Library Malaria Bulletin No. 32: March 1-15, 2002
TRILINGUAL EDUCATIONAL MALARIA
CD-ROM IS NOW AVAILABLE FREE OF CHARGE
The malaria educational site from Royal
Perth Hospital, is now available in French, English and Spanish.
The English site can be accessed at:
The site contains sections on
Diagnosis, Prophylaxis, Treatment and
History as well as an innovative interactive
"Test & Teach" self assessment
module. It is an ideal site for Clinicians, Scientists,
Healthcare Professionals and Students. The MK IV version of a
trilingual (English/Spanish/French) CD-ROM (Proudly sponsored by
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only limited internet access. (The CD-ROM is now being used by
medical/educational institutions in 126 countries).
A/Principal Scientist, Division of Laboratory
Perth Hospital, Wellington St., Perth Western Australia 6000
E-Mail: [email protected]
Sciences and Malaria
West African Journal of Medicine.
20(2):152-7, 2001 Apr-Jun.
Knowledge and home
management of malaria fever by mothers and care givers of under
Fawole OI. Onadeko MO.
Department of Preventive and Social
Medicine, College of Medicine,
Hospital, Ibadan, Nigeria.
This study documents the knowledge and
home management practices of 376
mothers and care
givers of under five children on malaria fever. Results revealed
that both the knowledge and case management practices were poor
as only 179 (46.8%) knew how malaria was transmitted. Of those
who knew malaria could be prevented, clearing of bushes and
gutters was the commonly stated method (78 or 21.8%), followed
by the use of traditional herbs. 'Agbo' by 75(20.9%) mothers.
The elders and friends were stated to be the major source of
knowledge about malaria by 141(37.5%) mothers.
Knowledge scores was significantly
higher in older mothers, among the educated, and skilled mothers
(P<0.05). As regards practices,
self-medication with modern drugs was common,
these drugs had been given in the home by 265(70.5%) mothers
while "Agbo", had been used by 95(25.5%) mothers
before presenting at the clinic. Paracetamol was the modern drug
often used (217 or 81.8%). Followed by chloroquine (57 or
21.5%). However, drug treatment practice were often incorrect.
Chloroquine was prescribed correctly by 15(26.3%) mothers, while
109(50.2%) gave the correct dose of paracetamol. Only 16(4.3%)
of the children received anti-malarial on the day the illness
began. There is the need for education programmes on malaria for
mothers, especially for young, illiterate and unskilled mothers,
including the family elders.
Rev Saude Publica 2002 Feb;36(1):75-80
plasticity of Anopheles darlingi's (Diptera, Culicidae) biting
activity patterns in the state of Amapa, Brazil.
Instituto de Pesquisas Cientificas e Tecnologicas do Estado do
Amapa (IEPA), Amapa, Brazil.
OBJECTIVE: To assess the variation in Anopheles darlingi's
biting activity compared to An. marajoara in the same locality
and to biting activity data from other regions. METHODS: Using
human bait, eight observations of the biting activity of An.
darlingi and An. marajoara were carried out during 1999 and 2000
in the municipality of Sao Raimundo do Pirativa, state of Amapa,
Brazil. Each observation consisted of three consecutive 13-hour
collections, close to full moon. There were shifts of collectors
in the observation points and nocturnal periods. RESULTS: An.
darlingi revealed considerable plasticity of biting activity in
contrast to An. marajoara, which showed well-defined crepuscular
biting peaks. No significant correlation between density and
biting activity was found, but a significant correlation existed
between time and proportional crepuscular activity, indicating
underlying ecological processes not yet understood. Two of the
four available data sets having multiple observations at one
locality showed considerable plasticity of this species' biting
patterns as well. CONCLUSION: Intra-population variation of
biting activity can be as significant as inter-population
variation. Some implications in malaria vector control and
specific studies are also discussed.
Proc R Soc Lond B Biol Sci 2002 Feb 22;269(1489):431-6
A large gene family
for putative variant antigens shared by human and rodent malaria
Janssen CS, Barrett MP, Turner CM, Phillips RS.
Division of Infection and Immunity, IBLS, University of Glasgow,
Glasgow G12 8QQ, UK.
