Library Malaria Bulletin: April 6-19, 2001
Social Sciences and
Impact of asymptomatic malaria parasitaemia on cognitive function
school achievement of schoolchildren in the Yemen Republic.
Al Serouri AW. Grantham-McGregor SM. Greenwood B.
Parasitology. 121 ( Pt 4):337-45, 2000 Oct.
Asymptomatic malaria parasitaemia is prevalent among schoolchildren
many countries. The relationship between asymptomatic parasitaemia
children's cognitive functions was examined in a case control study
then in a natural experiment. A group (n = 445) of asymptomatic
parasitaemic boys were compared with a group of non-parasitaemic
boys (n =
142) matched for grade and school on their performance on a battery
cognitive tests. Two weeks later the parasitaemic children were
re-screened and 150 children of those who remained parasitaemic
matched for grade and school with 150 children who were no longer
parasitaemic. These children were then re-tested and their
function compared. Initially, after controlling for age,
background and nutritional status the parasitaemic children
worse than the non-parasitaemic children in fine motor function
There was no difference in change in cognitive test scores between
who became non-parasitaemic and those who remained parasitaemic.
children who initially had the highest parasite density improved
in 2 fine motor tests and a picture memory test. We were unable to
benefit from losing parasitaemia over a 2 week period, but it
possible that parasitaemia may affect cognition and longer term
should be conducted.
Cost analysis of malaria patients in
Taikkyi Township Myanmar.
Lwin AM. Umenai T.
Asia-Pacific Journal of Public Health. 11(2):94-100, 1999.
A hospital and clinic-based study was
conducted in one malaria endemic area, Taikkyi Township, Yangon Division,
Myanmar, for analysis of cost incurred by different types of malaria cases
and the factors influencing the cost of illness from July to October 1995.
A total of 100 patients admitted to hospital and 100 patients receiving
ambulatory care from malaria clinics were interviewed using a structured
questionnaire. Total cost of one episode of malaria was estimated to be
kyats 559 for ambulatory care, kyats 2582 for an uncomplicated admitted
case, kyats 4056 for one episode of cerebral malaria, kyats 4568 for one
episode of other severe and complicated malaria and kyats 4758 for one
episode of malaria with other disease. This study showed that the cost of
illness for patients attending outpatient malaria clinics who received
early diagnosis and prompt treatment was four to seven times cheaper than
the cost of illness for hospitalized malaria cases. Multivariate analysis
revealed the factors that contributed to high cost of care. Duration of
illness before getting any type of treatment was the key factor that
contributed to high or low cost of care. Long duration of illness before
getting any type of treatment can lead to high malaria parasite density,
long duration of actual illness and high total attendance cost. Therefore,
it is recommended that people from malaria endemic areas should be
informed to seek early treatment from health staff, and primary health
care services should be made accessible to people who live in malaria
endemic areas. The information obtained from this study will be useful in
planning future malaria control programs and influencing policy makers to
focus on timely and effective treatment of non-severe cases, which can
save a large amount of economic loss due to treatment of severe malaria.
Community knowledge and perceptions about
malaria and practices influencing malaria control in Mpumalanga Province, South
Govere J. Durrheim D. la Grange K. Mabuza A. Booman M.
South African Medical Journal. 90(6):611-6, 2000 Jun.
OBJECTIVE: To assess community knowledge
and perceptions about malaria and its control in a rural setting. DESIGN:
Descriptive cross-sectional survey. SETTING: Tonga district with a
population of 116,418, seasonal malaria with an annual incidence of 3,200
cases. SUBJECTS: Female heads of 299 randomly selected households.
METHODOLOGY: A total of 299 households were selected from a random sample
of 30 clusters. Community knowledge and perceptions about malaria and its
control were assessed by interviews with the female head of each of the
299 selected households. RESULTS: Respondents ranked malaria as the third
most serious health problem facing the community after TB and AIDS.
Seventy-two per cent (214/299) of respondents reported that they knew what
malaria disease was and of these, 92.1% (197/214) mentioned mosquito bites
as the cause of malaria. The respondents' understanding of the causal role
of mosquitoes in malaria was significantly related to their knowledge
about disease symptoms (P < 0.001). Reported community compliance with
the malaria control programme (MCP) was satisfactory; 86.6% (259/299) of
respondents reported that their homes had been sprayed during the past 2
years but 10.0% (30/299) did not know why homes were sprayed. Hospitals or
clinics were the facilities where respondents most commonly sought
treatment for fever; 66.9% (200/299) reported that they would seek
treatment immediately after the onset of high fever. Specific practices
such as replastering or washing of inside walls compromised the
effectiveness of the MCP. Personal preventive measures were sometimes used
against malaria (50.8%, 152/299) and use was positively associated with
education level (P = 0.001). Respondents expressed their desire for more
information about malaria and their willingness to contribute to the
control of malaria in their community. CONCLUSION: The survey collected
information which was directly relevant to the development of health
education messages to increase community awareness of the problem of
malaria, to emphasise the importance of early diagnosis and prompt
treatment of malaria, to improve community understanding of the function
of indoor residual spraying, and to enlighten the population of the role
of mosquitoes in malaria transmission and the availability and benefits of
personal protection measures against mosquito bites.
Economic burden of malaria illness on
households versus that of all other illness episodes: a study in five
malaria holo-endemic Nigerian communities.
Onwujekwe O. Chima R. Okonkwo P.
Health Policy. 54(2):143-59, 2000 Nov 17.
compared the financial and economic costs of malaria attack to that of a
combination of other illness episodes on households in five malaria holo-endemic
rural communities. The data was collected from household heads or their
representatives using pre-tested interviewer-administered questionnaire.
Information was collected on the amount of money household spent to treat
both malaria and other illnesses respectively, together with the time lost
due to both the groups of illnesses within 1 month prior to the interview.
The findings showed that the cost of treating malaria illness accounted
for 49.87% of curative health care costs incurred by the households.
Average malaria expenditure was $1.84 per household per month, while it
was $2.60 per month for the combination of other illness episodes. The
average person-days lost due to malaria and the combination of other
illnesses were almost equal. If the financial costs of treating malaria
and other illnesses are combined, this cost will deplete 7.03% of the
monthly average household income, with treatment of malaria illness alone
depleting 2.91%. Thus, malaria is a big contributor to the economic burden
of disease, in malaria holo-endemic communities. Community-effective
malaria control programs are needed to reduce this burden on the
Mol Pharmacol 2001 May;59(5):1298-1306
Diamidine Compounds: Selective Uptake and
Targeting in Plasmodium falciparum.
Stead AM, Bray PG, Edwards IG, DeKoning HP, Elford BC, Stocks PA,
Department of Pharmacology and Therapeutics, The University of
Liverpool, Liverpool, United Kingdom.
Extensive drug resistance in Plasmodium falciparum emphasizes the
urgent requirement for novel antimalarial agents. Here we report
potent antimalarial activity of a number of diamidine compounds. The
lead compound pentamidine is concentrated 500-fold by erythrocytes
infected with P. falciparum. Pentamidine accumulation can be blocked
by inhibitors of hemoglobin digestion, suggesting that the drug binds
to ferriprotoporphyrin IX (FPIX). All of the compounds bound to FPIX
in vitro and inhibited the formation of hemozoin. Furthermore,
inhibitors of hemoglobin digestion markedly antagonized the
antimalarial activity of the diamidines, indicating that binding to
FPIX is crucial for the activity of diamidine drugs. Pentamidine was
not accumulated into uninfected erythrocytes. Pentamidine transport
into infected cells exhibits an initial rapid phase, nonsaturable in
the micromolar range and sensitive to inhibition by furosemide and
glibenclamide. Changing the counter-ion in the order Cl(-) < Br(-)
< NO(2)(-) < I(-) <SCN(-) markedly stimulated pentamidine
transport. These data suggest that pentamidine is transported although
a pore or ion channel with properties similar to those of the recently
characterized 'induced permeability pathway' on the infected red cell
membrane. In summary, the diamidines exhibit two levels of selectivity
against P. falciparum. The route of entry and molecular target are
both specific to malaria-infected cells and are distinct from targets
in other protozoa. Drugs that target the hemoglobin degradation
pathway of malaria parasites have a proven record of accomplishment.
The employment of induced permeability pathways to access this target
represents a novel approach to antiparasite chemotherapy and offers an
additional level of selectivity.
PMID: 11306715 [PubMed - as supplied by publisher]
Bull Mem Acad R Med Belg 2000;155(5-6):218-26
Natural history of Plasmodium falciparum malaria
and determining factors of the acquisition of antimalaria immunity in
two endemic areas, Dielmo and Ndiop (Senegal).
- Rogier C.
