Library Malaria Bulletin No. 18: July 31-Aug 9, 2001
Sciences and Malaria
Trans R Soc Trop Med Hyg 2001 May-Jun;95(3):233-8
Vector-borne infections in the tropics and
health policy issues in the twenty-first century.
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool
L3 5QA, UK.
Over the past 2 decades scientific advances and evolving
strategies have significantly contributed to improved tools for
control of vector-borne infections. These are:
diagnostics--rapid assessment methods, non-invasive or minimally
so yet sensitive and specific; new chemotherapeutics; pyrethroid
insecticides and biological insecticidal products; refined
strategies, such as combination therapy, rotation of
insecticides for resistance management, community-directed
treatment, standardized monitoring and evaluation to define
programme progress; better epidemiological knowledge through
improved identification of parasites and vectors; GIS, remote
sensing and climate models which provide tools for epidemic
prediction, planning control programmes and permit effective
policy analysis; greater involvement of NGDOs (non-governmental
development organizations) and CSOs (civil society
organizations) in control; advent of donation programmes which
involve community-based or directed mass drug distribution.
Future problems could be: (1) the over-emphasis on inflexible
financing by the insistence of donors on SWAps (sector-wide
investment), (2) the over-reliance on pyrethroid pesticides, (3)
the over-expectation that basic research will provide new drugs
and vaccines for resource-poor settings in the necessary time
scales, and (4) the failure to recognize that biological
processes have an inherent capacity for change which outstrips
the capacity of health services to respond. Malaria is a
paradigm of an 'emerging disease'. (5) The challenge of
implementing a 'vertical' approach to disease control within
national health programmes, in the face of significant donor
opposition to such programmes is a challenge even when such
approaches will secure a 'public good'.
Niger Postgrad Med J 2001 Mar;8(1):1-6
Knowledge and Management of Malaria in under
Five Children by Primary Health Care Workers in Ibadan
South-East Local Government Area.
Fawole OI, Onadeko MO.
Department of Preventive and Social Medicine, College Of
Medicine, University of Ibadan, lbadan, Nigeria.
The results of a survey of the knowledge and management
practices of 61 health workers in five primary health care
facilities in Ibadan South-east LGA are presented. In addition,
30 health workers were observed as they managed children with
fever and the parasite status of 92 children diagnosed to have
malaria was determined. Results revealed that 62(67.4%) children
had the malaria parasite. Knowledge of some basic concepts was
fairly adequate as the majority 46(75.401o) knew the cause of
malaria. Treatment practices were poor as only 34(55.7010) and
39(63.9%) health workers respectively prescribed chloroquine and
paracetamol correctly. Observation revealed that history taking
and physical examinations were rudimentary. Scores out of 100 on
correct prescriptions of chloroquine and paracetamol were 60.1
and 76.8 respectively. There is an urgent need for periodic
education programmes, especially for health workers with many
years of experience to help them maintain clinical skills and
refresh their knowledge.
J Infect Dis 2001 Sep 1;184(5):627-32
The influence of placental malaria
infection and maternal hypergammaglobulinemia on transplacental
transfer of antibodies and igg subclasses in a rural west
Okoko BJ, Wesumperuma LH, Ota MO, Pinder M, Banya W, Gomez
SF, McAdam KP, Hart AC.
Vaccine Trial Unit, Medical Research Council, Fajara, Banjul,
The Gambia, West Africa.
Two hundred thirteen mother-baby pairs in The Gambia were
studied to determine the influence of placental malaria
infection and maternal hypergammaglobulinemia on transplacental
antibody transfer. Antibody transfer for herpes simplex virus 1
(HSV-1), respiratory syncytial virus (RSV), and varicella-zoster
virus (VZV) was significantly reduced by placental malaria
infection by 69%, 58%, and 55%, respectively. Maternal
hypergammaglobulinemia was associated with a significant
reduction in antibody transfer for HSV-1, RSV, VZV, and
pneumococcus by 89%, 90%, 91%, and 88%, respectively. In
addition, placental malaria infection was associated with a
significant reduction in transfer of IgG1, IgG2, and IgG4
(P<.01, P=.01, and P=.03, respectively) but not of IgG3
(P=.59). Maternal hypergammaglobulinemia significantly impaired
the transfer of IgG1 and IgG2 (P=.01) but not of IgG3 or IgG4
(P=.62 and P=.59, respectively). Placental malaria infection and
maternal hypergammaglobulinemia were associated with reduction
in the transplacental transfer of these specific antibodies,
IgG1, and IgG2 in this Gambian population.
J Infect Dis 2001 Sep 1;184(5):618-26
Acquisition and Decay of Antibodies to
Pregnancy-Associated Variant Antigens on the Surface of
Plasmodium falciparum-Infected Erythrocytes That Protect against
Staalsoe T, Megnekou R, Fievet N, Ricke CH, Zornig HD, Leke
R, Taylor DW, Deloron P, Hviid L.
Centre for Medical Parasitology, Copenhagen University Hospital
(Rigshospitalet) and Institute for Medical Microbiology and
Immunology, University of Copenhagen, 2200 Copenhagen N,
Otherwise clinically immune women in areas endemic for malaria
are highly susceptible to Plasmodium falciparum malaria during
their first pregnancy. Pregnancy-associated malaria (PAM) is
characterized by placental accumulation of infected erythrocytes
that adhere to chondroitin sulfate A (CSA). Susceptibility to
PAM decreases with increasing parity, apparently due to
acquisition of antibodies directed against the variant surface
antigens (VSAs) that mediate the adhesion to CSA (VSA(CSA)).