A major mechanism whereby malaria parasites evade the host
immune response to give chronic infections in patients' blood
for months, or even years, is antigenic variation. In order to
generate variant antigens, parasites require large multigene
families. Although several gene families involved in these
phenomena have been identified in the human malaria Plasmodium
falciparum, to date no variant antigen gene families have been
identified in malaria species that will infect widely used
rodent laboratory hosts. Here we present, for the first time, to
our knowledge, a large multigene family conserved in both rodent
and human malarias, which is a strong candidate as a major
variant antigen gene family. In each of four species of
Plasmodium, three rodent malarias and the human pathogen P.
vivax, homologues of the gene family were found to have a
conserved three-exon structure. In the rodent malaria P.
chabaudi, transcription of members of the gene family was
developmentally regulated with maximum expression in late
trophozoite stages, which is the developmental stage known to
express variant antigen proteins.
Mol Ecol 2001 Nov;10(11):2577-91
structure of the malaria mosquito Anopheles arabiensis across
Nigeria suggests range expansion.
Onyabe D Y, Conn J E.
Department of Biology, The University of Vermont, Burlington
Ten microsatellite loci, four located within and six outside
chromosome inversions, were employed to study the genetic
structure of Anopheles arabiensis across the ecological zones of
Nigeria (arid savannah in the north gradually turns into humid
forest in the south). Regardless of location within or outside
inversions, genetic variability at all loci was characterized by
a reduction in both the number of alleles per locus and
heterozygosity from savannah to forest. Across all loci, all but
one allele in the forest also occurred in the savannah, whereas
at least 78 alleles in the savannah were missing in the forest.
Genetic differentiation increased with geographical distance;
consequently, genetic distances between zones exceeded those
within zones. The largest genetic distances were between
localities at the extremes of the transect (range F(ST) =
0.196-0.258 and R(ST) = 0.183-0.468) and were as large as those
between A. arabiensis and Anopheles gambiae s.s. Gene flow
across the country was very low, so that Nm between the extremes
of the transect was < 1. These data suggest that A.
arabiensis has extended its range from the savannah into the
forest during which it experienced a reduction in effective
population size due to sequential founder effects. Gene flow
post range expansion appears too restricted by geographical
distance to homogenize the gene pool of A. arabiensis across
Clin Exp Immunol 2002 Jan;127(1):158-64
High prevalence of
co-factor independent anticardiolipin antibodies in malaria
Consigny PH, Cauquelin B, Agnamey P, Comby E, Brasseur P,
Ballet JJ, Roussilhon C.
Laboratoire de Parasitologie, UPRES-3234, Faculte de
Medecine-Pharmacie, Rouen, France.
Anticardiolipin antibodies (aCL) were investigated in 137
individuals chronically exposed to malaria and living in Africa
and Asia. They belonged to several groups according to parasite
(Plasmodium falciparum or vivax) and clinical manifestations
(i.e. asymptomatic parasite carriers, acute uncomplicated attack
or severe malaria episodes). aCL were measured in an enzyme
immunoassay (ELISA) performed in the presence of either goat
serum (aCLs) or gelatin (aCLg). In a group of 53 patients with
autoimmune manifestations (i.e. antiphospholipid syndrome and/or
lupus), detection of IgG but not IgM aCL was markedly reduced in
the presence of gelatin. In malaria donors, high prevalence of
serum co-factor-independent IgG and IgM were detected, and the
presence of goat serum in the assay consistently decreased their
detection. aCLg levels were found to be related to the
clinical/endemic status of donors. IgG aCLg were found to be
higher in asymptomatic P. falciparum carriers than in patients
with uncomplicated acute or cerebral malaria. IgM aCLg were
higher in the cerebral malaria group than in groups with
uncomplicated acute malaria patients or asymptomatic
individuals. Data suggest that using a serum co-factor
independent, sensitive ELISA, aCL are commonly detected during
malarial infections and related to malarial infection status.
Clin Exp Immunol 2002 Jan;127(1):151-7
and apoptosis among T cells from patients under treatment for
Plasmodium falciparum malaria.
Kemp K, Akanmori BD, Adabayeri V, Goka BQ, Kurtzhals JA, Behr
C, Hviid L.
Centre for Medical Parasitology at Department of Infectious
Diseases, Copenhagen University Hospital (Rigshospitalet) and
Institute for Medical Microbiology and Immunology, University of
Copenhagen, Copenhagen, Denmark.
