611 research outputs found
Checking it once, checking it twice
No full textPublished as:
Broad, R., & Cavanagh, J. (1996, Dec 08). Checking it once, checking it twice. The Washington Pos
Parasite and host factors that drive heterogeneity in human malaria
No full textMalaria affects over half of the world’s population and causes half a million deaths
annually, especially in Sub-Saharan Africa. Four species of the apicomplexan
Plasmodium parasite (P. falciparum, P. ovale, P. malariae and P. vivax) are
responsible for malaria in Africa. Both parasite and host factors contribute to
heterogeneity in the risk of developing malaria, clinical manifestation of the disease as
well as the number of treatments required to clear parasites. The epidemiology of the
different species, and the role of exposure to mixed-species Plasmodium co-infections
in generating heterogeneity remains poorly studied. Being an obligate intracellular
parasite the blood-stage life cycle of the Plasmodium parasite takes place in the
erythrocytes of the human host. The surfaces of these erythrocytes are the medically
important ABO blood group antigens that have been reported to influence the
susceptibility or otherwise of an individual developing severe malaria. In this thesis I
have considered the contributions of the species of Plasmodium parasites and the ABO
blood group of the host in driving heterogeneity in human malaria.
The aims of this thesis were to determine:
(i) the seroepidemiology of the different Plasmodium species in two
mesoendemic African populations (Zimbabwe and Sudan);
(ii) to determine if heterogeneity in clinical presentations of malaria (history
of fever, body temperature and parasitaemia) and response to drug
treatment is related to exposure to single vs. mixed-Plasmodium species
infection;
(iii) the spatial and temporal dynamics of malaria prevalence and Plasmodium
species distribution in a mesoendemic village in eastern Sudan;
(iv) gene expression changes in 3D7 P. falciparum parasites as they infect
erythrocytes of different ABO blood group donors.
For aims (i to iii) I developed an enzyme-linked immunosorbent assay using antigens
derived from Plasmodium merozoite surface protein 1, also known as MSP-119, to
detect IgG antibodies to all four malaria parasite species in Zimbabwean and Sudanese
populations. In the Zimbabwean study, plasma samples from 100 individuals each
(aged 5-18 years) from three villages (Burma Valley, Mutoko and Chiredzi) were
screened for exposure to Plasmodium parasites. In Daraweesh, Sudan, plasma samples
from 333 individuals (aged 1-74 years) who had experienced a first malaria episode
between 1990 and 2000 were recruited into the study. For study aim (iv) I cultured a
single clone of 3D7 P. falciparum parasite using erythrocytes of individuals of
different ABO blood group types, harvested parasite RNA and sequenced it to
determine gene expression changes in the different hosts.
I showed that human IgG antibodies to MSP-119 antigens of the four Plasmodium
species are species-specific and do not cross-react. In both study populations almost
all antibody responses involved P. falciparum, and single-species responses were
almost exclusively directed against P. falciparum antigens. Mixed-species responses
accounted for more than a third of responses, and were associated with chloroquine
treatment failure, with significantly high proportion of individuals with mixed-species
infections requiring repeated treatment with chloroquine/sulfadoxine-pyrimethamine
for parasite clearance. This finding highlights the need for a sensitive method for
detecting mixed-species malaria infections to enable the assessment of the true
prevalence and magnitude of the disease burden caused by the non-falciparum species
in endemic populations. Drug treatment failures associated with mixed species
infections have significant impact on malaria morbidity and mortality. Treatment
failure or partial parasite clearance has the potential to allow dormant liver stages of
P. vivax and P. ovale to become a source of parasite reservoir for onward transmission.
Furthermore, untreated low-grade chronic infections caused by P. malariae have been
reported to cause systemic diseases many years after the primary infection. Spatial
analysis of malaria epidemiology showed that malaria parasite transmission in
Daraweesh was focal, and that infections are not randomly distributed in the village.
Two space-time clusters of significantly increased malaria risk were identified (1993-
1999, and 1998-1999) with marked variations between households, but little or no
variation in the species of Plasmodium over time. Similarly, multiple significant
clusters were identified for the parasite species; three for P. falciparum, two for P.
vivax and P. malariae, and one for P. ovale. These clusters had overlapping time
frames, with some of the species significantly infecting the same households. This
suggests that even in a small geographic area malaria transmission shows
heterogeneity, and that such data can provide useful information to guide malaria
control efforts. Finally, I demonstrated that 3D7 P. falciparum parasite growth was
similar in the erythrocytes of different blood group donors, and provide preliminary
data to show that the non-coding RNA gene, PF3D7_1370800, is differentially
expressed in blood group A donors relative to blood groups B and O donors. Further
research is needed to better understand the role of this gene in malaria pathology.
