Bulletin—May 5-20, 2001
Sciences and Malaria
Trop Med Int Health 2001 Apr;6(4):280-95
- Comparison of the cost and
cost-effectiveness of insecticide-treated bednets and residual
house-spraying in KwaZulu-Natal, South Africa.
Goodman CA, Mnzava AE, Dlamini SS, Sharp BL, Mthembu DJ,
Health Policy Unit, Department of Public Health and Policy,
London School of Hygiene and Tropical Medicine, Keppel Street,
London WC1E 7HT, UK. catherine.goodma[email protected]
Residual house-spraying (RHS) has been the mainstay of South
African malaria prevention for more than 50 years, but it has
been argued that insecticide-treated bednets (ITBN) could be a
more effective and appropriate method of control. To provide a
rational basis for choosing between the interventions, a trial
was conducted during 1998 and 1999 in northern KwaZulu-Natal
to collect comparable data on the effectiveness, acceptability
and cost of the two interventions. The current practice of
house-spraying once a year was compared with ITBN, distributed
free to households and retreated annually at several specific
centres. The base case results show ITBN to be significantly
more effective in preventing malaria cases than RHS (overall
adjusted rate ratio of 0.69), and also more costly, with an
incremental economic cost per person of ITBN compared with RHS
of R8.68 (US$1.42) per year, giving a gross incremental cost
per case averted of R111 ($18) (1999 prices). Estimating the
number of deaths averted, based on the average case fatality
rate, gave a gross incremental cost per death averted of R11
718 ($1915). The additional cases averted were estimated to
lead to drug cost savings of around R1 ($0.16) per capita per
year, giving a net cost per case averted of R98 ($16), and net
cost per death averted of R10 377 ($1696). Although the
finding that the economic costs of ITBN were higher than those
for RHS was relatively robust to parameter variations, the
extent of the cost margin was sensitive to changes in the
price and useful life of the net, and the price of the
insecticide. Moreover, a switch to ITBN could lead to net
financial savings if the price per net fell below $3.57
(R21.85), or if a change in policy allowed a significant
reduction in the number of permanent full-time malaria control
staff. In view of the greater effectiveness of ITBN, policy
makers may view ITBN as a cost-effective use of resources,
even if the economic costs are higher. If ITBN are
implemented, close monitoring will be required of use,
retreatment and useful life of nets, and resistance to
insecticides, to assess any change over time in relative
cost-effectiveness, and any threat to the role of the
programme as a barrier to the spread of malaria transmission
to other areas.
PMID: 11348519 [PubMed - in process]
- Health Policy Plan 2001 May;16(2):171-9
- Changing roles of grass-root level health
workers in Kerala, India.
Nair V, Thankappan K, Sarma P, Vasan R.
Kerala Health Services and. Achutha Menon Centre for Health
Science Studies, Sree Chitra Tirunal Institute for Medical
Sciences and Technology, Thiruvananthapuram, Kerala, India.
OBJECTIVE: Multipurpose health workers (MPWs) are envisioned
as key personnel in the delivery of primary health care. We
evaluated their role and participation in implementing
different national health programmes in Kerala, INDIA: DESIGN:
Cross-sectional, community-based survey. PARTICIPANTS: We
selected three out of the 14 districts in KERALA:
Three-hundred and twenty-six MPWs (95 male and 231 female)
from 44 randomly selected primary health centres from the
three districts were questioned using a structured pre-tested
questionnaire that sought information regarding the provision
of health services by the MPWs to eligible beneficiaries in
the community. We randomly selected 90 subcentres (30 from
each district) and 750 households using a cluster sampling
technique, and conducted household surveys to compare the
actual delivery of services at the doorstep with that reported
by the MPWS: Work sampling of MPWs was also performed to
examine the fieldwork time spent by them on implementing
individual national health programmes. These data were
supplemented with focus group discussions and personal
interviews of MPWs and household members. RESULTS: MPWs
consistently 'over-reported' their performance when
self-reported information was compared with that obtained from
household surveys. Male MPWs concentrated on the National
Malaria Eradication Programme and health education while
female workers focused on the family welfare and immunization
programmes. Key national health programmes (such as for
tuberculosis and acute respiratory infection) were neglected
by all MPWS: MPWs were aware of health problems of the
elderly, but were not adequately trained nor officially
expected to deliver any services in these fields. CONCLUSIONS:
Grass-root level workers apportion more time to select
national health programmes to the detriment of other health
programmes, thereby negating their multipurpose role. Our
study emphasizes the need for interventions to derive
'multipurpose benefits' from the MPWS:
PMID: 11358918 [PubMed - in process]
Trans R Soc Trop Med Hyg 2001 Mar-Apr;95(2):125-6
- Refugee health in the tropics. Malaria
control in Afghan refugee camps: novel solutions.
HealthNet International, P. O. Box 889, University Town,
- [email protected]
Malaria is one of the major communicable diseases to occur in
refugee camps. Prevention of mortality by establishing good
case management is always the priority. Various types of
personal protection or vector control measures may be applied
depending on local transmission conditions and stage of the
emergency. The range of interventions applied in Afghan
refugee camps, the factors influencing choice and the
relevance to emergencies in other parts of the world are
PMID: 11355539 [PubMed - in process]
Trop Med Int Health 2001 Apr;6(4):273-9
- Malaria diagnosis and treatment
administered by teachers in primary schools in Tanzania.
Magnussen P, Ndawi B, Sheshe AK, Byskov J, Mbwana K.
Danish Bilharziasis Laboratory, Charlottenlund, Denmark;
Primary Health Care Institute, Iringa, Tanzania; School of
Environmental Health, Tanga, Tanzania; District Medical
Office, Ministry of Health, Pangani, Tanzania.