This study found that levels of VSA(CSA)-specific antibodies
depend on endemicity, that anti-VSA(CSA) IgG is acquired during
gestation week 20, and that plasma levels of the antibodies
decline during the postpartum period. There is evidence that
VSA(CSA)-specific antibodies are linked to placental infection
and that high antibody levels contribute to the control of
placental infection by inhibiting parasite adhesion to CSA. Data
suggest that VSA(CSA) is a target for vaccination against PAM.
Proc Natl Acad Sci U S A 2001 Aug 7 [epub ahead of print]
Exploring the transcriptome of the malaria
Kappe SH, Gardner MJ, Brown SM, Ross J, Matuschewski K,
Ribeiro JM, Adams JH, Quackenbush J, Cho J, Carucci DJ, Hoffman
SL, Nussenzweig V.
Michael Heidelberger Division, Department of Pathology, Kaplan
Cancer Center, New York University School of Medicine, New York,
NY 10016; The Institute for Genomic Research, 9712 Medical
Center Drive, Rockville, MD 20850; Research Computing Resource,
New York University Medical Center, New York, NY 10016; Medical
Entomology Section, Laboratory of Parasitic Diseases, National
Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, MD 20892-0425; Department of
Biological Sciences, University of Notre Dame, Notre Dame, IN
46556; Malaria Program, Naval Medical Research Center, Silver
Spring, MD 20910; and Celera Genomics, 45 West Gude Drive,
Rockville, MD 20850.
Most studies of gene expression in Plasmodium have been
concerned with asexual and/or sexual erythrocytic stages.
Identification and cloning of genes expressed in the
preerythrocytic stages lag far behind. We have constructed a
high quality cDNA library of the Plasmodium sporozoite stage by
using the rodent malaria parasite P. yoelii, an important model
for malaria vaccine development. The technical obstacles
associated with limited amounts of RNA material were overcome by
PCR-amplifying the transcriptome before cloning. Contamination
with mosquito RNA was negligible. Generation of 1,972 expressed
sequence tags (EST) resulted in a total of 1,547 unique
sequences, allowing insight into sporozoite gene expression. The
circumsporozoite protein (CS) and the sporozoite surface protein
2 (SSP2) are well represented in the data set. A blastx search
with all tags of the nonredundant protein database gave only 161
unique significant matches (P(N) </= 10(-4)), whereas 1,386
of the unique sequences represented novel sporozoite-expressed
genes. We identified ESTs for three proteins that may be
involved in host cell invasion and documented their expression
in sporozoites. These data should facilitate our understanding
of the preerythrocytic Plasmodium life cycle stages and the
development of preerythrocytic vaccines.
Braz J Infect Dis 2001 Apr;5(2):67-72
Atovaquone and Proguani Hydrochloride
Compared with Chloroquine or Pyrimethamine/Sulfodaxine for
Treatment of Acute Plasmodium falciparum Malaria in Peru.
Llanos-Cuentas A, Campos P, Clendenes M, Canfield J,
Alexander von Humboldt Tropical Medicine Institute, Universidad
Peruana Cayetano Heredia, Lima, Peru.
The efficacy and safety of a fixed-dose combination of
atovaquone and proguanil hydrochloride (Malarone(TM)) were
compared with chloroquine or pyrimethamine/sulfadoxine in
patients with acute falciparum malaria in northern Peru.
Patients were initially randomized to receive 1,000 mg
atovaquone and 400 mg proguanil hydrochloride daily for 3 days
(n=15) or 1,500 mg chloroquine (base) over a 3 day period (n=14)
(phase 1). The cure rate with chloroquine was lower than
expected and patients were subsequently randomized to receive a
single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine
(n=9) or atovaquone/proguanil as before (n=5) (phase 2). In
phase 1, atovaquone/proguanil was significantly more effective
than chloroquine (cure rate 100% [14/14] vs. 8% [1/13],
P<0.0001). In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine
were both highly effective (cure rates 100% [5/5] and 100%
[7/7]). There were no significant differences between treatment
groups in parasite or fever clearance times. Adverse events were
typical of malarial symptoms and did not differ significantly
between groups. Overall efficacy of atovaquone/proguanil was
100% for treatment of acute falciparum malaria in a region with
a high prevalence of chloroquine resistance.
Trans R Soc Trop Med Hyg 2001 May-Jun;95(3):320-4
Compliance to correct dose of chloroquine in
uncomplicated malaria correlates with improvement in the
condition of rural Nigerian children.
Okonkwo PO, Akpala CO, Okafor HU, Mbah AU, Nwaiwu O.
Department of Pharmacology and Therapeutics, University of
Nigeria Teaching Hospital, PMB 01129, Enugu, Nigeria. [email protected]
Non-compliance to correct dosing is thought to be one of the
main causes of treatment failure of chloroquine in the home
management of childhood malaria. There are few studies of
compliance to drugs used for tropical diseases. In order to
study compliance in the rural setting, chloroquine syrup was
packaged with a novel pictorial insert for compliance to correct
dosing. Compliance was assessed in a field trial in September
1996-December 1997, involving 632 children with uncomplicated
malaria in Udi local government area in Nigeria. Written
informed consent was obtained from mothers/guardians before
children were enrolled in the study. There were 3 arms to the
trial: control villages (group I) received chloroquine syrup
without further intervention, group II received a pictorial
insert with chloroquine syrup, and group III received
chloroquine syrup, the pictorial insert and verbal instructions.
Each group was made up of 3 health centres. Compliance was
assessed by volumetric measurement of the chloroquine syrup left
in 30-mL bottles and by questionnaires administered to
mothers/helpers of the children. Control villages recorded full
compliance for 36.5 +/- 4.4% of the children, group II for 51.9
+/- 7.9% and group III for 73.3 +/- 4.2%. There was a
significant correlation (P < 0.0001) between full compliance,
improvement and time for improvement of the condition. This
study is deemed important because it focuses on children, who
bear the greatest burden of malaria. It is unique for
introducing a pictorial insert that illiterate villagers, who
may not understand the use of age or weight in drug dispensing,
may utilize as a substitute.