Laboratoire d'epidemiologie du paludisme, Institut Pasteur de Dakar,
Development of new anti malaria strategies and particularly vaccines,
needs an in-depth understanding of the relationships between
transmission, infection, immunity, morbidity and mortality. The
intensive and longitudinal collection of entomological,
parasitological and clinical data from the Senegalese populations of
Dielmo (250-300 inhab.), exposed to a perennial and intense
transmission (about 200 infective bites/person/year) and of Ndiop
(300-350 inhab.), exposed to a seasonal transmission (about 20
infective bites/person/year), allows to respond to many questions
about this subject. The existence of a pyrogenic threshold effect of
parasitaemia allows the individual diagnosis of malaria attacks. The
initial intensity of clinical manifestations does not differ
perceptibly among children and adults, is not related to the duration
of the attacks, is not predictive of their severity, and the clearance
of parasites and manifestations is longer among youngest persons. The
risk of malaria attacks is lower as one gets older and among carriers
of AS haemoglobin, is higher when transmission increases and during
pregnancy up to three month after delivery, and vary between children.
The risk of malaria attack per infective bite is negatively related to
the intensity of transmission. Because of their high sensitivity in
malaria case detection, this type of small community-based studies are
powerful and useful for the identification of protective immunological
mechanisms as well as for testing rapidly and cheaply the clinical
efficacy of any intervention such as antimalarial vaccines and drug
therapy or prophylaxis.
PMID: 11304957 [PubMed - in process]
Indian J Malariol 1999 Mar-Jun;36(1-2):42-8
A controlled study on haemograms of malaria
patients in Calcutta.
- Biswas R, Sengupta G, Mundle M.
All India Institute of Hygiene and Public Health, 110 Chittaranjan
Avenue, Calcutta-700 073, India.
A study was carried out at the Urban Health Centre, Chetla, Calcutta
to evaluate the efficacy of quantitative buffy coat (QBC) analysis of
haemograms in malaria patients suffering from fever with bodyache and
chill and/or rigour attending the Fever Treatment Depot during a three
months period (March-June 1996) who had undergone both malaria
parasite study and haematological investigation by the QBC method from
blood samples collected by finger prick. To avoid bias, malaria
parasite studies and haemograms were done separately, and
investigators were kept 'blind' about the results of other
investigations. The haematological findings obtained of 180
slide-positive malaria cases were compared with a sample of 177 age-
and sex-matched slide-negative controls selected by random sampling.
The results revealed that haemoglobin levels (g%), haematocrit values
(%), WBC and platelet counts of malaria cases were significantly lower
than in the matched controls. Thus, QBC estimation correlates well
with existing knowledge about malarial haematology. This relatively
easier, quicker and reliable method of taking haemograms may be
recommended for field testing for assessing haematological parameters
of malaria cases under field conditions, before its introduction for
PMID: 11304918 [PubMed - in process]
Indian J Malariol 1999 Mar-Jun;36(1-2):33-41
Patterns of parasitaemia, antibodies, complement
and circulating immune complexes in drug-suppressed simian Plasmodium
- Biswas S.
Malaria Research Centre (ICMR), 22 Sham Nath Marg, Delhi-110 054,
Rhesus monkeys were inoculated intravenously with 1 x 10(4) P.
knowlesi infected erythrocytes. After about three days prepatency,
peripheral smears were found positive and the animals were cured with
chloroquine phosphate when parasitaemia reached about 15-25 per cent.
The monkeys were repeatedly exposed with three bouts of infection. The
first and second bouts were cured but after the third challenge, all
10 monkeys showed a longer prepatent period, lower parasitaemia and
then self-recovery. Sera were collected in different phases of
infection to assess immune responses. Antimalarial IgG and IgM
responses were measured by ELISA. The presence of IgM antibody was
associated with every bout of infection. With repeated infections
until self-recovery, a substantial amount of IgG was found in
circulation. A significant level of schizont-infected cell
agglutination antibody was also detected in the animals after survival
from challenge infection. Antigen-specific circulating immune
complexes, both of IgG and IgM types, appeared in various phases of
infection, but their appearance did not coincide with the acquired
immune responses of the animals. During the self-recovery phase,
almost all monkeys had an elevated level of serum C3 and C4.
PMID: 11304917 [PubMed - in process]
Indian J Malariol 1999 Mar-Jun;36(1-2):12-8
Naturally occurring plasmodia-specific
circulating immune complexes in individuals of malaria endemic areas
Tyagi P, Biswas S.
Malaria Research Centre, 22 Sham Nath Marg, Delhi-110 054, India.
Blood samples collected from individuals belonging to malaria endemic
areas were assayed for antigen-specific circulating immune complexes
in polyethylene glycol precipitates of serum by enzyme immunoassay.
Sera were tested from patients with acute P. vivax and P. falciparum
infections, from clinically immune individuals and also from healthy
normals. Circulating immune complexes (CICs) containing immunoglobulin
G and M isotypes were found to be abundant in individuals with ongoing
and past infections and also in clinically immune donors. In patients
with acute infection but without any past history of malaria, CICs of
IgM type were found to be significantly higher. Demonstration of
antigen/antibody specific CICs could be a useful indicator of active,
ongoing and recent/past infection, also of the status of immune
responses of individuals belonging to various endemic areas.
PMID: 11304915 [PubMed - in process]
Am J Trop Med Hyg 2000 Jun;62(6):726-32
Dry season refugia of malaria-transmitting
mosquitoes in a dry savannah zone of east Africa.
- Charlwood JD, Vij R, Billingsley PF.
Department of Entomology, University of Wageningen, The Netherlands. [email protected]
Dry season survival of Anopheles funestus, Anopheles gambiae and
Anopheles arabiensis in the Kilombero valley a dry savannah zone of
east Africa, was investigated with over 400 collections from 23 areas,
covering 300 sq km of the valley. Anopheles gambiae was found only in
association with humans, in forested areas of high annual rainfall,
while An. funestus occurred at high densities at the valley edge where
large non-moving bodies of water remained. A large population of An.
arabiensis was present along the river system throughout the middle of
the valley, and mosquitoes probably derived from this population were
occasionally caught in villages bordering the valley. No evidence was
obtained of aestivation in any mosquito species. Anopheles gambiae was
the most long lived, 6.3% compared to 2.0% of the An. arabiensis and
4% of the An. funestus surviving for four or more gonotrophic cycles,
the approximate duration of the extrinsic cycle of most malaria
parasites. Oocysts of malaria parasites were found in 5.4% of An.
funestus and 2.3% of An. arabiensis from villages. Oocyst rates in An.
funestus differed significantly between areas but not between houses
within areas. Anopheles funestus is the most important dry season
malaria vector in the valley, and remains in foci closely associated
with groups of houses. All three species survive at high densities but
as otherwise hidden refugia populations.
PMID: 11304064 [PubMed - in process]
Am J Trop Med Hyg 2000 Jun;62(6):693-7
Assessing drug sensitivity of Plasmodium vivax to
halofantrine or choroquine in southern, central Vietnam using an
extended 28-day in vivo test and polymerase chain reaction genotyping.
- Taylor WR, Doan HN, Nguyen DT, Tran TU, Fryauff DJ, Gomez-Saladin
E, Kain KC, Le DC, Baird JK.
US NAMRU-2, Jakarta, Indonesia.
Chloroquine-resistant Plasmodium vivax malaria is emerging in Oceania,
Asia, and Latin America. We assessed the drug sensitivity of P. vivax
to chloroquine or halofantrine in two villages in southern, central
Vietnam. This area has chloroquine-resistant Plasmodium falciparum but
no documented chloroquine-resistant P. vivax. Standard dose
chloroquine (25 mg/kg, over 48 hours) or halofantrine (8 mg/kg, 3
doses) was administered to 29 and 25 patients, respectively. End
points were parasite sensitivity or resistance determined at 28 days.
Of the evaluable patients, 23/23 100% (95% confidence interval [CI]
85.1-100) chloroquine and 21/24 (87.5%) (95% CI 67.6-97.3)
halofantrine-treated patients were sensitive. Three halofantrine
recipients had initial clearance but subsequent recurrence of their
parasitemias. Genotyping of the recurrent and Day 0 parasitemias
differed, suggesting either new infections or relapses of liver
hypnozoites from antecedent infections. Among these Vietnamese
patients, P. vivax was sensitive to chloroquine and halofantrine.
Genotyping was useful for differentiating the recurrent vivax
PMID: 11304056 [PubMed - in process]
Am J Trop Med Hyg 2000 Jun;62(6):686-92
Predictors of chloroquine treatment failure in
children and adults with falciparum malaria in Kampala, Uganda.
- Dorsey G, Kamya MR, Ndeezi G, Babirye JN, Phares CR, Olson JE,
Katabira ET, Rosenthal PJ.
Department of Medicine, San Francisco General Hospital and The
University of California 94143-0811, USA.
Chloroquine-resistant falciparum malaria is a serious problem in much
of sub-Saharan Africa. However, it is desirable to continue to use
chloroquine as first-line therapy for uncomplicated malaria where it
remains clinically effective. To identify predictors of chloroquine
treatment failure, a 14-day clinical study of chloroquine resistance
in patients with uncomplicated falciparum malaria was performed in
Kampala, Uganda. Among the 258 patients (88% follow-up), 47% were
clinical failures (early or late treatment failure) and 70% had
parasitological resistance (RI-RIII). Using multivariate analysis, an
age less than five (odds ratio [OR] = 3.4, 95% CI = 1.8-6.3) and a
presenting temperature over 38.0 degreesC (OR = 2.0, 95% CI = 1.1-3.7)
were independent predictors of treatment failure. In addition,
patients who last took chloroquine 3 to 14 days prior to study entry
were significantly more likely to be treatment failures compared to
patients with very recent (less than 3 days) or no recent chloroquine
use. In areas with significant chloroquine resistance, easily
identifiable predictors of chloroquine treatment failure might be used
to stratify patients into those for whom chloroquine use is acceptable
and those for whom alternative treatment should be used.
