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Results

The safety and efficacy of umbilical cord blood transfusion in severe malarialanaemia in children. 22 May 2006

Severe anemia in young children is a major public health problem in the malaria-endemic regions of Africa. Emergency blood transfusion can be a life-saving procedure in the management of these children, the majority of which are aged less than 12 months. Despite World Health Organisation recommendations, most hospitals rely on relative donation of blood for transfusion and in many cases blood is not available when required. I have demonstrated in a feasibility study that umbilical cord blood, which is otherwise discarded, can be collected in sufficient volumes on an African labour ward to be of use in the treatment of severe anaemia associated with malaria. If cord blood can be safely collected and screened in this setting, it could have a major impact on the management of severe malarial anaemia in children but also benefit other patient groups requiring scarce blood. This strategic research project aims to address the practical issues that need to be resolved before routine cord blood collection and transfusion can be recommended for wider application. These are: To demonstrate the minimum contamination rates with which umbilical cord blood can be collected in the African setting. To establish a safe, pragmatic and ethical screening strategy for transfusion transmissible infections in cord blood. To demonstrate the safety and efficacy of cord blood transfusion in the treatment of severe malarial anaemia in children. I aim to carry out this study at KEMRI/Wellcome Trust Unit, Kilifi, Kenya where there is the necessary paediatric and laboratory support and follow up mechanisms in the community are well established.

Supplementary funding 30 Aug 2006

One third of the world's population uses biomass fuel (burned animal or plant material) for cooking and heating and many of these people are also infected with HIV. Smoke from biomass fuel use is associated with an increased incidence of respiratory infections among adults and children, as is HIV infection. Smoke exposure alters pulmonary defence mechanisms, including macrophage function, cytokine production and epithelial inflammation. The precise mechanism by which BMF smoke increases susceptibility to respiratory infection and the interaction of these effects with HIV infection, which also causes pulmonary inflammation, are unknown. This study will test the hypothesis that biomass fuel use has an adverse effect on pulmonary defence in HIV infected adults by causing altered macrophage function, lung inflammation and increased HIV replication in pulmonary cells. The effects of BMF particulate exposure on human alveolar macrophages will first be defined in vitro using normal cells and then studied in alveolar macrophages from HIV infected and uninfected adults environmentally exposed to BMF in Malawi. HIV viral loads in lung lavage samples obtained from BMF exposed and unexposed HIV infected adults will be compared and the effect of in vitro BMF particulate challenge on viral replication determined.

Amount: £23,067
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

The effect of biomass fuel smoke on pulmonary defence in a population at risk from HIV-related pneumonia. 09 May 2006

One third of the world s population uses biomass fuel (burned animal or plant material) for cooking and heating and many of these people are also infected with HIV. Smoke from biomass fuel use is associated with an increased incidence of respiratory infections among adults and children, as is HIV infection. Smoke exposure alters pulmonary defence mechanisms, including macrophage function, cytokine production and epithelial inflammation. The precise mechanism by which BMF smoke increases suscep tibility to respiratory infection and the interaction of these effects with HIV infection, which also causes pulmonary inflammation, are unknown. This study will test the hypothesis that biomass fuel use has an adverse effect on pulmonary defence in HIV infected adults by causing altered macrophage function, lung inflammation and increased HIV replication in pulmonary cells. The effects of BMF particulate exposure on human alveolar macrophages will first be defined in vitro using normal ce lls and then studied in alveolar macrophages from HIV infected and uninfected adults environmentally exposed to BMF in Malawi. HIV viral loads in lung lavage samples obtained from BMF exposed and unexposed HIV infected adults will be compared and the effect of in vitro BMF particulate challenge on viral replication determined.

Amount: £526,053
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Supplement to cover the costs of implementing the KPMG report. 27 Oct 2005

This is a proposal for 'Core Funding' for the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW) for the period 1995-1998. The requested funding will enable MLW to continue to provide a research platform for studies in tropical disease in Malawi, in the context of the national medical school (The College of Medicine [COM]) and the national teaching hospital. Research in MLW addresses important local problems, aiming to conduct high quality studies in collaboration with local COM scientists in order to improve understanding, inform policy and strengthen local research capacities. Core funding will enable MLW to support the 9 Wellcome Trust Fellowships, 4 Wellcome Trust Projects and 2 other Projects currently in progress, and other studies being submitted or planned, for which support has so far been channelled through the Director's Research Leave Fellowship. MLW's research themes are centred on malaria (pathogenesis, pathology, treatment and studies of other causes of the major malarial complications - severe anaemia and coma) and disease due to HIV-related pathogens (S pneumoniae, non-typhi Salmonellae, M tuberculosis). Studies of the interactions of malaria and HIV are also completed and ongoing. With shared topics, laboratories and clinics, many studies have been complementary, providing opportunities for linked research.