Trans R Soc Trop Med Hyg 2001 May-Jun;95(3):315-9
Can pretreatment screening for dhps and dhfr
point mutations in Plasmodium falciparum infections be used to
predict sulfadoxine-pyrimethamine treatment failure?
Omar SA, Adagu IS, Warhurst DC.
Biomedical Sciences Research Centre, Kenya Medical Research
Institute, P.O. Box 54840, Mbagathi Road, Nairobi, Kenya.
This study examines the relationship between malaria treatment
failure after sulfadoxine-pyrimethamine (S-P) chemotherapy and
presence of mutations in the Plasmodium falciparum
dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr)
genes (associated with resistance in vitro to S and P) before
treatment. In Kenya, 38 malaria patients in a holoendemic area,
and 21 in an epidemic area, participated in the trial in
1997-98. In the 2 areas, drug failure occurred in 76% and 75% of
cases where any mutation in dhfr was seen (positive predictive
values 76% and 75%: P = 0.003 and 0.008) and an identical
association was seen with dhfr Asn-108. In the holoendemic area
all occurrences of > or = 2 mutations in dhfr predicted drug
failure. Only 3 instances were seen in the epidemic focus, but
treatment failed in all. Only in the epidemic focus, 7 (88%) of
8 occurrences of > or = 1 mutations in dhps, and all
occurrences of the Gly-437 allele of dhps, predicted failure.
Association between mutations in dhps and mutations in dhfr was
noted in the combined sites, irrespective of outcome. Although
this makes the relationship of combined dhfr and dhps mutations
to failure more difficult to interpret, it nevertheless supports
S-P selection acting on both genes. In the holoendemic site,
treatment success increased with age. In this location, acquired
immunity may mask the impact of mutations in dhps, since
sulfadoxine is a less effective treatment than pyrimethamine.
Trans R Soc Trop Med Hyg 2001 May-Jun;95(3):267-9
Validity of Lot Quality Assurance Sampling to
optimize falciparum malaria surveys in low-transmission areas.
Rabarijaona L, Rakotomanana F, Ranaivo L, Raharimalala L,
Modiano D, Boisier P, De Giorgi F, Raveloson N, Jambou R.
Pasteur Institute of Madagascar, University of Rome, Italy.
To control the reappearance of malaria in the Madagascan
highlands, indoor house-spraying of DDT was conducted from 1993
until 1998. Before the end of the insecticide-spraying programme,
a surveillance system was set up to allow rapid identification
of new malaria epidemics. When the number of suspected clinical
malaria cases notified to the surveillance system exceeds a
predetermined threshold, a parasitological survey is carried out
in the community to confirm whether or not transmission of
falciparum malaria is increasing. Owing to the low specificity
of the surveillance system, this confirmation stage is essential
to guide the activities of the control programme. For this
purpose, Lot Quality Assurance Sampling (LQAS), which usually
requires smaller sample sizes, seemed to be a valuable
alternative to conventional survey methods. In parallel to a
conventional study of Plasmodium falciparum prevalence carried
out in 1998, we investigated the ability of LQAS to rapidly
classify zones according to a predetermined prevalence level.
Two prevalence thresholds (5% and 15%) were tested using various
sampling plans. A plan (36, 2), meaning that at least 2
individuals found to be positive among a random sample of 36,
enabled us to classify a community correctly with a sensitivity
of 100% and a specificity of 94%. LQAS is an effective tool for
rapid assessment of falciparum malaria prevalence when
monitoring malaria transmission.
Parasite Immunol 2001 Aug;23(8):435-44
Immunogenicity of recombinant fragments of
Plasmodium falciparum acidic basic repeat antigen produced in
Kushwaha A, Rao PP, Suresh Rp, Chauhan VS.
International Centre for Genetic Engineering and Biotechnology,
Aruna Asaf Ali Marg, New Delhi, India.
The acidic basic repeat antigen (ABRA) of Plasmodium falciparum
is a potential vaccine candidate against erythrocytic stages of
malaria. We report, for the first time, the immunological
characteristics of recombinant ABRA constructs. The recombinant
proteins representing different fragments of ABRA were expressed
in Escherichia coli, either as fusions with maltose binding
protein or as 6X histidine tagged molecules, and purified by
affinity chromatography. Immunogenicity studies with these
constructs in rabbits and mice indicated that the N-terminal
region is the least immunogenic part of ABRA. T-cell
proliferation experiments in mice immunized with these
constructs revealed that the T-cell epitopes were localized in
the middle portion of the protein. More importantly, the
purified immunoglobulin G specific to middle and C-terminal
fragments prevented parasite growth at levels approaching
80-90%. We found that these proteins were also recognized by
sera from P. falciparum-infected patients from Rourkela, a
malaria endemic zone of India. Our immunogenicity results
suggest that potential of ABRA as a vaccine candidate antigen
should be investigated further.
Ann Trop Med Parasitol 2001 Jul;95(5):445-9
Apparent drug failure following artesunate
treatment of Plasmodium falciparum malaria in Freetown, Sierra
Leone: four case reports.
Sahr F, Willoughby VR, Gbakima AA, Bockarie MJ.
College of Medicine and Allied Health Sciences, University of
Sierra Leone, Private Mail Bag, Freetown, Sierra Leone.