PMID: 11304055 [PubMed - in process]
Am J Trop Med Hyg 2000 Jun;62(6):670-4
Severe anemia in young children after high and
low malaria transmission seasons in the Kassena-Nankana district of
- Koram KA, Owusu-Agyei S, Utz G, Binka FN, Baird JK, Hoffman SL,
Noguchi Memorial Institute for Medical Research, University of Ghana,
Legon. [email protected]
Malaria and anemia accounted for 41% and 18% respectively of hospital
deaths in the Kassena-Nankana district of northern Ghana during 1996.
We measured hemoglobin (Hb), malaria prevalence, and anthropometric
indices of 6--24-month-old infants and young children randomly
selected from this community at the end of the high (May-October, n =
347) and low (November-April, n = 286) malaria transmission seasons.
High transmission season is characterized by rainfall (the equivalent
of 800-900 mm/yr.), while the remaining months receive less than 50
mm/yr. Severe anemia, defined as Hb < 6.0 g/dL, was 22.1% at the
end of the high transmission season compared to 1.4% at the end of the
low transmission season (Odds Ratio [OR] = 20.1; 95% CI: 7.1-55.3).
Parasitemia was 71% and 54.3% at these time points (OR = 2.1; 95% CI:
1.5-2.9). Nutritional anemia appeared to have little impact upon this
seasonal difference since anthropometric indices were comparable.
Although the relative contributions of other causes of severe anemia
were not assessed, repeated malaria infections may be a primary
determinant of severe anemia among infants and young children during
the high transmission season.
PMID: 11304052 [PubMed - in process]
Am J Trop Med Hyg 2000 Jun;62(6):663-9
The influence of zinc supplementation on
morbidity due to Plasmodium falciparum: a randomized trial in
preschool children in Papua New Guinea.
- Shankar AH, Genton B, Baisor M, Paino J, Tamja S, Adiguma T, Wu L,
Rare L, Bannon D, Tielsch JM, West KP Jr, Alpers MP.
Department of International Health, Johns Hopkins School of Hygiene
and Public Health, Baltimore, Maryland 21205, USA.
Zinc is crucial for normal immune function and can reduce morbidity
from multiple infectious diseases. To determine the influence of zinc
on malaria morbidity we conducted a randomized placebo-controlled
trial of daily zinc supplementation in children residing in a malaria
endemic region of Papua New Guinea. A total of 274 preschool children
aged 6 to 60 months were given 10 mg elemental zinc (n = 136) or
placebo (n = 138) for 6 days a week for 46 weeks. Slide-confirmed
malaria episodes were detected by surveillance of cases self-reporting
to a local health center. Cross-sectional surveys were conducted at
the beginning, middle, and end of the study to assess infection rates,
parasite density, spleen enlargement, and hemoglobin levels. Zinc
supplementation resulted in a 38% (95% CI 3-60, P = 0.037) reduction
in Plasmodium falciparum health center-based episodes, defined as
parasitemia > or = 9200 parasites/microl with axial temperature
> or = 37.5 degreesC or reported fever. Episodes accompanied by any
parasitemia were also reduced by 38% (95% CI 5-60, P = 0.028), and
episodes with parasitemia > or = 100,000/microl were reduced by 69%
(95% CI 25-87, P = 0.009). There was no evidence of the effects of
zinc on Plasmodium vivax morbidity or on health center attendance for
causes other than P. falciparum. Zinc had no consistent effect on
cross-sectional malariometric indices. Although P. falciparum
prevalence tended to be lower at the end of the study in children
given the placebo, such changes were absent at the mid-study survey.
These results suggest that improved dietary zinc intake may reduce
morbidity due to P. falciparum.
PMID: 11304051 [PubMed - in process]
J Med Chem 2001 Mar 15;44(6):873-85
Inhibition of heme detoxification processes
underlies the antimalarial activity of terpene isonitrile compounds
from marine sponges.
Wright AD, Wang H, Gurrath M, Konig GM, Kocak G, Neumann G, Loria
P, Foley M, Tilley L.
Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6,
Bonn 53115, Germany.
A series of terpene isonitriles, isolated from marine sponges, have
previously been shown to exhibit antimalarial activities. Molecular
modeling studies employing 3D-QSAR with receptor modeling
methodologies performed with these isonitriles showed that the modeled
molecules could be used to generate a pharmacophore hypothesis
consistent with the experimentally derived biological activities. It
was also shown that one of the modeled compounds, diisocyanoadociane
(4), as well as axisonitrile-3 (2), both of which have potent
antimalarial activity, interacts with heme (FP) by forming a
coordination complex with the FP iron. Furthermore, these compounds
were shown to inhibit sequestration of FP into beta-hematin and to
prevent both the peroxidative and glutathione-mediated destruction of
FP under conditions designed to mimic the environment within the
malaria parasite. By contrast, two of the modeled diterpene
isonitriles, 7-isocyanoamphilecta-11(20),15-diene (12) and
7-isocyano-15-isothiocyanatoamphilecta-11(20)-ene (13), that displayed
little antimalarial activity also showed little inhibitory activity in
these FP detoxification assays. These studies suggest that the active
isonitrile compounds, like the quinoline antimalarials, exert their
antiplasmodial activity by preventing FP detoxification. Molecular
dynamics simulations performed with diisocyanoadociane (4) and
axisonitrile-3 (2) allowed their different binding to FP to be
PMID: 11300869 [PubMed - as supplied by publisher]
Ann Trop Med Parasitol 2001 Mar;95(2):133-40
Low incidence of the severe complications of
malaria and absence of malaria-specific mortality, in Tensa,
Sundergarh district, Orissa state, India, an area hyper-endemic for
Prusty SK, Das BS.
BIM Hospital, Tensa, Sundergargh, Orissa, India.
The incidence of severe malaria and malaria-specific mortality were
investigated in a hospital, for miners and their families, at Tensa in
the Sundergarh district of Orissa state in India. Tensa lies in area
where malaria (predominantly caused by Plasmodium falciparum) is
hyper-endemic. The hospital records for 1995-1999 showed that,
although annual admissions for malaria increased over the study
period, there were very few admissions for severe, complicated malaria
and no reports of malaria-specific deaths. Most of the patients who
had been admitted with cerebral malaria either came from areas around
but not within the town of Tensa or were recent arrivals in the town.
It appears that the outcome of malaria is influenced not only by the
intensity of local transmission (which affects the immunological
status of the human hosts) but also by social factors such as the
education and health-seeking behaviour of the local population and the
health-care facilities available. The low incidence of severe malaria
observed in Tensa was probably the result of patients presenting early
in the course of their illness and taking antimalarial treatment, iron
supplementation and supportive therapy at the appropriate times.
PMID: 11299120 [PubMed - in process]
Ann Trop Med Parasitol 2001 Mar;95(2):117-32
Geographical patterns of allelic diversity in the
Plasmodium falciparum malaria-vaccine candidate, merozoite surface
Hoffmann EH, da Silveira LA, Tonhosolo R, Pereira FJ, Ribeiro WL,
Tonon AP, Kawamoto F, Ferreira MU.
Department of Parasitology, Institute for Biomedical Sciences,
University of Sao Paulo, Sao Paulo, Brazil.
The polymorphic merozoite surface protein-2 (MSP-2) of Plasmodium
falciparum is a major malaria-vaccine candidate. In the present study,
PCR and hybridization with allelic-specific probes were used to type
the Msp-2 gene from isolates from hypo-endemic Brazil (N = 113), meso-endemic
Vietnam (N = 208) and holo-endemic Tanzania (N = 67). The typing
methods were designed to group isolates into the dimorphic allelic
families FC27 and IC1 and to detect possible between-family
recombination events. The analysis was complemented by a comparison of
156 Msp-2 sequences from the GenBank database with 12 additional
sequences obtained during the present study. Statistically significant
differences were detected in pair-wise comparisons of the distribution
of Msp-2 allelic types in Brazil and Vietnam, and in Brazil and
Tanzania, but not in Vietnam and Tanzania. The extent of allelic
diversity in the Msp-2 gene, as estimated by the total number of
different alleles found in a given parasite population and the mean
multiplicity of infections, clearly paralleled the levels of malaria
endemicity in the study areas. However, no correlation between age and
multiplicity of infections was found in the subjects. The patterns of
Msp-2 diversity in Brazil appeared to be temporally stable, since no
significant difference was observed in the distribution of Msp-2
allelic types among isolates collected, 10-13 years apart, in the same
area of Rondonia. Despite the extensive sequence diversity found in
Msp-2 alleles, especially in the central repetitive region of the
molecule, several instances of identical or nearly identical alleles
were found among isolates from different countries and regions,
possibly as a result of extensive homoplasy. No recombinant allele was
detected by molecular typing in any of the study sites, and the
GenBank database included only 12 recombinant sequences (representing
7% of all reported Msp-2 sequences), all of them with an IC1-type 5'
end and an FC27-type 3' end. A single, putative, crossover site was
characterised for all recombinant alleles. Most of the allelic
diversity observed was therefore attributable to variation in the
repetitive region of the gene, instead of recombination between
alleles of dimorphic families (as commonly found, for example, in the
Msp-1 gene). The implications of these findings for studies on the
genetic and antigenic diversity of malarial parasites are discussed.
