Malcolm E Molyneux

Publications (138)985.12 Total impact

• Article: The alveolar microenvironment of patients infected with Human Immunodeficiency Virus does not modify alveolar macrophage interactions with Streptococcus pneumoniae.

  Stephen B Gordon, R Thomas Jagoe, Elizabeth R Jarman, James C North, Alison Pridmore, Janelisa Musaya, Neil French, Eduard E Zijlstra, Malcolm E Molyneux, Robert C Read
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  ABSTRACT: Objectives: We tested the hypothesis that HIV infection results in activation of alveolar macrophages, and that this might be associated with impaired defence against pneumococcus.Methods: We compared alveolar macrophages and lymphocytes in 131 bronchoalveolar lavage samples from HIV-infected and healthy controls using inflammatory gene microarrays, flow cytometry, real-time PCR and ELISA to determine the pattern of macrophage activation associated with HIV infection and the effect of this activation on defence against pneumococcus. We used interferon gamma priming to mimic the cellular milieu in HIV infected lungs. InnateDB and Biolayout 3D were used to analyse the interactions of the upregulated genes.Measurements and main results: Alveolar macrophages from HIV infected adults showed increased gene expression and cytokine production in a classical pattern. Bronchoalveolar lavage from HIV infected subjects showed excess CD8+ lymphocytes with activated phenotype. TLR4 expression was increased in macrophages from HIV infected subjects but function was similar between the groups; lung lavage fluid did not inhibit TLR function in transfected HeLa cells. Alveolar macrophages from HIV infected subjects showed normal binding and internalisation of opsonized pneumococci, with or without IFN-γ priming.Conclusion: Alveolar macrophages from HIV infected subjects show classical activation compared to healthy controls but this does not alter macrophage interactions with pneumococci.
  Clinical and vaccine immunology: CVI 04/2013; · 2.37 Impact Factor
• Article: Complement activation and the resulting placental vascular insufficiency drives fetal growth restriction associated with placental malaria.

  Andrea L Conroy, Karlee L Silver, Kathleen Zhong, Monique Rennie, Peter Ward, J Vidya Sarma, Malcolm E Molyneux, John Sled, Joseph F Fletcher, Stephen Rogerson, Kevin C Kain
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  ABSTRACT: Placental malaria (PM) is a major cause of fetal growth restriction, yet the underlying mechanism is unclear. Complement C5a and C5a receptor levels are increased with PM. C5a is implicated in fetal growth restriction in non-infection-based animal models. In a case-control study of 492 pregnant Malawian women, we find that elevated C5a levels are associated with an increased risk of delivering a small-for-gestational-age infant. C5a was significantly increased in PM and was negatively correlated with the angiogenic factor angiopoietin-1 and positively correlated with angiopoietin-2, soluble endoglin, and vascular endothelial growth factor. Genetic or pharmacological blockade of C5a or its receptor in a mouse model of PM resulted in greater fetoplacental vessel development, reduced placental vascular resistance, and improved fetal growth and survival. These data suggest that C5a drives fetal growth restriction in PM through dysregulation of angiogenic factors essential for placental vascular remodeling resulting in placental vascular insufficiency.
  Cell host & microbe 02/2013; 13(2):215-26. · 13.02 Impact Factor
• Article: Prevalence of Raised Intracranial Pressure in Cerebral Malaria Detected by Optic Nerve Sheath Ultrasound.

  Nicholas A V Beare, Simon J Glover, Susan Lewallen, Terrie E Taylor, Simon P Harding, Malcolm E Molyneux
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  ABSTRACT: We aimed to use optic nerve sheath (ONS) ultrasound to determine the prevalence of raised intracranial pressure (ICP) in African children with cerebral malaria (CM); if increased, ONS diameter is associated with poor outcome. We measured ONS diameter in 101 children with CM and 11 children with malaria and impaired consciousness in Malawi. The prevalence of raised ICP detected by increased ONS diameter was 49%. Case fatality was similar in children with increased ONS diameter on admission (9/55) and those children without increased ONS diameter (11/57). Neurological sequelae were more common in those children with increased ONS diameter (7/46 versus 2/46, P < 0.05). Lumbar puncture (LP) opening pressure was elevated in 95% of 46 children who underwent LP. In Malawian children with CM, raised ICP is less commonly detected by ONS ultrasound than LP. This study suggests that raised ICP is not universal in CM and that other mechanisms may account for coma.
  The American journal of tropical medicine and hygiene 10/2012; · 2.59 Impact Factor
• Article: The effects of malaria and intermittent preventive treatment during pregnancy on fetal anemia in Malawi.

  Elizabeth T Rogawski, Ebbie Chaluluka, Malcolm E Molyneux, Gaoqian Feng, Stephen J Rogerson, Steven R Meshnick
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  ABSTRACT: Background. Fetal anemia is common in malarious areas and is a risk factor for infant morbidity and mortality. Malaria during pregnancy may cause decreased cord hemoglobin (Hb) and fetal anemia among newborns. Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is protective against malaria but may also affect hematopoiesis and contribute to fetal anemia. Methods. Peripheral, placental, and cord blood were examined for malaria parasitemia and Hb concentration in a cross-section of 3848 mothers and infants delivered at Queen Elizabeth Central Hospital in Blantyre, Malawi between 1997 and 2006. Unconditional linear and logistic regressions were performed with multiple imputation for missing covariates to assess the associations between malaria, IPTp with SP, and fetal anemia. Results. The overall prevalence of fetal anemia was 7.9% (n = 304). Malaria parasitemia at delivery was associated with an adjusted decrease in cord Hb of -0.24 g/dL (95% confidence interval [CI], -.42 to -.05). The adjusted prevalence odds ratio for the effect of malaria on fetal anemia was 1.41 (95% CI, 1.05-1.90). Primigravidae who did not take IPTp had infants at highest risk for fetal anemia, and density of parasitemia was correlated with the decrease in cord Hb. There was no significant association between SP use and cord Hb or fetal anemia. Conclusions. Malaria during pregnancy, but not IPTp, decreases cord Hb and is a risk factor for fetal anemia in Malawi. Intermittent preventive treatment during pregnancy with SP may continue to be safe and effective in preventing malaria during pregnancy and fetal anemia despite development of SP resistance.
  Clinical Infectious Diseases 07/2012; 55(8):1096-102. · 9.15 Impact Factor
• Article: Reply to harrington et Al.

  Steve M Taylor, Alejandro L Antonia, Victor Mwapasa, Gaoqian Feng, Malcolm E Molyneux, Feiko O Ter Kuile, Steven R Meshnick, Stephen J Rogerson
  Clinical Infectious Diseases 06/2012; 55(7):1026-7. · 9.15 Impact Factor
• Article: Clinical manifestations of new versus recrudescent malaria infections following anti-malarial drug treatment.

  Ayesha M Shaukat, Elizabeth A Gilliams, Leo J Kenefic, Matthew B Laurens, Fraction K Dzinjalamala, Osward M Nyirenda, Phillip C Thesing, Christopher G Jacob, Malcolm E Molyneux, Terrie E Taylor, Christopher V Plowe, Miriam K Laufer
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  ABSTRACT: BACKGROUND: Distinguishing new from recrudescent infections in post-treatment episodes of malaria is standard in anti-malarial drug efficacy trials. New infections are not considered malaria treatment failures and as a result, the prevention of subsequent episodes of malaria infection is not reported as a study outcome. However, in moderate and high transmission settings, new infections are common and the ability of a short-acting medication to cure an initial infection may be outweighed by its inability to prevent the next imminent infection. The clinical benefit of preventing new infections has never been compared to that of curing the initial infection. METHODS: Children enrolled in a sulphadoxine-pyrimethamine efficacy study in Blantyre, Malawi from 1998-2004 were prospectively evaluated. Six neutral microsatellites were used to classify new and recrudescent infections in children aged less than 10 years with recurrent malaria infections. Children from the study who did not experience recurrent parasitaemia comprised the baseline group. The odds of fever and anaemia, the rate of haemoglobin recovery and time to recurrence were compared among the groups. RESULTS: Fever and anemia were more common among children with parasitaemia compared to those who remained infection-free throughout the study period. When comparing recrudescent vs. new infections, the incidence of fever was not statistically different. However, children with recrudescent infections had a less robust haematological recovery and also experienced recurrence sooner than those whose infection was classified as new. CONCLUSIONS: The results of this study confirm the paramount importance of providing curative treatment for all malaria infections. Although new and recrudescent infections caused febrile illnesses at a similar rate, recurrence due to recrudescent infection did have a worsened haemological outcome than recurrence due to new infections. Local decision-makers should take into account the results of genotyping to distinguish new from recrudescent infections when determining treatment policy on a population level. It is appropriate to weigh recrudescent malaria more heavily than new infection in assessing treatment efficacy.
  Malaria Journal 06/2012; 11(1):207. · 3.19 Impact Factor
• Article: Plasma concentrations of parasite histidine-rich protein 2 distinguish between retinopathy-positive and retinopathy-negative cerebral malaria in Malawian children.

  Karl B Seydel, Lindsay L Fox, Simon J Glover, Mathew J Reeves, Paul Pensulo, Alice Muiruri, Ashley Mpakiza, Malcolm E Molyneux, Terrie E Taylor
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  ABSTRACT: Brain histology and ophthalmoscopy suggest that approximately 25% of children with World Health Organization-defined cerebral malaria (CM) have a nonmalarial cause of death. Misclassification complicates clinical care, confounds studies of association, and may obfuscate successes in malaria control. Retinopathy predicts intracerebral parasite sequestration with >90% sensitivity and specificity, but detecting retinopathy requires well-trained personnel and expensive equipment. We investigated the utility of plasma concentrations of parasite histidine-rich protein 2 (pHRP2), a Plasmodium-specific protein, as a predictor of intracerebral parasite sequestration at autopsy and of malaria retinopathy on clinical examination in patients with clinically defined CM. In 64 autopsy cases, 47 of whom had histological evidence of sequestration, the sensitivity and specificity of a plasma pHRP2 level of >1700 ng/mL were 98% and 94%, respectively, and the area under the receiver operating characteristic (AUROC) curve was 0.98. In a separate, prospectively studied group of 101 children with clinically defined CM, of whom 71 had retinopathy, the same pHRP2 cutoff predicted retinopathy-positivity with a sensitivity of 90% and specificity of 87% (AUROC, 0.90). Elevated plasma pHRP2 concentrations can identify Malawian children with histologically confirmed or retinopathy-positive CM and is a more field-friendly approach to confirming the diagnosis than post mortem sampling or ophthalmoscopy.
  The Journal of Infectious Diseases 05/2012; 206(3):309-18. · 6.41 Impact Factor
• Article: Novel biomarker combination improves the diagnosis of serious bacterial infections in Malawian children.

  Adam D Irwin, Fiona Marriage, Limangeni A Mankhambo, Ipd Study Group, Graham Jeffers, Ruwanthi Kolamunnage-Dona, Malcolm Guiver, Brigitte Denis, Elizabeth M Molyneux, Malcolm E Molyneux, Philip J Day, Enitan D Carrol
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  ABSTRACT: BACKGROUND: High throughput technologies offer insight into disease processes and heightens opportunities for improved diagnostics. Using transcriptomic analyses, we aimed to discover and to evaluate the clinical validity of a combination of reliable and functionally important biomarkers of serious bacterial infection (SBI). METHODS: We identified three previously reported biomarkers of infection (neutrophil gelatinase-associated lipocalin (NGAL), granulysin and resistin) and measured gene expression using quantitative real-time PCR. Protein products related to the three transcripts were measured by immunoassays. RESULTS: Relative gene expression values of NGAL and resistin were significantly increased, and expression of granulysin significantly decreased in cases compared to controls. Plasma concentrations of NGAL and resistin were significantly increased in children with confirmed SBI compared to children with no detectable bacterial infection (NBI), and to controls (287 versus 128 versus 62 ng/ml and 195 versus 90 versus 18 ng/ml, respectively, p < 0.05). Plasma protein concentrations of NGAL and resistin were significantly increased in non-survivors compared to survivors (306 versus 211 and 214 versus 150 ng/ml, p = 0.02). The respective areas under the curve (AUC) for NGAL, resistin and procalcitonin in predicting SBI were 0.79, 0.80 and 0.86, whilst a combination of NGAL, resistin and procalcitonin achieved an AUC of 0.90. CONCLUSIONS: We have demonstrated a unique combination of diagnostic biomarkers of SBI using transcriptomics, and demonstrated translational concordance with the corresponding protein. The addition of NGAL and resistin protein measurement to procalcitonin significantly improved the diagnosis of SBI.
  BMC Medical Genomics 05/2012; 5(1):13. · 3.69 Impact Factor
• Article: Antenatal receipt of sulfadoxine-pyrimethamine does not exacerbate pregnancy-associated malaria despite the expansion of drug-resistant Plasmodium falciparum: clinical outcomes from the QuEERPAM study.

  Steve M Taylor, Alejandro L Antonia, Ebbie Chaluluka, Victor Mwapasa, Gaoqian Feng, Malcolm E Molyneux, Feiko O ter Kuile, Steven R Meshnick, Stephen J Rogerson
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  ABSTRACT: Antenatal intermittent preventive therapy with 2 doses of sulfadoxine-pyrimethamine (IPTp-SP) is the mainstay of efforts in sub-Saharan Africa to prevent pregnancy-associated malaria (PAM). Recent studies report that drug resistance may cause IPTp-SP to exacerbate PAM morbidity, raising fears that current policies will cause harm as resistance spreads. We conducted a serial, cross-sectional analysis of the relationships between IPTp-SP receipt, SP-resistant Plasmodium falciparum, and PAM morbidity in delivering women during a period of 9 years at a single site in Malawi. PAM morbidity was assessed by parasite densities, placental histology, and birth outcomes. The prevalence of parasites with highly SP-resistant haplotypes increased from 17% to 100% (P < .001), and the proportion of women receiving full IPTp (≥2 doses) increased from 25% to 82% (P < .001). Women who received full IPTp with SP had lower peripheral (P = .018) and placental (P < .001) parasite densities than women who received suboptimal IPTp (<2 doses). This effect was not significantly modified by the presence of highly SP-resistant haplotypes. After adjustment for covariates, the receipt of SP in the presence of SP-resistant P. falciparum did not exacerbate any parasitologic, histologic, or clinical measures of PAM morbidity. In this longitudinal study of malaria at delivery, the receipt of SP as IPTp did not potentiate PAM morbidity despite the increasing prevalence and fixation of SP-resistant P. falciparum haplotypes. Even when there is substantial resistance, SP may be used in modified IPTp regimens as a component of comprehensive antenatal care.
  Clinical Infectious Diseases 03/2012; 55(1):42-50. · 9.15 Impact Factor
• Article: Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria: a retrospective case-control study*.

  Andrea L Conroy, Simon J Glover, Michael Hawkes, Laura K Erdman, Karl B Seydel, Terrie E Taylor, Malcolm E Molyneux, Kevin C Kain
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  ABSTRACT: To investigate the relationship among the angiopoietin-Tie-2 system, retinopathy, and mortality in children with cerebral malaria. A case-control study of retinopathy-positive vs. retinopathy-negative children with clinically defined cerebral malaria. Queen Elizabeth Central Hospital in Blantyre, Malawi. One hundred fifty-five children presenting with severe malaria and meeting a strict definition of clinical cerebral malaria (Blantyre Coma Score ≤ 2, Plasmodium falciparum parasitemia, no other identifiable cause for coma) were included in the study. None. Clinical and laboratory parameters were recorded at admission and funduscopic examinations were performed. Admission levels of angiopoietin-1, angiopoietin-2, and a soluble version of their cognate receptor were measured by enzyme-linked immunosorbent assay. We show that angiopoietin-1 levels are decreased and angiopoietin-2 and soluble Tie-2 levels are increased in children with cerebral malaria who had retinopathy compared with those who did not. Angiopoietin-2 and soluble Tie-2 were independent predictors of retinopathy (adjusted odds ratio [95% CI], angiopoietin-2, 4.3 [1.3-14.6], p = .019; soluble Tie-2, 9.7 [2.1-45.8], p = .004). Angiopoietin-2 and soluble Tie-2 were positively correlated with the number of hemorrhages, the severity or retinal whitening, and the extent of capillary whitening observed on funduscopic examination (p < .05 after adjustment for multiple comparisons). Angiopoietin-2 and soluble Tie-2 levels were elevated in children with cerebral malaria who subsequently died and angiopoetin-2 was an independent predictor of death (adjusted odds ratio: 3.9 [1.2-12.7], p = .024). When combined with clinical parameters, angiopoetin-2 improved prediction of mortality using logistic regression models and classification trees. These results provide insights into mechanisms of endothelial activation in cerebral malaria and indicate that the angiopoietin-Tie-2 axis is associated with retinopathy and mortality in pediatric cerebral malaria.
  Critical care medicine 03/2012; 40(3):952-9. · 6.37 Impact Factor
• Article: Supraorbital postmortem brain sampling for definitive quantitative confirmation of cerebral sequestration of Plasmodium falciparum parasites.

  Danny A Milner, Clarissa Valim, Robert Luo, Krupa B Playforth, Steve Kamiza, Malcolm E Molyneux, Karl B Seydel, Terrie E Taylor
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  ABSTRACT: The conventional clinical case definition of cerebral malaria (CM) is imprecise but specificity is improved by a definitive clinical feature such as retinopathy or confirming sequestration of parasites in a post-mortem examination of the brain. A full autopsy is often not possible, since it is costly and may encounter resistance of the deceased's family. We have assessed the use of a cytological smear of brain tissue, obtained post-mortem by supraorbital sampling, for the purpose of quantifying cerebral sequestration in children with fatal malaria in Blantyre, Malawi. We have compared this method to histological quantification of parasites at autopsy. The number of parasites present on cytological smears correlated with the proportion of vessels parasitized as assessed by histology of fixed and stained brain tissue. Use of cytological results in addition to the standard clinical case definition increases the specificity of the clinical case definition alone from 48.3% to 100% with a minimal change in sensitivity. Post-mortem supraorbital sampling of brain tissue improves the specificity of the diagnosis of fatal cerebral malaria and provides accurate quantitative estimates of cerebral sequestration. This tool can be of great value in clinical, pathogenetic, and epidemiological research studies on cerebral malaria.
  The Journal of Infectious Diseases 01/2012; 205(10):1601-6. · 6.41 Impact Factor
• Source

  Available from: Melita A Gordon

  Article: Genotypic homogeneity of multidrug resistant S. Typhimurium infecting distinct adult and childhood susceptibility groups in Blantyre, Malawi.

  Chisomo L Msefula, Robert A Kingsley, Melita A Gordon, Elizabeth Molyneux, Malcolm E Molyneux, Calman A MacLennan, Gordon Dougan, Robert S Heyderman
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  ABSTRACT: Nontyphoidal Salmonella (NTS) serovars are a common cause of bacteraemia in young children and HIV-infected adults in Malawi and elsewhere in sub-Saharan Africa. These patient populations provide diverse host-immune environments that have the potential to drive bacterial adaptation and evolution. We therefore investigated the diversity of 27 multidrug resistant (MDR) Salmonella Typhimurium strains isolated over 6 years (2002-2008) from HIV-infected adults and children and HIV-uninfected children. Sequence reads from whole-genome sequencing of these isolates using the Illumina GA platform were mapped to the genome of the laboratory strain S. Typhimurium SL1344 excluding homoplastic regions that contained prophage and insertion elements. A phylogenetic tree generated from single nucleotide polymorphisms showed that all 27 strains clustered with the prototypical MDR strain D23580. There was no clustering of strains based on host HIV status or age, suggesting that these susceptible populations acquire S. Typhimurium from common sources or that isolates are transmitted freely between these populations. However, 7/14 of the most recent isolates (2006/2008) formed a distinct clade that branched off 22 SNPs away from the cluster containing earlier isolates. These data suggest that the MDR bacterial population is not static, but is undergoing microevolution which might result in further epidemiology change.
  PLoS ONE 01/2012; 7(7):e42085. · 4.09 Impact Factor
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  Available from: PubMed Central

  Article: Human cerebral malaria and Plasmodium falciparum genotypes in Malawi.

  Danny A Milner, Jimmy Vareta, Clarissa Valim, Jacqui Montgomery, Rachel F Daniels, Sarah K Volkman, Daniel E Neafsey, Daniel J Park, Stephen F Schaffner, Nira C Mahesh, [......], Amanda K Lukens, Daria Van Tyne, Roger C Wiegand, Pardis C Sabeti, Karl B Seydel, Simon J Glover, Steve Kamiza, Malcolm E Molyneux, Terrie E Taylor, Dyann F Wirth
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  ABSTRACT: 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. The 24 SNP assay was used to determine predominant genotypes in blood and tissues from autopsy and clinical patients with cerebral malaria. 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. 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.
  Malaria Journal 01/2012; 11:35. · 3.19 Impact Factor
• Source

  Available from: PubMed Central

  Article: Evoked potentials in pediatric cerebral malaria.

  Minal Bhanushali, Terrie E Taylor, Malcolm E Molyneux, Monica Sapuwa, Eunice Mwandira, Gretchen L Birbeck
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  ABSTRACT: Cortical evoked potentials (EP) provide localized data regarding brain function and may offer prognostic information and insights into the pathologic mechanisms of malaria-mediated cerebral injury. As part of a prospective cohort study, we obtained somatosensory evoked potentials (SSEPs) and brainstem auditory EPs (AEPs) within 24 hours of admission on 27 consecutive children admitted with cerebral malaria (CM). Children underwent follow-up for 12 months to determine if they had any long term neurologic sequelae. EPs were obtained in 27 pediatric CM admissions. Two children died. Among survivors followed an average of 514 days, 7/25 (28.0%) had at least one adverse neurologic outcome. Only a single subject had absent cortical EPs on admission and this child had a good neurologic outcome. Among pediatric CM survivors, cortical EPs are generally intact and do not predict adverse neurologic outcomes. Further study is needed to determine if alterations in cortical EPs can be used to predict a fatal outcome in CM.
  Neurology International 11/2011; 3(3):e14.
• Article: Etiology of suspected pneumonia in adults admitted to a high-dependency unit in Blantyre, Malawi.

  Thomas K Hartung, Daniel Chimbayo, Joep J G van Oosterhout, Tarsizio Chikaonda, Gerard J J van Doornum, Eric C J Claas, Willem J G Melchers, Malcolm E Molyneux, Ed E Zijlstra
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  ABSTRACT: The microbiologic etiology of severe pneumonia in hospitalized patients is rarely known in sub-Saharan Africa. Through a comprehensive diagnostic work-up, we aimed to identify the causative agent in severely ill patients with a clinical picture of pneumonia admitted to a high-dependency unit. A final diagnosis was made and categorized as confirmed or probable by using predefined criteria. Fifty-one patients were recruited (45% females), with a mean age of 35 years (range = 17-88 years), of whom 11(22%) died. Forty-eight (94%) of the patients were seropositive for human immunodeficiency virus; 14 (29%) of these patients were receiving antiretroviral treatment. Final diagnoses were bacterial pneumonia (29%), Pneumocystis jirovecii pneumonia (27%), pulmonary tuberculosis (22%), and pulmonary Kaposi's sarcoma (16%); 39 (77%) of these cases were confirmed cases. Fifteen (29%) patients had multiple isolates. At least 3 of 11 viral-positive polymerase chain reaction (PCR) results of bronchoalveolar lavage fluid were attributed clinical relevance. No atypical bacterial organisms were found.
  The American journal of tropical medicine and hygiene 07/2011; 85(1):105-12. · 2.59 Impact Factor
• Article: Liver pathology in Malawian children with fatal encephalopathy.

  Richard Whitten, Danny A Milner, Matthew M Yeh, Steve Kamiza, Malcolm E Molyneux, Terrie E Taylor
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  ABSTRACT: A common clinical presentation of Plasmodium falciparum is parasitemia, complicated by an encephalopathy for which other explanations cannot be found, termed cerebral malaria-an important cause of death in young children in endemic areas. Our objective was to study hepatic histopathology in Malawian children with fatal encephalopathy, with and without P falciparum parasitemia, to assess the contributions of severe malaria. We report autopsy results from a series of 87 Malawian children who died between 1996 and 2008. Among 75 cases with P falciparum parasitemia, 51 had intracerebral sequestered parasites, whereas 24 without sequestered parasites had other causes of death revealed by autopsy including 4 patients with clinicopathologic findings which may represent Reye syndrome. Hepatic histology in parasitemic cases revealed very limited sequestration of parasites in hepatic sinusoids, even in cases with extensive sequestration elsewhere, but increased numbers of hemozoin-laden Kupffer cells were invariably present with a strong association with histologic evidence of cerebral malaria by quantitative analysis. Of 12 patients who were consistently aparasitemic during their fatal illness, 5 had clinicopathologic findings which may represent Reye syndrome. Hepatic sequestration of parasitized erythrocytes is not a feature of fatal malaria in Malawian children, and there is no structural damage in the liver. Reye syndrome may be an important cause of fatal encephalopathy in children in Malawi with and without peripheral parasitemia and warrants close scrutiny of aspirin use in malaria-endemic areas.
  Human pathology 03/2011; 42(9):1230-9. · 3.03 Impact Factor
• Article: Redefining cerebral malaria by including malaria retinopathy.

  Nicholas A V Beare, Susan Lewallen, Terrie E Taylor, Malcolm E Molyneux
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  ABSTRACT: Accurate diagnosis of cerebral malaria (CM) is important for patient management, epidemiological and end point surveillance, and enrolling patients with CM in studies of pathogenesis or therapeutic trials. In malaria-endemic areas, where asymptomatic Plasmodium falciparum parasitemia is common, a positive blood film in a comatose individual does not prove that the coma is due to malaria. A retinopathy consisting of two unique features - patchy retinal whitening and focal changes of vessel color - is highly specific for encephalopathy of malarial etiology. White-centered retinal hemorrhages are a common but less specific feature. Either indirect or direct ophthalmoscopy can be used to identify the changes, and both procedures can be learned and practiced by nonspecialist clinicians. In view of its important contributions to both clinical care and research, examination of the retina should become a routine component of the assessment of a comatose child or adult when CM is a possible diagnosis.
  Future Microbiology 03/2011; 6(3):349-55. · 3.82 Impact Factor
• Source

  Available from: PubMed Central

  Article: Comparative population structure of Plasmodium malariae and Plasmodium falciparum under different transmission settings in Malawi.

  Marian C Bruce, Allan Macheso, Alex McConnachie, Malcolm E Molyneux
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  ABSTRACT: Described here is the first population genetic study of Plasmodium malariae, the causative agent of quartan malaria. Although not as deadly as Plasmodium falciparum, P. malariae is more common than previously thought, and is frequently in sympatry and co-infection with P. falciparum, making its study increasingly important. This study compares the population parameters of the two species in two districts of Malawi with different malaria transmission patterns--one seasonal, one perennial--to explore the effects of transmission on population structures. Six species-specific microsatellite markers were used to analyse 257 P. malariae samples and 257 P. falciparum samples matched for age, gender and village of residence. Allele sizes were scored to within 2 bp for each locus and haplotypes were constructed from dominant alleles in multiple infections. Analysis of multiplicity of infection (MOI), population differentiation, clustering of haplotypes and linkage disequilibrium was performed for both species. Regression analyses were used to determine association of MOI measurements with clinical malaria parameters. Multiple-genotype infections within each species were common in both districts, accounting for 86.0% of P. falciparum and 73.2% of P. malariae infections and did not differ significantly with transmission setting. Mean MOI of P. falciparum was increased under perennial transmission compared with seasonal (3.14 vs 2.59, p = 0.008) and was greater in children compared with adults. In contrast, P. malariae mean MOI was similar between transmission settings (2.12 vs 2.11) and there was no difference between children and adults. Population differentiation showed no significant differences between villages or districts for either species. There was no evidence of geographical clustering of haplotypes. Linkage disequilibrium amongst loci was found only for P. falciparum samples from the seasonal transmission setting. The extent of similarity between P. falciparum and P. malariae population structure described by the high level of multiple infection, the lack of significant population differentiation or haplotype clustering and lack of linkage disequilibrium is surprising given the differences in the biological features of these species that suggest a reduced potential for out-crossing and transmission in P. malariae. The absence of a rise in P. malariae MOI with increased transmission or a reduction in MOI with age could be explained by differences in the duration of infection or degree of immunity compared to P. falciparum.
  Malaria Journal 02/2011; 10:38. · 3.19 Impact Factor
• Article: Glycerol adjuvant therapy in adults with bacterial meningitis in a high HIV seroprevalence setting in Malawi: a double-blind, randomised controlled trial.

  Katherine Mb Ajdukiewicz, Katharine E Cartwright, Matthew Scarborough, James B Mwambene, Patrick Goodson, Malcolm E Molyneux, Eduard E Zijlstra, Neil French, Christopher Jm Whitty, David G Lalloo
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  ABSTRACT: Southern Africa has a high incidence of bacterial meningitis in adults, often associated with HIV co-infection. Mortality exceeds 50%, even with appropriate antibiotic therapy, and is not improved with corticosteroids. Glycerol adjuvant therapy reduces long-term morbidity in bacterial meningitis in children, and its use is being promoted. We aimed to assess the effectiveness of glycerol as an adjuvant therapy for adults with bacterial meningitis in Africa. The study was done in two phases. First, in an open-label dose-finding study, 45 adult patients with symptoms, signs, and cerebrospinal fluid findings consistent with bacterial meningitis received either 50 mL, 75 mL, or 100 mL of glycerol four times a day for 4 days. We then did a randomised, double-blind, placebo-controlled trial of oral glycerol in adults with bacterial meningitis. Patients with clinical and cerebrospinal fluid findings suggestive of bacterial meningitis were randomly assigned in blocks of 12 by use of a random number list produced by an independent statistician to receive either glycerol or an equivalent volume of sugar solution. Glycerol and placebo were indistinguishable by colour or taste. The primary outcome was mortality at 40 days, with secondary outcomes including disability and mortality restricted to pneumococcal disease. All patients were analysed for the primary outcome excluding those who were lost to follow-up. This trial is registered at controlled-trials.com, number ISRCTN70121840. 75 mL glycerol four times a day was the highest tolerated dose, and was used for the main study. 265 patients were assigned treatment: 137 glycerol and 128 placebo. The trial was stopped early on the advice of the data and safety monitoring board after a planned interim analysis. By day 40, 61 (49%) of 125 patients in the placebo group and 86 (63%) of 136 in the glycerol group had died (adjusted odds ratio 2.4, 95% CI 1.3-4.2, p=0.003). There was no benefit from glycerol for death and disability by day 40, and glycerol did not improve death and disability by day 40 or death at day 40 in patients with proven bacterial disease or pneumococcal disease. Two serious adverse events occurred that were possibly due to the study drug. Oral glycerol therapy cannot be recommended as an adjuvant therapy in adults with bacterial meningitis in resource-poor settings with a high HIV prevalence. Meningitis Research Foundation.
  The Lancet Infectious Diseases 02/2011; 11(4):293-300. · 17.39 Impact Factor
• Source

  Available from: James P Stewart

  Article: The IL1RN promoter rs4251961 correlates with IL-1 receptor antagonist concentrations in human infection and is differentially regulated by GATA-1.

  Enitan D Carrol, Antony Payton, Deborah Payne, Fabio Miyajima, Mas Chaponda, Limangeni A Mankhambo, Daniel L Banda, Elizabeth M Molyneux, Helen Cox, Greg Jacobson, Daniel F Carr, Malcolm E Molyneux, James P Stewart, John P Quinn, C Anthony Hart, William E Ollier
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  ABSTRACT: IL-1R antagonist (IL-1Ra) is required for adequate host defense in invasive pneumococcal disease (IPD). The minor allele of an IL1RN gene (C/T) promoter polymorphism (rs4251961) has been shown to be associated with decreased IL-1Ra production in healthy adults. We genotyped 299 children with IPD, and examined 19 IL1RN haplotype-tagging single-nucleotide polymorphisms. Human embryonic kidney HEK293(T) cells were transfected with the promoter reporter plasmid pGL3p containing either allelic variant C (pGL3pCC) or T (pGL3pTT) with or without cotransfection with an expression construct overexpressing the globin transcription factor GATA-1. Plasma IL-1Ra concentrations were significantly higher in nonsurvivors compared with survivors (p < 0.0005), and the C allele of rs4251961 was associated with a significant increase in plasma IL-1Ra concentrations (p = 0.01) during the acute illness of IPD. These findings were validated in a cohort of 276 treatment-naive HIV-infected adults, with borderline significance (p = 0.058). Functional analyses demonstrated that the activity of the promoter constructs containing the T allele increased ~6-fold as compared with basal activity, and that containing the C allele by ~9-fold (p < 0.001) in the presence of GATA-1. Our findings suggest that the IL-1Ra single-nucleotide polymorphism rs4251961 plays a key role in the pathophysiology of IPD and in other human infections.
  The Journal of Immunology 02/2011; 186(4):2329-35. · 5.79 Impact Factor