A school health programme in Mwera Division, Pangani District
included treatment of malaria attacks occurring in children
during school time. A combination of symptoms (headache,
muscle/joint pains, feeling feverish) and oral temperature
>/= 37.5 degrees C was used for the diagnosis of malaria.
Chloroquine (25 mg/kg given over 3 days) was used for
treatment. Malariometric surveys on children aged 7-15 years
(mean 10 years) were conducted once a year (1995-1997).
Plasmodium falciparum accounted for 100% of infections and the
parasite prevalence varied between 32.7 and 35.3% from 1995 to
1997. The number of malaria cases (cases/1000 registered
school children) diagnosed and treated by school teachers was
159 (67) in 1995, 324 (124) in 1996, 348 (128) in 1997 and 339
(108) in 1998. Children in grades 1-4 (age 7-13) accounted for
64.6% of cases. Symptoms and oral temperature were recorded
for 1258 children. Of those, 992 (78.9%) complained of fever
and at least one other symptom when presenting to teachers, 98
(7.8%) had fever as their only complaint and 168 (13.5%)
presented without a perception of fever, but with other
symptoms. Of these children, 36 (21.4%) had a temperature
>/=37.5 degrees C. The sensitivity of 'feeling feverish'
was 96.5% with a specificity of 54.5%. The positive predictive
value of feeling feverish was 89.9% and the negative
predictive value 78.6%. Blood slides were prepared from 55.3
and 37.2% of children diagnosed by teachers during 1995 and
1996, respectively, and 71.4% were found positive. Among
children who fulfilled the algorithm criteria 75.0% had a
positive blood slide. With little training and regular
supervision it was feasible for school teachers to make a
presumptive diagnosis of malaria. We conclude that teachers
can play a major role in school health programmes and are
willing to be involved in health matters as long as they are
supported by health and educational authorities.
PMID: 11348518 [PubMed - in process]
- Am J Trop Med Hyg 2000 Jul-Aug;63(1-2):90-3
Enhanced development in nature of larval
Anopheles arabiensis mosquitoes feeding on maize pollen.
Ye-Ebiyo Y, Pollack RJ, Spielman A.
Department of Immunology and Infectious Diseases, Harvard
School of Public Health, Boston, Massachusetts 02115, USA.
To determine whether pollen produced by maize (Zea m. mays)
may contribute to the development of larval Anopheles gambiae
complex mosquitoes, the main African vectors of malaria, we
correlated duration of larval development, pupation success,
and size of the resulting adults with degree of access to this
potential nutriment. Maize pollen is abundant during the wet
season on the surface of water near maize plantings in a
malaria-endemic region of Ethiopia, and larval Anopheles
arabiensis readily ingest these particles in nature. Larvae
develop to the pupal stage more rapidly, more frequently, and
produce larger adults where maize pollen is abundant than do
those that have little access to this food. The force of
transmission of malaria in sub-Saharan Africa might be reduced
if maize plantings were excluded from the immediate vicinity
of homes or, perhaps, if pollen of such maize were to express
PMID: 11358003 [PubMed - in process]
Am J Trop Med Hyg 2000 Jul-Aug;63(1-2):80-4
- A trial for a DNA diagnosis of Plasmodium
vivax malaria recently reemerging in the Republic of Korea
using microtiter plate hybridization assay.
Chai JY, Park YK, Guk SM, Oh KH, Oh MD, Lee SH, Kim HS,
Department of Parasitology, Seoul National University College
of Medicine, Institute of Endemic Diseases, Seoul National
University Medical Research Center, Korea. [email protected]
The polymerase chain reaction-based microtiter plate
hybridization (PCR-MPH) assay was utilized for a DNA diagnosis
of Plasmodium vivax malaria, which has recently reemerged in
the Republic of Korea. The subjects were 18 parasite-proven
patients and 5 healthy controls. Follow-up blood samples were
collected from 4 patients after a standard course of
treatment. Polymerase chain reaction and electrophoresis of
all the patients' blood showed a prominent band at the 138
base pair area, but not in the controls or after treating the
patients. Hybridization of the PCR products with known
species-specific probes of the 18S rRNA of various malaria
species revealed strong positive reactions against the
Plasmodium vivax-specific probe (absorbance 1.30-1.90 at 405
nm) in all of the patients. The absorbance was positively
correlated with the degree of blood parasitemia, but with a
borderline significance. Sequencing of the probe region of the
Korean P. vivax revealed no significant variations from the
typical P. vivax. The results show that the PCR-MPH is a
highly useful technique for the DNA diagnosis of Korean vivax
PMID: 11358001 [PubMed - in process]
Am J Trop Med Hyg 2000 Jul-Aug;63(1-2):76-9
- Use of the Parasight-F diagnostic test
for imported malaria in a travel clinic.
Bouchaud O, Houze S, Longuet C, di Piazza JP, Ruggieri C,
Secardin Y, Coulaud JP, Le Bras J.
Department of Infectious and Tropical Diseases, H pital Bichat-Claude
Bernard, Paris, France. [email protected]
The Parasight-F test based on the detection of a soluble
antigen specific for Plasmodium falciparum is designed for the
immediate diagnosis of malaria infection. We evaluated its use
by clinicians during consultations. This prospective study of
its diagnostic utility in febrile patients consulting a travel
clinic on their return from areas endemic for malaria was
conducted between May 1996 and May 1997. The Parasight-F test
was performed by the clinician with confirmation by means of
standard microscopic examination of venous blood. One-hundred
and forty patients were enrolled. Forty-three (31%) cases of
malaria were identified by microscopic examination.
Thirty-eight were due to P. falciparum. The Parasight-F tests
yielded 6 false-positive and 3 false-negative results compared
to the microscopic findings. The specificity and sensitivity
for the diagnosis of P. falciparum malaria were 94% and 92%.
These results show that the Parasight-F test alone cannot
replace microscopic diagnosis of malaria in travel clinics.