Amount: £22,127
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Supplementary funding 14 Dec 2005

This is a proposal for 'Core Funding' for the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW) for the period 1995-1998. The requested funding will enable MLW to continue to provide a research platform for studies in tropical disease in Malawi, in the context of the national medical school (The College of Medicine [COM]) and the national teaching hospital. Research in MLW addresses important local problems, aiming to conduct high quality studies in collaboration with local COM scientists in order to improve understanding, inform policy and strengthen local research capacities. Core funding will enable MLW to support the 9 Wellcome Trust Fellowships, 4 Wellcome Trust Projects and 2 other Projects currently in progress, and other studies being submitted or planned, for which support has so far been channelled through the Director's Research Leave Fellowship. MLW's research themes are centred on malaria (pathogenesis, pathology, treatment and studies of other causes of the major malarial complications - severe anaemia and coma) and disease due to HIV-related pathogens (S pneumoniae, non-typhi Salmonellae, M tuberculosis). Studies of the interactions of malaria and HIV are also completed and ongoing. With shared topics, laboratories and clinics, many studies have been complementary, providing opportunities for linked research.

Amount: £83,917
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Supplement for Amos Phiri MSc 09 May 2006

This is a proposal for 'Core Funding' for the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW) for the period 1995-1998. The requested funding will enable MLW to continue to provide a research platform for studies in tropical disease in Malawi, in the context of the national medical school (The College of Medicine [COM]) and the national teaching hospital. Research in MLW addresses important local problems, aiming to conduct high quality studies in collaboration with local COM scientists in order to improve understanding, inform policy and strengthen local research capacities. Core funding will enable MLW to support the 9 Wellcome Trust Fellowships, 4 Wellcome Trust Projects and 2 other Projects currently in progress, and other studies being submitted or planned, for which support has so far been channelled through the Director's Research Leave Fellowship. MLW's research themes are centred on malaria (pathogenesis, pathology, treatment and studies of other causes of the major malarial complications - severe anaemia and coma) and disease due to HIV-related pathogens (S pneumoniae, non-typhi Salmonellae, M tuberculosis). Studies of the interactions of malaria and HIV are also completed and ongoing. With shared topics, laboratories and clinics, many studies have been complementary, providing opportunities for linked research.

Amount: £41,035
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Masters degree for Malawi Programme Lab Support Staff - Mr Amos Phiri 19 Jul 2006

This is a proposal for 'Core Funding' for the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW) for the period 1995-1998. The requested funding will enable MLW to continue to provide a research platform for studies in tropical disease in Malawi, in the context of the national medical school (The College of Medicine [COM]) and the national teaching hospital. Research in MLW addresses important local problems, aiming to conduct high quality studies in collaboration with local COM scientists in order to improve understanding, inform policy and strengthen local research capacities. Core funding will enable MLW to support the 9 Wellcome Trust Fellowships, 4 Wellcome Trust Projects and 2 other Projects currently in progress, and other studies being submitted or planned, for which support has so far been channelled through the Director's Research Leave Fellowship. MLW's research themes are centred on malaria (pathogenesis, pathology, treatment and studies of other causes of the major malarial complications - severe anaemia and coma) and disease due to HIV-related pathogens (S pneumoniae, non-typhi Salmonellae, M tuberculosis). Studies of the interactions of malaria and HIV are also completed and ongoing. With shared topics, laboratories and clinics, many studies have been complementary, providing opportunities for linked research.

Amount: £42,342
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Supplement for internet connection and health & safety equipment 19 Jul 2006

This is a proposal for 'Core Funding' for the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW) for the period 1995-1998. The requested funding will enable MLW to continue to provide a research platform for studies in tropical disease in Malawi, in the context of the national medical school (The College of Medicine [COM]) and the national teaching hospital. Research in MLW addresses important local problems, aiming to conduct high quality studies in collaboration with local COM scientists in order to improve understanding, inform policy and strengthen local research capacities. Core funding will enable MLW to support the 9 Wellcome Trust Fellowships, 4 Wellcome Trust Projects and 2 other Projects currently in progress, and other studies being submitted or planned, for which support has so far been channelled through the Director's Research Leave Fellowship. MLW's research themes are centred on malaria (pathogenesis, pathology, treatment and studies of other causes of the major malarial complications - severe anaemia and coma) and disease due to HIV-related pathogens (S pneumoniae, non-typhi Salmonellae, M tuberculosis). Studies of the interactions of malaria and HIV are also completed and ongoing. With shared topics, laboratories and clinics, many studies have been complementary, providing opportunities for linked research.