All together, these findings will aid malaria researchers and other stakeholders in
making informed choices about tools for diagnosing Plasmodium species, and control
programmes targeting eradication of malaria caused by all Plasmodium species, as is
the case of incorporating these findings into current malaria research in Sudan
A Malaria Vaccine Based on the Polymorphic Block 2 Region of MSP-1 that Elicits a Broad Serotype-Spanning Immune Response
No full textPolymorphic parasite antigens are known targets of protective immunity to malaria, but this antigenic variation poses challenges to vaccine development. A synthetic MSP-1 Block 2 construct, based on all polymorphic variants found in natural Plasmodium falciparum isolates has been designed, combined with the relatively conserved Block 1 sequence of MSP-1 and expressed in E. coli. The MSP-1 Hybrid antigen has been produced with high yield by fed-batch fermentation and purified without the aid of affinity tags resulting in a pure and extremely thermostable antigen preparation. MSP-1 hybrid is immunogenic in experimental animals using adjuvants suitable for human use, eliciting antibodies against epitopes from all three Block 2 serotypes. Human serum antibodies from Africans naturally exposed to malaria reacted to the MSP-1 hybrid as strongly as, or better than the same serum reactivities to individual MSP-1 Block 2 antigens, and these antibody responses showed clear associations with reduced incidence of malaria episodes. The MSP-1 hybrid is designed to induce a protective antibody response to the highly polymorphic Block 2 region of MSP-1, enhancing the repertoire of MSP-1 Block 2 antibody responses found among immune and semi-immune individuals in malaria endemic areas. The target population for such a vaccine is young children and vulnerable adults, to accelerate the acquisition of a full range of malaria protective antibodies against this polymorphic parasite antigen.</p
Permeability-enhancing effects of three laurate-disaccharide monoesters across isolated rat intestinal mucosae
No full textLaurate (C12)-sucrose esters are established intestinal epithelial permeation enhancers (PEs) with potential for use in oral delivery. Most studies have examined blends of ester rather than specific monoesters, with little variation on the sugar moiety. To investigate the influence of varying the sugar moiety on monoester performance, we compared three monoesters: C12-sucrose, C12-lactose, and C12-trehalose. The assays were: critical micellar concentration (CMC) in Krebs-Henseleit buffer, MTS and lactate dehydrogenase assays in Caco-2 cells, transepithelial electrical resistance (TEER) and apparent permeability coefficient (Papp) of [14C] mannitol across isolated rat intestinal mucosae, and tissue histology. For CMC, the rank order was C12-trehalose (0.21 mM) < C12-sucrose (0.34 mM) < C12-lactose (0.43 mM). Exposure to Caco-2 cells for 120 min produced TC50 values in the MTS assay from 0.1 to 0.4 mM. Each ester produced a concentration-dependent decrease in TEER across rat mucosae with 80% reduction seen with 8 mM in 5 min, but C12-trehalose was less potent. C12-sucrose and C12-lactose increased the Papp of [14C] mannitol across mucosae with similar potency and efficacy, whereas C12-trehalose was not as potent or efficacious, even though it still increased flux. In the presence of the three esters, gross intestinal histology was unaffected except at 8 mM for C12-sucrose and C12-lactose. In conclusion, the three esters enhanced permeability likely via tight junction modulation in rat intestinal tissue. C12-trehalose was not quite as efficacious, but neither did it damage tissue to the same extent. All three can be considered as potential PEs to be included in oral formulations
Author Correction: Diagnosis of colour vision deficits using eye movements
No full textThe original version of this Article contained an error in Reference 21, which was incorrectly given as: Screening for color blindness using optokinetic nystagmus. Investig. Ophthalmol. Vis. Sci. 25, 463 (1984). The correct reference is listed below: Cavanagh, P., Anstis, S. & Mather, G. Screening for color blindness using optokinetic nystagmus. Investigative ophthalmology & visual science 25, 463–466 (1984). The original Article has been corrected
Supporting the development of number fact knowledge in five- and six-year-olds
No full textThis paper focuses on children’s number fact knowledge from a study that explored the impact of using multiplication and division contexts for developing number understanding with 34 five- and six-year-old children from diverse cultural and linguistic backgrounds. After a series of focused lessons, children’s knowledge of number facts, including single digit addition, subtraction, and doubles had improved. However, they did not always apply this knowledge to relevant problem-solving situations. The magnitude of the numbers did not necessarily determine the difficulty level for achieving automaticity of number fact knowledge
Extensive antigenic polymorphism within the repeat sequence of the Plasmodium falciparum merozoite surface protein 1 block 2 is incorporated in a minimal polyvalent immunogen.