PMID: 11358000 [PubMed - in process]
Mol Biochem Parasitol 2001 Apr 25;114(1):89-94
- A phylogenetic comparison of gene trees
constructed from plastid, mitochondrial and genomic DNA of
Rathore D, Wahl AM, Sullivan M, McCutchan
Laboratory of Parasitic Diseases, National Institute of
Allergy and Infectious Diseases, National Institutes of
Health, 4 Center Drive MSC 0425, 20892-0425, Bethesda, MD, USA
Gene trees of Plasmodium species have been reported for the
nuclear encoded genes (e.g. the Small Subunit rRNA) and a
mitochondrial encoded gene, cytochrome b. Here, we have
analyzed a plastid gene coding for caseinolytic protease ClpC,
whose structure, function and evolutionary history have been
studied in various organisms. This protein possesses a 220-250
amino acid long AAA domain (ATPases associated with a variety
of cellular activities) that belongs to the Walker super
family of ATPases and GTPases. We have sequenced the AAA motif
of this gene, encoding the protein from nine different species
of Plasmodium infecting rodents, birds, monkeys, and humans.
The codon usage and GC content of each gene were nearly
identical in contrast to the widely varying nucleotide
composition of genomic DNAs. Phylogenetic trees derived from
both DNA and inferred protein sequences have consistent
topologies. We have used the ClpC sequence to analyze the
phylogenetic relationship among Plasmodium species and
compared it with those derived from mitochondrial and genomic
sequences. The results corroborate well with the trees
constructed using the mitochondrially encoded cytochrome b.
However, an important element distinguishes the trees: the
placement of Plasmodium elongatum near the base of the plastid
tree, indicating an ancient lineage of parasites in birds that
branches from the tree prior to other lineages of avian
malaria and the human parasite, P. falciparum.
PMID: 11356517 [PubMed - in process]
Parasitol Res 2001 Apr;87(4):264-8
- Cytoadherence of the malaria-infected
erythrocyte membrane to C32 melanoma cells after merozoites
are released from parasitized infected cells.
Winograd E, Robles WM, Caldas ML, Cortes GT.
Laboratorio de Biologia Celular, Instituto Nacional de Salud,
- [email protected]
Infections with the human malaria parasite Plasmodium
falciparum are characterized by cytoadherence of infected
erythrocytes to the venular endothelium of several organs.
Video microscopy studies have shown that at the end of the
asexual life of P. falciparum, the residual body containing
haemozoin is released to the extracellular environment along
with merozoites, leaving behind an infected erythrocyte
"ghost". It is possible that these infected
erythrocyte "ghosts" could remain sequestered within
the blood vessels of patients infected with P. falciparum even
after merozoites have been released from infected
erythrocytes. In this study an in vitro cytoadherence assay
was developed to show that infected erythrocyte
"ghosts" can interact with C32 melanoma cells.
Adherent infected erythrocyte "ghosts" contain some
of the subcellular compartments of the malaria-infected red
blood cell such as the tubo-vesicular membrane network and
remnants of the parasitophorous vacuolar membrane, but lack
PMID: 11355673 [PubMed - in process]
Trans R Soc Trop Med Hyg 2001 Mar-Apr;95(2):225-32
- Genotyping of Plasmodium
falciparum infections by PCR: a comparative multicentre study.
Farnert A, Arez AP, Babiker HA, Beck HP, Benito A, Bjorkman
A, Bruce MC, Conway DJ, Day KP, Henning L, Mercereau-Puijalon
O, Ranford-Cartwright LC, Rubio JM, Snounou G, Walliker D,
Zwetyenga J, do Rosario VE.
Division of Infectious Diseases, Department of Medicine,
Karolinska Institutet, Huddinge University Hospital, 14186
Huddinge, Sweden. [email protected]
Genetic diversity of malaria parasites represents a major
issue in understanding several aspects of malaria infection
and disease. Genotyping of Plasmodium falciparum infections
with polymerase chain reaction (PCR)-based methods has
therefore been introduced in epidemiological studies.
Polymorphic regions of the msp1, msp2 and glurp genes are the
most frequently used markers for genotyping, but methods may
differ. A multicentre study was therefore conducted to
evaluate the comparability of results from different
laboratories when the same samples were analysed. Analyses of
laboratory-cloned lines revealed high specificity but varying
sensitivity. Detection of low-density clones was hampered in
multiclonal infections. Analyses of isolates from Tanzania and
Papua New Guinea revealed similar positivity rates with the
same allelic types identified. The number of alleles detected
per isolate, however, varied systematically between the
laboratories especially at high parasite densities. When the
analyses were repeated within the laboratories, high agreement
was found in getting positive or negative results but with a
random variation in the number of alleles detected. The msp2
locus appeared to be the most informative single marker for
analyses of multiplicity of infection. Genotyping by PCR is a
powerful tool for studies on genetic diversity of P.
falciparum but this study has revealed limitations in
comparing results on multiplicity of infection derived from
different laboratories and emphasizes the need for highly
standardized laboratory protocols.
PMID: 11355566 [PubMed - in process]
Trans R Soc Trop Med Hyg 2001 Mar-Apr;95(2):179-82
- Persistence of Plasmodium falciparum
HRP-2 in successfully treated acute falciparum malaria.
Mayxay M, Pukrittayakamee S, Chotivanich K, Looareesuwan S,
Faculty of Tropical Medicine, Mahidol University, 420/6
Rajvithi Road, Bangkok 10400, Thailand.
The potential for Plasmodium falciparum histidine-rich
protein-2 (PfHRP-2) dipstick tests to predict antimalarial
treatment failure was investigated in a prospective study in
Thailand of 38 patients admitted with severe malaria and 54
hospitalized with uncomplicated P. falciparum infections. Of
these, 40 had subsequent recrudescence of their infections.