Four cases of Plasmodium falciparum malaria who presented in
Sierra Leone in November-December 2000 apparently failed to
respond to treatment with artesunate. Three (75%) of the cases
fulfilled the World Health Organization's criteria for late
treatment failure. Although artesunate ranks only sixth as the
first-line drug used by clinicians for the treatment of
uncomplicated malaria in Sierra Leone, it is widely sold over
the counter in pharmacies in the country. The indiscriminate and
injudicious use of artesunate among the Sierra Leonean
population is likely to increase the level and frequency of
resistance among the local strains of P. falciparum. It is
recommended that artesunate be reserved for patients who fail to
respond to treatment with another of the antimalarial drugs
available. Even then, the artesunate should preferably be used
in combination with other, longer-acting antimalarial drugs, to
slow the development of further resistance.
Ann Trop Med Parasitol 2001 Jul;95(5):437-444
Malaria diagnosis and treatment under the
strategy of the integrated management of childhood illness (IMCI):
relevance of laboratory support from the rapid
immunochromatographic tests of ICT Malaria P.f/P.v and OptiMal.
Tarimo DS, Minjas JN, Bygbjerg IC.
Department of Parasitology and Medical Entomology, Institute of
Public Health, Muhimbili University College of Health Sciences,
University of Dar es Salaam, P.O. Box 65001, Dar es Salaam,
Tanzania, and Department of International Health, Institute of
Public Health, University of Copenhagen, Panum Institute,
Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
The algorithm developed for the integrated management of
childhood illness (IMCI) provides guidelines for the treatment
of paediatric malaria. In areas where malaria is endemic, for
example, the IMCI strategy may indicate that children who
present with fever, a recent history of fever and/or pallor
should receive antimalarial chemotherapy. In many holo-endemic
areas, it is unclear whether laboratory tests to confirm that
such signs are the result of malaria would be very relevant or
useful. Children from a holo-endemic region of Tanzania were
therefore checked for malarial parasites by microscopy and by
using two rapid immunochromatographic tests (RIT) for the
diagnosis of malaria (ICT Malaria P.f/P.v and OptiMal((R))). At
the time they were tested, each of these children had been
targeted for antimalarial treatment (following the IMCI
strategy) because of fever and/or pallor. Only 70% of the 395
children classified to receive antimalarial drugs by the IMCI
algorithm had malarial parasitaemias (68.4% had Plasmodium
falciparum trophozoites, 1.3% only P. falciparum gametocytes,
0.3% P. ovale and 0.3% P. malariae). As indicators of P.
falciparum trophozoites in the peripheral blood, fever had a
sensitivity of 93.0% and a specificity of 15.5% whereas pallor
had a sensitivity of 72.2% and a specificity of 50.8%. The RIT
both had very high corresponding sensitivities (of 100.0% for
the ICT and 94.0% for OptiMal) but the specificity of the ICT
(74.0%) was significantly lower than that for OptiMal (100.0%).
Fever and pallor were significantly associated with the P.
falciparum asexual parasitaemias that equalled or exceeded the
threshold intensity (2000/&mgr;l) that has the optimum
sensitivity and specificity for the definition of a malarial
episode. Diagnostic likelihood ratios (DLR) showed that a
positive result in the OptiMal test (DLR = infinity) was a
better indication of malaria than a positive result in the ICT (DLR
= 3.85). In fact, OptiMal had diagnostic reliability (0.93)
which approached that of an ideal test and, since it only
detects live parasites, OptiMal is superior to the ICT in
monitoring therapeutic responses. Although the RIT may seem
attractive for use in primary health facilities because
relatively inexperienced staff can perform them, the high cost
of these tests is prohibitive. In holo-endemic areas, use of RIT
or microscopical examination of bloodsmears may only be relevant
when malaria needs to be excluded as a cause of illness (e.g.
prior to treatment with toxic or expensive drugs, or during
malaria epidemics). Wherever the effective drugs for the
first-line treatment of malaria are cheap (e.g. chloroquine and
Fansidar), treatment based on clinical diagnosis alone should
prove cost-saving in health facilities without microscopy.
Rev Saude Publica 2001 Jun;35(3):224-31
A mathematical model for malaria transmission
relating global warming and local socioeconomic conditions.
Departamento de Matematica Aplicada, Instituto de Matematica,
Estatistica e Computacao Cientifica, Universidade Estadual de
Campinas, Campinas, SP, Brasil.
OBJECTIVE: Sensitivity analysis was applied to a mathematical
model describing malaria transmission relating global warming
and local socioeconomic conditions. METHODS: A previous
compartment model was proposed to describe the overall
transmission of malaria. This model was built up on several
parameters and the prevalence of malaria in a community was
characterized by the values assigned to them. To assess the
control efforts, the model parameters can vary on broad
intervals. RESULTS: By performing the sensitivity analysis on
equilibrium points, which represent the level of malaria
infection in a community, the different possible scenarios are
obtained when the parameters are changed. CONCLUSIONS: Depending
on malaria risk, the efforts to control its transmission can be
guided by a subset of parameters used in the mathematical model.
Southeast Asian J Trop Med Public Health 2001
Preliminary studies of Anopheles mosquitos in
eight provinces in Lao PDR.
Vythilingam I, Keokenchan K, Phommakot S, Nambanya S,
Institute for Medical Research, Jalan Pahang, Kuala Lumpur,
Malaria vector surveys were carried out in 8 provinces in Lao
PDR in 1999. The surveys were conducted in 4 provinces -
Savannakhet, Champasak, Luang Perbang and Sayaboury in May and
in another 4 provinces - Bolikhamsay, Sarvan, Sekong and
Vientiane in December 1999. Bare leg collection were carried out
indoors and outdoors from 6 pm to 5 am. All anopheline mosquitos
were identified, dissected and the gut, gland and ovaries were
examined. A total of 438 Anopheles mosquitos belonging to 19
species were obtained. Of these only 3 species were found to be
infected with oocysts - An. maculatus, An. dirus and An. minimus.