Email: [email protected]
Available evidence suggests that Plasmodium falciparum malaria
causes activation and reallocation of T cells, and that these in
vivo primed cells re-emerge into the periphery following drug
therapy. Here we have examined the cytokine production capacity
and susceptibility to programmed cell death of peripheral T
cells during and after the period of antimalarial treatment. A
high proportion of peripheral CD3+ cells had an activated
phenotype at and shortly after time of admission (day 0) and
initiation of therapy. This activation peaked around day 2, and
at this time-point peripheral T cells from the patients could be
induced to produce cytokines at conditions of limited cytokine
response in cells from healthy control donors. Activated CD8hi
and TCR-gammadelta+ cells were the primary IFN-gamma producers,
whereas CD4+ cells constituted an important source of TNF-alpha.
The proportion of apoptotic T cells was elevated at admission
and peaked 2 days later, while susceptibility to
activation-induced cell death in vitro remained increased for at
least 1 week after admission. Taken together, the data are
consistent with the concept of malaria-induced reallocation of
activated T cells to sites of inflammation, followed by their
release back into the peripheral blood where they undergo
apoptotic death to re-establish immunological homeostasis as
inflammation subsides. However, the high proportion of
pre-apoptotic cells from the time of admission suggests that
apoptosis also contributes to the low frequency and number of T
cells in the peripheral circulation during active disease.
Insect Mol Biol 2001 Oct;10(5):427-35
A multiplex PCR-based
method derived from random amplified polymorphic DNA (RAPD)
markers for the identification of species of the Anopheles
minimus group in Southeast Asia.
Kengne P, Trung H D, Baimai V, Coosemans M, Manguin S.
IRD, Department of Societe & Sante, Montpellier, France.
Effective control of Anopheles minimus s.l., an important
malaria vector in Southeast Asia, is based on the accurate
identification of species within An. minimus complex, which
cannot be distinguished using morphological characters. Derived
from individual random amplified polymorphic DNA markers,
sequence characterized amplified regions were analysed for the
design of species-specific paired-primers. Combination of these
primers resulted in the development of a simple, robust
multiplex PCR able to identify both species An. minimus A and C
belonging to the complex, hybrids AC, and three sympatric and
closely related species, An. aconitus, An. pampanai and An.
varuna. Hybrids AC do not possess alleles of both parents but
exhibit novel adaptive potentials resulting from recombination
among parental genes leading to hybrizyme.
Parasitol Int 2002 Mar;51(1):99-103
Stage specificity of
Plasmodium falciparum telomerase and its inhibition by berberine.
Sriwilaijareon N, Petmitr S, Mutirangura A, Ponglikitmongkol
M, Wilairat P.
Department of Biochemistry, Faculty of Science, Mahidol
University, Rama 6 Road, 10400, Bangkok, Thailand
Telomerase activity in synchronized Plasmodium falciparum during
its erythrocytic cycle was examined using the TRAP assay.
Telomerase activity was detected at all stages of the parasite
intraerythrocyte development, with higher activity in
trophozoite and schizont stages compared with ring form.
Berberine, extracted from Arcangelisia flava (L.) Merr.,
inhibited telomerase activity in a dose-dependent manner over a
range of 30--300 &mgr;M, indicating that P. falciparum
telomerase might be a potential target for future malaria
Parasitol Int 2002 Mar;51(1):17-23
A rodent malaria,
Plasmodium berghei, is experimentally transmitted to mice by
merely probing of infective mosquito, Anopheles stephensi.
Matsuoka H, Yoshida S, Hirai M, Ishii A.
Department of Medical Zoology, Jichi Medical School, Minami-kawachi,
329-0498, Tochigi, Japan
We found that infection of a rodent malaria, Plasmodium berghei,
occurred when the sporozoites were injected into the skin, the
muscle, the peritoneal cavity and the tail end. Mice, which were
injected with sporozoites in the tail end and had the site cut 5
min later, did not develop malaria. We also found that mice
developed malaria when malaria infective mosquitoes, Anopheles
stephensi, were forced not to take blood but only to probe into
the skin. Moreover, the mice probed by the infective mosquitoes
were protected from malaria infection if the site was treated
with Kyu (heat treatment) after the mosquitoes had probed. These
findings indicate that malaria infection occurs not only by
blood feeding of the infective mosquito but also by probing of
the mosquito. Sporozoites injected into the skin remain at the
injected site for at least 5 min, then migrate to the blood
vessels and invade into the blood stream. At present, the
mechanism is not clear, although we propose here the existence
of the skin stage of malaria parasites before the liver stage
and the blood stage.