Overall, 89% of patients with severe malaria and 61% of
patients with uncomplicated malaria had positive PfHRP-2
dipstick tests for > 2 weeks following the start of
treatment. Persistence was correlated positively with
admission parasite counts, PfHRP-2 intensity scores and
disease severity. PfHRP-2 tests which remained positive for
> 2 weeks and PfHRP-2 reactive intensity scores on
admission, at day 7 and day 14 did not predict treatment
failure independent of admission parasitaemia. Freezing and
thawing the blood samples did not significantly affect PfHRP-2
results tested by the dipstick technique. The PfHRP-2 dipstick
test provides a useful indicator of recent severe malaria, but
does not predict the therapeutic response.
PMID: 11355555 [PubMed - in process]
Trans R Soc Trop Med Hyg 2001 Mar-Apr;95(2):149-52
- The lower susceptibility to Plasmodium
falciparum malaria of Fulani of Burkina Faso (west Africa) is
associated with low frequencies of classic malaria-resistance
Modiano D, Luoni G, Sirima BS, Lanfrancotti A, Petrarca V,
Cruciani F, Simpore J, Ciminelli BM, Foglietta E, Grisanti P,
Bianco I, Modiano G, Coluzzi M.
Dipartimento di Biologia Molecolare, Cellulare e Animale,
Universita di Camerino, Italy.
- [email protected]
The gene frequencies in 1993-94 for haemoglobin S, haemoglobin
C, alpha-3.7 deletional thalassaemia, G6PDA-, HLAB*5301 were
estimated in Fulani, Mossi and Rimaibe ethnic groups of
Burkina Faso, West Africa. The aim of the study was to verify
whether the previously reported Fulani lower susceptibility to
Plasmodium falciparum malaria was associated with any of these
malaria-resistance genes. Similar frequencies for haemoglobin
S were recorded in the 3 ethnic groups (0.024 +/- 0.008, 0.030
+/- 0.011, 0.022 +/- 0.013; in Mossi, Rimaibe and Fulani,
respectively). The Mossi and Rimaibe showed higher frequencies
when compared to Fulani for haemoglobin C (0.117 +/- 0.018,
0.127 +/- 0.020, 0.059 +/- 0.020), alpha-3.7 deletional
thalassaemia (0.227 +/- 0.040, 0.134 +/- 0.032, 0.103 +/-
0.028), G6PDA- (0.196 +/- 0.025, 0.187 +/- 0.044, 0.069 +/-
0.025) and HLA B*5301 (0.189 +/- 0.038, 0.202 +/- 0.041, 0.061
+/- 0.024). Among Fulani the proportion of individuals not
having any of these protective alleles was more than 3-fold
greater than in the Mossi-Rimaibe group (56.8% vs 16.7%; P
< 0.001). These findings exclude the involvement of these
genetic factors of resistance to P. falciparum in the lower
susceptibility to malaria of Fulani. This evidence, in
association with the previously reported higher immune
reactivity to malaria of Fulani, further supports the
existence in this ethnic group of unknown genetic factor(s) of
resistance to malaria probably involved in the regulation of
humoral immune responses.
PMID: 11355545 [PubMed - in process]
Trans R Soc Trop Med Hyg 2001 Mar-Apr;95(2):137-8
- A double-blind randomized therapeutic
trial of insect repellents for the prevention of malaria in
McGready R, Simpson JA, Htway M, White NJ, Nosten F,
Shoklo Malaria Research Unit, P.O. Box 46, Mae Sot, Tak 63110,
PMID: 11355542 [PubMed - in process]
Antimicrob Agents Chemother 2001 Jun;45(6):1847-53
- Human malaria in immunocompromised mice:
new in vivo model for chemotherapy studies.
Moreno A, Badell E, Van Rooijen N, Druilhe P.
Biomedical Parasitology Unit, Pasteur Institute, 75724 Paris
Cedex 15, France.
We have recently designed a new Plasmodium falciparum mouse
model and documented its potential for the study of immune
effector mechanisms. In order to determine its value for drug
studies, we evaluated its response to existing antimalarial
drugs compared to that observed in humans. Immunocompromised
BXN (bg/bg xid/xid nu/nu) mice were infected with either the
sensitive NF54 strain or the multiresistant T24 strain and
then treated with chloroquine, quinine, mefloquine, or
dihydroartemisinin. A parallelism was observed between
previously reported human responses and P.
falciparum-parasitized human red blood cell (huRBC)-BXN mouse
responses to classical antimalarial drugs, measured in terms
of speed of decrease in parasitemia and of morphological
alterations of the parasites. Mice infected with the sensitive
strain were successfully cured after treatment with either
chloroquine or mefloquine. In contrast, mice infected with the
multiresistant strain failed to be cured by chloroquine or
quinine but thereafter responded to dihydroartemisinin
treatment. The speed of parasite clearance and the
morphological alterations induced differed for each drug and
matched previously reported observations, hence stressing the
relevance of the model. These data thus suggest that P.
falciparum-huRBC-BXN mice can provide a valuable in vivo
system and should be included in the short list of animals
that can be used for the evaluation of P. falciparum responses
PMID: 11353636 [PubMed - in process]
Antimicrob Agents Chemother 2001 Jun;45(6):1803-9
- Population pharmacokinetics of
intramuscular quinine in children with severe malaria.
Krishna S, Nagaraja NV, Planche T, Agbenyega T, Bedo-Addo
G, Ansong D, Owusu-Ofori A, Shroads AL, Henderson G, Hutson A,
Derendorf H, Stacpoole PW.
Department of Infectious Diseases, St. George's Hospital
Medical School, Cranmer Terrace, London SW17 ORE, United
We present the first population pharmacokinetic analysis of
quinine in patients with Plasmodium falciparum malaria.