PMID: 11299119 [PubMed - in process]
Trop Med Int Health 2001 Mar;6(3):196-201
Rapid therapeutic response onset of a new
pharmaceutical form of chloroquine phosphate 300 mg: effervescent
Yanze MF, Duru C, Jacob M, Bastide JM, Lankeuh M.
Laboratoire de Galenique, Pharmacotechnie et Biopharmacie, UFR de
sciences pharmaceutiques, Universite de Montpellier I, France. [email protected]
OBJECTIVE: To compare the efficiency, safety and taste of two
pharmaceutical forms of chloroquine phosphate 300 mg: effervescent
tablets against uncoated tablets. METHOD: An open randomized study
with 60 adults who suffered from acute uncomplicated Plasmodium
falciparum malaria in three health centres in Nkongsamba health
district, Cameroon. RESULTS: Mean times to fever clearance, symptoms
clearance and asexual parasites clearance were longer in the uncoated
tablets group: 36 h (range 24-48 h, SD = 16.8) vs. 60 h (range 24-96
h, SD = 31.2, P = 0.001) for fever clearance, 36 h (24-48 h, SD =
16.8) vs. 48 h (24-72, SD = 24, P = 0.001) for symptoms clearance and
48 h (24-72, SD = 1) vs. 72 h (48-96, SD = 24, P = 0.001) for
parasitaemia clearance. Uncoated tablets took significantly longer to
achieve 50% reduction of the initial asexual parasite density:
(mean/SD) 19.2 h/7 vs. 52.8 h/16.8, P < 0.00001. The adverse
effects in the two groups were similar, P > 0.05. The cure rate at
day 7 in the two groups was similar, P > 0.05. There was no
chloroquine resistance in the effervescent tablets group but one RI
and one RII resistance in the uncoated tablets group. The taste of the
two pharmaceutical forms was significantly different, P < 0.00001.
Effervescent tablets tasted sweet (score = 7.93), whereas uncoated
tablets were bitter (score = 2.07). CONCLUSION: Effervescent tablets
of chloroquine phosphate 300 mg work faster than uncoated tablets and
because of their safe use and sweet taste achieve good therapeutic
PMID: 11299036 [PubMed - in process]
Cytokine 2001 Apr 7;14(1):11-8
The role of tumour necrosis factor-alpha in the
pathogenesis of complicated falciparum malaria.
Department of Internal Medicine, Bnai Zion Medical Center, Haifa,
Plasmodium falciparum malaria is the most important parasitic
infection of humans and is one of the most serious health problems
facing the inhabitants of developing countries. It is responsible for
about 2 million deaths every year. To date there is no specific
treatment for the disease apart from anti-malarials. The declining
sensitivity to these drugs is a serious therapeutic problem, while no
safe and effective vaccine is likely to be available for general use
in the near future. There is now abundant laboratory and clinical
evidence to suggest that tumour necrosis factor-alpha (TNF-alpha)
plays a major role in the pathogenesis of complicated falciparum
malaria. Modulation of TNF-alpha response in combination with the
current anti-malarial drugs, may represent a novel approach to the
treatment of the serious complications associated with the disease.
Copyright 2001 Academic Press.
PMID: 11298488 [PubMed - in process]
Med Vet Entomol 2001 Mar;15(1):97-104
Olyset Net efficacy against pyrethroid-resistant
Anopheles gambiae and Culex quinquefasciatus after 3 years' field use
in C te d'Ivoire.
N'Guessan R, Darriet F, Doannio JM, Chandre F, Carnevale P.
Institute Pierre Richet, Bouake, C te d'Ivoire.
Pyrethroid-impregnated bednets are advocated for personal protection
against malaria vectors. To avoid the need for periodic re-treatment,
it would be advantageous to have nets that retain insecticidal
efficacy for years and withstand repeated washing. Such a type of
commercially produced bednet with permethrin 2% incorporated in
polyethylene fibres (trademark Olyset Net supplied by Sumika Life-Tech
Co., Osaka, Japan) was evaluated against mosquitoes in veranda-trap
huts at Yaokoffikro, near Bouake, C te d'Ivoire, by standard WHOPES
phase II procedures. Four Olyset Nets were compared with a standard
untreated polyester net as control. They comprised three examples
previously used in a village for over 3 years (one washed, one dirty,
one very dirty) and a previously unused Olyset Net, newly unwrapped,
from the same original batch. Bioassays with 3 min exposure of
susceptible Anopheles gambiae Giles (Diptera: Culicidae) gave >99%
mortality of female mosquitoes tested on the 'new' Olyset Net. The
used Olyset Nets gave mortality rates averaging 83% for the washed
net, 85% for the dirty net and 55% for the very dirty net (within 24-h
following 3 min exposure). Thus, Olyset Nets were found to remain
remarkably effective against susceptible An. gambiae for at least 3
years under field conditions. Wild pyrethroid-resistant populations of
Culex quinquefasciatus Say and An. gambiae (savanna cytotype with 96%
kdr) were assessed during June-August 1999 for their responses to
sleepers protected by nets in the experimental huts. With regard to
hut entry by foraging female mosquitoes, Olyset Nets showed some
deterrency against An. gambiae (44% reduction by the new net,
approximately 20% by the dirty nets, none by the washed net), but not
against Cx. quinquefasciatus. Among mosquitoes entering the hut with
untreated control net, 30-34% tried to leave (exophily) but were
caught in the verandah trap. The permethrin repellency of Olyset Nets
increased exophily by 19% for An. gambiae and 14% for Cx.
quinquefasciatus. Blood-feeding rates were 16% An. gambiae and 35% Cx.
quinquefasciatus in the hut with sleeper under the untreated net
(showing considerable prevention of biting), 22-26% of both species in
huts with washed or dirty used Olyset Nets (not significantly
different from control), while the biting success rate of Cx.
quinquefasciatus (but not kdr An. gambiae) was more than halved by the
'new' Olyset Net. Mortality rates of pyrethroid-resistant An. gambiae
and Cx. quinquefasciatus from the huts were, respectively, 3% and 8%
with the untreated polyester net, 27.5% and 17% with the 'new' Olyset,
15% and 17.5% with the washed Olyset, 16-25% and 17-20% with dirty old
Olyset Nets. Kill differences between nets are significantly different
for both An. gambiae and Cx. quinquefasciatus. Unfortunately the
washed used Olyset Net showed least activity against resistant
mosquitoes, despite its greatest activity against susceptible An.
gambiae. In each case there was evidence that a high proportion of
mosquitoes failed to feed through the net (many of them dying from
starvation when they could not leave the closed hut), with indications
that dirty Olyset nets enhanced this protective value.
PMID: 11297108 [PubMed - in process]
Med Vet Entomol 2001 Mar;15(1):58-63
Quantification of pyrethroid insecticides from
treated bednets using a mosquito recombinant glutathione S-transferase.
Enayati AA, Vontas JG, Small GJ, McCarroll L, Hemingway J.
Cardiff School of Biosciences, Cardiff University, Wales, UK.
Recombinant glutathione S-transferase (agGST1-6) from the malaria
vector mosquito Anopheles gambiae Giles (Diptera: Culicidae) was
expressed in Escherichia coli using a pET3a vector system. The
expressed enzyme was biochemically active with reduced glutathione (GSH)
and 1-chloro-2,4-dinitrobenzene (CDNB). Activity of agGST1-6 with GSH
and CDNB was inhibited to different degrees by both alpha-cyano and
non-alpha-cyano pyrethroid insecticides. This inhibition was used to
develop an assay for quantification of pyrethroids. Standard curves of
insecticide concentration against percentage of enzyme inhibition or
volume of iodine solution were established by spectrophotometry and
iodine volumetric titration, respectively, for permethrin and
deltamethrin. These assays allowed estimation of pyrethroid
concentrations both spectrophotometrically and visually. For the
residue assay of each insecticide, a cut-off point of 50% of the
initial pyrethroid impregnation concentration was used, which should
differentiate between biologically active and inactive treated bednets.
The cross-reactivity of the primary permethrin photodegradants
(3-phenoxyalcohol and 3-phenoxybenzoic acid) with the recombinant
agGST1-6 was assayed in the same system. No agGST1-6 inhibition by the
insecticide metabolites was observed, suggesting that the system is
unaffected by primary permethrin metabolites and will accurately
measure insecticide parent compound concentrations. The estimated
pyrethroid insecticide concentrations, given spectrophotometrically
and by iodine titration assay, were comparable to those obtained by
direct HPLC quantification of residues extracted from bednets. Hence,
it should be relatively easy to adapt this method to produce a test
kit for residue quantification in the field.
