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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathophysiology of hypoglycaemia in children with acute falciparum malaria, a frequent and serious complication, is unknown due to absence of data on glucose kinetics. We investigated the correlation between basal glucose production and plasma glucose concentration in 20 children (8 girls) with acute, uncomplicated falciparum malaria by infusion of [6,6-2H2]glucose. Median plasma glucose concentration was 4.5 (range 2.1-6.5) mmol/L and the median glucose production 5.0 (range 4.1-8.4) mg/kg/min. There was a positive correlation between basal glucose production and plasma glucose concentration (r = 0.53, P = 0.016). There was no correlation between the rate of glucose production and the plasma concentrations of alanine, lactate, counter-regulatory hormones or cytokines. It was concluded that, in children with acute uncomplicated falciparum malaria, endogenous glucose production is an important determinant of plasma glucose concentration, contrary to previous findings in adults with malaria, in whom peripheral uptake seems to be more important than glucose production in determining plasma glucose concentration.
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PMID:The relationship between glucose production and plasma glucose concentration in children with falciparum malaria. 901 7

The immunodominant region on the circumsporozoite surface (CS) protein of the malaria parasite Plasmodium falciparum contains 37 repeated copies of a asparagine-alanine-asparagine-proline (NANP) motif NMR studies of linear synthetic peptides containing one, two or three repeat units provided evidence for nascent type I beta-turns within the NPNA cadence in aqueous solution. The beta-turns could be stabilised upon substituting proline for alpha-methylproline (p(Me)) in the dodecamer (NP(Me)NA)3, without loss of the ability to elicit antibodies cross-reactive with P. falciparum sporozoites. In this work, four 4 ns MD simulations of the dodecapeptide Acetyl-(NP(Me)NA)3, in water, using NOE distance restraints, using 3J-coupling constant restraints, using both these restraints and without restraints, were carried out to determine the conformations of this peptide in aqueous solution. An unrestrained MD simulation of the unmethylated Ac-(NPNA)3 peptide in water was also carried out to investigate the effect of the additional methyl groups on the structure and dynamics of the peptide. The application of NOE distance restraints and 3J-coupling constant restraints leads to contradictory results, probably due to different averaging time scales inherent to the measurement of these data, which exceed the 100 ps averaging applied in the simulations. The additional methyl groups lead to more compact structures, which display enhanced local fluctuations. The central tetrapeptide adopts a type I beta-turn, while the outer motifs display more conformational variability. The three motifs in the methylated dodecamer peptide, however, adopt frequently in the distance restrained MD simulation a compact structure such that the outer motifs appear to form a hydrophobic core by stacking of their two proline rings. This arrangement also suggests how a peptide containing multiple tandemly linked copies of a stable beta-turn NPNA motif might adopt a folded stem-like structure, which conceivably may be of biological relevance in the native CS protein.
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PMID:Dynamical studies of peptide motifs in the Plasmodium falciparum circumsporozoite surface protein by restrained and unrestrained MD simulations. 913 27

To evaluate glucose kinetics in children with falciparum malaria, basal glucose production and gluconeogenesis and an estimate of the flux of the gluconeogenic precursors were measured in Kenyan children with uncomplicated falciparum malaria before (n = 11) and during infusion of alanine (1.5 mg/kg.min; n = 6). Glucose production was measured by [6,6-2H2]glucose, gluconeogenesis by mass isotopomer distribution analysis of glucose labeled by [2-13C]glycerol. Basal plasma glucose concentration ranged from 2.1-5.5 mmol/L, and basal glucose production ranged from 3.3-7.3 mg/kg.min. Glucose production was largely derived from gluconeogenesis (73 +/- 4%; range, 52-93%). During alanine infusion, plasma glucose increased by 0.4 mmol/L (P = 0.03), glucose production increased by 0.8 mg/kg.min (P = 0.02), and gluconeogenesis increased by 0.8 mg/kg.min (P = 0.04). We conclude that glucose production in children with uncomplicated falciparum malaria is largely dependent on gluconeogenesis. However, gluconeogenesis is potentially limited by insufficient precursor supply. These data indicate that in children with falciparum malaria, gluconeogenesis fails to compensate in the presence of decreased glycogen flux to glucose, increasing the risk of hypoglycemia.
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PMID:Glucose homeostasis in children with falciparum malaria: precursor supply limits gluconeogenesis and glucose production. 925 27