Ghanaian children (n = 120; aged 12 months to 10 years) with
severe malaria received an intramuscular loading dose of
quinine dihydrochloride (20 mg/kg of body weight). A
two-compartment model with first-order absorption and
elimination gave post hoc estimates for pharmacokinetic
parameters that were consistent with those derived from
non-population pharmacokinetic studies (clearance [CL] = 0.05
liter/h/kg of body weight; volume of distribution in the
central compartment [V(1)] = 0.65 liter/kg; volume of
distribution at steady state = 1.41 liter/kg; half-life at
beta phase = 19.9 h). There were no covariates (including age,
gender, acidemia, anemia, coma, parasitemia, or anticonvulsant
use) that explained interpatient variability in
weight-normalized CL and V(1). Intramuscular quinine was
associated with minor, local toxicity in some patients (13 of
108; 12%), and 11 patients (10%) experienced one or more
episodes of postadmission hypoglycemia. A loading dose of
intramuscular quinine results in predictable population
pharmacokinetic profiles in children with severe malaria and
may be preferred to the intravenous route of administration in
PMID: 11353629 [PubMed - in process]
J Biol Chem 2001 May 14
- The binding of the circumsporozoite
protein to cell surface proteoglycans is required for
plasmodium sporozoite attachment to target cells.
Pinzon-Ortiz C, Friedman J, Esko J, Sinnis P.
Medical and Molecular Parasitology, New York University School
of Medicine, New York, NY 10010.
The major surface protein of malaria sporozoites, the
circumsporozoite protein, binds to heparan sulfate
proteoglycans on the surface of hepatocytes. It has been
proposed that this binding event is responsible for the rapid
and specific localization of sporozoites to the liver after
their injection into the skin by an infected Anopheline
mosquito. Previous in vitro studies performed under static
conditions have failed to demonstrate a significant role for
HSPGs during sporozoite invasion of cells. We performed
sporozoite attachment and invasion assays under more dynamic
conditions and found a dramatic decrease in sporozoite
attachment to cells in the presence of heparin. In contrast to
its effect on attachment, heparin does not appear to have an
effect on sporozoite invasion of cells. When substituted
heparins were used as competitive inhibitors of sporozoite
attachment, we found that sulfation of the glycosaminoglycan
chains at both the N- and O- positions was important for
sporozoite adhesion to cells. We conclude that the binding of
the circumsporozoite protein to hepatic heparan sulfate
proteoglycans is likely to function during sporozoite
attachment in the liver and that this adhesion event depends
on the sulfated glycosaminoglycan chains of the proteoglycans.
PMID: 11352923 [PubMed - as supplied by publisher]
Pharmacol Res 2001 Apr;43(4):363-7
- Aminonaphthoquinones-a novel class of
compounds with potent antimalarial activity against plasmodium
Kapadia GJ, Azuine MA, Balasubramanian V, Sridhar R.
Laboratory of Natural Drug Products, Department of
Pharmaceutical Sciences, School of Pharmacy, Howard
University, 2300 4th Street, NW, Washington DC 20059, USA
Malaria is a major tropical disease, which kills two million
people annually. The population at risk from this disease has
increased because of the difficulties in eradicating the
mosquito vector in the endemic regions and the emergence and
spread of parasite resistance to all the commonly used
antimalarials. Since antimalarials are the major arsenal for
treatment of the disease, there is an urgent need for newer
drugs with novel mechanisms of action, which will be effective
against all strains of the parasite. As a part of our
anti-infective drug discovery program, we have investigated 18
compounds including several synthetic and natural
naphthoquinones as potential antimalarial agents. We have
identified aminonaphthoquinones, as a class of antimalarial
compounds with antimalarial activity against Plasmodium
falciparum. Among these compounds,
2-amino-3-chloro-1,4-naphthoquinone is the most potent. It had
an IC(50)of 0.18 &mgr; M (37.3 ng ml(-1)) against the W2
clone, and is more potent than chloroquine, which had an
IC(50)of 0.23 &mgr; M (72 ng ml(-1)). It was also active
against the D6 clone. In general, 2-amino-1,4-naphthoquinone
analogs and the 4-amino-1,2-napthoquinone analog showed
promising antimalarial activity in the bioassay. In contrast,
a number of 2-hydroxy-1,4-naphthoquinones and dimeric quinones
were less active. Copyright 2001 Academic Press.
PMID: 11352541 [PubMed - in process]
Am J Physiol Cell Physiol 2001 Jun;280(6):C1576-87
- Perturbation of the pump-leak balance for
Na(+) and K(+) in malaria-infected erythrocytes.
Staines HM, Ellory JC, Kirk K.
University Laboratory of Physiology, Oxford OX1 3PT, United
In human erythrocytes infected with the mature form of the
malaria parasite Plasmodium falciparum, the cytosolic
concentration of Na(+) is increased and that of K(+) is
decreased. In this study, the membrane transport changes
underlying this perturbation were investigated using a
combination of (86)Rb(+), (43)K(+), and (22)Na(+) flux
measurements and a semiquantitative hemolysis technique. From
>15 h postinvasion, there appeared in the infected
erythrocyte membrane new permeation pathways (NPP) that caused
a significant increase in the basal ion permeability of the
erythrocyte membrane and that were inhibited by furosemide
(0.1 mM). The NPP showed the selectivity sequence Cs(+) >
Rb(+) > K(+) > Na(+), with the K(+)-to-Na(+)
permeability ratio estimated as 2.3. From 18 to 36 h
postinvasion, the activity of the erythrocyte Na(+)/K(+) pump
increased in response to increased cytosolic Na(+) (a
consequence of the increased leakage of Na(+) via the NPP) but
underwent a progressive decrease in the latter 12 h of the
parasite's occupancy of the erythrocyte (36-48 h postinvasion).