Parasitol Int 2002 Mar;51(1):1-7
Mycobacterium bovis BCG producing the circumsporozoite protein
of Plasmodium falciparum FCC-1/HN strain induces strong immune
responses in BALB/c mice.
Zheng C, Xie P, Chen Y.
Institute of Infectious and Parasitic Diseases, The First
Affiliated Hospital of Chongqing Medical University, 400016,
Chongqing, PR China
The current vaccine against tuberculosis, Mycobacterium bovis
strain bacillue Calmette--Guerin (BCG), offers potential
advantages as a live, innately immunogenic vaccine vehicle for
expression and delivery of protective recombinant antigens.
Malaria is one of the severest parasitic diseases in humans
especially in the developing world. No efficacious vaccine is
currently available. However, circumsporozoite protein (CSP) is
a malaria vaccine candidate currently undergoing clinical
trials. We analyzed the immune response to recombinant BCG (rBCG)
vaccine expressing Plasmodium falciparum CSP (BCG-CSP) under the
control of heat shock protein 70 promoter in BALB/c mice. The
lymphocytes proliferative response to P. falciparum soluble
antigen was significantly higher than those in the groups of BCG
and normal saline, and the production of cytokines (IFN-gamma
and IL-2) in response to malaria antigen was significantly
higher in rBCG and BCG groups than control group of normal
saline. A specific IgG antibody response against P. falciparum
antigen of CSP was also characterized. The booster injection
could enhance the production of cytokine, proliferation
responses of spleen lymphocytes and the antibodies titer of
BCG-CSP. The results in the study demonstrated that rBCG vaccine
producing CSP is an appropriate vaccine for further evaluation
in non-human primates.
Microbes Infect 2002 Feb;4(2):175-82
Basis for antifolate
action and resistance in malaria.
National Center for Genetic Engineering and Biotechnology,
National Science and Technology Development Agency, Rama 6 Road,
10400, Bangkok, Thailand
Resistance to antifolates of the malaria parasite Plasmodium
falciparum stems from stepwise mutations of the target enzyme
dihydrofolate reductase (DHFR). New drugs can be developed
against resistant parasites, which are assumed to have limited
possibilities in mutations. Mechanisms of resistance other than
reduced binding of inhibitors to mutant enzymes may be possible
and need to be further explored. New synergistic combinations of
drugs targeting DHFR and dihydropteroate synthase may be
employed, with new provisions against development of resistance.
Microbes Infect 2002 Feb;4(2):165-74
resistance of Plasmodium falciparum to antimalarial drugs.
Department of Biomolecular Sciences, University of Manchester
Institute of Science and Technology (UMIST), P.O. Box 88, M60
1QD, Manchester, UK
Chemotherapy and chemoprophylaxis are the principal means of
combating malaria parasite infections in the human host. In the
last 75 years, since the introduction of synthetic antimalarials,
only a small number of compounds have been found suitable for
clinical usage, and this limited armoury is now greatly
compromised by the spread of drug-resistant parasite strains.
Our current knowledge of the molecular mechanisms underlying
resistance in the lethal species Plasmodium falciparum is
Int J Pharm 2002 Mar 20;235(1-2):229-236
from transdermal adhesive formulations and in vitro permeation
across human epidermal membranes.
Chedgzoy P, Winckle G, Heard CM.
Welsh School of Pharmacy, Cardiff University, CF10 3XF, Cardiff,
Malarial resistance is an escalating global problem and
consequently new and more efficacious treatments to combat
malaria are urgently needed. The transdermal delivery of anti-malarials
may provide an effective alternative or adjunct to conventional
regimens. Triclosan is widely used as an anti-bacterial agent
and it has recently been demonstrated that this compound has
anti-malarial properties. Its high lipophilicity makes it a
potential candidate for delivery across the skin and this paper
examines in vitro the potential for the transdermal delivery of
triclosan from 'drug-in-glue' formulations. Model patches were
prepared using DuroTak(R) 2287, 2516 and 2051 acrylic polymer
adhesives loaded with 0, 30 and 50 mg per 0.785 cm(minus sign2)
triclosan and dissolution was measured over a 12-h period. There
was no apparent difference between the adhesives at the 30 mg
patch loading, but at 50 mg, the trend for increased release was
2051>2516>2287. No significant burst effect was apparent.