Amount: £15,912
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Supplementary funding 19 Jul 2006

This is a proposal for 'Core Funding' for the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW) for the period 1995-1998. The requested funding will enable MLW to continue to provide a research platform for studies in tropical disease in Malawi, in the context of the national medical school (The College of Medicine [COM]) and the national teaching hospital. Research in MLW addresses important local problems, aiming to conduct high quality studies in collaboration with local COM scientists in order to improve understanding, inform policy and strengthen local research capacities. Core funding will enable MLW to support the 9 Wellcome Trust Fellowships, 4 Wellcome Trust Projects and 2 other Projects currently in progress, and other studies being submitted or planned, for which support has so far been channelled through the Director's Research Leave Fellowship. MLW's research themes are centred on malaria (pathogenesis, pathology, treatment and studies of other causes of the major malarial complications - severe anaemia and coma) and disease due to HIV-related pathogens (S pneumoniae, non-typhi Salmonellae, M tuberculosis). Studies of the interactions of malaria and HIV are also completed and ongoing. With shared topics, laboratories and clinics, many studies have been complementary, providing opportunities for linked research.

Amount: £200,000
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Supplement for building maintenance 30 Aug 2006

This is a proposal for 'Core Funding' for the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW) for the period 1995-1998. The requested funding will enable MLW to continue to provide a research platform for studies in tropical disease in Malawi, in the context of the national medical school (The College of Medicine [COM]) and the national teaching hospital. Research in MLW addresses important local problems, aiming to conduct high quality studies in collaboration with local COM scientists in order to improve understanding, inform policy and strengthen local research capacities. Core funding will enable MLW to support the 9 Wellcome Trust Fellowships, 4 Wellcome Trust Projects and 2 other Projects currently in progress, and other studies being submitted or planned, for which support has so far been channelled through the Director's Research Leave Fellowship. MLW's research themes are centred on malaria (pathogenesis, pathology, treatment and studies of other causes of the major malarial complications - severe anaemia and coma) and disease due to HIV-related pathogens (S pneumoniae, non-typhi Salmonellae, M tuberculosis). Studies of the interactions of malaria and HIV are also completed and ongoing. With shared topics, laboratories and clinics, many studies have been complementary, providing opportunities for linked research.

Amount: £140,684
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

OPEN ACCESS. 30 Aug 2006

Not available

Amount: £10,000
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Mechanisms of Leishmania attachment in the sand fly vector. 09 Feb 2006

In the sand fly vector Leishmania parasites must negotiate various barriers togenerate transmissible infections and ensure continuation of the life cycle. One of the most important is the establishment of a parasite population beyondthe initial multiplication phase in the blood meal. This has received much attention, particularly in the L. major-P.papatasi parasite-vector combination, and established an important paradigm. The major surface glycoconjugate lipophosphoglycan (LPG) has been shown to act as the parasite ligand, and LPG galactose residues bind to a sand fly galectin receptor on themidgut epithelium. Attachment of promastigotes to the midgut enables the parasites to persist when the blood meal remnants are defecated. However, recent unpublished work in the Volf lab indicates that the ligands and receptors involved in attachment are different in most parasite-vector combinations. LPG-galectin binding appears to be confined to "restricted" vectors (such as P. papatasi) that will only transmit one species of Leishmania. However, the majority of vectors, including those responsible for transmission of visceral leishmaniasis, are "permissive", and in these attachment appears to be mediated via a different mechanism. The purpose of this project is to identify the ligands and receptors involved in this novel mechanism.