Incorporation of the measured ion transport rates into a
mathematical model of the human erythrocyte indicates that the
induction of the NPP, together with the impairment of the
Na(+)/K(+) pump, accounts for the altered Na(+) and K(+)
levels in the host cell cytosol, as well as predicting an
initial decrease, followed by a lytic increase in the volume
of the host erythrocyte.
PMID: 11350753 [PubMed - in process]
Infect Immun 2001 Jun;69(6):4048-54
- Disruption of Plasmodium falciparum
Chitinase Markedly Impairs Parasite Invasion of Mosquito
Tsai YL, Hayward RE, Langer RC, Fidock DA, Vinetz
WHO Collaborating Center for Tropical Diseases, Department of
Pathology, University of Texas Medical Branch, Galveston,
To initiate invasion of the mosquito midgut, Plasmodium
ookinetes secrete chitinolytic activity to penetrate the
peritrophic matrix surrounding the blood meal. While ookinetes
of the avian malaria parasite Plasmodium gallinaceum appear to
secrete products of two chitinase genes, to date only one
chitinase gene, PfCHT1, has been identified in the nearly
completed Plasmodium falciparum strain 3D7 genome database. To
test the hypothesis that the single identified chitinase of P.
falciparum is necessary for ookinete invasion, the PfCHT1 gene
was disrupted 39 bp upstream of the stop codon.
PfCHT1-disrupted parasites had normal gametocytogenesis,
exflagellation, and ookinete formation but were markedly
impaired in their ability to form oocysts in Anopheles
freeborni midguts. Confocal microscopy demonstrated that the
truncated PfCHT1 protein was present in mutant ookinetes but
that the concentration of mutant PfCHT1 within the apical end
of the ookinetes was substantially reduced. These data suggest
that full-length PfCHT1 is essential for intracellular
trafficking and secretion and that the PfCHT1 gene product is
necessary for ookinetes to invade the mosquito midgut.
PMID: 11349075 [PubMed - in process]
Infect Immun 2001 Jun;69(6):4041-7
- Knockout of the rodent malaria parasite
chitinase pbcht1 reduces infectivity to mosquitoes.
Dessens JT, Mendoza J, Claudianos C, Vinetz JM, Khater E,
Hassard S, Ranawaka GR, Sinden RE.
Department of Biology, Imperial College of Science,
Technology, and Medicine, London SW7 2AZ, United Kingdom.
During mosquito transmission, malaria ookinetes must cross a
chitin-containing structure known as the peritrophic matrix
(PM), which surrounds the infected blood meal in the mosquito
midgut. In turn, ookinetes produce multiple chitinase
activities presumably aimed at disrupting this physical
barrier to allow ookinete invasion of the midgut epithelium.
Plasmodium chitinase activities are demonstrated targets for
human and avian malaria transmission blockade with the
chitinase inhibitor allosamidin. Here, we identify and
characterize the first chitinase gene of a rodent malaria
parasite, Plasmodium berghei. We show that the gene, named
PbCHT1, is a structural ortholog of PgCHT1 of the avian
malaria parasite Plasmodium gallinaceum and a paralog of
PfCHT1 of the human malaria parasite Plasmodium falciparum.
Targeted disruption of PbCHT1 reduced parasite infectivity in
Anopheles stephensi mosquitoes by up to 90%. Reductions in
infectivity were also observed in ookinete feeds-an artificial
situation where midgut invasion occurs before PM
formation-suggesting that PbCHT1 plays a role other than PM
disruption. PbCHT1 null mutants had no residual ookinete-derived
chitinase activity in vitro, suggesting that P. berghei
ookinetes express only one chitinase gene. Moreover, PbCHT1
activity appeared insensitive to allosamidin inhibition, an
observation that raises questions about the use of allosamidin
and components like it as potential malaria
transmission-blocking drugs. Taken together, these findings
suggest a fundamental divergence among rodent, avian, and
human malaria parasite chitinases, with implications for the
evolution of Plasmodium-mosquito interactions.
PMID: 11349074 [PubMed - in process]
Infect Immun 2001 Jun;69(6):3845-52
- Human Antibodies against Plasmodium
falciparum Liver-Stage Antigen 3 Cross-React with Plasmodium
yoelii Preerythrocytic-Stage Epitopes and Inhibit Sporozoite
Invasion In Vitro and In Vivo.
Brahimi K, Badell E, Sauzet JP, BenMohamed L, Daubersies P,
Guerin-Marchand C, Snounou G, Druilhe P.
Laboratoire de Parasitologie Biomedicale, Institut Pasteur,
75015 Paris Cedex 15, France.
The Plasmodium falciparum liver-stage antigen 3 (LSA3), a
recently identified preerythrocytic antigen, induces
protection against malaria in chimpanzees. Using antibodies
from individuals with hyperimmunity to malaria affinity
purified on recombinant or synthetic polypeptides of LSA3, we
identified four non-cross-reactive B-cell epitopes in
Plasmodium yoelii preerythrocytic stages. On sporozoites the
P. yoelii protein detected has a molecular mass similar to
that of LSA3. T-cell epitopes cross-reacting with P. yoelii
were also demonstrated using peripheral blood lymphocytes from
LSA3-immunized chimpanzees. In contrast, no cross-reactive
epitopes were found in Plasmodium berghei. LSA3-specific human
antibodies exerted up to 100% inhibition of in vitro invasion
of P. yoelii sporozoites into mouse hepatocytes. This strong
in vitro activity was reproduced in vivo by passive transfer
of LSA3 antibodies. These results indicate that the homologous
epitopes may be biologically functional and suggest that P.
yoelii could be used as a model to assess the antisporozoite
activity of anti-LSA3 antibodies.
PMID: 11349050 [PubMed - in process]
Infect Immun 2001 Jun;69(6):3713-8
- Antibodies to variant antigens on the
surfaces of infected erythrocytes are associated with
protection from malaria in ghanaian children.
