Background
Chronic intravascular hemolysis leads to nitric oxide (NO) depletion and pulmonary hypertension in sickle cell disease. To test whether this pathophysiology occurs in malaria, we examined 53 children admitted to hospital with severe malaria (excluding cerebral malaria) and 31 age-matched controls in Mali.
Methods
Severity of hemolysis was assessed from plasma free hemoglobin (Hb) and arginase-1 levels. NO metabolism was assessed by whole blood nitrite levels and plasma NO consumption. Effects on the cardiovascular system and endothelial function were assessed by using echocardiography to measure peak tricuspid regurgitant jet velocity (TRV) and from plasma levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP) and soluble vascular cell adhesion molecule-1 (sVCAM-1).
Results
Children with severe malaria had higher plasma Hb and arginase-1 levels, reduced whole blood nitrite levels and increased NO consumption relative to controls. They also had increased pulmonary arterial pressures (p < 0.05) with elevated levels of NT-proBNP and sVCAM-1 (p < 0.001).
Conclusions
Children with severe malaria have increased pulmonary pressures and myocardial wall stress. These complications are consistent with NO depletion from intravascular hemolysis, and indicate that the pathophysiologic cascade from intravascular hemolysis to NO depletion and its cardiopulmonary effects is activated in children with severe malaria.
Nucleotide sequence analysis of the mxcQ and mxcE loci, required for the synthesis of methanol dehydrogenase in Methylobacterium organophilum XX, has revealed two open reading frames that show significant similarity to sequences of prokaryotic two-component systems, especially MxaY and MxaX proteins of another met h y lotro phic bacterium, Paracoccus denitrificans. Cel Ifree extracts and DNA-column-fractionated proteins from wild-type M. organophilum XX cells grown on methanol or succinate contained protein(s) that were able to bind specifically to the upstream region of methanol dehydrogenase large subunit gene (mxaF). In contrast, cell-free extracts from mxcQ and mxcE mutant strains of M. organophilum XX had zero or reduced binding activity towards the promoter fragments of the mxaF gene. This is consistent with the involvement of the mxcQ and mxcE genes in transcriptional regulation of methanol dehydrogenase synthesis. Analyses of sequential deletions of the mxaf upstream region have defined the functional boundary of the promoter/operator region of this gene and identified one nucleotide segment as essential to the activation of mxaf.
Annually, CDI adds billions of dollars to US healthcare costs compared with just a few years ago, and reflects a new and profound pattern of morbidity and mortality. As this disease changes, our knowledge and practice patterns must adjust to meet the current challenge of CDI.
Transmissible spongiform encephalopathies (TSEs) are a group of progressive, fatal neurodegenerative disorders that share a common spongiform histopathology. TSEs may be transmitted in a sporadic, familial, iatrogenic, or zoonotic fashion. The putative infectious agent of TSE, the prion, represents a novel paradigm of infectious disease with disease transmission in the absence of nucleic acid. Several small but spectacular epidemics of TSEs in man have prompted widespread public health and food safety concerns. Although TSEs affect a comparatively small number of individuals, prion research has revealed fascinating insights of direct relevance to common illnesses. This paper reviews recent advances that have shed new light on the nature of prions and TSEs.
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