All these species were found biting both indoors and outdoors.
An. aconitus was the predominant species obtained in the
December collection but its vectorial status remains unknown.
Southeast Asian J Trop Med Public Health 2001
Can treatment of P. vivax lead to a
unexpected appearance of falciparum malaria?
Mason DP, Krudsood S, Wilairatana P, Viriyavejakul P,
Silachamroon U, Chokejindachai W, Singhasivanon P, Supavej S,
McKenzie FE, Looareesuwan S.
Faculty of Tropical Medicine, Mahidol University, Bangkok,
Thailand. [email protected]
Of 994 patients admitted to the Bangkok Hospital for Tropical
Diseases for P. vivax malaria, 104 (10.5%) experienced
appearance of Plasmodiumfalciparum following drug treatment for
P. vivax . In all patients, P. falciparum parasites were not
found by microscopic examination upon admission. The mean time
for P. falciparum appearance was 12.6 days after the
commencement of chloroquine treatment. Patients experiencing
appearance of P. falciparum had significantly lower hematocrit,
and greater initial P. vivax parasite counts. We use a
mathematical model to explore the consequences of chloroquine
treatment of such mixed infections. Both clinical results and
features of the model suggest that such "hidden
infections" may be quite common, and that the appearance of
P. falciparum may be stimulated by treatment of P. vivax.
Southeast Asian J Trop Med Public Health 2001
Frequency of early rising parasitemia in
falciparum malaria treated with artemisinin derivatives.
Silachamroon U, Phumratanaprapin W, Krudsood S,
Treeprasertsuk S, Budsaratid V, Pornpininworakij K, Wilairatan
P, Looareesuwan S.
Department of Clinical Tropical Medicine, Faculty of Tropical
Medicine, Mahidol University, Bangkok, Thailand.
To define the frequency of the early rising of parasitemia in
falciparum malaria patients treated with artemisinin
derivatives, a retrospective chart review of 497 patients
admitted to the Hospital for Tropical Diseases, Bangkok in 1996
was carried out. Early rising parasitemia, defined as an
increase in the parasite count over the baseline pretreatment
level during the first 24 hours of treatment, was found in
59/229 episodes (25.8%) of uncomplicated, and 111/268 episodes
(41.3%) of complicated falciparum malaria. All uncomplicated
cases were successfully treated without developing any
complications. There were 2 deaths and 13 changes of drug
regimen in the complicated group. Only one of these unfavorable
responses was due to parasite response. Early rising parasitemia
was very common in falciparum malaria treated with artemisinin
derivatives, despite their ability to clear the parasitemia, and
did not indicate failure of the drug used.
Southeast Asian J Trop Med Public Health 2001
Drug resistant malaria on the Thai-Myanmar
and Thai-Cambodian borders.
Wongsrichanalai C, Sirichaisinthop J, Karwacki JJ, Congpuong
K, Miller RS, Pang L, Thimasarn K.
Armed Forces Research Institute of Medical Sciences (AFRIMS),
We describe the changing epidemiology of drug resistant malaria
in Thailand over the past decade. Factors determining the
characteristic patterns of the development and spread of
resistance to anti-malarial drugs on the Thai-Cambodian border
and the Thai-Myanmar border are explored, namely, population
dynamics, drug usage and malaria control measures. The
introduction of artesunate-mefloquine combination in selected
areas along the two borders in 1995 is believed to be one of the
multiple factors responsible for stabilizing the multidrug
resistance problems in Thailand today. Other control measures
and inter-governmental co-operation must continue to be
strengthened in order to limit the spread of drug resistance
malaria in the Southeast Asian region.
Parasitol Res 2001 Jul;87(7):553-5
Plasmodium falciparum: in vitro growth
inhibition by febrile temperatures.
Long HY, Lell B, Dietz K, Kremsner PG.
Department of Parasitology, Institute of Tropical Medicine,
University of Tubingen, Germany.
Febrile episodes are the hallmark of malarial infection. We
determined the inhibitory effect of febrile temperatures on the
in vitro growth of Plasmodium falciparum. Parasites were
cultured at various temperatures between 37 degrees C and 40
degrees C for 4 days. A logistic decrease in parasitaemia as a
function of temperature was observed for continuous cultures.
Incubation of synchronized cultures for different lengths of
time during the parasite cycle showed a strong increase of
growth inhibition with the maturing of parasites. Febrile
temperatures inhibit parasite growth and long, high fevers
during malaria may be beneficial for parasite clearance.
Parasitol Res 2001 Jul;87(7):530-3
Plasmodium falciparum transmission intensity
and infection rates in children in Gabon.
Sylla EH, Lell B, Kun JF, Kremsner PG.
Laboratoire de Recherche, Hjpital Albert Schweitzer, Lambarene,
Several factors can determine the outcome of a malarial
infection. Studies on susceptibility or resistance to malarial
infection can be confounded by differences in transmission. In
the present study, the relationship between vector abundance and
Plasmodium falciparum infection rate of Gabonese children was
studied. Indoor human bait catches were conducted in the houses
of two groups of children, those who had been found earlier to
be either frequently (> 3 infections per year) or rarely
(< 0.5 infections per year) infected with P. falciparum. The
human biting rate was 12 and 31 bites per person per night
during the dry and the rainy season, with 3% and 16% Anopheles,
respectively. Anopheles gambiae and A. moucheti were found to be
the only vectors involved in the transmission of malaria in this
area. No significant difference in the abundance and the rate of
P. falciparum infection of the Anopheles mosquitoes was found
among children rarely or frequently infected. Differences in
transmission cannot account for differences in infection rates
in our study group. Hereditary and immunological factors seem to
be the primary determinants for the outcome of malarial
EMBO J 2001 Aug 1;20(15):3975-3983
P25 and P28 proteins of the malaria ookinete
surface have multiple and partially redundant functions.
Tomas AM, Margos G, Dimopoulos G, van Lin LH, de Koning-Ward
TF, Sinha R, Lupetti P, Beetsma AL, Rodriguez MC, Karras M,
Hager A, Mendoza J, Butcher GA, Kafatos F, Janse CJ, Waters AP,
Leiden University Medical Centre, Laboratory of Parasitology, PO
Box 9605, 2300 RC Leiden, The Netherlands, Imperial College of
Science, Technology and Medicine, Biology Department, Sir
Alexander Fleming Building, Imperial College Road, London SW7
2AZ, UK, European Molecular Biology Laboratory, Meyerhofstrasse
1, 69117 Heidelberg, Germany and Unit of Electron Microscopy and
Cryotechniques, Dipartimento Biologia Evolutiva, Universita di
Siena, Via P.A. Mattioli 4, 53100 Siena, Italy Corresponding [email protected]
The ookinete surface proteins (P25 and P28) are proven
antimalarial transmission-blocking vaccine targets, yet their
biological functions are unknown. By using single (Sko) and
double gene knock-out (Dko) Plasmodium berghei parasites, we
show that P25 and P28 share multiple functions during ookinete/oocyst
development. In the midgut of mosquitoes, the formation of
ookinetes lacking both proteins (Dko parasites) is significantly
inhibited due to decreased protection against lethal factors,
including protease attack. In addition, Dko ookinetes have a
much reduced capacity to traverse the midgut epithelium and to
transform into the oocyst stage. P25 and P28 are partially
redundant in these functions, since the efficiency of ookinete/oocyst
development is only mildly compromised in parasites lacking
either P25 or P28 (Sko parasites) compared with that of Dko
parasites. The fact that Sko parasites are efficiently
transmitted by the mosquito is a compelling reason for including
both target antigens in transmission-blocking vaccines.
J Ethnopharmacol 2001 Sep;77(1):91-8
A search for natural bioactive compounds in
Bolivia through a multidisciplinary approach. Part V. Evaluation
of the antimalarial activity of plants used by the Tacana
Deharo E, Bourdy G, Quenevo C, Munoz V, Ruiz G, Sauvain M.
Institut de Recherche pour le Developpement (IRD), CP 9214, La
One hundred and twenty-five extracts of 122 different plant
species traditionally used by the Tacana, a native community
living in lowland forest at the base of the last foothills of
the Cordillera Oriental of the Bolivian Andes, were screened for
antimalarial activity in vitro on Plasmodium falciparum
chloroquine resistant (D2) and sensitive strains (F32), and were
evaluated in vivo on rodent malaria Plasmodium berghei. Five
ethanolic stembark extracts showed marked activity either in
vitro or in vivo, and only one of them, Bowdichia virgilioides
being traditionally used against malaria, was active in vitro
(IC50=1 &mgr;g/ml on both strains) and in vivo (51% at 100
mg/kg). Other active extracts were from Caesalpinia pluviosa
bark displaying activity in vitro against chloroquine resistant
strain (IC50 8.3 &mgr;g/ml), traditionally used against
dysentery; two Lauraceae bark extracts, Nectandra aff. hihua and
Licaria canella respectively used for construction purposes and
against stomach ache, both displaying activity in vitro against
P. falciparum sensible and resistant strains (IC50 around 4
&mgr;g/ml); finally, the bark of a strongly aromatic
Burseraceae, Protium glabrescens exuding an anti-inflammatory
and analgesic resin, was active in vivo only (61% at 100 mg/kg).
Results are discussed in relation with Tacana traditional
Vaccine 2001 Aug 14;19(31):4487-95
Plasmodium falciparum circumsporozoite (CS)
protein peptides specifically bind to HepG2 cells.
Suarez JE, Urquiza M, Puentes A, Garcia JE, Curtidor H,
Ocampo M, Lopez R, Rodriguez LE, Vera R, Cubillos M, Torres MH,
Universidad Nacional de Colombia, Hospital San Juan de Dios,
Instituto de Inmunologia, Avda 1 No 10-01, AA 44709, Bogota,
Hepatocyte invasion by malaria parasites is mediated by specific
molecular interactions. Several lines of evidence suggest the
importance of the surface plasmodial circumsporozoite (CS)
protein in the sporozoite invasion of hepatocytes.
Identification of the sequences involved in binding to
hepatocytes is an important step towards understanding the
structural basis for the sporozoite-hepatocyte interaction. In
this study, binding assays between Plasmodium falciparum CS
peptides and HepG2 cells were performed. Fifteen overlapping
residue 20 mer long peptides, spanning the entire CS sequence,
were tested in HepG2 cell binding assays. Five High Binding
Activity Peptides (HBAPs) to HepG2 cells were identified: 4593,
(NANPNANPNANP); 4383, (&Nmacr;SRSLGEN&Dmacr;DG&Nmacr;NEDNEKLR);
4388, (GNGQGHN&Mmacr;PNDPNRNV&Dmacr;ENA); 4389, (HN&Mmacr;PNDPNRNV&Dmacr;ENANA&Nmacr;SA)
and 4390, (DPNRNV&Dmacr;ENANA&Nmacr;SAVKN&Nmacr;N).