PMID: 11297102 [PubMed - in process]
Med Vet Entomol 2001 Mar;15(1):105-12
Combined pyrethroid and carbamate 'two-in-one'
treated mosquito nets: field efficacy against pyrethroid-resistant
Anopheles gambiae and Culex quinquefasciatus.
Guillet P, N'Guessan R, Darriet F, Traore-Lamizana M, Chandre F,
Institut Pierre Richet, Bouake, C te d'Ivoire.
- [email protected]
A new approach is proposed in the treatment of mosquito nets, using a
'two-in-one' combination of pyrethroid and non-pyrethroid insecticides
applied to different parts of bednets. The objectives are mainly to
overcome certain limitations of pyrethroid-impregnated bednets
currently recommended for malaria control purposes. Apart from
developing alternatives to pyrethroid dependency, we sought to
counteract pyrethroid irritant effects on mosquitoes (excito-repellency)
and resistance to pyrethroids. The idea takes advantage of the
presumed host-seeking behaviour of mosquitoes confronted by a net
draped over a bed, whereby the mosquito may explore the net from the
top downwards. Thus, nets could be more effective if treated on the
upper part with residual non-irritant insecticide (carbamate or
organophosphate) and with a pyrethroid on the lower part. Sequential
exposure to different insecticides with distinct modes of action is
equivalent to the use of a mixture as a potential method of managing
insecticide resistance. We also intended to improve the control of
nuisance mosquitoes, especially Culex quinquefasciatus Say (Diptera:
Culicidae) that often survive pyrethroids, in order to encourage
public compliance with use of insecticide-treated nets (ITNs).
Polyester bednets were pretreated with residual pyrethroid (bifenthrin
50 mg/m2 or deltamethrin 25 mg/m2) on the lower half and with
carbamate (carbosulfan 300 mg/m2) on the upper half to minimize
contact with net users. Unreplicated examples of these 'two-in-one'
treated nets were field-tested against wild mosquitoes, in comparison
with an untreated net and bednets treated with each insecticide alone,
including PermaNet wash-resistant formulation of deltamethrin 50
mg/m2. Overnight tests involved volunteers sleeping under the
experimental bednets in verandah-trap huts at Yaokofikro, near Bouake
in C te d'Ivoire, where the main malaria vector Anopheles gambiae
Giles, as well as Culex quinquefasciatus Say, are highly resistant to
pyrethroids. Efficacy of these ITNs was assessed in the huts by four
entomological criteria: deterrency and induced exophily (effects on
hut entry and exit), blood-feeding and mortality rates (immediate and
delayed). Overall, the best impact was achieved by the bednet treated
with carbosulfan alone, followed by 'two-in-one' treatments with
carbosulfan plus pyrethroid. Blood-feeding rates were 13% An. gambiae
and 17% Cx. quinquefasciatus in huts with untreated nets, but only 3%
with carbosulfan ITNs, 7-11% with combined ITN treatment, 6-8% An.
gambiae and 12-14% Cx. quinquefasciatus with pyrethroid alone.
Mosquitoes that entered the huts were killed sooner by nets with
combined treatment than by pyrethroid alone. Mortality-rates in
response to ITNs with carbosulfan (alone or combined with pyrethroid)
were significantly greater for Cx. quinquefasciatus, but not for An.
gambiae, compared to ITNs with only pyrethroid. About 20% of sleepers
reported potential side-effects (headache and/or sneezing) from use of
ITN treated with carbosulfan alone. Further development of this new
'two-in-one' ITN concept requires a range of investigations (choice of
effective products, cost-benefit analysis, safety, etc.) leading to
factory production of wash-resistant insecticidal nets treated with
PMID: 11297094 [PubMed - in process]
Med Vet Entomol 2001 Mar;15(1):1-11
Impact of irrigation on malaria in Africa: paddies
Ijumba JN, Lindsay SW.
Tropical Pesticides Research Institute, Arusha, Tanzania. [email protected]
The high population growth rate of the African continent has led to an
increased demand for food and is in danger of outstripping
agricultural production. In order to meet this need, many governments
have sought ways of improving food production by initiating
large-scale irrigation projects, involving reclamation of arid and
semi-arid areas for the cultivation of crops. Although crop irrigation
promises one solution to alleviating hunger and encourages economic
growth, irrigation has often been blamed for aggravating disease in
local communities. Malaria is one of the major tropical diseases
associated with irrigation schemes, and changes in the transmission
pattern of this disease following irrigation development have been a
perennial subject of debate. It has often been assumed that high
numbers of malaria vector Anopheles mosquitoes (Diptera: Culicidae)
resulting from irrigation schemes lead inevitably to increased malaria
in local communities. However, recent studies in Africa have revealed
a more complex picture. Increased numbers of vectors following
irrigation can lead to increased malaria in areas of unstable
transmission, where people have little or no immunity to malaria
parasites, such as the African highlands and desert fringes. But for
most of sub-Saharan Africa, where malaria is stable, the introduction
of crop irrigation has little impact on malaria transmission. Indeed,
there is growing evidence that for many sites there is less malaria in
irrigated communities than surrounding areas. The explanation for this
finding is still unresolved but, in some cases at least, can be
attributed to displacement of the most endophilic and anthropophilic
malaria vector Anopheles funestus Giles by An. arabiensis Patton with
lower vectorial capacity, as the latter thrives more than the former
in ricefields. Similarly, among members of the An. gambiae complex,
some cytotypes of An. gambiae sensu stricto are more vectorial than
others. For example, the Mopti form has high vectorial capacity and
breeds perennially in irrigated sites, whereas the savanna form is
often sympatric but more seasonal. Also we suggest that many
communities near irrigation schemes benefit from the greater wealth
created by these schemes. Consequently irrigation communities often
have greater use of bednets, better access to improved healthcare and
receive fewer infective bites compared with those outside such
development schemes. Thus, in most cases, irrigation schemes in Africa
do not appear to increase malaria risk, except in areas of unstable
transmission. However, developers should take the opportunity to
improve health-care facilities for local communities when planning
irrigation schemes wherever they occur.
PMID: 11297093 [PubMed - in process]
J Med Entomol 2001 Mar;38(2):341-3
Occurrence of Anopheles hermsi (Diptera: Culicidae)
in Arizona and Colorado.
Hayden CW, Fink TM, Ramberg FB, Mare JC, Mead DG.
Department of Veterinary Science and Microbiology, University of
Arizona, Tucson 85721, USA.
Historically, malaria was a significant cause of morbidity and
mortality throughout the western United States, and Anopheles
freeborni Aitken was thought to be the vector west of the Continental
Divide. In 1989, Anopheles hermsi Barr & Guptavanij was described
and subsequently found to be an effective laboratory vector of
Plasmodium. The adults of these two species are morphologically
indistinguishable, and therefore polymerase chain reaction was used to
analyze the DNA from 48 mosquitoes collected in Arizona and Colorado
(identified morphologically as An. freeborni). All specimens were
identified as An. hermsi. This was the first report of An. hermsi in
Arizona and Colorado and indicated that this Anopheles species
historically may have been a malaria vector in these two western
PMID: 11296846 [PubMed - in process]
J Med Entomol 2001 Mar;38(2):242-4
Attraction of Anopheles (Diptera: culicidae) to
volatile chemicals in Western Kenya.
Murphy MW, Dunton RF, Perich MJ, Rowley WA.
Department of Entomology, Iowa State University, Ames 50011, USA.
Anopheles gambiae s.l. and Anopheles funestus Giles are the primary
vectors of malaria in East Africa. Identification of host-location
olfactory cues may increase trap sensitivity for vector control and
surveillance programs. Solid-state army miniature light traps were
operated near sleeping humans in huts at night without lights and
augmented with the potential attractants: L-lactic acid, Limburger
cheese volatiles, hexanoic acid, and carbon dioxide. Mosquito response
varied between species and gender. Female An. funestus exhibited a
greater response to traps baited with L-lactic acid in combination
with carbon dioxide than carbon dioxide alone in two different
PMID: 11296830 [PubMed - in process]
Mol Biochem Parasitol 2001 Apr;113(2):271-8
Gene targeting in the rodent malaria parasite
Mota MM, Thathy V, Nussenzweig RS, Nussenzweig V.
Michael Heidelberger Division, Department of Pathology (MSB131), New
York University Medical Center, 550 First Avenue, 10016, New York, NY,
It is anticipated that the sequencing of Plasmodium falciparum genome
will soon be completed. Rodent models of malaria infection and stable
transformation systems provide powerful means of using this
information to study gene function in vivo. To date, gene targeting
has only been developed for one rodent malaria species, Plasmodium
berghei. Another rodent species, Plasmodium yoelii, however, is
favored to study the mechanisms of protective immunity to the pre-erythrocytic
stages of infection and vaccine development. In addition, it offers
the opportunity to investigate unique aspects of pathogenesis of blood
stage infection. Here, we report on the stable transfection and gene
targeting of P. yoelii. Purified late blood stage schizonts were used
as targets for electroporation with a plasmid that contains a
pyrimethamine-resistant form of the P. berghei dihydrofolate
reductase-thymidylate synthase (Pbdhfr-ts) fused to green fluorescent
protein (gfp) gene. After drug selection, fluorescent parasites
contained intact, non-rearranged plasmids that remain stable under
drug-pressure. In addition, we used another dhfr-ts/gfp based plasmid
to disrupt the P. yoelii trap (thrombospondin-related anonymous
protein) locus by site-specific integration. The phenotype of P.
yoelii TRAP knockout was identical to that previously reported for the
P. berghei TRAP knockout. In the absence of TRAP, the erythrocytic
cycle, gametocyte and oocyst development of the mutant parasites were
indistinguishable from wild type (WT). Although the sporozoites
appeared morphologically normal, they failed to glide and to invade
the salivary glands of mosquitoes.