By US standards, about half of African children are malnourished, although most appear clinically normal. It is possible that precursor supply for gluconeogenesis is limited to a greater extent in these seemingly malnourished African children than in healthy children, consequently limiting glucose production. Since in malaria peripheral glucose utilization is increased, precursor supply could play an even more critical role in maintaining glucose production in African children suffering from falciparum malaria. We studied the effect of alanine infusion (1.5 mg/kg/min) on glucose production (measured by infusion of [6,6-2H2]glucose) and plasma glucose concentration in 10 consecutive children with acute, uncomplicated falciparum malaria. By US standards, six children were below the 10th percentile of weight for height and seven were below the 10th percentile of height for age. Plasma concentrations of alanine increased during alanine infusion from 153 +/- 21 to 468 +/- 39 mumol/l, whereas plasma lactate concentrations did not change (1.4 +/- 0.2 vs. 1.3 +/- 0.2 mmol/l). Plasma glucose concentration and glucose production did not change during alanine infusion: 4.6 +/- 0.3 vs. 4.5 +/- 0.3 mmol/l and 5.8 +/- 0.4 vs. 5.7 +/- 0.3 mg/kg/min, respectively. Gluconeogenic precursor supply is sufficient for maintainance of glucose production in African children with uncomplicated malaria who are malnourished by US standards.
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PMID:The influence of alanine infusion on glucose production in 'malnourished' African children with falciparum malaria. 930 29

Immunity against the human malaria parasite Plasmodium falciparum was induced using somatic transgene immunization, a method to effectively target B lymphocytes in vivo. A single inoculation of plasmid DNA containing an immunoglobulin heavy-chain gene coding in the complementarity-determining region 3 for three repeats of the sequence Asn-Ala-Asn-Pro (NANP), a B-cell epitope of P.falciparum sporozoites, induced antibodies against NANP in all mice. A booster with an antibody antigenized with the NANP peptide, or challenge with P. falciparum sporozoites, demonstrated the establishment of immunologic memory. Immunity to a parasite antigen can be induced by exploiting mechanisms in which B lymphocytes are both the source of the immunogen as well as the effector mechanism of immunity. The results indicate that somatic transgene immunization is a potential approach for vaccination against foreign pathogens.
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PMID:Immunity to Plasmodium falciparum malaria sporozoites by somatic transgene immunization. 930 3

Transmission-blocking vaccines based on sexual-stage surface antigens of Plasmodium falciparum may assist in the control of this lethal form of human malaria. Two vaccine candidates, Pfs25 and Pfs28, were produced as single recombinant fusion proteins. The 39-kDa chimeric proteins, having a C-terminal His6 tag, were secreted by Saccharomyces cerevisiae, using the prepro-alpha-factor leader sequence. Pfs25-28 fusion proteins were significantly more potent than either Pfs25 or Pfs28 alone in eliciting antibodies in mice that blocked oocyst development in Anopheles freeborni mosquitoes: complete inhibition of oocyst development in the mosquito midgut was achieved with fewer vaccinations, at a lower dose, and for a longer duration than with either Pfs25 or Pfs28 alone. Increased antigen-specific immunoglobulin G titers and highly significant lymphoproliferative stimulation by Pfs28-containing antigens suggest the presence of an immunodominant helper T-cell epitope in the Pfs28 portion of the fusion proteins. This epitope may be responsible for the enhanced humoral response to both Pfs25 and Pfs28 antigens. Protein production of the fusion protein was improved 12-fold by converting Pfs28 codons to yeast-preferred codons (TBV28), using a modified ADH2 promoter and incorporating a (Glu-Ala)2 repeat after the Kex2 cleavage site.
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PMID:Saccharomyces cerevisiae-secreted fusion proteins Pfs25 and Pfs28 elicit potent Plasmodium falciparum transmission-blocking antibodies in mice. 942 39

We investigated the pathophysiology of hypoglycaemia in severe malaria in African children, especially the potential importance of glycerol as a substrate for gluconeogenesis, and whether substrate limitation contributes to hypoglycaemia in severe disease. Of 171 children with moderate or severe malaria, 16% were hypoglycaemic on admission, while at least 9% of children with severe malaria treated with quinine and a concurrent 4% dextrose infusion had a definite episode of hypoglycaemia after admission. Blood levels of gluconeogenic precursors are as high (alanine and lactate) or higher (glycerol) in those with either hypoglycaemia on or after admission as they are in children never having an episode of hypoglycaemia. Among children with severe malaria, however, those having a definite episode of hypoglycaemia at some stage are more acidotic and have greater evidence of renal impairment than those who are never hypoglycaemic (mean base excess -14.4 vs. -7.2, p < 0.001, mean creatinine 97 vs. 64, p < 0.001 and mean urea 8.1 vs. 5.8, p = 0.03, respectively). These data do not support a role for reduced gluconeogenic substrate supply in the pathogenesis of hypoglycaemia in severe childhood malaria, but do support the hypothesis that gluconeogenesis is impaired. Commonly-used bedside blood glucose monitoring devices may overestimate blood glucose measurements in the normal range, and paradoxically may also seriously overestimate the frequency of hypoglycaemia.
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PMID:Hypoglycaemia on and after admission in Kenyan children with severe malaria. 960 71

The Ala-Idowa health centre was established in 1980 to serve the two contiguous communities of Ala and Idowa with population of 3960 and 6580 respectively. Situated reasonably between the two communities, there is adequate physical accessibility to the health centre from both sides. The population structure of the combined community was determined through a household survey involving 125 households selected systematically from the total of 2500 households. A comparison is presented between this structure and that of the population of attendees at the outpatient department of the Ala/Idowa health centre as recorded in the outpatient register with a view to discerning differentials in utilisation among different age groups. The data showed that those under the age of 15 years made more use of the health centre services than any other age group. Also, of the total of 958 patients for whom a diagnosis was recorded, 565 (56%) presented with an infection or infestation alone while another 4% presented with an infection together with another condition. Malaria accounted for 358 (63.4%) of all reported cases of infection/infestation. It is hoped that the findings of this study can be used to further target health centre services at the appropriate groups within the community as well as directed to those conditions, particularly communicable and preventable, that continue to exert great morbidity on the populations of developing communities.
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PMID:Utilisation differentials in a rural Nigerian health centre. 964 57

The efficacy of sulphadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Africa is increasingly compromised by development of resistance. The occurrence of mutations associated with the active site sequence in the Plasmodium falciparum genes coding for dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) is associated with in vitro resistance to pyrimethamine and sulphadoxine. This study investigates the occurrence of these mutations in infected blood samples taken from Tanzanian children before treatment with S/P and their relationship to parasite breakthrough by day 7. The results show that alleles of DHPS (436-alanine, 437-alanine and 540-lysine) were significantly reduced in prevalence on day 7 after S/P treatment. In this area, a DHPS with 436-serine, 437-glycine and 540-glutamate appears to play a major role in resistance to S/P in vivo. Evidence for the influence of mutations in the DHFR gene in this investigation is not clear, probably because of the high prevalence of 'resistance-related' mutations at day 0 in the local parasite population. For apparently the same reason, it was not possible to show a statistical association between S/P resistance and the presence of particular polymorphisms in the DHFR and DHPS genes before treatment.
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PMID:Polymorphisms in the dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) genes of Plasmodium falciparum and in vivo resistance to sulphadoxine/pyrimethamine in isolates from Tanzania. 973 30

The inhibition of cysteine proteases is being studied as a strategy to combat parasitic diseases such as Chagas' disease, leishmaniasis, and malaria. Cruzain is the major cysteine protease of Trypanosoma cruzi, the etiologic agent of Chagas' disease. A crystal structure of cruzain, covalently inactivated by fluoromethyl ketone inhibitor 1 (Cbz-Phe-Ala-FMK), was used as a template to design potential inhibitors. Conformationally constrained gamma-lactams containing electrophilic aldehyde (12, 17, 18, 25, 26, and 29) or vinyl sulfone (43, 44, and 46) units were synthesized. Constrained lactam 26 had IC50 values of ca. 20 nM against the Leishmania major protease and ca. 50 nM versus falcipain, an important cysteine protease isolated from Plasmodium falciparum. However, all of the conformationally constrained inhibitors were weak inhibitors of cruzain, compared to unconstrained peptide aldehyde (e.g. 5 ) and vinyl sulfone inhibitors (e.g. 48, which proved to be an excellent inhibitor of cruzain with an apparent second order inhibition rate constant (k(inact)/Ki) of 634,000s(-1)M(-1). A significant reduction in activity was also observed with acyclic inhibitors 30 and 51 containing alpha-methyl phenylalanine residues at the P2 position. These data indicate that the pyrrolidinone ring, especially the quarternary center at P2, interferes with the normal substrate binding mode with cruzain, but not with falcipain or the leishmania protease.
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PMID:Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. 992 4


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