Patches of 50 mg per 0.785 cm(2) were then used to determine the
permeation of triclosan across heat-separated human epidermal
membranes in Franz diffusion cells, over a period of 48 h. The
above general trend was reflected in the steady state flux
values obtained: 2051:16.91 &mgr;g cm(minus sign2) h(minus
sign1) (S.E.M. 1.29), 2516:15.05 &mgr;g cm(minus sign2)
h(minus sign1) (S.E.M. 1.00), 2287 12.83 &mgr;g cm(minus
sign2) h(minus sign1) (S.E.M. 2.81). Although pharmacokinetic
data are not currently available to permit calculation of an
efficacious patch size, the transdermal delivery of triclosan is
Int J Pharm 2002 Mar
doxycycline to keratin, melanin and human epidermal tissue.
Banning TP, Heard CM.
Welsh School of Pharmacy, Cardiff University, CF10 3XF, Cardiff,
Doxycycline is licensed for the prophylaxis of malaria and
recent research has indicated the feasibility of delivering this
drug across the skin. The binding of doxycycline to keratin
could influence skin permeation rates and it has been suggested
that the interaction of anti-malarials with melanin may
contribute to side effects, such as retinal damage. Doxycycline
HCl was incubated with keratin (bovine horn), melanin (Sepia
officinalis) and human epidermal samples (native and delipidised).
Dose dependent binding of doxycycline to keratin and melanin was
observed, and was of similar magnitude for each protein.
However, the binding of doxycycline to melanin was lower by an
order of magnitude relative to data previously reported for some
other anti-malarials, and may indicate reduced side-effects.
Doxycycline also demonstrated significantly greater affinity for
native epidermal skin than for delipidised skin showing that
doxycycline, a charged polar molecule, has affinity for the
intercellular lipid matrix in addition to the proteinaceous
domain. For native skin it was estimated that saturation would
be reached at approximately 140 &mgr;g cm(minus sign2); for
delipidised skin it was estimated to be 60 &mgr;g cm(minus
sign2). Overall, the data suggested that the partition-diffusion
steps that are involved in transcellular permeation are
J Exp Med 2002 Mar 4;195(5):617-624
Natural Killer T
Cell Ligand alpha-Galactosylceramide Enhances Protective
Immunity Induced by Malaria Vaccines.
Gonzalez-Aseguinolaza G, Van Kaer L, Bergmann CC, Wilson JM,
Schmieg J, Kronenberg M, Nakayama T, Taniguchi M, Koezuka Y,
Department of Medical and Molecular Parasitology, New York
University School of Medicine, New York, NY 10010. Howard Hughes
Medical Institute, Department of Microbiology and Immunology,
Vanderbilt University School of Medicine, Nashville, TN 37232.
Department of Neurology, University of Southern California, Los
Angeles, CA 90033. Institute for Human Gene Therapy, University
of Pennsylvania, Philadelphia, PA 19104. Division of
Developmental Immunology, La Jolla Institute of Allergy and
Immunology, San Diego, CA 92121. Department of
MolecularImmunology, Chiba University School of Medicine, Chiba
260, Japan. Pharmaceutical Research Laboratory, Kirin Brewery
Co., Ltd., Gunma 370, Japan.
The important role played by CD8(+) T lymphocytes in the control
of parasitic and viral infections, as well as tumor development,
has raised the need for the development of adjuvants capable of
enhancing cell-mediated immunity. It is well established that
protective immunity against liver stages of malaria parasites is
primarily mediated by CD8(+) T cells in mice. Activation of
natural killer T (NKT) cells by the glycolipid ligand, alpha-galactosylceramide
(alpha-GalCer), causes bystander activation of NK, B, CD4(+),
and CD8(+) T cells. Our study shows that coadministration of
alpha-GalCer with suboptimal doses of irradiated sporozoites or
recombinant viruses expressing a malaria antigen greatly
enhances the level of protective anti-malaria immunity in mice.
We also show that coadministration of alpha-GalCer with various
different immunogens strongly enhances antigen-specific CD8(+) T
cell responses, and to a lesser degree, Th1-type responses. The
adjuvant effects of alpha-GalCer require CD1d molecules,
Valpha14 NKT cells, and interferon gamma. As alpha-GalCer
stimulates both human and murine NKT cells, these findings
should contribute to the design of more effective vaccines
against malaria and other intracellular pathogens, as well as
J Biol Chem 2002 Mar 4
not thioredoxin-1 is a substrate of thioredoxin peroxidase-1
from Drosophila melanogaster - Isolation and characterization of
a second thioredoxin in D. melanogaster and evidence for
distinct biological functions of Trx-1 and Trx-2.