PMID: 11295181 [PubMed - in process]
Mol Biochem Parasitol 2001 Apr;113(2):251-60
Gene discovery in Plasmodium chabaudi by genome
Janssen CS, Barrett MP, Lawson D, Quail MA, Harris D, Bowman S,
Phillips RS, Turner CM.
Division of Infection & Immunity, IBLS, University of Glasgow, G12
8QQ, Glasgow, UK
The first genome survey sequencing of the rodent malaria parasite
Plasmodium chabaudi is presented here. In 766 sequences, 131 putative
gene sequences have been identified by sequence similarity database
searches. Further, 7 potential gene families, four of which have not
previously been described, were discovered. These genes may be
important in understanding the biology of malaria, as well as offering
potential new drug targets. We have also identified a number of
candidate minisatellite sequences that could be helpful in genetic
studies. Genome survey sequencing in P. chabaudi is a productive
strategy in further developing this in vivo model of malaria, in the
context of the malaria genome projects.
PMID: 11295179 [PubMed - in process]
J Infect Dis 2001 May 1;183(9):1417-20
Polymorphisms in the Plasmodium falciparum pfcrt
and pfmdr-1 Genes and Clinical Response to Chloroquine in Kampala,
Dorsey G, Kamya MR, Singh A, Rosenthal PJ.
Department of Medicine, San Francisco General Hospital, University of
California, San Francisco, CA 94143-0811, USA.
- [email protected]
The molecular mechanism of chloroquine resistance in Plasmodium
falciparum remains uncertain. Polymorphisms in the pfcrt and pfmdr-1
genes have been associated with chloroquine resistance in vitro,
although field studies are limited. In evaluations of known
polymorphisms in parasites from patients with uncomplicated malaria in
Kampala, Uganda, the presence of 8 pfcrt mutations and 2 pfmdr-1
mutations did not correlate with clinical response to therapy with
chloroquine. Most notably, the pfcrt lysine-->threonine mutation at
position 76, which recently correlated fully with chloroquine
resistance in vitro, was present in 100% of 114 isolates, of which
about half were from patients who recovered clinically after
chloroquine therapy. These results suggest that, although key pfcrt
polymorphisms may be necessary for the elaboration of resistance to
chloroquine in areas with high levels of chloroquine resistance, other
factors, such as host immunity, may contribute to clinical outcomes.
PMID: 11294677 [PubMed - in process]
J Infect Dis 2001 May 1;183(9):1388-94
Regulatory Interactions between Iron and Nitric
Oxide Metabolism for Immune Defense against Plasmodium falciparum
Fritsche G, Larcher C, Schennach H, Weiss G.
Department of Internal Medicine, University Hospital, Innsbruck,
Iron chelation therapy of Plasmodium falciparum infection alleviates
the clinical course of cerebral malaria in children. This study
assessed the underlying mechanisms of this therapy. Cytokine
stimulation of human (intestinal cell line DLD-1) or murine cells (murine
macrophage cell line RAW 264.7) resulted in increased nitric oxide
(NO) formation and decreased survival of plasmodia within cocultured
human erythrocytes. The addition of desferrioxamine (DFO) before
cytokine treatment increased both NO formation and parasite killing
but had no effect in the presence of the inhibitor of NO formation,
L-N6-(1-iminoethyl)-lysine. Moreover, peroxynitrite, which is formed
after chemical reaction of NO with superoxide, appears to be the
principal effector molecule for macrophage-mediated cytotoxicity
toward P. falciparum, and interferon-gamma is a major regulatory
cytokine for this process. The effect of DFO on the clearance of
plasmodia appears to be due to enhanced generation of NO, rather than
to limitation of iron availability to the parasite.
PMID: 11294671 [PubMed - in process]
Lancet 2001 Mar 31;357(9261):1014-6
Chronic nervous-system effects of long-term
occupational exposure to DDT.
van Wendel de Joode B, Wesseling C, Kromhout H, Monge P, Garcia M,
Dichlorodiphenyltrichloroethane (DDT) is a compound with moderate
toxicity that is judged to be safe for occupational use, although
little is known about its long-term effects on the human nervous
system. We investigated chronic nervous-system effects of long-term
occupational exposure to DDT by comparing the neurobehavioural
performance of retired malaria-control workers with a reference group
of retired guards and drivers. DDT-exposed workers did worse on tests
assessing various neurobehavioural functions than controls;
performance significantly deteriorated with increasing years of DDT
application. Our results could not be explained by exposure to
cholinesterase-inhibiting pesticides or other potential confounding
PMID: 11293598 [PubMed - in process]
Parasitol Res 2001 Mar;87(3):239-44
In vitro and in vivo antimalarial activity of
ferrochloroquine, a ferrocenyl analogue of chloroquine against
chloroquine-resistant malaria parasites.
Delhaes L, Abessolo H, Biot C, Berry L, Delcourt P, Maciejewski L,
Brocard J, Camus D, Dive D.
INSERM Unite 167, Institut Pasteur, Lille, France.
Previous studies have shown that ferrochloroquine (FQ) exhibited an
antimalarial activity against Plasmodium spp. The present work
confirmed this activity, described the curative effect on P. vinckei
and investigated the FQ toxicity in vitro and in vivo. The in vitro
and in vivo growth inhibition of P. falciparum and P. berghei N,
respectively, showed that FQ antimalarial activity was 1.5-10 times
more potent than chloroquine. FQ completely inhibited the in vivo
development of both chloroquine-susceptible and resistant P. vinckei
strains and protected mice from lethal infection at a dose of 8.4 mg
kg(-1) day(-1) given for 4 days subcutaneously or orally. This
curative effect was 5-20 times more potent than chloroquine, according
to the strains' resistance to chloroquine. At this curative dose, no
clinical changes were observed in mice up to 14 days after the last
administration. Nevertheless, the acute toxicity and lethality of
ferrochloroquine seemed to be dependent on gastric surfeit. The FQ
security index determined in vitro confirmed that it might be a
PMID: 11293573 [PubMed - in process]
J Biol Chem 2001 Apr 5; [epub ahead of print]
Functional equivalence of structurally distinct
ribosomes in the malaria parasite, plasmodium berghei.
- Free article full-text at http://www.jbc.org
van Spaendonk RM, Ramesar J, van Wigcheren A, Eling W, Beetsma AL,
van Gemert GJ, Hooghof J, Janse CJ, Waters AP.
Department of Parasitology, Leiden University Medical Centre, Leiden,
Zuid Holland 2333 AL.
Unlike most eukaryotes many apicomplexan parasites contain only a few
unlinked copies of ribosomal RNA (rRNA) genes. Based on stage specific
expression of these genes and structural differences between the rRNA
molecules it has been suggested that Plasmodium spp. produce
functionally different ribosomes in different developmental stages.
This hypothesis was investigated through comparison of the structure
of the large subunit (LSU) rRNA molecules of the rodent malaria
parasite, Plasmodium berghei and by disruption of both of the rRNA
gene units that are exclusively transcribed during development of this
parasite in the mosquito (S-type rRNA gene units). In contrast to the
human parasite, Plasmodium falciparum, we did not find evidence for
structural differences in core regions of the distinct LSU rRNAs that
are known to be associated with catalytic activity including the
GTP-ase site that varies in P. falciparum. Knockout (ko) P. berghei
parasites lacking either of the S-type gene units were able to
complete development in both the vertebrate and mosquito hosts. These
results formally exclude the hypothesis that two functionally
different ribosome types distinct from the predominantly blood stage
expressed A-type ribosomes, are required for development of all
Plasmodium species in the mosquito. The maintenance of two
functionally equivalent rRNA genes might now be explained as a gene
Infect Immun 2001 May;69(5):3286-94
Specificity of the protective antibody response to
apical membrane antigen 1.
Hodder AN, Crewther PE, Anders RF.