Amount: £267,962
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Pilot survey of medical history archives at Liverpool School of Tropical Medicine. 18 Mar 2007

Pilot survey of medical history archives at Liverpool School of Tropical Medicine

Amount: £11,350
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Functional investigation of Plasmodium falciparum var genes expressed at high levels in the tissue of Malawian paediatric malaria patients 05 Dec 2006

My current work has identified that a limited number of variants of the major further investigate the tissue-specific localisation of particular var/PfEMP1 determine if certain var/PfEMP1 types are associated with diagnoses such as ceinvestigate the phenomenon suggested by my current study that a restricted numdetermine which adhesive domains compose each variant, and which subtypes are express these adhesive domains and perform binding assays with candidate recepmeasure level of expression of adhesive domains in the tissues of a large numbber of patients to investigate associations with diagnosis and tissue localisation

Amount: £546,859
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

The role of von Willebrand Factor (VWF) in malaria pathogenesis. 16 Oct 2006

The pathogenicity of Plasmodium falciparum is thought to relate to the unique ability of infected erythrocytes to adhere to and subsequently activate the vascular endothelium. The primary process of cytoadherence has been studied in detail and a large number of receptors have been identified as being able to mediate binding of infected erythrocytes (IE). Host endothelia have differential receptor expression, for example cerebral endothelium has little or no CD36 which could influence parasite sequestration, limiting it to IE able to bind to other receptors. Recently however sequestration of IE to brain endothelium by CD36-binding variants has been demonstrated in paediatric cerebral malaria through bridging by platelets. Our recent work has shown that levels of von Willebrand factor (VWF) and its pro-peptide are elevated in malaria, indicating fulminant and specific endothelial activation and providing a mechanism for platelet accumulation on endothelium. The aims of this study ar e; i) To confirm the increased regulated expression of VWF in malaria. ii) To elucidate its potential role in the platelet bridging adhesion mechanism, including VWF multimerisation and proteolytic turnover. iii) To investigate the molecular mechanisms of VWF-mediated cytoadherence. iv) To examine its significance in paediatric disease.

Amount: £307,716
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Ex vivo combined co-cultures of host cells, plasma and parasites isolated from patients: a new approach to cerebral malaria pathogenesis. 05 Dec 2006

The overall objective of this project is to analyse interactions between the different elements of the host (endothelium, plasma and platelets) and parasite present within brain post-capillary venules, and leading to the microvascular lesion during CM. For this, I will study the responsiveness of EC isolated from CM patients (post-mortem) to pro-inflammatory stimulation, compared to tissue-derived cells from non-fatal malaria patients (needle aspirate). In addition to endothelium, parasites will be isolated from all patients, and I will compare cytotoxicity levels among diagnostic groups. Thiswill be performed by measurement of endothelial alteration after cytoadherenceof parasite only, or clumped with platelets on human brain EC. Finally, I will set up a 'single patient' ex vivo model of CM pathogenesis by culturing EC, parasites and platelet-rich plasma isolated from the same patients. I willmeasure variations in endothelial permeability, electrical resistance and viability. By restricting in vitro bias, this model will allow more precise analysis of parameters involved in endothelial impairment in CM.

Amount: £275,473
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Supplement for biochemistry equipment 28 May 2007

This is a proposal for 'Core Funding' for the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW) for the period 1995-1998. The requested funding will enable MLW to continue to provide a research platform for studies in tropical disease in Malawi, in the context of the national medical school (The College of Medicine [COM]) and the national teaching hospital. Research in MLW addresses important local problems, aiming to conduct high quality studies in collaboration with local COM scientists in order to improve understanding, inform policy and strengthen local research capacities. Core funding will enable MLW to support the 9 Wellcome Trust Fellowships, 4 Wellcome Trust Projects and 2 other Projects currently in progress, and other studies being submitted or planned, for which support has so far been channelled through the Director's Research Leave Fellowship. MLW's research themes are centred on malaria (pathogenesis, pathology, treatment and studies of other causes of the major malarial complications - severe anaemia and coma) and disease due to HIV-related pathogens (S pneumoniae, non-typhi Salmonellae, M tuberculosis). Studies of the interactions of malaria and HIV are also completed and ongoing. With shared topics, laboratories and clinics, many studies have been complementary, providing opportunities for linked research.

