facilitate the structure-based design of potential antimicrobial agents targeting two of the most serious human diseases, tuberculosis and malaria..

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J Assoc Physicians India 2001 Dec;49:1161-4

.Asymptomatic malarial parasitaemia in Tamil Nadu.

Rajendran P, Rajesh PK, Thyagarajan SP, Balakrishnan P, Hari R, Joyee AG, Kurien T, Krishnmurthy P, Jacob V; STD Study Group.

Department of Microbiology, Dr. AL Mudaliar Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai, Tamil Nadu.

AIM: The aim of the study was to determine the community prevalence of asymptomatic malarial parasitaemia in the state of Tamil Nadu. METHODS: Free medical camps were organised in three randomly selected districts of Tamil Nadu, namely Dindigul, Ramnad and Thanjavur districts in November, 1997. Proportionate to population size cluster survey method was followed to collect peripheral blood smear by finger prick from 30 clusters in each district. Fifteen households were randomly selected from each district with the target age group of 15-45 years. Peripheral blood smears were stained by Leishman’s stain and the slides were examined end to end by two independent experts to diagnose malarial parasites. RESULTS: The male:female ratio of the population studied was 1:1.6. Asymptomatic malaria was identified in 17 out of 569 individuals screened with a positive rate of 2.9% (CI 1.5-4.3). Out of the 17 malarial positive peripheral smears 15 were P. vivax and only two were P. falciparum with the predominance of gametocyte stage. CONCLUSION: This study reaffirms the prevalence of asymptomatic malaria in Tamil Nadu especially with P. vivax..

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J Assoc Physicians India 2001 Dec;49:1155-60

Multicentric clinical trials for safety and efficacy evaluation of alpha;beta arteether in complicated P. falciparum malaria.

Asthana OP, Srivastava JS, Pandey TK, Vishwanathan KA, Dev V, Mahapatra KM, Nayak NC, Balsara AB, Mandal OP, Gupta N, Mishra SK, Mohanty S, Sathpathy S, Das BS, Patnaik JK, Sathpathy SK, Dash B.

Central Drug Research Institute, Lucknow.

OBJECTIVE: To evaluate efficacy of alpha;beta arteether in patients of P. falciparum malaria presenting with complications was undertaken in a multicentric clinical trial. METHOD: Each patient who consented to undergo clinical trial with parenteral Arteether was treated with a fixed dose schedule of Arteether given intramuscularly in a dose of 150 mg once a day on three consecutive days. Every patient was followed upto 28 days with clinical, haematological and parasitological monitoring every day upto one week and thereafter at 14, 21 and 28 days. The response was assessed in terms of fever clearance time, parasite clearance time, cure rate and parasite reappearance rate. RESULTS: A total of 211 patients of P. falciparum malaria were included in the study from four centres (Bhilai, Guwahati, Jamshedpur and Rourkela). Results of this study showed that fever clearance time ranged between 24-168 hours, parasite clearance time ranged between 24-120 hours and overall mortality ranged between 4-8.5%. Out of 211, only 14 patients expired during the study, of these, 10 patients expired within first two days i.e. before completing the three day schedule of arteether therapy. Tolerability to arteether injection was good in all these patients and no untoward effects were experienced or reported during the study. Overall cure rate observed in these studies was 93%. CONCLUSION: This study shows a rapid parasite and fever clearance in patients of complicated P. falciparum malaria..

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Br J Clin Pharmacol 2002 May;53(5):492-500

Dose-finding and efficacy study for i.m. artemotil (beta-arteether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria.

Looareesuwan S, Oosterhuis B, Schilizzi BM, Sollie FA, Wilairatana P, Krudsood S, Lugt CB, Peeters PA, Peggins JO.

Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand, Pharma Bio-Research Group BV, Zuidlaren, the Netherlands, ARTECEF BV, Maarssen, the Netherlands and Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, DC 20307, USA.

AIMS: The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether. METHODS: In part I of the study three different artemotil dose regimens were explored in three groups of 6-9 patients for dose finding: 3.2 mg kg-1 on day 0 and 1.6 mg kg-1 on days 1-4 (treatment A), 1.6 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment B), 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment C). In part II of the study, artemotil treatments A and C were compared in three groups of 20-22 patients with standard i.m. artemether treatment: 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment R). RESULTS: Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P=0.0408) and for difference C vs R it was 2, 19 h (P=0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentration-time profiles of artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial artemotil plasma concentrations. Pharmacokinetic-pharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to artemotil during approximately the first 2 days of treatment, and suggested that artemotil has a slower rate of absorption than artemether. Safety assessment, including neurological and audiometric examinations showed no clinically relevant findings. Adverse events before and during treatment included headache, dizziness, nausea, vomiting and abdominal pain. These are characteristic of acute malaria infections and resolved during treatment. CONCLUSIONS: The optimum dose regimen for artemotil in this study was identical to the standard dose regimen of artemether. The findings that artemotil is more slowly absorbed from the i.m. injection site than artemether, and that early systemic availability may be insufficient for an immediate onset of parasite clearance contributed to the decision to choose a higher loading dose of artemotil (divided over two injection sites) and to omit the fifth dose in later studies. With this optimized dosing schedule, the more pronounced depot characteristics of i.m. artemotil can be an advantage, since it may allow shorter hospitalization.