The Cooperative Research Center for Vaccine Technology and The Walter
and Eliza Hall Institute of Medical Research, Melbourne, Victoria,
Apical membrane antigen 1 (AMA1) is considered one of the leading
candidates for inclusion in a vaccine against blood stages of
Plasmodium falciparum. Although the ama1 gene is relatively conserved
compared to those for some other potential vaccine components,
numerous point mutations have resulted in amino acid substitutions at
many sites in the polypeptide. The polymorphisms in AMA1 have been
attributed to the diversifying selection pressure of the protective
immune responses. It was therefore of interest to investigate the
impact of sequence diversity in P. falciparum AMA1 on the ability of
anti-AMA1 antibodies to inhibit the invasion of erythrocytes in vitro
by P. falciparum merozoites. For these studies, we used antibodies to
recombinant P. falciparum 3D7 AMA1 ectodomain, which was prepared for
testing in early clinical trials. Antibodies were raised in rabbits to
the antigen formulated in Montanide ISA720, and human antibodies to
AMA1 were isolated by affinity purification from the plasma of adults
living in regions of Papua New Guinea where malaria is endemic. Both
rabbit and human anti-AMA1 antibodies were found to be strongly
inhibitory to the invasion of erythrocytes by merozoites from both the
homologous and two heterologous lines of P. falciparum. The inhibitory
antibodies targeted both conserved and strain-specific epitopes within
the ectodomain of AMA1; however, it appears that the majority of these
antibodies reacted with strain-specific epitopes in domain I, the
N-terminal disulfide-bonded domain, which is the most polymorphic
region of AMA1.
PMID: 11292751 [PubMed - in process]
Infect Immun 2001 May;69(5):3190-6
Perturbation and Proinflammatory Type Activation of
Vdelta1(+) gammadelta T Cells in African Children with Plasmodium
Hviid L, Kurtzhals JA, Adabayeri V, Loizon S, Kemp K, Goka BQ, Lim
A, Mercereau-Puijalon O, Akanmori BD, Behr C.
Centre for Medical Parasitology at Department of Infectious Diseases,
Copenhagen University Hospital (Rigshospitalet) and Institute for
Medical Microbiology and Immunology, University of Copenhagen,
gammadelta T cells have variously been implicated in the protection
against, and the pathogenesis of, malaria, but few studies have
examined the gammadelta T-cell response to malaria in African
children, who suffer the large majority of malaria-associated
morbidity and mortality. This is unfortunate, since available data
suggest that simple extrapolation of conclusions drawn from studies of
nonimmune adults ex vivo and in vitro is not always possible. Here we
show that both the frequencies and the absolute numbers of gammadelta
T cells are transiently increased following treatment of Plasmodium
falciparum malaria in Ghanaian children and they can constitute 30 to
50% of all T cells shortly after initiation of antimalarial
chemotherapy. The bulk of the gammadelta T cells involved in this
perturbation expressed Vdelta1 and had a highly activated phenotype.
Analysis of the T-cell receptors (TCR) of the Vdelta1(+) cell
population at the peak of their increase showed that all expressed
Vgamma chains were used, and CDR3 length polymorphism indicated that
the expanded Vdelta1 population was highly polyclonal. A very high
proportion of the Vdelta1(+) T cells produced gamma interferon, while
fewer Vdelta1(+) cells than the average proportion of all CD3(+) cells
produced tumor necrosis factor alpha. No interleukin 10 production was
detected among TCR-gammadelta(+) cells in general or Vdelta1(+) cells
in particular. Taken together, our data point to an immunoregulatory
role of the expanded Vdelta1(+) T-cell population in this group of
semi-immune P. falciparum malaria patients.
PMID: 11292740 [PubMed - in process]
J Mol Biol 2001 Apr 13;307(5):1381-94
Inhibitory and Blocking Monoclonal Antibody
Epitopes on Merozoite Surface Protein 1 of the Malaria Parasite
Uthaipibull C, Aufiero B, Syed SE, Hansen B, Patino JA, Angov E,
Ling IT, Fegeding K, Morgan WD, Ockenhouse C, Birdsall B, Feeney J,
Lyon JA, Holder AA.
Merozoite surface protein 1 (MSP-1) is a precursor to major antigens
on the surface of Plasmodium spp. merozoites, which are involved in
erythrocyte binding and invasion. MSP-1 is initially processed into
smaller fragments; and at the time of erythrocyte invasion one of
these of 42 kDa (MSP-1(42)) is subjected to a second processing,
producing 33 kDa and 19 kDa fragments (MSP-1(33) and MSP-1(19)).
Certain MSP-1-specific monoclonal antibodies (mAbs) react with
conformational epitopes contained within the two epidermal growth
factor domains that comprise MSP-1(19), and are classified as either
inhibitory (inhibit processing of MSP-1(42) and erythrocyte invasion),
blocking (block the binding and function of the inhibitory mAb), or
neutral (neither inhibitory nor blocking). We have mapped the epitopes
for inhibitory mAbs 12.8 and 12.10, and blocking mAbs such as 1E1 and
7.5 by using site-directed mutagenesis to change specific amino acid
residues in MSP-1(19) and abolish antibody binding, and by using
PEPSCAN to measure the reaction of the antibodies with every
octapeptide within MSP-1(42). Twenty-six individual amino acid residue
changes were made and the effect of each on the binding of mAbs was
assessed by Western blotting and BIAcore analysis. Individual changes
had either no effect, or reduced, or completely abolished the binding
of individual mAbs. No two antibodies had an identical pattern of
reactivity with the modified proteins. Using PEPSCAN each mAb reacted
with a number of octapeptides, most of which were derived from within
the first epidermal growth factor domain, although 1E1 also reacted
with peptides spanning the processing site. When the single amino acid
changes and the reactive peptides were mapped onto the
three-dimensional structure of MSP-1(19), it was apparent that the
epitopes for the mAbs could be defined more fully by using a
combination of both mutagenesis and PEPSCAN than by either method
alone, and differences in the fine specificity of binding for all the
different antibodies could be distinguished. The incorporation of
several specific amino acid changes enabled the design of proteins
that bound inhibitory but not blocking antibodies. These may be
suitable for the development of MSP-1-based vaccines against malaria.
Copyright 2001 Academic Press.
PMID: 11292349 [PubMed - in process]
Am J Trop Med Hyg 2000 May;62(5):590-7
Vitamin A supplementation and other predictors of
anemia among children from Dar Es Salaam, Tanzania.
Villamor E, Mbise R, Spiegelman D, Ndossi G, Fawzi WW.
Department of Nutrition, Harvard School of Public Health, Boston,
Massachusetts 02115, USA.
The associations of hemoglobin, hematocrit, and packed cell volume
with socioeconomic factors, malaria, human immunodeficiency virus
(HIV) infection, and nutritional status were examined among 687
children admitted to hospital with pneumonia participating in a double
blind, placebo-controlled trial of vitamin A supplementation. Children
were randomized to receive 2 doses of vitamin A (200,000 IU) or
placebo at baseline, and additional doses at 4 and 8 months after
discharge from hospital. Hemoglobin levels were measured at enrollment
and, on a subset of 161 children, during follow-up. At baseline,
hemoglobin concentration was positively associated with the number of
possessions in the household, maternal level of education and quality
of water supply, and inversely related to malaria infection after
controlling for potential confounding variables. Children infected
with HIV experienced a significant fall in mean hemoglobin levels over
time. The risk of developing severe anemia (< 7 g/dL) during
follow-up was lower for children who were breastfed for longer than 18
months as compared to those with less than 6 months of breastfeeding
(adjusted prevalence ratio = 0.14, 95% confidence interval [CI] =
0.02, 0.93; P = 0.04), and higher for children over two years of age
as compared to 6 to 11 months-old infants (adjusted prevalence ratio =
8.11, 95% CI = 1.2, 55.8; P = 0.03). Children with repeated diagnoses
of malaria had 4.1 times the risk of developing severe anemia than did
children without the diagnosis (95% CI = 1.3, 13.5; P = 0.02). Vitamin
A supplements were associated with an overall nonsignificant reduction
of 14% in the risk of developing severe anemia (adjusted prevalence
ratio = 0.86, 95% CI = 0.37, 1.99; P = 0.73). We conclude that
malaria, HIV infection, low socioeconomic status, and short duration
of breastfeeding are strong and independent determinants of adverse
hematologic profiles in this population.
PMID: 11289670 [PubMed - in process]
Am J Trop Med Hyg 2000 May;62(5):566-72
Antibody responses to Plasmodium falciparum:
evolution according to the severity of a prior clinical episode and
association with subsequent reinfection.
Luty AJ, Ulbert S, Lell B, Lehman L, Schmidt-Ott R, Luckner D,
Greve B, Matousek P, Schmid D, Herbich K, Dubois B, Deloron P,
Department of Parasitology, Institute for Tropical Medicine,
University of Tubingen, Germany.
We measured sporozoite- and total parasite antigen-specific IgG and
IgM antibodies before and after treatment in matched groups of
Gabonese children who presented with either mild or severe Plasmodium
falciparum malaria. We investigated the influence of various
parameters on these antibody responses, including clinical
presentation, age, and post-treatment reinfection profiles. IgG but
not IgM responses were strongly influenced by both clinical and
parasitological status. IgG responses to the repeat region of the
circumsporozoite protein, which were low at admission, particularly so
in those with severe anemia, increased after treatment but showed no
association with either age or reinfection profiles. Total parasite
antigen-specific IgG responses were strongly influenced by
parasitological status, and also differed significantly when
segregated according to clinical status at admission, age, and
reinfection histories. Most notably, anti-parasite IgG responses
measured when children were parasite-free were higher and a good
indicator of recent reinfections in those who presented with mild
rather than with severe malaria. The profile of responses in the
latter group suggests some immune system dysfunction, which may
reflect the induction of tolerance to parasite antigens.