The HBAP HepG2 interaction is independent of charge and
amino-acid composition, but sequence dependent. Four HBAPs
(4383, 4388, 4389 and 4390) are bound with similar affinity to a
50 kDa molecule. These HBAPs define three Hepatocyte Binding
Sequences (HBSs): HBS-1, located between residues 68 and 87 (HBAP
4383); HBS-11, the repeat NANP region (HBAP 4593), for which
anti repeat antibodies are able to specifically inhibit
sporozoite invasion of hepatocytes have been reported; and
HBS-111, between residues 286 and 315 (HBAPs 4388, 4388 and
4390), respectively. Interestingly, HBS 111 carries two
earlier-reported B-epitopes (underlined) in peptides 4388, 4389
and 4390 (GNGQGHNMPNDPNRNVD ENANANSAVKNN) in its sequence. The
HBSs reported here show lesser interspecie-variability than the
entire protein in species invading the same kind of hepatic
cells. This data supports these HBSs' important role in
CS-protein function; they could be used as ligand by the
sporozoite to invade hepatic cells.
Vaccine 2001 Aug 14;19(31):4445-51
Biodegradable PLGA microspheres as a delivery
system for malaria synthetic peptide SPf66.
Rosas JE, Hernandez RM, Gascon AR, Igartua M, Guzman F,
Patarroyo ME, Pedraz JL.
Pharmacy and Pharmaceutical Technology Laboratory, Pharmacy
Faculty, University of the Basque Country (UPV-EHU), Paseo de la
Universidad no.7, 01006, Vitoria-Gasteiz, Spain
SPf66 is the first chemically synthesised vaccine to elicit a
partial protective immune response against malaria. The
aluminium hydroxide (alum)-adsorbed SPf66 vaccine is weakly
immunogenic and of poor to moderate efficacy in humans. To
investigate the possibility of improving SPf66 vaccine
immunogenicity, a delivery system based on poly-D,L-lactide-co-glycolide
(PLGA) microspheres was developed and the immune response
induced after its subcutaneous administration into mice was
evaluated. Microspheres were prepared by a solvent
extraction/double emulsion (w/o/w) method and characterised for
morphology, size, peptide loading, release profile and peptide
integrity. The in vitro and in vivo results obtained showed that
there was no apparent effect of the encapsulation procedure on
SPf66 integrity and immunogenicity. The subcutaneous
administration of microspheres showed a significantly higher
immune response (serum IgG levels) than that obtained with alum
adsorbed SPf66 and it was comparable to that of SPf66 emulsified
with Freund's adjuvant (FA). These observations illustrate the
potential of PLGA microspheres as a delivery system for
chemically synthesised antigens.
J Antimicrob Chemother 2001 Aug;48(2):179-184
Ferrocene-chloroquine analogues as
antimalarial agents: in vitro activity of ferrochloroquine
against 103 Gabonese isolates of Plasmodium falciparum.
Pradines B, Fusai T, Daries W, Laloge V, Rogier C, Millet P,
Panconi E, Kombila M, Parzy D.
Unite de Parasitologie, Institut de Medecine Tropicale du
Service de Sante des Armees, Bd C. Livon, Parc Le Pharo, BP 46,
13998 Marseille Armees, France. Service Medical, 6ieme Bataillon
d'Infanterie de Marine, Libreville, Gabon. Centre Labusquiere,
Universite de Bordeaux II, Bordeaux, France. Institut de
Recherche Pierre Fabre, Labege Innopole, France. Departement de
Parasitologie-Mycologie-Medecine Tropicale, Faculte de Medecine
et des Sciences de la Sante, Libreville, Gabon.
The in vitro activities of ferrochloroquine, chloroquine,
quinine, mefloquine, halofantrine, amodiaquine, primaquine,
atovaquone and artesunate were evaluated against Plasmodium
falciparum isolates from children with uncomplicated malaria
from Libreville (Gabon), using an isotopic, micro, drug
susceptibility test. The IC(50) values for ferrochloroquine were
in the range 0.43-30.9 nM and the geometric mean IC(50) for the
103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the
geometric means for chloroquine, quinine, mefloquine,
amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM
and 7.6 &mgr;M, respectively. Ferrochloroquine was active
against P. falciparum isolates, 95% of which showed in vitro
resistance to chloroquine. Weak positive significant
correlations were observed between the responses to
ferrochloroquine and that to chloroquine, amodiaquine and
quinine, but too low to suggest cross-resistance. There was no
significant correlation between the response to ferrochloroquine
and those to mefloquine, halofantrine, primaquine, atovaquone or
artesunate. Ferrochloroquine may be an important alternative
drug for the treatment of chloroquine-resistant malaria.
J Am Mosq Control Assoc 2001 Jun;17(2):131-6
Concurrent control of mosquitoes and domestic
pests by use of deltamethrin-treated curtains in the New Delhi
Municipal Committee, India.
Ansari MA, Razdan RK.
Malaria Research Centre, Delhi, India.
A field trial was conducted in Block F of the Moti Bagh area of
New Delhi Municipal Committee to demonstrate composite control
of Anopheles stephensi and Aedes aegypti by spraying
deltamethrin at 100 mg/m2 on window and door curtains of
habitations. Results revealed drastic reduction (87.9-93.7%, P
< 0.05) of target species in the experimental area. The
impact of deltamethrin-treated curtains was also evident against
nontarget species (67.9-85.7%. P < 0.05). Treated curtains
provided 100% kill of An. stephensi and Ae. aegypti for 3-4
months, followed by a gradual decline in successive months. Use
of deltamethrin-treated curtains resulted in 92.0 reduction in
slide positivity rate and 95.4% reduction in malaria cases per
thousand population. The cost of deltamethrin treatment was Rs
41.15 (<$1 U.S.) per house per annum. Insecticide-treated
mosquito window and door curtains, along with legislative
measures, may provide cost-effective concurrent control of
mosquitoes and other domestic pests.