Bauer H, Kanzok SM, Schirmer RH.
Biochemiezentrum Heidelberg, Heidelberg University, Heidelberg,
As Drosophila melanogaster does not contain glutathione
reductase the thioredoxin system has a key function for
glutathione disulfide reduction in insects (Kanzok S. M.,
Fechner A., Bauer H. et al. Science 291, 643-647). In view of
these unique conditions, the protein systems participating in
peroxide metabolism and in redox signaling are of special
interest. The genes for a second thioredoxin (DmTrx-2) and a
thioredoxin peroxidase (DmTPx-1) were cloned and expressed, and
the proteins were characterized. In its disulfide form, the 13
kDa protein thioredoxin-2 is a substrate of thioredoxin
reductase-1 (K(m) = 5.2 &mgr;M, k(cat) = 14.5 s(-1)) and in
its dithiol form an electron donor of TPx-1 (K(m) = 9 &mgr;M,
k(cat) = 5.4 s(-1) ). DmTrx-2 is capable to reduce glutathione
disulfide with a second order rate constant of 0.01 &mgr;M(-1)
min(-1) at pH 7.4 and 25 C. Western blot analysis indicated that
this thioredoxin represents up to 1% of the extractable protein
of D. melanogaster Schneider cells or whole fruit flies.
Recombinant thioredoxin peroxidase-1 (subunit M(r) = 23 kDa) was
found to be a decameric protein that can efficiently use Trx-2
but not Trx-1 as a reducing substrate. The new electron pathway
found in D. melanogaster is also representative for insects that
serve as vectors of disease. As a first step we have cloned and
functionally expressed the gene that is the orthologue of
DmTrx-2 in the malaria mosquito Anopheles gambiae.
Ultrasound Obstet Gynecol 2002
uteroplacental blood flow in pregnancies complicated by
Dorman EK, Shulman CE, Kingdom J, Bulmer JN, Mwendwa J, Peshu
N, Marsh K.
Kenya Medical Research Institute (KEMRI), Centre for
Geographical Medicine Research, Coast, Kilifi, Kenya, London
School of Hygiene and Tropical Medicine, London, University of
Oxford, Institute of Molecular Medicine, John Radcliffe
Hospital, Oxford, Department of Pathology, University of
Newcastle, Royal Victoria Infirmary, Newcastle upon Tyne, UK,
Department of Maternal-Fetal Medicine, Mount Sinai Hospital,
University of Toronto, Toronto, Ontario, Canada and Department
of Obstetrics and Gynaecology, Homerton Hospital, London, UK.
Objective: In endemic areas, maternal malaria infection is
usually asymptomatic. However, it is known that infected
maternal erythrocytes sequester in the intervillous space of the
placenta. There is a strong association between placental
malaria infection and both low birth weight (LBW) and severe
maternal anemia. We aimed to determine whether impaired
uteroplacental blood flow might account for the low infant birth
weight associated with maternal falciparum malaria infection.
METHODS: This observational study was carried out during a large
double-blind, randomized, controlled trial of an antimalarial
drug intervention for primigravidae. Nine hundred and
ninety-five women were recruited from the antenatal clinic at a
district hospital on the Kenya coast and had at least one
Doppler ultrasound scan. Uterine artery resistance index and the
presence or absence of a diastolic notch were recorded. In the
third trimester, blood was taken for hemoglobin and malaria
film. RESULTS: Malaria infection at 32--35 weeks of gestation
was associated with abnormal uterine artery flow velocity
waveforms on the day of blood testing (relative risk (RR) 2.11,
95% confidence interval (CI) 1.24--3.59, P = 0.006). This
association persisted after controlling for pre-eclampsia.
Impaired uteroplacental blood flow in the women studied was also
predictive of poor perinatal outcome, including low birth
weight, preterm delivery and perinatal death. The risk of
preterm delivery in women with histological evidence of past
placental malaria infection was more than twice that of women
without infection (RR 2.33, 95% CI 1.31--4.13, P = 0.004).