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West Indian Med J 2001 Dec;50(4):319-21

Identification of Anopheles aquasalis as a possible vector of malaria in Guyana, South America.

Laubach HE, Validum L, Bonilla JA, Agar A, Cummings R, Mitchell C, Cuadrado RR, Palmer CJ.

College of Medical Sciences, Nova Southeastern University, 3200 South University Drive, Ft Lauderdale, FL 33328, USA.

Adult female mosquitoes were collected in Mahdia, Guyana, to determine the incidence of malaria in Anopheles species found during the month of June 2000. Centers for Disease Control miniature white (incandescent) light traps, model 512, and miniature black (ultraviolet) light traps, model 912, were used to capture female mosquitoes. Numbers of mosquitoes collected were compared between white and black light traps and between traps set outside and inside of buildings. Adult female Anopheles mosquitoes were identified and an ELISA dipstick test for Plasmodium vivax and Plasmodium falciparum was performed on each mosquito. An aquasalis, An oswaldoi, and An braziliensis were attracted to white light traps. An triannulatus and An darlingi were collected from black light traps. Approximately the same numbers of all female Anopheles mosquitoes 28/45 (62%) were caught inside buildings as outside. Numbers of female non-anopheles mosquitoes captured in light traps varied between the traps set outside of buildings and inside of buildings with bright light traps collecting 91/122 (75%). A total of 45 Anopheles mosquitoes were captured and 122 non-anopheles species. Of the two known vectors of malaria in Guyana, An darlingi mosquitoes were not infected with P vivax but An aquasalis was found to be a carrier. The findings of this study suggest a need for further surveying and identification of current malaria vectors in Guyana.

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J Infect Dis 2002 May 15;185(10):1538-41

Central role of the spleen in malaria parasite clearance.

Chotivanich K, Udomsangpetch R, McGready R, Proux S, Newton P, Pukrittayakamee S, Looareesuwan S, White NJ.

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

In acute malaria, red blood cells (RBCs) that have been parasitized, but no longer contain a malaria parasite, are found in the circulation (ring-infected erythrocyte surface antigen [RESA]-RBCs). These are thought to arise by splenic removal of dead or damaged intraerythrocytic parasites and return of the intact RBCs to the circulation. In a study of 5 patients with acute falciparum malaria who had previously undergone splenectomy, it was found that none of these 5 patients had any circulating RESA-RBCs, in contrast to the uniform finding of RESA-RBCs in all patients with acute malaria and intact spleens. Parasite clearance after artesunate treatment was markedly prolonged, although the parasites appeared to be dead and could not be cultured ex vivo. These observations confirm the central role of the spleen in the clearance of parasitized RBCs after antimalarial treatment with an artemisinin derivative. Current criteria for high-grade antimalarial drug resistance that are based on changes in parasitemia are not appropriate for asplenic patients.

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Ann Trop Med Parasitol 2002 Jan;96(1):75-82

Dynamics of the malaria-vector populations in coastal Lagos, south-western Nigeria.

Awolola TS, Okwa, Hunt RH, Ogunrinade AF, Coetzee M.

Public Health Division, Nigerian Institute of Medical Research, Lagos, Nigeria. Email: [email protected]

An entomological study was carried out in coastal Lagos, south-western Nigeria, to explore the role of Anopheles gambiae s.l. and An. moucheti in the transmission of Plasmodium falciparum in this holo-endemic area. Mosquitoes were caught, on human bait at night and by pyrethrum-spray catches during the day, twice a month throughout 2000. Of the 1812 Anopheles mosquitoes collected, An. gambiae s.l., the predominant vector species, represented 78.7% while the other 21.3% were An. moucheti. The results of a PCR-based test identified 56.8% of the mosquitoes of the An. gambiae complex collected as An. gambiae s.s., 36.9% as An. melas and 6.3% as An. arabiensis. Anopheles gambiae s.s. was predominantly recorded in the wet season, biting females being collected from May to October, with a peak in July. Anopheles melas and An. moucheti were present throughout the year-long study whereas An. arabiensis was mainly found in the dry season. The results of ELISA-based analyses of bloodmeals indicated that An. gambiae s.s., An. melas and An. moucheti were predominantly anthropophagic whereas An. arabiensis was largely zoophagic. Among all of the females investigated, 3.6% of the An. gambiae s.s., 1.9% of the An. melas, 1.8% of the An. moucheti and 0% of the An. arabiensis were found to be infected with P. falciparum (i.e. carrying the parasite’s circumsporozoite antigen). The corresponding proportions for the females collected during the dry season were 1.3%, 2.3%, 2.7% and 0%. The entomological inoculation rates for An. melas and An. moucheti were significantly higher during the dry season than at other times of the year. Taken together, these results indicate that An. melas and An. moucheti maintain transmission of P. falciparum during the dry season, while the biting population ofAn. gambiae s.s. is relatively small.