Indian J Med Sci 2001 Jan;55(1):43-6
Seasonal variations in incidence of severe
and complicated malaria in central India.
Madhavan KT, Jajoo UN, Bhalla A.
Deptt. of Medicine, MGIMS, Sevagram, Wardha.
The geographical position and climate of India is favorable for
the transmission of malarial infection. The maximum prevalence
of malaria in most parts of India is from July to November
months. Rainfall provides mosquitoes, a breeding ground giving
rise to epidemics. We studied the seasonal variation in cases of
severe and complicated malaria presenting at MGIMS, Sevagram,
Wardha (Vidarbha region in Maharashtra) over a period of three
years. The findings of peak of malaria observed during
September-November during three years period points to the fact
that the increase in vector breeding after rainy season is
responsible for the upsurge in the malarial cases during these
months. This also indicates that this area (Vidarbha) has an
unstable transmission of malaria.
Bull World Health Organ 2001;79(7):648-56
Three case definitions of malaria and their
effect on diagnosis, treatment and surveillance in Cox's Bazar
Montanari RM, Bangali AM, Talukder KR, Baqui A, Maheswary NP,
Gosh A, Rahman M, Mahmood AH.
WHO Dhaka, Bangladesh.
In countries where malaria is endemic, routine blood slide
examinations remain the major source of data for the public
health surveillance system. This approach has become inadequate,
however, as the public health emphasis has changed from
surveillance of laboratory-confirmed malaria infections to the
early detection and treatment of the disease. As a result, it
has been advocated that the information collected about malaria
be changed radically and should include the monitoring of
morbidity and mortality, clinical practice and quality of care.
To improve the early diagnosis and prompt treatment (EDPT) of
malaria patients, three malaria case definitions (MCDs) were
developed, with treatment and reporting guidelines, and used in
all static health facilities of Cox's Bazar district, Bangladesh
(population 1.5 million). The three MCDs were: uncomplicated
malaria (UM); treatment failure malaria (TFM); and severe
malaria (SM). The number of malaria deaths was also reported.
This paper reviews the rationale and need for MCDs in malaria
control programmes and presents an analysis of the integrated
surveillance information collected during the three-year period,
1995-97. The combined analysis of slide-based and clinical data
and their related indicators shows that blood slide analysis is
no longer used to document fever episodes but to support EDPT,
with priority given to SM and TFM patients. Data indicate a
decrease in the overall positive predictive value of the three
MCDs as malaria prevalence decreases. Hence the data quantify
the extent to which the mainly clinical diagnosis of UM leads to
over-diagnosis and over-treatment in changing epidemiological
conditions. Also the new surveillance data show: a halving in
the case fatality rate among SM cases (from 6% to 3.1%)
attributable to improved quality of care, and a stable
proportion of TFM cases (around 7%) against a defined population
denominator. Changes implemented in the EDPT of malaria patients
and in the surveillance system were based on existing staff
capacity and routine reporting structures.
J Med Entomol 2001 Jul;38(4):531-6
Effect of permethrin-impregnated nets on
exiting behavior, blood feeding success, and time of feeding of
malaria mosquitoes (Diptera: Culicidae) in western Kenya.
Mathenge EM, Gimnig JE, Kolczak M, Ombok M, Irungu LW, Hawley
Department of Zoology, University of Nairobi, Kenya.
The impact of permethrin-treated bednets on the feeding and
house entering/exiting behavior of malaria vectors was assessed
in two studies in western Kenya. In one study, matched pairs of
houses were allocated randomly to receive bednets or no bednets.
Exiting mosquitoes were collected in Colombian curtains hung
around half of each house; indoor resting mosquitoes were
collected by pyrethrum spray catches. The number of Anopheles
gambiae Giles and An. arabiensis Patton estimated to have
entered the houses was unaffected by the presence of bednets;
Anopheles funestus Giles was less likely to enter a house if
bednets were present. Anopheles gambiae and An. funestus were
less likely to obtain a blood meal and significantly more likely
to exit houses when bednets were present. No difference was
detected in An. arabiensis rates of blood feeding and exiting.
In a second experiment, hourly night biting collections were
done on 13 nights during the rainy season to assess whether
village-wide use of permethrin-treated bednets caused a shift in
the time of biting of malaria vectors. A statistically
significant shift was detected in the biting times of An.
gambiae s.l., although the observed differences were small. No
change was observed in the hourly distribution of An. funestus
biting. Our study demonstrated that, at least in the short-term,
bednets reduced human-vector contact and blood feeding success
but did not lead to changes in the biting times of the malaria
vectors in western Kenya.
Curr Drug Targets 2000 Jul;1(1):59-83
Proteases involved in erythrocyte invasion by
the malaria parasite: function and potential as chemotherapeutic
Division of Parasitology, National Institute for Medical
Research, Ridgeway, Mill Hill, London NW7 1AA, U.K.
Malaria places an increasing burden on global public health
resources. In the face of growing resistance of the malaria
parasite to available antimalarial drugs, there is a need for
new drugs and the identification of new chemotherapeutic
targets. The malaria parasite has a complex life cycle which
includes a number of obligate intracellular stages. Clinical
malaria results from cyclic asexual replication of the
blood-stage parasite in circulating erythrocytes of the human
host. Erythrocyte entry and host cell rupture require the
activity of parasite proteases, and these enzymes are,
therefore, attractive targets for rational approaches to new
drug development. Malarial proteases play a role in at least two
distinct aspects of host cell invasion; modification of parasite
proteins involved in host cell recognition and entry; and
restructuring of the host cell itself, during and following
invasion, and in order to allow parasite release from the host
cell. This review details recent advances in the identification
of these proteases, describes current understanding of their
activation and functional role, and discusses their potential as
targets for protease inhibitor-based drugs.