PMID: 11289665 [PubMed - in process]
Am J Trop Med Hyg 2000 May;62(5):545-51
The potential impact of integrated malaria
transmission control on entomologic inoculation rate in highly endemic
Killeen GF, McKenzie FE, Foy BD, Schieffelin C, Billingsley PF,
Department of Tropical Medicine, School of Public Health and Tropical
Medicine, Center for Infectious Diseases, Tulane University Health
Sciences Center, New Orleans, Louisiana 70112-2824, USA.
We have used a relatively simple but accurate model for predicting the
impact of integrated transmission control on the malaria entomologic
inoculation rate (EIR) at four endemic sites from across sub-Saharan
Africa and the southwest Pacific. The simulated campaign incorporated
modestly effective vaccine coverage, bed net use, and larval control.
The results indicate that such campaigns would reduce EIRs at all four
sites by 30- to 50-fold. Even without the vaccine, 15- to 25-fold
reductions of EIR were predicted, implying that integrated control
with a few modestly effective tools can meaningfully reduce malaria
transmission in a range of endemic settings. The model accurately
predicts the effects of bed nets and indoor spraying and demonstrates
that they are the most effective tools available for reducing EIR.
However, the impact of domestic adult vector control is amplified by
measures for reducing the rate of emergence of vectors or the level of
infectiousness of the human reservoir. We conclude that available
tools, including currently neglected methods for larval control, can
reduce malaria transmission intensity enough to alleviate mortality.
Integrated control programs should be implemented to the fullest
extent possible, even in areas of intense transmission, using simple
models as decision-making tools. However, we also conclude that to
eliminate malaria in many areas of intense transmission is beyond the
scope of methods which developing nations can currently afford. New,
cost-effective, practical tools are needed if malaria is ever to be
eliminated from highly endemic areas.
PMID: 11289662 [PubMed - in process]
Am J Trop Med Hyg 2000 May;62(5):535-44
A simplified model for predicting malaria
entomologic inoculation rates based on entomologic and parasitologic
parameters relevant to control.
Killeen GF, McKenzie FE, Foy BD, Schieffelin C, Billingsley PF,
Department of Tropical Medicine, School of Public Health and Tropical
Medicine, Center for Infectious Diseases, Tulane University Health
Sciences Center, New Orleans, Louisiana 70112-2824, USA.
Malaria transmission intensity is modeled from the starting
perspective of individual vector mosquitoes and is expressed directly
as the entomologic inoculation rate (EIR). The potential of individual
mosquitoes to transmit malaria during their lifetime is presented
graphically as a function of their feeding cycle length and survival,
human biting preferences, and the parasite sporogonic incubation
period. The EIR is then calculated as the product of 1) the potential
of individual vectors to transmit malaria during their lifetime, 2)
vector emergence rate relative to human population size, and 3) the
infectiousness of the human population to vectors. Thus, impacts on
more than one of these parameters will amplify each other's effects.
The EIRs transmitted by the dominant vector species at four
malaria-endemic sites from Papua New Guinea, Tanzania, and Nigeria
were predicted using field measurements of these characteristics
together with human biting rate and human reservoir infectiousness.
This model predicted EIRs (+/- SD) that are 1.13 +/- 0.37 (range =
0.84-1.59) times those measured in the field. For these four sites,
mosquito emergence rate and lifetime transmission potential were more
important determinants of the EIR than human reservoir infectiousness.
This model and the input parameters from the four sites allow the
potential impacts of various control measures on malaria transmission
intensity to be tested under a range of endemic conditions. The model
has potential applications for the development and implementation of
transmission control measures and for public health education.
PMID: 11289661 [PubMed - in process]
Southeast Asian J Trop Med Public Health 2000 Sep;31(3):515-20
Introduction of a rapid dipstick assay for the
detection of Leptospira-specific immunoglobulin m antibodies in the
laboratory diagnosis of leptospirosis in a hospital in Makassar,
Hatta M, Smits HL, Gussenhoven GC, Gooskens J.
Department of Medical Microbiology, Faculty of Medicine, Hasanuddin
University, Makassar, Indonesia.
An easy, rapid and robust dipstick assay for detection of leptospira-specific
immunoglobulin M (IgM) antibodies was evaluated on 403 patients
admitted for hospitalization because of fever. The clinical symptoms
and signs of 35 patients were consistent with leptospirosis. The final
diagnosis for the remaining patients was as follows: 136 with typhoid
fever, 82 with hepatitis, 74 with malaria, 48 with infections of the
respiratory tract, and 20 with fever of unknown origin. The clinical
diagnosis of leptospirosis was confirmed for 24 (68.6%) patients by
the combined results of the microscopic agglutination test (MAT), the
reference test for leptospirosis, and of IgM ELISA, a standard
laboratory test for the serodiagnosis of leptospirosis. In addition,
serum specimens from 8 (2.2%) patients with a final clinical diagnosis
other than leptospirosis were found to be positive in MAT and/or IgM
ELISA. Compared with the results of MAT and IgM ELISA a sensitivity of
91.6% and specificity of 93.6% was calculated for the dipstick assay.
Most of the serum samples from the laboratory confirmed patients gave
a moderate to strong staining intensity of the antigen band of the
dipstick and were easy to read. The results demonstrate that the
dipstick assay is convenient to use and allows the rapid and accurate
confirmation of patients with clinical suspicion of leptospirosis in
areas where the disease is endemic.
PMID: 11289012 [PubMed - in process]
Southeast Asian J Trop Med Public Health 2000 Sep;31(3):444-7
Promotion of insecticide-treated mosquito nets in
Lin K, Aung S, Lwin S, Min H, Aye NN, Webber R.
Vector Borne Diseases Control Project, Department of Health, Yangon,
A simple health promotion message administered by village midwives
raised bednet usage to over 60% in trial hamlets in north Shan State,
Myanmar. Treatment of the nets in the study villages produced a
reduction in malaria cases. Most villagers were prepared to buy their
nets at market prices and were willing to pay for the cost of
re-treatment of nets, but very poor, members of the Wa ethnic group
required a half-price subsidy for them to afford them. The use of
insecticide treated bednets was felt to be appropriate for undeveloped
and remote areas of the country where malaria control was difficult.
PMID: 11288998 [PubMed - in process]
Southeast Asian J Trop Med Public Health 2000 Sep;31(3):439-43
Characterization of specific monoclonal antibodies
for detection of mefloquine in body fluids.
Trisirivanich S, Laothavorn J, Na-Bangchang K, Khusmith S.
Department of Microbiology and Immunology, Faculty of Tropical
Medicine, Mahidol University, Bangkok, Thailand.
Specific monoclonal antibodies (MAbs) to mefloquine conjugated to
bovine serum albumin (mefloquine-BSA) were produced by hybridoma
technology. The mefloquine-BSA was synthesized by converting
mefloquine into hemisuccinate followed by convalently linked to bovine
serum albumin (BSA) and coupling with N,N' disuccinimidyl carbonate
(DSC). The conjugate was purified by Sephadex G-75 gel filtration
using 0.01 M PBS pH 7.2. An average of 19.34 molecules of mefloquine
were conjugated to each molecule of protein determined by differential
UV absorption spectra of hapten and protein carrier. Sixteen
monoclones producing antibody specific to mefloquine were screened by
indirect ELISA using homologous antigens. The specificity of MAbs was
determined by reacting with BSA and the structurally related
antimalarial drug, quinine. Three, three, five and two MAbs belonged
to IgG1, IgG2a, IgG2b and IgG3, respectively. Most of the MAbs
slightly reacted with quinine-BSA due to the closely related structure
of mefloquine to quinine. The selected MAb designated 11F9(G5)G9 which
showed no cross reaction with quinine-BSA gave high reactivity with
blood samples from malaria patients previously treated with mefloquine
when compared to normal blood by indirect ELISA. The preliminary
results indicated that such specific MAb could be used as antibody
probe for detection of mefloquine in biological fluids.
PMID: 11288997 [PubMed - in process]
Southeast Asian J Trop Med Public Health 2000 Sep;31(3):434-8
Modeling factors influencing malaria incidence in
Cho-Min-Naing, Lertmaharit S, Kamol-Ratanakul P, Saul A.
Malaria and Arbovirus Unit, Queensland Institute of Medical Research
This is a documentary study to determine factors influencing malaria
incidence in Myanmar. The period of study covered was from 1989 to
1998 using time series data. Multiple regression analysis was
performed on the dependent variable, yearly incidence of malaria in
Myanmar, with hypothesized independent variables including variables
related to epidemiology, demography, service and socioeconomic status.
Malaria incidence was inversely associated with the government budget
for malaria control at the 5% level and with the case fatality rate of
malaria at the 10% level. Other variables: yearly gross domestic
product, yearly proportion of Plasmodium falciparum cases and yearly
DDT use of spraying displayed expected signs but were not
PMID: 11288996 [PubMed - in process]