Amount: £35,264
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Malarial disease in children - Extenstion to ophthalmological studies in Blantyre 2007-8. 27 Oct 2006

In malarious areas most P falciparum infections cause either few symptoms or none, but an important minority progress to severe disease. In three linked studies we propose to investigate the acquisition of specific humoral immunity in infancy and mechanisms of severe disease in Malawian children infected with P falciparum. In Study I we will follow cohorts of HIV-infected and HIV-uninfected infants, identifying and characterising malaria infections, illnesses and responses to treatment. We will measure functional humoral responses directed against three separate targets - variant specific antigens on the infected red cell surface (mediating cytoadherence); merozoite surface protein-1 (mediating invasion of red cells by merozoites); and a putative malaria toxin (mediating fever). In each case we will compare responses between HIV-infected and HIV-uninfected infants, and analyse malarial infections and illnesses according to antecedent serological status. This study will increase our understanding of specific mechanisms of protection against malaria, and of the impact of HIV on these mechanisms. Study II is an investigation of pathogenesis in severe malaria. We postulate that platelets mediate the adhesion of parasitised red blood cells (pRBC) to each other and to endothelial cells and monocytes, thus contributing to pathology. We will study the in vitro adherence between pRBC (from both mild and severe malaria cases) and (a) other pRBCs, (b) cultured human cerebral endothelial cells and (c) host monocytes, analysing the ligands on both pRBC and host cells that mediate these adhesions. In Study III we will investigate retinopathy and intracranial pressure (ICP) in patients with malarial coma. We will use ultrasonography of the optic nerve - a non-invasive, quick and safe measure of intracranial pressure - to study levels and changes in IPC in relation to clinical characteristics and prognosis, and in relation to the unique retinopathy of malaria. We will test the hypothesis that retinal whitening is associated with increased ICP and that a common mechanism in brain and retina may underlie both phenomena.

Amount: £15,200
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Malarial disease in children - 6 months extension 19 Sep 2007

In malarious areas most P falciparum infections cause either few symptoms or none, but an important minority progress to severe disease. In three linked studies we propose to investigate the acquisition of specific humoral immunity in infancy and mechanisms of severe disease in Malawian children infected with P falciparum. In Study I we will follow cohorts of HIV-infected and HIV-uninfected infants, identifying and characterising malaria infections, illnesses and responses to treatment. We will measure functional humoral responses directed against three separate targets - variant specific antigens on the infected red cell surface (mediating cytoadherence); merozoite surface protein-1 (mediating invasion of red cells by merozoites); and a putative malaria toxin (mediating fever). In each case we will compare responses between HIV-infected and HIV-uninfected infants, and analyse malarial infections and illnesses according to antecedent serological status. This study will increase our understanding of specific mechanisms of protection against malaria, and of the impact of HIV on these mechanisms. Study II is an investigation of pathogenesis in severe malaria. We postulate that platelets mediate the adhesion of parasitised red blood cells (pRBC) to each other and to endothelial cells and monocytes, thus contributing to pathology. We will study the in vitro adherence between pRBC (from both mild and severe malaria cases) and (a) other pRBCs, (b) cultured human cerebral endothelial cells and (c) host monocytes, analysing the ligands on both pRBC and host cells that mediate these adhesions. In Study III we will investigate retinopathy and intracranial pressure (ICP) in patients with malarial coma. We will use ultrasonography of the optic nerve - a non-invasive, quick and safe measure of intracranial pressure - to study levels and changes in IPC in relation to clinical characteristics and prognosis, and in relation to the unique retinopathy of malaria. We will test the hypothesis that retinal whitening is associated with increased ICP and that a common mechanism in brain and retina may underlie both phenomena.

Amount: £119,247
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Liverpool-Oxford Tropical link (LOTLink) in Clinical Pharmacology RENEWAL. 20 Feb 2007

The principle goal of this proposal is to maintain and continue the development of the Liverpool Oxford Tropical Link (LOTLink) started in 2002. This initiative, shared between the Liverpool and Oxford major overseas programmes (MOPs), has established a state of the art bioanalytical facility in Liverpool based on LCMS analytical platforms. LOTLink provides training and support in bioanalysis which are central to the clinical trials activities of the MOPs. LOTLink offers validated assays for cur rently used antimalarials, Anti-TB and Antiretrovirals and has the capacity and potential to expand this list in line with MOP needs. The ability to accurately measure drugs, metabolites (and more recently identify specific proteins) in biological fluids is an important element of many of the field investigations underway and planned in the MOPs. The data from these studies is used to improve the delivery and deployment of effective chemotherapy and to better understand the issues which influenc e the outcome of therapeutic interventions. LOTLink is committed to the development of capacity in the MOPs which has been partially achieved in this first period of funding. We request the salary and consumable costs to ensure the viability of this initiative is maintained for a further three years.

Amount: £281,658
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine