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Danny A Milner - One of the best experts on this subject based on the ideXlab platform.
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quantitative assessment of multiorgan sequestration of parasites in fatal pediatric Cerebral Malaria
The Journal of Infectious Diseases, 2015Co-Authors: Danny A Milner, Rachel E Factor, R A Carr, Steve Kamiza, Richard O. Whitten, Charles Frantzreb, Alana Pradham, Krupa B Playforth, George N Liomba, Charles DzamalalaAbstract:: Children in sub-Saharan Africa continue to acquire and die from Cerebral Malaria, despite efforts to control or eliminate the causative agent, Plasmodium falciparum. We present a quantitative histopathological assessment of the sequestration of parasitized erythrocytes in multiple organs obtained during a prospective series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi, on pediatric patients who died from Cerebral Malaria and controls. After the brain, sequestration of parasites was most intense in the gastrointestinal tract, both in patients with Cerebral Malaria and those with parasitemia in other organs. Within cases of histologically defined Cerebral Malaria, which includes phenotypes termed "sequestration only" (CM1) and "sequestration with extravascular pathology" (CM2), CM1 was associated with large parasite numbers in the spleen and CM2 with intense parasite sequestration in the skin. A striking histological finding overall was the marked sequestration of parasitized erythrocytes across most organs in patients with fatal Cerebral Malaria, supporting the hypothesis that the disease is, in part, a result of a high level of total-body parasite sequestration.
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brain swelling and death in children with Cerebral Malaria
The New England Journal of Medicine, 2015Co-Authors: Karl B Seydel, Danny A Milner, Clarissa Valim, Gretchen L Birbeck, Samuel D Kampondeni, Michael J Potchen, Francis Muwalo, William G Bradley, Simon J Glover, Colleen A HammondAbstract:BackgroundCase fatality rates among African children with Cerebral Malaria remain in the range of 15 to 25%. The key pathogenetic processes and causes of death are unknown, but a combination of clinical observations and pathological findings suggests that increased brain volume leading to raised intracranial pressure may play a role. Magnetic resonance imaging (MRI) became available in Malawi in 2009, and we used it to investigate the role of brain swelling in the pathogenesis of fatal Cerebral Malaria in African children. MethodsWe enrolled children who met a stringent definition of Cerebral Malaria (one that included the presence of retinopathy), characterized them in detail clinically, and obtained MRI scans on admission and daily thereafter while coma persisted. ResultsOf 348 children admitted with Cerebral Malaria (as defined by the World Health Organization), 168 met the inclusion criteria, underwent all investigations, and were included in the analysis. A total of 25 children (15%) died, 21 of whom...
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pulmonary pathology in pediatric Cerebral Malaria
Human Pathology, 2013Co-Authors: Danny A Milner, Rachel E Factor, Rich O Whitten, R A Carr, Steve Kamiza, Geraldine S Pinkus, Malcolm E MolyneuxAbstract:Summary Respiratory signs are common in African children where Malaria is highly endemic, and thus, parsing the role of pulmonary pathology in illness is challenging. We examined the lungs of 100 children from an autopsy series in Blantyre, Malawi, many of whom death was attributed to Plasmodium falciparum Malaria. Our aim was to describe the pathologic manifestations of fatal Malaria; to understand the role of parasites, pigment, and macrophages; and to catalog comorbidities. From available patients, which included 55 patients with Cerebral Malaria and 45 controls, we obtained 4 cores of lung tissue for immunohistochemistry and morphological evaluation. We found that, in patients with Cerebral Malaria, large numbers of Malaria parasites were present in pulmonary alveolar capillaries, together with extensive deposits of Malaria pigment (hemozoin). The number of pulmonary macrophages in this vascular bed did not differ between patients with Cerebral Malaria, nonCerebral Malaria, and nonMalarial diagnoses. Comorbidities found in some Cerebral Malaria patients included pneumonia, pulmonary edema, hemorrhage, and systemic activation of coagulation. We conclude that the respiratory distress seen in patients with Cerebral Malaria does not appear to be anatomic in origin but that increasing Malaria pigment is strongly associated with Cerebral Malaria at autopsy.
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human Cerebral Malaria and plasmodium falciparum genotypes in malawi
Malaria Journal, 2012Co-Authors: Danny A Milner, Jimmy Vareta, Clarissa Valim, Jacqui Montgomery, Rachel F Daniels, Sarah K VolkmanAbstract:Background: Cerebral Malaria, a severe form of Plasmodium falciparum infection, is an important cause of mortality in sub-Saharan African children. A Taqman 24 Single Nucleotide Polymorphisms (SNP) molecular barcode assay was developed for use in laboratory parasites which estimates genotype number and identifies the predominant genotype. Methods: The 24 SNP assay was used to determine predominant genotypes in blood and tissues from autopsy and clinical patients with Cerebral Malaria. Results: Single genotypes were shared between the peripheral blood, the brain, and other tissues of Cerebral Malaria patients, while Malaria-infected patients who died of non-Malarial causes had mixed genetic signatures in tissues examined. Children with retinopathy-positive Cerebral Malaria had significantly less complex infections than those without retinopathy (OR = 3.7, 95% CI [1.51-9.10]).The complexity of infections significantly decreased over the Malaria season in retinopathy-positive patients compared to retinopathy-negative patients. Conclusions: Cerebral Malaria patients harbour a single or small set of predominant parasites; patients with incidental parasitaemia sustain infections involving diverse genotypes. Limited diversity in the peripheral blood of Cerebral Malaria patients and correlation with tissues supports peripheral blood samples as appropriate for genome-wide association studies of parasite determinants of pathogenicity.
Malcolm E Molyneux - One of the best experts on this subject based on the ideXlab platform.
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Cerebral Malaria in children using the retina to study the brain
Brain, 2014Co-Authors: Malcolm E Molyneux, Terrie E. Taylor, Valerie A White, Nicholas A V Beare, Ian J C Maccormick, Valentina Barrera, Paul HiscottAbstract:Cerebral Malaria is a dangerous complication of Plasmodium falciparum infection, which takes a devastating toll on children in sub-Saharan Africa. Although autopsy studies have improved understanding of Cerebral Malaria pathology in fatal cases, information about in vivo neurovascular pathogenesis is scarce because brain tissue is inaccessible in life. Surrogate markers may provide insight into pathogenesis and thereby facilitate clinical studies with the ultimate aim of improving the treatment and prognosis of Cerebral Malaria. The retina is an attractive source of potential surrogate markers for paediatric Cerebral Malaria because, in this condition, the retina seems to sustain microvascular damage similar to that of the brain. In paediatric Cerebral Malaria a combination of retinal signs correlates, in fatal cases, with the severity of brain pathology, and has diagnostic and prognostic significance. Unlike the brain, the retina is accessible to high-resolution, non-invasive imaging. We aimed to determine the extent to which paediatric Malarial retinopathy reflects cerebrovascular damage by reviewing the literature to compare retinal and Cerebral manifestations of retinopathy-positive paediatric Cerebral Malaria. We then compared retina and brain in terms of anatomical and physiological features that could help to account for similarities and differences in vascular pathology. These comparisons address the question of whether it is biologically plausible to draw conclusions about unseen Cerebral vascular pathogenesis from the visible retinal vasculature in retinopathy-positive paediatric Cerebral Malaria. Our work addresses an important cause of death and neurodisability in sub-Saharan Africa. We critically appraise evidence for associations between retina and brain neurovasculature in health and disease, and in the process we develop new hypotheses about why these vascular beds are susceptible to sequestration of parasitized erythrocytes.
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pulmonary pathology in pediatric Cerebral Malaria
Human Pathology, 2013Co-Authors: Danny A Milner, Rachel E Factor, Rich O Whitten, R A Carr, Steve Kamiza, Geraldine S Pinkus, Malcolm E MolyneuxAbstract:Summary Respiratory signs are common in African children where Malaria is highly endemic, and thus, parsing the role of pulmonary pathology in illness is challenging. We examined the lungs of 100 children from an autopsy series in Blantyre, Malawi, many of whom death was attributed to Plasmodium falciparum Malaria. Our aim was to describe the pathologic manifestations of fatal Malaria; to understand the role of parasites, pigment, and macrophages; and to catalog comorbidities. From available patients, which included 55 patients with Cerebral Malaria and 45 controls, we obtained 4 cores of lung tissue for immunohistochemistry and morphological evaluation. We found that, in patients with Cerebral Malaria, large numbers of Malaria parasites were present in pulmonary alveolar capillaries, together with extensive deposits of Malaria pigment (hemozoin). The number of pulmonary macrophages in this vascular bed did not differ between patients with Cerebral Malaria, nonCerebral Malaria, and nonMalarial diagnoses. Comorbidities found in some Cerebral Malaria patients included pneumonia, pulmonary edema, hemorrhage, and systemic activation of coagulation. We conclude that the respiratory distress seen in patients with Cerebral Malaria does not appear to be anatomic in origin but that increasing Malaria pigment is strongly associated with Cerebral Malaria at autopsy.
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The platelet count in Cerebral Malaria, is it useful to the clinician?
American Journal of Tropical Medicine and Hygiene, 2010Co-Authors: Yamikani Chimalizeni, Kondwani Kawaza, Terrie E. Taylor, Malcolm E MolyneuxAbstract:We conducted this study to determine the prognostic significance of the platelet count in children with Cerebral Malaria. We studied children with Cerebral Malaria admitted to the pediatric research ward at Queen Elizabeth Central Hospital, Malawi. We analyzed 1,811 children with Cerebral Malaria and compared them with 521 children with bacterial meningitis. There was a significant difference in platelet counts between children with Cerebral Malaria and those with meningitis. Among children with Cerebral Malaria, there was no relationship between the platelet count and either the admission coma score or the eventual outcome. Those with Malarial retinopathy were more thrombocytopenic than those without. Our results suggest that the platelet count is not prognostic in Malawian children with Cerebral Malaria.
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retinal pathology of pediatric Cerebral Malaria in malawi
PLOS ONE, 2009Co-Authors: Valerie A White, Malcolm E Molyneux, Susan Lewallen, Nicholas A V Beare, Terrie E. TaylorAbstract:Introduction The causes of coma and death in Cerebral Malaria remain unknown. Malarial retinopathy has been identified as an important clinical sign in the diagnosis and prognosis of Cerebral Malaria. As part of a larger autopsy study to determine causes of death in children with coma presenting to hospital in Blantyre, Malawi, who were fully evaluated clinically prior to death, we examined the histopathology of eyes of patients who died and underwent autopsy. Methodology/Principal Findings Children with coma were admitted to the pediatric research ward, classified according to clinical definitions as having Cerebral Malaria or another cause of coma, evaluated and treated. The eyes were examined by direct and indirect ophthalmoscopy. If a child died and permission was given, a standardized autopsy was carried out. The patient was then assigned an actual cause of death according to the autopsy findings. The eyes were examined pathologically for hemorrhages, cystoid macular edema, parasite sequestration and thrombi. They were stained immunohistochemically for fibrin and CD61 to identify the components of thrombi, β-amyloid precursor protein to detect axonal damage, for fibrinogen to identify vascular leakage and for glial fibrillary acidic protein to detect gliosis. Sixty-four eyes from 64 patients were examined: 35 with Cerebral Malaria and 29 with comas of other causes. Cerebral Malaria was distinguished by sequestration of parasitized erythrocytes, the presence and severity of retinal hemorrhages, the presence of cystoid macular edema, the occurrence and number of fibrin-platelet thrombi, the presence and amount of axonal damage and vascular leakage. Conclusions/Significance We found significant differences in retinal histopathology between patients who died of Cerebral Malaria and those with other diagnoses. These histopathological findings offer insights into the etiology of Malarial retinopathy and provide a pathological basis for recently described retinal capillary non-perfusion in children with Malarial retinopathy. Because of the similarities between the retina and the brain it also suggests mechanisms that may contribute to coma and death in Cerebral Malaria.
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Retinal findings predictive of outcome in Cerebral Malaria
Transactions of The Royal Society of Tropical Medicine and Hygiene, 1996Co-Authors: Susan Lewallen, Terrie E. Taylor, Helen Bakker, Bridget Wills, Paul Courtright, Malcolm E MolyneuxAbstract:Abstract The pathogenesis of Cerebral Malaria is poorly understood. Direct and indirect ophthalmoscope examinations of 141 Malawian children with strictly defined Cerebral Malaria revealed 2 distinct and prognostically significant findings: papilloedema and extramacular retinal oedema. The relative risk of death in patients with papilloedema was 6·7 times that in patients without papilloedema. Extramacular retinal oedema was associated with a 2·9 fold increase in the relative risk of dying. The mortality rate in patients with neither of these signs was only 1·3% compared to an overall mortality rate of 9·2%. The clinical and laboratory features associated with each of these ophthalmological findings were different, suggesting that there may be at least 2 different pathogenetic processes in patients with Cerebral Malaria.
Nicholas J White - One of the best experts on this subject based on the ideXlab platform.
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the murine Cerebral Malaria phenomenon
Trends in Parasitology, 2010Co-Authors: Nicholas J White, Gareth D H Turner, Isabelle M Medana, Arjen M DondorpAbstract:P.berghei ANKA infection in CBA or CB57BL/6 mice is used widely as a murine ‘model’ of human Cerebral Malaria (HCM), despite markedly different histopathological features. The pathology of the murine model is characterised by marked inflammation with little or no intraCerebral sequestration of parasitised erythrocytes, whereas HCM is associated with intense intraCerebral sequestration, often with little inflammatory response. There are now more than ten times as many studies each year of the murine model than on HCM. Of 48 adjunctive interventions evaluated in the murine model, 44 (92%) were successful, compared with only 1 (6%) of 17 evaluated in HCM during the same period. The value of the mouse model in identifying pathological processes or therapeutic interventions in human Cerebral Malaria is questionable.
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Intracranial pressure in childhood Cerebral Malaria
Transactions of The Royal Society of Tropical Medicine and Hygiene, 1991Co-Authors: D. Waller, Jane Crawley, François Nosten, D. Chapman, S. Krishna, Charles Craddock, David C. Brewster, Nicholas J WhiteAbstract:Abstract Lumbar punctures were performed in 40 Gambian children with acute Cerebral Malaria aged between 18 months and 10 years. The mean opening pressure was elevated in 32 (80%) of the children, but was not significantly different in the 14 fatal cases compared with survivors: 110 (standard deviation 71) versus 131 (58) mm of cerebrospinal fluid respectively. Cerebral perfusion pressures were also similar in the 2 groups: 64 (20) mm Hg versus 64 (11) mm Hg respectively. There was no clear clinical evidence of raised intracranial pressure, and no evidence of deterioration immediately following lumbar puncture. Nevertheless brain swelling, and consequent brain-stem compression, may contribute to a fatal outcome in Cerebral Malaria—particularly in those children who die from sudden respiratory arrest. A prospective evaluation of osmotic agents in childhood Cerebral Malaria seems to be justified.
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neurological sequelae of Cerebral Malaria in children
The Lancet, 1990Co-Authors: D R Brewster, Dominic P Kwiatkowski, Nicholas J WhiteAbstract:: Out of 604 Gambian children admitted with falciparum Malaria to one hospital between September and December, 1988, 308 had Cerebral Malaria and 203 were severely anaemic (haemoglobin less than 60 g/l). 14% of those with Cerebral Malaria died, as did 7.8% of those with severe anaemia. 32 (12%) of children surviving Cerebral Malaria had residual neurological deficit. 69 other children were admitted with clinical features strongly suggestive of Cerebral Malaria but with negative blood films; 16 of these died and 3 had residual neurological deficits. The commonest sequelae of Cerebral Malaria were hemiplegia (23 cases), cortical blindness (11), aphasia (9), and ataxia (6). Factors predisposing to sequelae included prolonged coma, protracted convulsions, severe anaemia, and a biphasic clinical course characterised by recovery of consciousness followed by recurrent convulsions and coma. At follow up 1-6 months later over half these children had made a full recovery, but a quarter were left with a major residual neurological deficit. Cerebral Malaria in childhood may be an important cause of neurological handicap in the tropics.
Terrie E. Taylor - One of the best experts on this subject based on the ideXlab platform.
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Cerebral Malaria in children using the retina to study the brain
Brain, 2014Co-Authors: Malcolm E Molyneux, Terrie E. Taylor, Valerie A White, Nicholas A V Beare, Ian J C Maccormick, Valentina Barrera, Paul HiscottAbstract:Cerebral Malaria is a dangerous complication of Plasmodium falciparum infection, which takes a devastating toll on children in sub-Saharan Africa. Although autopsy studies have improved understanding of Cerebral Malaria pathology in fatal cases, information about in vivo neurovascular pathogenesis is scarce because brain tissue is inaccessible in life. Surrogate markers may provide insight into pathogenesis and thereby facilitate clinical studies with the ultimate aim of improving the treatment and prognosis of Cerebral Malaria. The retina is an attractive source of potential surrogate markers for paediatric Cerebral Malaria because, in this condition, the retina seems to sustain microvascular damage similar to that of the brain. In paediatric Cerebral Malaria a combination of retinal signs correlates, in fatal cases, with the severity of brain pathology, and has diagnostic and prognostic significance. Unlike the brain, the retina is accessible to high-resolution, non-invasive imaging. We aimed to determine the extent to which paediatric Malarial retinopathy reflects cerebrovascular damage by reviewing the literature to compare retinal and Cerebral manifestations of retinopathy-positive paediatric Cerebral Malaria. We then compared retina and brain in terms of anatomical and physiological features that could help to account for similarities and differences in vascular pathology. These comparisons address the question of whether it is biologically plausible to draw conclusions about unseen Cerebral vascular pathogenesis from the visible retinal vasculature in retinopathy-positive paediatric Cerebral Malaria. Our work addresses an important cause of death and neurodisability in sub-Saharan Africa. We critically appraise evidence for associations between retina and brain neurovasculature in health and disease, and in the process we develop new hypotheses about why these vascular beds are susceptible to sequestration of parasitized erythrocytes.
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Pentoxifylline as an adjunct therapy in children with Cerebral Malaria.
Malaria Journal, 2010Co-Authors: Bertrand Lell, Terrie E. Taylor, Carsten Köhler, B Wamola, C Olola, Esther Kivaya, Gilbert Kokwaro, David Wypij, Sadik Mithwani, Peter G. KremsnerAbstract:Background Pentoxifylline (PTX) affects many processes that may contribute to the pathogenesis of severe Malaria and it has been shown to reduce the duration of coma in children with Cerebral Malaria. This pilot study was performed to assess pharmacokinetics, safety and efficacy of PTX in African children with Cerebral Malaria.
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The platelet count in Cerebral Malaria, is it useful to the clinician?
American Journal of Tropical Medicine and Hygiene, 2010Co-Authors: Yamikani Chimalizeni, Kondwani Kawaza, Terrie E. Taylor, Malcolm E MolyneuxAbstract:We conducted this study to determine the prognostic significance of the platelet count in children with Cerebral Malaria. We studied children with Cerebral Malaria admitted to the pediatric research ward at Queen Elizabeth Central Hospital, Malawi. We analyzed 1,811 children with Cerebral Malaria and compared them with 521 children with bacterial meningitis. There was a significant difference in platelet counts between children with Cerebral Malaria and those with meningitis. Among children with Cerebral Malaria, there was no relationship between the platelet count and either the admission coma score or the eventual outcome. Those with Malarial retinopathy were more thrombocytopenic than those without. Our results suggest that the platelet count is not prognostic in Malawian children with Cerebral Malaria.
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retinal pathology of pediatric Cerebral Malaria in malawi
PLOS ONE, 2009Co-Authors: Valerie A White, Malcolm E Molyneux, Susan Lewallen, Nicholas A V Beare, Terrie E. TaylorAbstract:Introduction The causes of coma and death in Cerebral Malaria remain unknown. Malarial retinopathy has been identified as an important clinical sign in the diagnosis and prognosis of Cerebral Malaria. As part of a larger autopsy study to determine causes of death in children with coma presenting to hospital in Blantyre, Malawi, who were fully evaluated clinically prior to death, we examined the histopathology of eyes of patients who died and underwent autopsy. Methodology/Principal Findings Children with coma were admitted to the pediatric research ward, classified according to clinical definitions as having Cerebral Malaria or another cause of coma, evaluated and treated. The eyes were examined by direct and indirect ophthalmoscopy. If a child died and permission was given, a standardized autopsy was carried out. The patient was then assigned an actual cause of death according to the autopsy findings. The eyes were examined pathologically for hemorrhages, cystoid macular edema, parasite sequestration and thrombi. They were stained immunohistochemically for fibrin and CD61 to identify the components of thrombi, β-amyloid precursor protein to detect axonal damage, for fibrinogen to identify vascular leakage and for glial fibrillary acidic protein to detect gliosis. Sixty-four eyes from 64 patients were examined: 35 with Cerebral Malaria and 29 with comas of other causes. Cerebral Malaria was distinguished by sequestration of parasitized erythrocytes, the presence and severity of retinal hemorrhages, the presence of cystoid macular edema, the occurrence and number of fibrin-platelet thrombi, the presence and amount of axonal damage and vascular leakage. Conclusions/Significance We found significant differences in retinal histopathology between patients who died of Cerebral Malaria and those with other diagnoses. These histopathological findings offer insights into the etiology of Malarial retinopathy and provide a pathological basis for recently described retinal capillary non-perfusion in children with Malarial retinopathy. Because of the similarities between the retina and the brain it also suggests mechanisms that may contribute to coma and death in Cerebral Malaria.
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Retinal findings predictive of outcome in Cerebral Malaria
Transactions of The Royal Society of Tropical Medicine and Hygiene, 1996Co-Authors: Susan Lewallen, Terrie E. Taylor, Helen Bakker, Bridget Wills, Paul Courtright, Malcolm E MolyneuxAbstract:Abstract The pathogenesis of Cerebral Malaria is poorly understood. Direct and indirect ophthalmoscope examinations of 141 Malawian children with strictly defined Cerebral Malaria revealed 2 distinct and prognostically significant findings: papilloedema and extramacular retinal oedema. The relative risk of death in patients with papilloedema was 6·7 times that in patients without papilloedema. Extramacular retinal oedema was associated with a 2·9 fold increase in the relative risk of dying. The mortality rate in patients with neither of these signs was only 1·3% compared to an overall mortality rate of 9·2%. The clinical and laboratory features associated with each of these ophthalmological findings were different, suggesting that there may be at least 2 different pathogenetic processes in patients with Cerebral Malaria.
Arjen M Dondorp - One of the best experts on this subject based on the ideXlab platform.
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the murine Cerebral Malaria phenomenon
Trends in Parasitology, 2010Co-Authors: Nicholas J White, Gareth D H Turner, Isabelle M Medana, Arjen M DondorpAbstract:P.berghei ANKA infection in CBA or CB57BL/6 mice is used widely as a murine ‘model’ of human Cerebral Malaria (HCM), despite markedly different histopathological features. The pathology of the murine model is characterised by marked inflammation with little or no intraCerebral sequestration of parasitised erythrocytes, whereas HCM is associated with intense intraCerebral sequestration, often with little inflammatory response. There are now more than ten times as many studies each year of the murine model than on HCM. Of 48 adjunctive interventions evaluated in the murine model, 44 (92%) were successful, compared with only 1 (6%) of 17 evaluated in HCM during the same period. The value of the mouse model in identifying pathological processes or therapeutic interventions in human Cerebral Malaria is questionable.