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Ann Trop Med Parasitol 2002 Jan;96(1):5-13

Intestinal helminths and malnutrition are independently associated with protection from cerebral malaria in Thailand.

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

Unite INSERM 511, Immunobiologie Cellulaire et Moleculaire des Infections Parasitaires, CHRU Pitie-Salpetriere, Paris, France. 
Email: [email protected]

Although human infection with Ascaris appears to be associated with protection from cerebral malaria, there are many potential socio-economic and nutritional confounders related to helminth infection that need to be considered. In a hospital-based study, 37 cases of cerebral malaria and 61 cases of non-severe malaria with high parasite biomass (i.e. hyperparasitaemia and/or circulating schizonts) answered a structured questionnaire and were screened for intestinal helminths. Logistic regression was then used to adjust for the potential confounders. The adjusted odds ratios (OR) and their 95% confidence intervals (CI) still showed a significant protective association for helminths (OR = 0.24; CI = 0.07-0.78, P = 0.02) and malnutrition (OR = 0.11; CI = 0.02-0.58; P = 0.01), with no evidence of interaction between the two. There was also a significant dose-effect trend for the helminth infections (P = 0.048). These results, despite coming from a hospital-based study, indicate that the apparent association between helminths and protection from cerebral malaria is not the result of socio-economic or nutritional confounders.

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Ann Trop Med Parasitol 2002 Jan;96(1):15-8

Multicentre study, in patients with imported malaria, on the sensitivity and specificity of a dipstick test (ICT Malaria P.f./P.v.) compared with expert microscopy.

Gatti S, Bernuzzi AM, Bisoffi Z, Raglio A, Gulletta M, Scaglia M; The Lombardy Region’s Study Group on International Health (SIRL).

Laboratory of Parasitology, Virology Service, IRCCS Policlinico San Matteo, Pavia, Italy

A prospective, multicentre study was carried out in Italy to assess the sensitivity and specificity of a rapid dipstick test (ICT Malaria P.f./P.v.) in the diagnosis of imported malaria caused by Plasmodium falciparum and other Plasmodium spp. The test is based on the detection of histidine-rich protein-2 (HRP-2) from P. falciparum and ‘panmalarial’ antigen in peripheral blood. The 241 subjects were international travellers or immigrants from areas where malaria is endemic. When compared with the microscopical examination of bloodsmears (used as the ‘gold standard’), the dipsticks were found to be 94.4% sensitive and 94.5% specific for pure infections with P. falciparum. The performance of the tests when used on patients infected with species other than P. falciparum or more than one Plasmodium spp. showed a high degree of variability. Although the dipsticks represent a very simple, rapid, and valuable diagnostic aid, they should not be considered a complete substitute for direct microscopical diagnosis using stained bloodsmears.

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Clin Diagn Lab Immunol 2002 May;9(3):720-722

Increased Levels of Soluble CD30 in Plasma of Patients with Plasmodium falciparum Malaria.

Kemp K, Kurtzhals JA, Akanmori BD, Adabayeri V, Goka BQ, Behr C, Hviid L.

Center for Medical Parasitology, Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), and Institute for Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark. Immunology Unit, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon. Department of Child Health, Korle-Bu Teaching Hospital, University of Ghana Medical School, Accra, Ghana. Unite d’Immunologie Moleculaire des Parasites, CNRS URA 1960, Institut Pasteur, Paris, France.

Levels of soluble CD30 (sCD30) in serum were elevated in patients with Plasmodium falciparum malaria but showed decline following treatment. The levels of sCD30 in serum were correlated significantly with the expression of gamma interferon by peripheral T cells. These data suggest that CD30(+) cells are upregulated during a malaria attack and that they may play a regulating role at the site of inflammation.

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Blood 2002 May 15;99(10):3863-6

Aotus New World monkeys: model for studying malaria-induced anemia.

Egan AF, Fabucci ME, Saul A, Kaslow DC, Miller LH.

Malaria Vaccines Section and Malaria Vaccine Development Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Falciparum malaria is a major cause of disease and death in African children and pregnant women, primarily due to severe anemia. We studied anemia in vaccinated Aotus monkeys during a second infection where the animals were considered to be semi-immune. Most animals had extremely low or undetectable levels of parasitemia; in some, anemia did not develop and reticulocytemia remained unchanged; in others, moderate to severe anemia developed with inappropriately low reticulocytemia indicating bone marrow dysfunction. Bone marrow rapidly responded after parasite clearance. The rapid drop in hematocrit despite extremely low to undetectable parasitemia indicated massive removal of uninfected red blood cells from the circulation that, in the presence of bone marrow dysfunction, led to severe anemia-the problem that occurs in African children. We demonstrate that Aotus monkeys are a nonhuman primate model to gain insight into the pathogenesis of severe anemia in African children. (Blood. 2002;99:3863-3866)

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Mol Biochem Parasitol 2002 Apr 30;121(1):21-31

Antibodies raised against receptor-binding domain of Plasmodium knowlesi Duffy binding protein inhibit erythrocyte invasion.

Singh AP, Puri SK, Chitnis CE.

Malaria Research Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), P.O. Box 10504, Aruna Asaf Ali Marg, 110067, New Delhi, India

Erythrocyte invasion by malaria parasites requires specific receptor-ligand interactions. Plasmodium vivax and Plasmodium knowlesi are completely dependent on binding the Duffy blood group antigen to invade human erythrocytes. P. knowlesi invades rhesus erythrocytes by multiple pathways using the Duffy antigen as well as alternative receptors. Plasmodium falciparum binds sialic acid residues on glycophorin A as well as other sialic acid-independent receptors to invade human erythrocytes. Parasite proteins that mediate these interactions belong to a family of erythrocyte binding proteins, which includes the P. vivax Duffy binding protein, 175 kDa P. falciparum erythrocyte binding antigen (EBA-175), P. knowlesi alpha protein, which binds human and rhesus Duffy antigens, and P. knowlesi beta and gamma proteins, which bind Duffy-independent receptors on rhesus erythrocytes. The receptor-binding domains of these proteins lie in conserved, N-terminal, cysteine-rich regions that are referred to as region II. Here, we have examined the feasibility of inhibiting erythrocyte invasion with antibodies directed against receptor-binding domains of erythrocyte binding proteins. Region II of P. knowelsi alpha protein (PkalphaRII), which binds the Duffy antigen, was expressed as a secreted protein in insect cells and purified from culture supernatants. Rabbit antibodies raised against recombinant PkalphaRII were tested for inhibition of erythrocyte binding and invasion. Antibodies raised against PkalphaRII inhibit P. knowlesi invasion of both human and rhesus erythrocytes. These data provide support for the development of recombinant vaccines based on the homologous binding domains of P. vivax Duffy binding protein and P. falciparum EBA-175.

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Trends Parasitol 2002 May;18(5):224-30

Combating malaria in Africa.

Trape JF, Pison G, Spiegel A, Enel C, Rogier C.

Institut de Recherche pour le Developpement (IRD, formerly ORSTOM), BP 1386, Dakar, Senegal

The spread of antimalarial drug resistance has major consequences for malaria control in tropical Africa. Here, the impact of chloroquine resistance on the burden of malaria is analyzed and its implications for the Roll Back Malaria initiative are examined. Malaria mortality has increased at least twofold during the past two decades. Combination therapy should be available for home treatment of young children. The potential toxicity of most antimalarials will require special surveillance programs. The main contribution to malaria control using methods to reduce the entomological inoculation rate is expected in areas with low or unstable transmission. Classic vector-control methods could potentially eliminate malaria in most urban areas and such programs deserve high priority.

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J Immunol Methods 2002 Apr 1;262(1-2):129-36

Comparison of murine Epo ELISA and Epo bioassays in detecting serum Epo levels during anemia associated with malaria infection.

Chang KH, Stevenson MM.

Institute of Parasitology, Macdonald Campus, McGill University, 21, 111 Lakeshore Road, Ste-Anne-de-Bellevue, H9X 1C9, Quebec, Canada

A highly sensitive sandwich ELISA specific for murine erythropoietin (mEpo) was developed using commercially available monoclonal anti-mouse Epo antibody and polyclonal anti-human Epo antibody. This newly developed Epo ELISA protocol and the traditional Epo bioassay method were used to analyze Epo production in response to anemia induced during blood-stage Plasmodium chabaudi AS (P. chabaudi AS) malaria infection in C57BL/6 mice. Both methods revealed an inverse correlation between the serum Epo concentration and hematocrit level, but Epo values estimated by the Epo bioassay were between 5- and 20-fold higher than those estimated by the ELISA. Further study demonstrated that the estimated Epo level in bioassay was strongly influenced by other cytokines present in the samples. Therefore, the Epo bioassay detects the net erythropoiesis promoting activities, whereas the ELISA method specifically measures the level of Epo in the samples. Combined with the Epo bioassay, the murine Epo ELISA will be an extremely useful tool in specifically measuring the Epo response and facilitating the understanding of mechanisms involved in the development of anemia-associated diseases using mouse models.

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Parasite Immunol 2002 Mar;24(3):131-40

The influence of gammadelta T cells on the CD4+ T cell and antibody response during a primary Plasmodium chabaudi chabaudi infection in mice.

Seixas E, Fonseca L, Langhorne J.

Division of Parasitology, National Institute for Medical Research, Mill Hill, London, UK.

A primary infection with Plasmodium chabaudi chabaudi (AS) is characterized by an expansion of gammadelta cells after the acute phase of infection in mice. This is particularly marked during chronic infections in B cell-deficient mice. Infections in gammadelta T cell-deficient mice suggest that, although these cells play some role in the control of parasitaemia and can produce interferon-gamma, they do not appear to be involved in the development of hypoglycaemia, loss of weight and temperature during a P. c. chabaudi infection. However, gammadelta T cells do influence the nature of the CD4+ T cell response during infection since, in their absence, Th2-like responses, such as interleukin (IL)-4 production and help for malaria-specific antibody responses, are more pronounced. This alteration in CD4+ T cells is reflected in a more rapid and greater immunoglobulin (Ig)G1 and IgG3 antibody response to the parasite. The large gammadelta T cell expansion normally observed in infected B cell-deficient mice did not take place in the absence of IL-2, and double-knockout mice lacking both B cells and functional IL-2 were highly susceptible to lethal infection with P. c. chabaudi. The majority of the single IL-2 knockout mice, in contrast, were able to control and clear a primary infection, suggesting that for the CD4+ T cell and antibody response, IL-2 could be replaced by other cytokines.

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Clin Infect Dis 2002 May 15;34(10):1317-22

Malaria in injection drug abusers in Vietnam.

Chau TT, Mai NT, Phu NH, Luxemburger C, Chuong LV, Loc PP, Trang TT, Vinh H, Cuong BM, Waller DJ, Sinh DX, Day NP, Hien TT, White NJ.

Centre for Tropical Diseases, Ho Chi Minh City, Vietnam. 
Email: [email protected]

A prospective case-control study was conducted in a referral hospital in Ho Chi Minh City, Vietnam, to compare the clinical and laboratory features and outcome of severe falciparum malaria in injection drug abusers (IDAs) with those of patients who had acquired malaria by mosquito bite. From 1991 to 1996, 70 IDAs were admitted to the hospital, of whom at least 32 had acquired malaria by needle sharing. Although IDAs were more likely than control patients with severe malaria to be malnourished and to have coincident hepatitis B, hepatitis C, and human immunodeficiency virus infections, the overall rates of mortality, complications, and recovery were similar in the 2 groups. The route of malaria acquisition did not affect the outcome of severe malaria. The management of severe malaria in IDAs is similar to that for other patients.

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J Clin Microbiol 2002 May;40(5):1854-7

Microsatellite characterization of Plasmodium falciparum from cerebral and uncomplicated malaria patients in southern Vietnam.

Ferreira MU, Nair S, Hyunh TV, Kawamoto F, Anderson TJ.

Department of Parasitology, Institute for Biomedical Sciences, University of Sao Paulo, Av. Prof. lineu Prestes 1374, 05508-900 Sao Paulo (SP), Brazil. [email protected]

If parasite genotype influences the clinical course of malaria, we expect that isolates from patients with similar pathology would be more closely related than would be expected by chance. To explore this prediction, we typed nine microsatellite markers in sympatric Plasmodium falciparum isolates from cerebral and uncomplicated malaria patients from Vietnam. Temporal structure and linkage disequilibrium were also examined in this data set.

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Med Trop (Mars) 2001;61(6):463-9

Effective control of malaria vectors requires precise identification of species.

[Article in French]

Manguin S, Mouchet J, Coosemans M.

Centre de Biologie et Gestion des Populations (CBGP), IRD-Montpellier, France. 
Email: [email protected]

Effective control of malaria vectors requires precise identification of species. This is especially important within complexes of species that cannot be distinguished based on morphological features. Two methods based on polymerase chain reaction (PCR) analysis have been developed to identify 2 species in the Anopheles minimus complex and 5 species of the Minimums group as well as 4 species of the Anopheles dirus complex. Association of oligonucleotide couples in the form of multiplex PCR has allowed development of two simple, reliable PCR techniques adapted to each one of these species complexes that comprise the major vectors of malaria in Southeast Asia. Specifically designed to meet the needs of entomologist working in the field for reliable, cost-effective tests, these techniques will facilitate assessment of the geographical distribution of each vector. These data will help to better target vector control measures.

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In Vivo 2002 Jan-Feb;16(1):67-70

Antagonist effect of chloroquine and tumor necrosis factor on hepatic oxidative stress and antioxidant defense in normal and Plasmodium yoelii nigeriensis-infected mice.

Siddiqi NJ, Alhomida AS, Dutta GP, Pandey VC.

Department of Biochemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. 
Email: [email protected]

BACKGROUND: Plasmodium yoelii nigeriensis (P. y. nigeriensis) produces lethal malaria infection in Swiss albino mice. Tumor necrosis factor (TNF) has been implicated in the pathogenesis of malaria by production of reactive oxygen species. Chloroquine is a traditionally used antimalarial and has been postulated to inhibit TNF secretion during malaria infection. OBJECTIVE: The study the comparative effect of chloroquine and TNF treatment on hepatic oxidative stress and antioxidant defense indices in normal and P. y. nigeriensis-infected mice. MATERIALS AND METHODS: The mice were divided into six groups, each consisting of four to six animals. They were normal mice, normal mice treated with chloroquine, normal mice treated with TNF-alpha, P. y. nigeriensis-infected mice, P. y. nigeriensis-infected mice treated with chloroquine and P. y. nigeriensis-infected mice treated with TNF-alpha. RESULTS: Chloroquine treatment of the normal mice caused no significant alterations in hepatic oxidative stress and antioxidant defense indices while TNF treatment of normal mice caused a significant decrease in hepatic superoxide dismutase. Chloroquine treatment of P. y. nigeriensis-infected mice caused a decrease in blood parasitemia which was accompanied by restoration of altered indices to near normal levels. However, TNF treatment of P. y. nigeriensis-infected mice had no effect on blood parasitemia but caused a significant increase of hepatic xanthine oxidase and lipid peroxidation and a decrease in the activity of hepatic superoxide dismutase. CONCLUSION: Exogenous TNF acts synergistically with P. y. nigeriensis infection to generate oxidative stress in the host and also causes an impairment of the antioxidant defense enzyme SOD, while chloroquine treatment reduces the severity of malaria infection by decreasing the blood parasitemia and also perhaps by inhibiting the TNF release.

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Pathol Biol (Paris) 2002 Apr;50(3):184-8

A comparative study of the in vivo sensitivity of Plasmodium falciparum to amodiaquine versus chloroquin

[Article in French]

Yavo W, Menan EI, Adjetey TA, Barro-Kiki PC, Nigue L, Konan YJ, Nebavi NG, Kone M.

Departement de parasitologie-mycologie, UFR des sciences pharmaceutiques et biologiques, 01 BPV 34 Abidjan, Cote d’Ivoire. 
Email: [email protected]

A comparative study of the in vivo sensitivity of Plasmodium falciparum to amodiaquine versus chloroquine has been made among children in Agou (south Cote d’Ivoire). In case of resistance to these drugs, the association of sulfadoxine-pyrimethamine was administered and followed by a J14 checking. We have noticed: (1) 8.47% of amodiaquinoresistance versus 36.96% of chloroquinoresistance (all these resistances are from type II), (2) a good clinical efficiency of the 4 amino quinoleines. Only 1.69% of the subjects having resistant stocks to amodiaquine have gone feverish down to J7 whereas 10.47% of subjects have clinically resisted to chloroquine, (3) a good tolerance of drugs and an excellent clinical and parasitological efficiency of the second intention treatment. These data are in favour of using first the 4 amino quinoleines (particularly the amodiaquine) in the treatment of simple bout of malaria to Plasmodium falciparum in this region. In case of resistance to these drugs, we recommend the couple sulfadoxine-pyrimethamine.

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QJM 2002 May;95(5):285-90

A pilot study of N-acetylcysteine as adjunctive therapy for severe malaria.

Watt G, Jongsakul K, Ruangvirayuth R.

Department of Retrovirology, USAMC, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, and the. Department of Internal Medicine, Maesod Hospital, Thailand.

BACKGROUND: The case fatality rate of severe malaria remains unacceptably high. N-acetylcysteine (NAC) is a safe compound that inhibits tumour necrosis factor (TNF) and impedes cytoadherence, both of which have been implicated in the pathogenesis of malaria complications. Aim: To evaluate NAC as adjunctive therapy in severe malaria. DESIGN: A placebo-controlled, double-blind prospective study, with serum lactate level as the principal objective measure of response. METHODS: Thirty adult males with severe, quinine-treated malaria received either 300 mg/kg of NAC or placebo, over 20 h. RESULTS: Serum lactate levels normalized twice as quickly after NAC (median 21 h, 95%CI 12-36 h) as after placebo (median 42 h, 95%CI 30-84 h; p=0.002, Mann-Whitney U test). Twenty-four hours after admission, 10/15 (67%) NAC-group patients but only 3/15 (20%) placebo-group patients had normal lactate concentrations (p=0.01, Fisher exact test). NAC-treated patients could be switched from intravenous to oral therapy earlier than individuals who received placebo (42 h vs. 51 h after admission) but the difference was not significant (p=0.28, Mann-Whitney U test). DISCUSSION: NAC’s mechanism of action in malaria is unclear, since it did not markedly alter plasma cytokine profiles. Trials of NAC adjunctive therapy for complicated malaria, with mortality as an endpoint, appear to be warranted.

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Arch Dis Child Fetal Neonatal Ed 2002 May;86(3):F182-F187

Changes in haemoglobin levels in infants in Malawi: effect of low birth weight and fetal anaemia.

Le Cessie S, Verhoeff FH, Mengistie G, Kazembe P, Broadhead R, Brabin BJ.

Department of Medical Statistics, Leiden University Medical Centre, The Netherlands Department of Paediatrics Department of Paediatrics, Lilongwe Central Hospital, Lilongwe, Malawi Department of Paediatrics, Queen Elizabeth Central Hospital, Blantyre, Malawi Emma Kinderziekenhuis, Academic Medical Centre, Amsterdam, The Netherlands and Tropical Child Health Group, Liverpool School of Tropical Medicine, Liverpool, UK.

Objectives: To examine the effect of low birth weight (LBW) and fetal anaemia (FA) on haemoglobin (Hb) patterns in infancy. To study the additional contribution of other risk factors known at birth. To examine the effect of iron supplementation during infancy on Hb levels. Methods: A stratified cohort of infants in Malawi (83 with LBW (< 2500 g), 111 with FA (cord Hb < 125 g/l), 31 with both LBW and FA, and 176 controls) was followed during infancy. Hb levels were measured at about 2, 4, 6, 9, and 12 months of age. Repeated measures models were used to describe the changes in Hb levels over time. Results: The mean Hb concentration in the control group was 95.5 g/l (95% confidence interval (CI) 92.5 to 98.5) at 2 months, 86.9 g/l (95% CI 84.4 to 89.4) at 9 months, and 898 g/l (95% CI 874 to 92.2) at 12 months. Differences between LBW infants and controls increased over time (difference at 12 months: 5.5 g/l (95% CI 1.3 to 9.7)). Infants with FA had borderline significantly lower Hb at 2 months (p = 0.07), but at 6 months their levels were similar to those of controls. The LBW infants and those with FA had the lowest Hb levels (difference from controls at 12 months 7.9 g/l). Parity, placental and maternal malaria at delivery, and sex significantly affected Hb levels after adjustment for LBW and FA. After iron supplementation, Hb significantly increased. Conclusions: Antimalarial control and iron supplementation throughout pregnancy should be increased to reduce the incidence of infant anaemia and improve child development and survival.

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Lancet 2002 Apr 20;359(9315):1404-6

Mechanism of protection induced by vitamin A in falciparum malaria.

Serghides L, Kain KC.

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

Supplementation with vitamin A potentiates host resistance to malaria, however, the underlying mechanism is unknown. We tested the effects of 9-cis-retinoic acid, a metabolite of vitamin A, on CD36 expression, non-opsonic phagocytic clearance of parasitised erythrocytes, and TNFalpha production in human monocytes and macrophages. We found reduced secretion of TNFalpha, upregulated CD36 expression, and increased phagocytosis of Plasmodium falciparum-parasitised erythrocytes. Increased parasite clearance and reduced proinflammatory cytokine responses to infection might partly explain the beneficial effects of supplementation with vitamin A in malaria.

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Lancet 2002 Apr 20;359(9315):1365-72

Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomised, multicentre trial.

Adjuik M, Agnamey P, Babiker A, Borrmann S, Brasseur P, Cisse M, Cobelens F, Diallo S, Faucher JF, Garner P, Gikunda S, Kremsner PG, Krishna S, Lell B, Loolpapit M, Matsiegui PB, Missinou MA, Mwanza J, Ntoumi F, Olliaro P, Osimbo P, Rezbach P, Some E, Taylor WR.

Navrongo Health Research Centre, Navrongo, Ghana.