CONCLUSIONS: Uteroplacental hemodynamics are altered in the
presence of maternal falciparum malaria infection. This may
account for some of the excess of LBW babies observed in malaria
endemic areas. Strategies that prevent or clear placental
malaria may confer perinatal benefit through preservation of
Clin Diagn Lab Immunol 2002 Mar;9(2):348-51
Role of Th1 and Th2
Cytokines in Immune Response to Uncomplicated Plasmodium
Torre D, Speranza F, Giola M, Matteelli A, Tambini R, Biondi
Department of Infectious Diseases, Regional Hospital and Macchi
Foundation. Institute of Infectious Diseases, University of
Brescia Brescia, Italy.
The relative balance between Th1 and Th2 cytokines appears
crucial, since the role of cytokines has been evaluated in
several studies by comparison of clinically heterogeneous groups
of patients. The aim of this study is to determine the role of
proinflammatory Th1 cytokines, interleukin-12 (IL-12) and gamma
interferon (IFN-gamma), and anti-inflammatory Th2 cytokines,
IL-4 and IL-10, in a homogeneous group of patients with
uncomplicated Plasmodium falciparum malaria. Levels of IL-12,
IFN-gamma, Il-4, and IL-10 in serum for 20 adult patients and 15
healthy control subjects were determined by an immunoenzymatic
assay. Serum levels of Th1 cytokines, IL-12 (8.6 plus minus 2.8
pg/ml; controls, 3.2 plus minus 0.7 pg/ml) and IFN-gamma (39.2
plus minus 67.6 pg/ml; controls, 8.4 plus minus 6.3 pg/ml), were
significantly increased at admission; 3 days later, levels of
IL-12 in serum remained significantly high (8.8 plus minus 2.6
pg/ml), whereas IFN-gamma levels returned to control values. The
anti-inflammatory response of Th2 cytokines (IL-10 and IL-4) was
distinct. Levels of IL-10 in serum were not significantly
increased at day 0 and day 3 (306.6 plus minus 200.4 pg/ml and
56.6 plus minus 38.4 pg/ml, respectively; controls, 17.4 plus
minus 9.0 pg/ml). In contrast, levels of IL-4 in serum were not
increased on admission (3.4 plus minus 1.2 pg/ml; controls, 2.4
plus minus 0.8 pg/ml), but at day 3 a moderate and significant
increase of IL-4 levels was observed (4.5 plus minus 1.7 pg/ml).
In conclusion, the increase of Th1 cytokine IL-12 and IFN-gamma
levels during the acute phase of uncomplicated P. falciparum
malaria may reflect an early and effective immune response
regulated by proinflammatory Th1 cytokines, and in particular
IFN-gamma may play a role in limiting progression from
uncomplicated malaria to severe and life-threatening
Parasite Immunol 2002 Feb;24(2):77-82
immunoglobulin (Ig)G subclass antibodies to crude asexual
Plasmodium falciparum lysates: evidence for association with
protection for IgG1 and disease for IgG2.
Ndungu FM, Bull PC, Ross A, Lowe BS, Kabiru E, Marsh K.
Kenya Medical Research Institute Centre for Geographical
Medicine Research-Coast, Kilifi, Kenya, Zoology Department,
Kenyatta University, Nairobi and Nuffield Department of Clinical
Medicine, University of Oxford, John Radcliffe Hospital,
Headington, Oxford, UK.
There is longstanding evidence for a role of immunoglobulin (Ig)G
in protection against malarial disease and infection. IgG1 and
IgG3 have been shown to be particularly efficient at associating
with monocytes in potentially protective mechanisms (i.e.
antibody-dependent cellular inhibition, opsonization and
phagocytosis). Conversely, there is some evidence that IgG2 (and
possibly IgG4) antibodies may be antagonistic to this
protection. The protective effect of IgG subclass antibody
activity present before the beginning of a malaria transmission
season (preseason antibody levels) against severe malaria has
not been tested in longitudinal studies. We measured IgG class
and subclass antibody levels specific to crude Plasmodium
falciparum lysates by enzyme linked immunosorbent assay in a
case--control study of 76 children on the coast of Kenya. The
mean optical density values for both IgG class and subclass
antibodies were not significantly different between the children
who developed severe malaria and those who remained healthy
during an observation period of two malaria transmission
seasons. However, elevated levels of IgG1 in relation to levels
of IgG2 and IgG4 antibodies were associated with protection from
severe malaria (P = 0center dot02). Conversely, elevated levels
of IgG2 in relation to IgG1 and IgG3 antibodies were associated
with a higher risk of developing severe malaria (P = 0center
Trends Parasitol 2001 Nov;17(11):538-45
language of var genes and Plasmodium falciparum sequestration.