Dodoo D, Staalsoe T, Giha H, Kurtzhals JA, Akanmori BD,
Koram K, Dunyo S, Nkrumah FK, Hviid L, Theander TG.
Immunology and Epidemiology Units, Noguchi Memorial Institute
for Medical Research, University of Ghana, Legon, Ghana.
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1)
is a variant antigen expressed on the surface of infected
erythrocytes. Each parasite genome contains about 40 PfEMP1
genes, but only 1 PfEMP1 gene is expressed at a given time.
PfEMP1 serves as a parasite-sequestering ligand to endothelial
cells and enables the parasites to avoid splenic passage.
PfEMP1 antibodies may protect from disease by inhibiting
sequestration, thus facilitating the destruction of infected
erythrocytes in the spleen. In this study, we have measured
antibodies in Ghanaian children to a conserved region of
PfEMP1 by enzyme-linked immunosorbent assay and antibodies to
variant molecules on erythrocytes infected with field isolates
of P. falciparum by flow cytometry. Based on close clinical
monitoring, the children were grouped into those who did
(susceptible) and those who did not (protected) have malaria
during the season. The prevalences of antibodies to both the
conserved PfEMP1 peptide and the variant epitopes were greater
than 50%, and the levels of immunoglobulin G (IgG) correlated
with age. The levels of antibodies to both the conserved
peptide and the variant epitopes were higher in protected than
in susceptible children. After correcting for the effect of
age, the levels of IgG to variant antigens on a Sudanese and a
Ghanaian parasite isolate remained significantly higher in
protected than in susceptible children. Thus, the levels of
IgG to variant antigens expressed on the surface of infected
erythrocytes correlated with protection from clinical malaria.
In contrast, the levels of IgG to a peptide derived from a
conserved part of PfEMP1 did not correlate with protection
PMID: 11349035 [PubMed - in process]
J Am Mosq Control Assoc 2001 Mar;17(1):13-22
- Insecticide-induced behavioral responses
of anopheles minimus, a malaria vector in Thailand.
Chareonviriyaphap T, Sungvornyothin S, Ratanatham S,
Faculty of Liberal Arts and Science, Kasetsart University,
This study was designed to determine the behavioral responses
of 2 test populations of Anopheles minimus females to DDT at 2
g/m2, deltamethrin at 0.0625 g/m2, and lambdacyhalothrin at
0.0369 g/m2 using an improved excito-repellency escape
chamber. One test population was colonized in 1993 and
referred to as a young colony. The 2nd field test population
was collected from Ta-Soa County, Tri-Yok District,
Kanchanaburi Province. in western Thailand and referred to as
a wild population. Results showed that females of both young
and wild test populations rapidly escaped from direct contact
with DDT, deltamethrin, and lambdacyhalothrin.
Lambdacyhalothrin exhibited the strongest irritant effect on
female mosquitoes, followed by DDT and deltamethrin. Fewer
females escaped from test chambers without direct contact with
treated surfaces but the response was significantly different
from that of the controls (P < 0.05). The noncontact
response is indicative of a noncontact repellent action. Both
contact irritancy and noncontact repellency are involved in
An. minimus escape responses. Experimental hut studies that
include monitoring of house-entering populations of An.
minimus are needed for a meaningful assessment of noncontact
PMID: 11345412 [PubMed - in process]
J Infect Dis 2001 Jun 1;183(11):1653-61
- Evidence for different mechanisms of
chloroquine resistance in 2 plasmodium species that cause
Nomura T, Carlton JM, Baird JK, del Portillo HA, Fryauff
DJ, Rathore D, Fidock DA, Su Xz, Collins WE, McCutchan TF,
Wootton JC, Wellems TE.
Laboratory of Parasitic Diseases, National Institute of
Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD, USA.
Chloroquine (CQ)-resistant Plasmodium vivax malaria was first
reported 12 years ago, nearly 30 years after the recognition
of CQ-resistant P. falciparum. Loss of CQ efficacy now poses a
severe problem for the prevention and treatment of both
diseases. Mutations in a digestive vacuole protein encoded by
a 13-exon gene, pfcrt, were shown recently to have a central
role in the CQ resistance (CQR) of P. falciparum. Whether
mutations in pfcrt orthologues of other Plasmodium species are
involved in CQR remains an open question. This report
describes pfcrt homologues from P. vivax, P. knowlesi, P.
berghei, and Dictyostelium discoideum. Synteny between the P.
falciparum and P. vivax genes is demonstrated. However, a
survey of patient isolates and monkey-adapted lines has shown
no association between in vivo CQR and codon mutations in the
P. vivax gene. This is evidence that the molecular events
PMID: 11343215 [PubMed - in process]
Blood 2001 May 15;97(10):3268-74
- Modifications in the CD36 binding domain
of the Plasmodium falciparum variant antigen are responsible
for the inability of chondroitin sulfate A adherent parasites
to bind CD36.
Gamain B, Smith JD, Miller LH, Baruch DI.
Laboratory of Parasitic Diseases, National Institute of
Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD; and the Department of Pathology,
Colorado State University, Fort Collins, CO.
Adhesion of mature Plasmodium falciparum parasitized
erythrocytes to microvascular endothelial cells or to placenta
contributes directly to the virulence and severe pathology of
P falciparum malaria. Whereas CD36 is the major endothelial
receptor for microvasculature sequestration, infected
erythrocytes adhering in the placenta bind chondroitin sulfate
A (CSA) but not CD36. Binding to both receptors is mediated by
different members of the large and diverse protein family P
falciparum erythrocyte membrane protein-1 (PfEMP-1) and
involves different regions of the molecule. The
PfEMP-1-binding domain for CD36 resides in the cysteine-rich
interdomain region 1 (CIDR-1). To explore why CSA-binding
parasites do not bind CD36, CIDR-1 domains from CD36- or
CSA-binding parasites were expressed in mammalian cells and
tested for adhesion. Although CIDR-1 domains from
CD36-adherent strains strongly bound CD36, those from
CSA-adherent parasites did not. The CIDR-1 domain has also
been reported to bind CSA. However, none of the CIDR-1 domains
tested bound CSA. Chimeric proteins between CIDR-1 domains
that bind or do not bind CD36 and mutagenesis experiments
revealed that modifications in the minimal CD36-binding region
(M2 region) are responsible for the inability of CSA-selected
parasites to bind CD36. One of these modifications, mapped to
a 3-amino acid substitution in the M2 region, ablated binding
in one variant and largely reduced binding of another. These
findings provide a molecular explanation for the inability of
placental sequestered parasites to bind CD36 and provide
additional insight into critical residues for the CIDR-1/CD36
interaction. (Blood. 2001;97:3268-3274)
PMID: 11342458 [PubMed - in process]
Rev Soc Bras Med Trop 2001 Jan;34(1):43-47
- Malaria in the State of
Bertoli M, Moitinho Md M.
Departamento de Analises Clinicas, Universidade Estadual de
Maringa, Maringa, PR, Brasil.
To collect data regarding registered cases of malaria in the
state of Parana, attendance reports of suspected cases of
malaria performed by Fundacao Nacional de Saude, Parana
regional center, were analyzed from January, 1994 through
December, 1999. Of 31,975 blood samples examined, 7.4% were
positive: 86.4% for Plasmodium vivax, 12.7% for P. falciparum,
0.04% for P. malariae and 0.9% for P. vivax and P. falciparum.
As to the epidemiological classification, 84.5% represented
heterochthonous cases and 15.5% represented autochthonous
cases. The municipalities showing higher rates of
autochthonous cases were Foz do Iguacu, Santa Terezinha do
Itaipu and Santa Helena, a region influenced by the Itaipu
reservoir, where prevention and control actions must be
PMID: 11340496 [PubMed - as supplied by publisher]
Ann Trop Med Parasitol 2001 Apr;95(3):237-43
- Madagascan isolates of Plasmodium
falciparum showing low sensitivity to artemether in vitro.
Randrianarivelojosia M, Raharimalala LA, Randrianasolo L,
Ratsimbasoa A, Rason MA, Ariey F, Jambou R.
Laboratoire de Paludisme, Institut Pasteur de Madagascar, B.P.
1274, (101) Antananarivo, Madagascar.
In Madagascar, although chloroquine (CQ) remains the
first-line treatment of choice for malaria, the gradual spread
of resistance to this antimalarial drug is of increasing
concern. As part of a larger investigation of the
effectiveness of the second- and third-line drugs used to
treat malaria, the in-vitro susceptibilities of Plasmodium
falciparum collected in Madagascar to CQ, mefloquine (MQ) and
artemether (ART) were therefore investigated. Median
inhibitory concentrations (IC(50)) were determined for
isolates collected from residents of two villages in the
foothills of the central highlands. The IC(50) for ART ranged
from 0.23-17.50 nM [N = 51; geometric mean = 4.02 nM; 95%
confidence interval (CI) = 2.99-5.05 nM], four isolates
exhibiting IC(50) (> 12 nM) indicative of resistance to
this drug. The artemether IC(50) were found to be correlated
with those of CQ (N = 46; Spearman's r = 0.51; P = 0.0002),
which varied widely (0.4-254.3 nM; mean = 23.4 nM; CI =
7.1-39.7 nM; N = 46). Five (11%) of the 46 isolates exposed to
CQ in vitro were considered resistant to this drug (i.e. to
have IC(50) > 100 nM), with IC(50) ranging from 109-245.3
nM (mean = 171.6 nM; CI = 110.4-232.8 nM). However, all the CQ-resistant
isolates were considered sensitive to ART and vice versa. All
the isolates tested also appeared sensitive to MQ (IC(50) =
2.21-43.1 nM; mean = 10.5 nM; CI = 7.95-13.07 nM; N = 46), the
IC(50) for MQ being correlated with those for CQ (N = 46;
Spearman's r =0.46; P = 0.001). There was no significant
correlation between ART and MQ activities. Although the sample
was fairly small, the present results indicate that P.
falciparum in Madagascar is generally becoming less sensitive
to CQ and ART. The observation of a correlation between the
IC(50) for these two drugs perhaps indicates that artemisinin
derivatives would be better used in combination with
antimalarial drugs other than 4-aminoquinolines.
PMID: 11339883 [PubMed - in process]
East Mediterr Health J 1999 Jul;5(4):698-705
- Bionomics of anopheline vectors in Zabid
District, Al-Hodeidah Governorate, Republic of Yemen.
al-Maktari MT, Bassiouny HK.
Medical Parasitology and Entomology Department, Faculty of
Medicine and Health Sciences, Sana'a University, Sana'a,
Republic of Yemen.
The bionomics of anopheline vectors were analysed in randomly
selected centres, representing fixed and spot-check stations.
Three anopheline species were found. Anopheles arabiensis was
the most prevalent species (84.2%) with a sporozoite rate of
0.7%, followed by A. culicifacies adenensis (14.9%) and A.
rhodesiensis rupicolus (0.9%). Maximum indoor resting density
was recorded during March, July and August. Positive sprayed
sites for females were higher in bedrooms (40.4%) than animal
sheds (26.9%). A total of 2560 anopheline larvae were
collected of which 79.5% were A. arabiensis, 19.4% were A.
culicifacies adenensis and 1.1% A. rhodesiensis rupicolus. A.
arabiensis was assumed to be the most efficient malaria vector
based on epidemiological evidence and the finding of natural
sporozoite infected females.
PMID: 11338692 [PubMed - in process]