No full textPolymorphism in pathogen antigens presents a complex challenge for vaccine design. A prime example is the N-terminal block 2 region of the Plasmodium falciparum merozoite surface protein 1 (MSP1), to which allele-specific antibodies have been associated with protection from malaria. In a Zambian population studied here, 49 of 91 alleles sampled were of the K1-like type (the most common of three block 2 types in all African populations), and most of these had unique sequences due to variation in tri- and hexapeptide repetitive motifs. There were significant negative correlations between allelic sequence lengths of different regions of the repeats, so the complete repeat sequence had less length variation than its component parts, suggesting a constraint on overall length. Diverse epitopes recognized by three murine monoclonal antibodies and 24 individual human sera were then mapped by using a comprehensive panel of synthetic peptides, revealing epitopes in all regions of the repeats. To incorporate these different epitopes in a single molecule, a composite sequence of minimal overall length (78 amino acids) was then designed and expressed as a recombinant antigen. More human immune sera reacted with this "K1-like Super Repeat" antigen than with proteins consisting of single natural allelic sequences, and immunization of mice elicited antibodies that recognized a range of five cultured parasite lines with diverse K1-like MSP1 block 2 repeat sequences. Thus, complex allelic polymorphism was deconstructed and a minimal composite polyvalent antigen was engineered, delivering a designed candidate sequence for inclusion in a malaria vaccine
Creating culturally-safe schools for Māori students
No full textIn order to better understand the present trends in New Zealand’s schooling contexts, there is a clarion call for educators to develop sensitivity and sensibility towards the cultural backgrounds and experiences of Māori students. This paper reports on the work of four scholars who share research that has been undertaken in educational settings with high numbers of Māori students, and discusses the importance of creating culturally-safe schools – places that allow and enable students to be who and what they are. The theoretical frameworks drawn on are based on both a life partnership analogy as well as on a socio-cultural perspective on human development and learning. The Māori worldview presented in this paper is connected to the Treaty of Waitangi, The Educultural Wheel and the Hikairo Rationale. Data were collected from two ethnographic case studies and analysed through these frameworks. Practical suggestions are then made for using restorative practices and creating reciprocal relationships in classrooms within an environment of care. The paper reports on an evidence-based approach to creating culturally-safe schools for Māori students
Barefoot running: Minimal shoes for minimal injury?
No full textRunning features repetitive, impactful movements resulting in 79% of runners getting injured each year (Altman & Davis, 2012). Ground reaction forces while running can reach between 2.5-2.8 times a person’s body weight and must be dissipated properly to prevent injury (Cavanagh & LaFortune, 1980). Rearfoot strikers generate a higher impact peak in comparison to forefoot strikers (Daoud et al, 2012). Running with shorter stride lengths can also reduce the peak vertical ground reaction force (Heiderscheit, Chumanov, Michalski, Wille, & Ryan, 2011). It is hypothesized that runners who are barefoot will run with shorter strides and a mid or forefoot strike pattern thus reducing the ground reaction force that must be absorbed by the limbs of the runner (Liebermen et al, 2010).Not peer reviewedStudent Research Day Poster (2020
FcγRIIa Polymorphism and Anti-Malaria-Specific IgG and IgG Subclass Responses in Populations Differing in Susceptibility to Malaria in Burkina Faso
No full textFcγRIIa is known to be polymorphic; and certain variants are associated with different susceptibilities to malaria. Studies involving the Fulani ethnic group reported an ethnic difference in FcγRIIa-R131H genotype frequencies between the Fulani and other sympatric groups. No previous studies have addressed these questions in Burkina Faso. This study aimed to assess the influence of FcγRIIa-R131H polymorphism on anti-falciparum malaria IgG and IgG subclass responses in the Fulani and the Mossi ethnic groups living in Burkina Faso. Healthy adults more than 20years old belonging to the Mossi or the Fulani ethnic groups were enrolled for the assessment of selected parasitological, immunological and genetic variables in relation to their susceptibility to malaria. The prevalence of the Plasmodium falciparum infection frequency was relatively low in the Fulani ethnic group compared to the Mossi ethnic group. For all tested antigens, the Fulani had higher antibody levels than the Mossi group. In both ethnic groups, a similar distribution of FcγRIIa R131H polymorphism was found. Individuals with the R allele of FcγRIIa had higher antibody levels than those with the H allele. This study confirmed that malaria infection affected less the Fulani group than the Mossi group. FcγRIIa-R131H allele distribution is similar in both ethnic groups, and higher antibody levels are associated with the FcγRIIa R allele compared to the H allele. © 2012 The Authors. Scandinavian Journal of Immunology © 2012 Blackwell Publishing Ltd
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