Smith JD, Gamain B, Baruch DI, Kyes S.
Dept of Pathology, Colorado State University, 80523, Fort
Collins, CO, USA
Sequestration and rosetting are key determinants of Plasmodium
falciparum pathogenesis. They are mediated by a large family of
variant proteins called P. falciparum erythrocyte membrane
protein 1 (PfEMP1). PfEMP1 proteins are multispecific binding
receptors that are transported to parasite-induced, 'knob-like'
binding structures at the erythrocyte surface. To evade immunity
and extend infections, parasites clonally vary their expressed
PfEMP1. Thus, PfEMP1 are functionally selected for binding while
immune selection acts to diversify the family. Here, we describe
a new way to analyse PfEMP1 sequence that provides insight into
domain function and protein architecture with potential
implications for malaria disease.
Trends Parasitol 2001 Nov;17(11):525-31
gametocyte sex ratios in malaria and related apicomplexan
West SA, Reece SE, Read AF.
Institute of Cell, Animal and Population Biology, University of
Edinburgh, EH9 3JT, Edinburgh, UK
'Survival of the fittest' is usually interpreted to mean that
natural selection favours genes that maximize their transmission
to the next generation. Here, we discuss recent applications of
this principle to the study of gametocyte sex ratios in malaria
and other apicomplexan parasites. Sex ratios matter because they
are an important determinant of fitness and transmission success
-- and hence of disease epidemiology and evolution. Moreover,
inbreeding rates can be estimated from gametocyte sex ratios.
The sex ratio is also an excellent model trait for testing the
validity of important components of what is being marketed as
J Biochem (Tokyo) 2002
Effect of antifungal
azoles on the heme detoxification system of malarial parasite.
Huy NT, Kamei K, Kondo Y, Serada S, Kanaori K, Takano R,
Tajima K, Hara S.
Department of Applied Biology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
Email: [email protected]
The antimalarial activities of some antifungal azole agents (ketoconazole,
miconazole, and clotrimazole) have been known for several years,
however, their antimalarial mechanism remains equivocal. Our
recent study showed that clotrimazole has a relative high
affinity for heme, inhibits reduced glutathione-dependent heme
catabolism, and enhances heme-induced hemolysis. In the present
study, we have found that clotrimazole can remove heme from
histidine rich peptide-heme complex, which initiates heme-polymerization
in malaria. In addition, we show that two other azoles (ketoconazole
and miconazole) behave similarly to clotrimazole in binding to
heme: they bind to heme with similar affinities, remove heme
from the histidine rich peptide-heme complex and from the
reduced glutathione-heme complex to form stable heme-azole
complexes with two nitrogenous ligands derived from the
imidazole moieties of two azole molecules. We have also revealed
that clotrimazole and miconazole have stronger promoting
activities for heme-induced hemolysis than ketoconazole,
implying that the stronger antimalarial activities of
clotrimazole and miconazole might arise from their stronger
ability to promote heme-induced hemolysis of clotrimazole and
clotrimazole than that of ketoconazole. These results also
suggest that ketoconazole and miconazole, like clotrimazole,
might possess an antimalarial mechanism relating to their
inhibition of heme polymerization and the degradation of reduced
Lancet Infect Dis 2001 Nov;1(4):242-50
chemotherapeutic options for malaria.
Department of Pharmacology and Therapeutics, and Wellcome Trust
Centre for Research in Clinical Tropical Medicine, University of
Email: [email protected]
Unlike HIV disease or tuberculosis, both of which are also major
threats to public health throughout the tropics, uncomplicated
malaria of whatever species can be cheaply and rapidly cured,
usually in outpatients. However, in common with both HIV and
tuberculosis, control of malaria is threatened by inadequate
resources and by drug resistance. Africa carries the greatest
burden of malaria mortality and morbidity; by no coincidence,
Africa is also the most resource-limited. The drugs for severe
disease (quinine and the artemisinins) are largely unaffected by
resistance so far, but the "first-line" drugs, mainly
used by outpatients (eg, chloroquine and
sulfadoxine-pyrimethamine), are a major cause for concern.
Although effective drugs are available they are mostly too
expensive for routine use. This article reviews the main drugs
for malaria and outlines the therapeutic use of these drugs for
uncomplicated and severe disease. The article then examines the
challenges faced in the processes of changing policy, and the
implementation of that policy shift.