BACKGROUND: Increasing drug resistance limits the choice of efficacious chemotherapy against Plasmodium falciparum malaria in Africa. Amodiaquine still retains efficacy against P falciparum in many African countries. We assessed the safety, treatment efficacy, and effect on gametocyte carriage of adding artesunate to amodiaquine in three randomised trials in Kenya, Senegal, and Gabon. METHODS: We enrolled 941 children (400 in Kenya, 321 in Senegal, and 220 in Gabon) who were 10 years or older and who had uncomplicated P falciparum malaria. Patients were randomly assigned amodiaquine (10 mg/kg per day for 3 days) plus artesunate (4 mg/kg per day for 3 days) or amodiaquine (as above) and placebo (for 3 days). The primary endpoints were parasitological cure rates at days 14 and 28. Analysis was by intention to treat and by an evaluability method. FINDINGS: Both regimens were well tolerated. Six patients in the amodiaquine-artesunate group and five in the amodiaquine group developed early, drug-induced vomiting, necessitating alternative treatment. By intention-to-treat analysis, the day-14 cure rates for amodiaquine-artesunate versus amodiaquine were: 175/192 (91%) versus 140/188 (74%) in Kenya (D=16.7% [95% CI 9.3-24.1], p<0.0001), 148/160 (93%) versus 147/157 (94%) in Senegal (-1.1% [-6.7 to 4.5], p=0.7), and 92/94 (98%) versus 86/96 (90%) in Gabon (8.3% [1.5-15.1], p=0.02). The corresponding rates for day 28 were: 123/180 (68%) versus 75/183 (41%) in Kenya (27.3% [17.5-37.2], p<0.0001), 130/159 (82%) versus 123/156 (79%) in Senegal (2.9% [-5.9 to 11.7], p=0.5), and 80/94 (85%) versus 70/98 (71%) in Gabon (13.7% [2.2-25.2], p=0.02). Similar rates were obtained by evaluability analysis. INTERPRETATION: The combination of artesunate and amodiaquine improved treatment efficacy in Gabon and Kenya, and was equivalent in Senegal. Amodiaquine-artesunate is a potential combination for use in Africa. Further investigations to assess the potential effect on the evolution of drug resistance, disease transmission, and safety of amodiaquine-artesunate are warranted.

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J Biol Chem 2002 Apr 25 – http://www.jbc.org

Processing of an apicoplast leader sequence in Plasmodium falciparum, and the identification of a putative leader cleavage enzyme.

Van Dooren GG, Su V, DiOmbrain MC, McFadden GI.

Plant Cell Biology Research Centre, School of Botany, University of Melbourne, School of Botany, Parkville, Victoria 3010.

The plastid (apicoplast) of the malaria-causing parasite Plasmodium falciparum was derived via a secondary endosymbiotic process. As in other secondary endosymbionts, numerous genes for apicoplast proteins are located in the nucleus and the encoded proteins are targeted to the organelle courtesy of a bipartite N-terminal extension. The first part of this leader sequence is a signal peptide that targets proteins to the secretory pathway. The second, so-called transit peptide region is required to direct proteins from the secretory pathway across the multiple membranes surrounding the apicoplast. In this paper we perform a pulse-chase experiment and N-terminal sequencing to show that the transit peptide of an apicoplast-targeted protein is cleaved, presumably upon import of the protein into the apicoplast. We identify a gene whose product likely performs this cleavage reaction, namely a stromal processing peptidase (SPP) homologue. In plants SPP cleaves the transit peptides of plastid-targeted proteins. The Plasmodium falciparum SPP homologue contains a bipartite N-terminal apicoplast-targeting leader. Interestingly, it shares this leader sequence with a delta-aminolevulinic acid dehydratase (ALAD) homologue via an alternative splicing event.

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J Nat Prod 2002 Apr 26;65(4):614-615

Efficacy of Scopadulcic Acid A against Plasmodium falciparum in Vitro.

Riel MA, Kyle DE, Milhous WK.

Department of Parasitology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910-7500.

Scoparia dulcis is a perennial herb widely distributed in many tropical countries. It is used as an herbal remedy for gastrointestinal and many other ailments, and in Nicaragua extracts are used to treat malaria. Phytochemical screening has shown that scopadulcic acid A (SDA), scopadulcic acid B (SDB), and semisynthetic analogues are pharmacologically active compounds from S. dulcis. SDB has antiviral activity against Herpes simplex virus type 1, antitumor activity in various human cell lines, and direct inhibitory activity against porcine gastric H(+), K(+)-ATPase. A methyl ester of scopadulcic acid B showed the most potent inhibitory activity against gastric proton pumps of 30 compounds tested in one study. Compounds with antiviral, antifungal, and antitumor activity often show activity against Plasmodium falciparum. In P. falciparum, the plasma membrane and food vacuole have H(+)-ATPases and the acidocalcisome has an H(+)-Ppase. These proton pumps are potential targets for antimalarial therapy and may have their function disrupted by compounds known to inhibit gastric proton pumps. We tested pure SDA and found in vitro activity against P. falciparum with an IC(50) of 27 and 19 &mgr;M against the D6 and W2 clones, respectively. The IC(50) against the multidrug-resistant isolate, TM91C235, was 23 &mgr;M..