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Severe Malaria (severe + malaria)

Distribution by Scientific Domains

Medical Sciences	71%
Life Sciences	21%

Distribution within Medical Sciences

Pharmacology & Pharmaceutical Medicine	29%
Pathology	19%

Selected Abstracts

Complement driven innate immune response to malaria: fuelling severe malarial diseases

CELLULAR MICROBIOLOGY, Issue 8 2010
Karlee L. Silver
Summary Severe malaria remains a major cause of global mortality. The innate immune response to infection is a key determinant of malaria severity and outcome. The complement system plays a key role in initiating and augmenting innate immune responses, including inflammation, endothelial activation, opsonization and coagulation, processes which have been implicated in malaria pathogenesis. In this review, we discuss the evidence supporting a role for excessive complement activation in the pathogenesis of severe malaria. [source]

Role of medicines in malaria control and elimination

DRUG DEVELOPMENT RESEARCH, Issue 1 2010
Marian Warsame
Abstract Antimalarial medicines constitute important tools to cure and prevent malaria infections, thereby averting death and disability; their role in reducing the transmission of malaria is becoming increasingly important. Effective medicines that are currently available include artemisinin-based combination therapies (ACTs) for uncomplicated malaria, parenteral and rectal formulations of artemisinin derivatives and quinine injectables for severe malaria, and primaquine as an anti-relapse agent. These medicines are not optimal, however, owing to safety considerations in specific risk groups, complex regimens, and less than optimal formulations. The efficacy of antimalarial medicines including currently used ACTs is threatened by parasite resistance. Resistance to artemisinins has recently been identified at the Cambodia,Thailand border. Intermittent preventive treatment is constrained by the lack of a replacement for sulfadoxine-pyrimethamine. Despite increasing financial support to procure medicines, access to medicines by populations at risk of malaria, particularly in African countries, remains poor. This is largely due to weak health systems that are unable to deliver quality diagnostics and medicines through an efficient supply chain system, close at hand to the sick patient, especially in remote rural areas. Health systems are also challenged by incorrect prescribing practices in the informal and often unregulated private sector (an important provider of medicines for malaria) and the proliferation of counterfeit and substandard medicines. The provision of a more equitable access to life-saving medicines requires no less than a steady drug development pipeline for new medicines tailored to meet the challenging conditions in endemic countries, ideally single dose, highly effective against both disease and relapse-causing parasites and infective forms, extremely safe and with a long shelf life, and made available at affordable prices. Drug Dev Res 71: 4,11, 2010. © 2010 Wiley-Liss, Inc. [source]

Induction of the vascular endothelial growth factor pathway in the brain of adults with fatal falciparum malaria is a non-specific response to severe disease

HISTOPATHOLOGY, Issue 2 2010
Isabelle M. Medana
Medana I M, Day N P J, Roberts R, Sachanonta N, Turley H, Pongponratn E, Hien T T, White N J. & Turner G D H (2010) Histopathology,57, 282,294 Induction of the vascular endothelial growth factor pathway in the brain of adults with fatal falciparum malaria is a non-specific response to severe disease Aims:, Pathological or neuroprotective mechanisms in the brain in severe malaria may arise from microvascular obstruction with malaria-parasitized erythrocytes. This study aimed to investigate the role of hypoxia and induction of the vascular endothelial growth factor (VEGF) pathway in the neuropathophysiology of severe malaria. Methods and results:, Immunohistochemistry was performed on post mortem brain tissue sections from 20 cases of severe malaria and examined for the expression of transcriptional regulators of VEGF [hypoxia-inducible factor-1 alpha (HIF-1,), HIF-2,], DEC-1, VEGF, VEGF receptors 1 and 2, and the activated, phosphorylated VEGF receptor 2 (pKDR). HIFs showed limited protein expression and/or translocation to cell nuclei in severe malaria, but DEC-1, which is more stable and regulated by HIF-1,, was observed. There was heterogeneous expression of VEGF and its receptors in severe malaria and non-malarial disease controls. pKDR expression on vessels was greater in malaria cases than in controls but did not correlate with parasite sequestration. VEGF uptake by malaria parasites was observed. Conclusions:, VEGF and its receptor expression levels in severe malaria reflect a non-specific response to severe systemic disease. Potential manipulation of events at the vasculature by the parasite requires further investigation. [source]

Ursodeoxycholic acid and artesunate in the treatment of severe falciparum malaria patients with jaundice

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2 2010
Sombat Treeprasertsuk
Abstract Background and Aims:,Plasmodium falciparum (PF) infection can lead to severe complications. Ursodeoxycholic acid (UDCA) is increasingly used for the treatment of cholestatic liver diseases. The present study aims to determine the effects of combined UDCA and artesunate compared to placebo and artesunate on the improvement of liver tests in severe PF jaundiced patients. Methods:, All severe PF jaundiced patients, aged , 15 years and diagnosed as having severe malaria according to WHO 2000 criteria, were enrolled. Patients with evidence of biliary obstruction, other cholestatic liver diseases and those who were pregnant were excluded. Patients were randomized to receive either oral UDCA or placebo for 2 weeks in additional to artesunate. All patients were admitted for at least 14 days to monitor the result of the treatment. Results:, Seventy-four severe PF malaria patients with jaundice were enrolled. Both groups had similar demographic and laboratory tests, with the exception being more males in the UDCA group than in the placebo group (P = 0.04). The median of percentage change of total bilirubin and aminotransferase levels at the end of weeks 1, 2, 3 and 4 showed no difference between the two groups. Only the median of percentage change of alkaline phosphatase at the end of week one compared with the baseline values showed less increment in the UDCA group than in the placebo group (P = 0.04). No serious adverse events were seen during the 4 weeks of follow up. Conclusions:, In severe PF malaria patients with jaundice, combined therapy with UDCA and artesunate is safe, but does not significantly improve liver tests compared to placebo and artesunate. [source]

Alterations in local chromatin environment are involved in silencing and activation of subtelomeric var genes in Plasmodium falciparum

MOLECULAR MICROBIOLOGY, Issue 1 2007
Till S. Voss
Summary Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by the var gene family, undergoes antigenic variation and plays an important role in chronic infection and severe malaria. Only a single var gene is transcribed per parasite, and epigenetic control mechanisms are fundamental in this strategy of mutually exclusive transcription. We show that subtelomeric upsB var gene promoters carried on episomes are silenced by default, and that promoter activation is sufficient to silence all other family members. However, they are active by default when placed downstream of a second active var promoter, underscoring the significance of local chromatin environment and nuclear compartmentalization in var promoter regulation. Native chromatin covering the SPE2 -repeat array in upsB promoters is resistant to nuclease digestion, and insertion of these regulatory elements into a heterologous promoter causes local alterations in nucleosomal organization and promoter repression. Our findings suggest a common logic underlying the transcriptional control of all var genes, and have important implications for our understanding of the epigenetic processes involved in the regulation of this major virulence gene family. [source]

Cellular stress and injury responses in the brains of adult Vietnamese patients with fatal Plasmodium falciparum malaria

NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 6 2001
I. M. Medana
Immunohistochemical techniques have been used to investigate specific patterns of potentially reversible cellular injury, DNA damage, and apoptosis in the brainstems of Vietnamese patients who died of severe Plasmodium falciparum malaria. The degree and pattern of neuronal and glial stress responses were compared between patients with cerebral and non-cerebral malaria (CM), and appropriate non-malaria infected controls. The following markers were examined: (i) heat shock protein 70 (HSP70), for reversible injury; (ii) heme oxygenase-1, for oxidative stress; (iii & iv) two DNA-repair proteins, poly(ADP) ribose polymerase (PARP) and DNA-dependent protein kinase catalytic subunit; (v) poly(ADP) ribose, an end-product of PARP activity; and (vi) caspase-3-active, for apoptosis. Stress responses were found in a range of cell types as reflected by the widespread expression of HSP70. Oxidative stress predominated in the vicinity of vessels and haemorrhages. Some degree of DNA damage was found in the majority of malaria patients, but the distribution and frequency of the damage was much less than that observed in controls with irreversible neuronal injury. Similarly, caspase-3-active expression, as a measure of apoptosis, was no higher in the majority of malaria patients than the negative control cases, although 40% of CM cases expressed caspase-3-active in a small number of neurones of the pontine nuclei or within swollen axons of the pontocerebellar and corticospinal tracts. In conclusion, cells within the brainstem of all patients who died from severe malaria showed staining patterns indicative of considerable stress response and reversible neuronal injury. There was no evidence for a specific pattern of widespread irreversible cell damage in those patients with cerebral malaria. [source]

A case study of severe malaria: implications for practice

NURSING IN CRITICAL CARE, Issue 5 2008
Katherine Bates
[source]

The development of the RTS,S malaria vaccine candidate: challenges and lessons

PARASITE IMMUNOLOGY, Issue 9 2009
W. R. BALLOU
Summary RTS,S is the world's most advanced malaria vaccine candidate and is intended to protect infants and young children living in malaria endemic areas of sub-Saharan Africa against clinical disease caused by Plasmodium falciparum. Recently, a pivotal Phase III efficacy trial of RTS,S began in Africa. The goal of the programme has been to develop a vaccine that will be safe and effective when administered via the Expanded Program for Immunization (EPI) and significantly reduce the risk of clinically important malaria disease during the first years of life. If a similar reduction in the risk of severe malaria and other important co-morbidities associated with malaria infection can be achieved, then the vaccine could become a major new tool for reducing the burden of malaria in sub-Saharan Africa. Encouraging data from the ongoing phase II programme suggest that these goals may indeed be achievable. This review discusses some of the unique challenges that were faced during the development of this vaccine, highlights the complexity of developing new vaccine technologies and illustrates the power of partnerships in the ongoing fight against this killer disease. [source]

Distinct pattern of class and subclass antibodies in immune complexes of children with cerebral malaria and severe malarial anaemia

PARASITE IMMUNOLOGY, Issue 6-7 2008
E. K. MIBEI
SUMMARY Plasmodium falciparum infection can lead to deadly complications such as severe malaria-associated anaemia (SMA) and cerebral malaria (CM). Children with severe malaria have elevated levels of circulating immune complexes (ICs). To further investigate the quantitative differences in antibody class/subclass components of ICs in SMA and CM, we enrolled 75 children with SMA and 32 children with CM from hospitals in western Kenya and matched them to 74 and 52 control children, respectively, with uncomplicated symptomatic malaria. Total IgG IC levels were always elevated in children with malaria upon enrolment, but children with CM had the highest levels of any group. Conditional logistic regression showed a borderline association between IgG4-containing IC levels and increased risk of SMA (OR = 3·11, 95% CI 1·01,9·56, P = 0·05). Total IgG ICs (OR = 2·84, 95% CI 1·08,7·46, P = 0·03) and IgE-containing ICs (OR = 6·82, OR 1·88,24·73, P , 0·01) were associated with increased risk of CM. These results point to differences in the contribution of the different antibody class and subclass components of ICs to the pathogenesis of SMA and CM and give insight into potential mechanisms of disease. [source]

Ascaris lumbricoides infection is associated with protection from cerebral malaria

PARASITE IMMUNOLOGY, Issue 3 2000
Mathieu Nacher
Following reports of increased IgE in severe malaria and hypothesizing that helminth coinfections could modify its outcome, we conducted a retrospective case,control study to establish whether helminths affect the evolution of Plasmodium falciparum malaria. Some 182 severe cases, 315 mild controls and 40 controls with circulating schizonts were examined for intestinal helminths. Comparing cerebral malaria with mild controls, Ascaris lumbricoides was associated with a protective adjusted odds ratio (OR) of 0.58 (0.32,1.03) P = 0.06, for coinfection with Ascaris and Necator americanus, OR = 0.39 (0.17,0.88) P = 0.02. Protection followed a dose,effect trend (P = 0.008). When comparing cerebral malaria cases and controls with circulating schizonts the OR was 0.25 (0.009,0.67) P = 0.006. We hypothesized that Ascaris infected patients may have had decreased cyto-adherence, possibly through endothelial cell receptor downregulation and/or decreased splenic clearance leading to the absence of selection of virulent P. falciparum strains. IgE-anti-IgE immune complexes resulting from helminth preinfection may have an important role in influencing clinical presentation of severe malaria, and in establishing malaria tolerance, through the CD23/NO pathway. [source]

Rapid gas chromatography/mass spectrometry quinine determination in plasma after automated solid-phase extraction

RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 17 2006
Richard Damien
The combined use of an automatic solid-phase extraction (SPE) apparatus with Oasis MCX cartridges and gas chromatography/mass spectrometry (GC/MS) to rapidly quantify quinine in biological samples with cyproheptadine as the internal standard is described. The selected ion monitoring mode, with the quantification ions m/z 136 and 287 (qualifier ions: m/z 261, 381 and 215, 96), allows the estimation of quinine levels, respectively. Separation was completed within 12.7,min. Excellent linearity was found up to 10 000,µg/L of plasma. The limit of detection (LOD) was 12.2,µg/L and the limit of quantification (LOQ) was 40.6,µg/L. High reproducibility (intra-assay CV range 1.9,4.3%, inter-assay CV range 2.2,11.3%) and accuracy values (intra-assay range 83.2,103.7%, inter-assay range 86.8,103.7%) were obtained. Recoveries were concentration-independent (97.2% and 89.8% for 4000 and 10 000,µg/L, respectively). This sensitive, simple assay for quinine in various matrices meets the current requirements for bioanalytical assays and may be used to monitor quinine levels in patients developing severe malaria with acute renal failure during hemofiltration. The optimal quinine dose in this situation is not really established and to improve clinical care, quinine concentrations might be explored to improve efficacy and minimise potential toxicity. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and convulsions

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2008
Simon N. Muchohi
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Midazolam (MDZ), a water-soluble benzodiazepine, can be administered via several routes, including intravenously (IV), intramuscularly (IM) and buccal routes to terminate convulsions. It may be a suitable alternative to diazepam to stop convulsions in children with severe malaria, especially at peripheral healthcare facilities. The pharmacokinetics of MDZ have not been described in African children, in whom factors such as the aetiology and nutritional status may influence the pharmacokinetics. WHAT THIS STUDY ADDS , Administration of MDZ (IV, IM, or buccal) at the currently recommended dose (0.3 mg kg,1) resulted in rapid achievement of median maximum plasma concentrations of MDZ within the range 64,616 ng ml,1, with few clinically significant cardio-respiratory effects. A single dose of MDZ rapidly terminated (within 10 min) seizures in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration, respectively. Although IM and buccal MDZ may be the preferred treatment for children in the pre-hospital settings the efficacy appears to be poorer. AIM To investigate the pharmacokinetics and clinical efficacy of intravenous (IV), intramuscular (IM) and buccal midazolam (MDZ) in children with severe falciparum malaria and convulsions. METHODS Thirty-three children with severe malaria and convulsions lasting ,5 min were given a single dose of MDZ (0.3 mg kg,1) IV (n = 13), IM (n = 12) or via the buccal route (n = 8). Blood samples were collected over 6 h post-dose for determination of plasma MDZ and 1,-hydroxymidazolam concentrations. Plasma concentration,time data were fitted using pharmacokinetic models. RESULTS Median (range) MDZ Cmax of 481 (258,616), 253 (96,696) and 186 (64,394) ng ml,1 were attained within a median (range) tmax of 10 (5,15), 15 (5,60) and 10 (5,40) min, following IV, IM and buccal administration, respectively. Mean (95% confidence interval) of the pharmacokinetic parameters were: AUC(0,,) 596 (327, 865), 608 (353, 864) and 518 (294, 741) ng ml,1 h; Vd 0.85 l kg,1; clearance 14.4 ml min,1 kg,1, elimination half-life 1.22 (0.65, 1.8) h, respectively. A single dose of MDZ terminated convulsions in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration. Four children (one in the IV, one in the IM and two in the buccal groups) had respiratory depression. CONCLUSIONS Administration of MDZ at the currently recommended dose resulted in rapid achievement of therapeutic MDZ concentrations. Although IM and buccal administration of MDZ may be more practical in peripheral healthcare facilities, the efficacy appears to be poorer at the dose used, and a different dosage regimen might improve the efficacy. [source]