Malaria. Channelling nutrients.
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Animals↗
Biomedical subjects
K Kirk
Publications and source records attributed to K Kirk.
3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC12 cells.
3,4-Dihydroxyphenylacetaldehyde (DOPAL) is a toxic metabolite formed by the oxidative deamination of dopamine. This aldehyde is mainly oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase (ALDH), but is also partly reduced to 3, 4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase (ARs). In a previous study, we found that rotenone, a complex I inhibitor, induced a rapid accumulation of DOPAL and DOPET in the medium of cultured PC12 cells. Here, we examined the potential role of DOPAL in the toxicity induced by complex I inhibition in PC12 cells and compared the effects of rotenone on concentrations of DOPAL and DOPET to those of MPP(+). DOPAL and DOPET levels were increased by rotenone but decreased by MPP(+). Inhibition of ALDH by daidzein reduced the formation of DOPAC and increased the accumulation of DOPAL. Inhibition of ARs (with AL1576) diminished DOPET formation and elevated DOPAL concentrations. Combined inhibition of ALDH and ARs markedly elevated DOPAL concentrations while diminishing DOPET and DOPAC levels. The elevation of DOPAL levels induced by combined inhibition of ALDH and ARs had no effect on cell viability. However, combined inhibition of ALDH and ARs potentiated rotenone-induced toxicity. Both the potentiation of toxicity and the increase in DOPAL levels were blocked by inhibition of monoamine oxidase with clorgyline indicating that accumulation of DOPAL was responsible for the potentiated rotenone-induced toxicity following combined inhibition of ALDH and ARs. Since complex I dysfunction is reported to be involved in the pathogenesis of Parkinson's disease, DOPAL potentiation of the deleterious effects of complex I inhibition may contribute to the specific vulnerability of dopaminergic neurons to injury.
1-Methyl-4-phenylpyridinium↗
Metabolic stress in PC12 cells induces the formation of the endogenous dopaminergic neurotoxin, 3,4-dihydroxyphenylacetaldehyde.
3,4-Dihydroxyphenylacetaldehyde (DOPAL) has been reported to be a toxic metabolite formed by the oxidative-deamination of dopamine (DA) catalyzed by monoamine oxidase. This aldehyde is either oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase, an NAD-dependent enzyme or reduced to 3, 4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase. In the present study we examined whether levels of DOPAL are elevated by inhibition of the mitochondrial respiratory chain. Using inhibitors of mitochondrial complexes I, II, III and IV we found that inhibition of complex I and III increased levels of DOPAL and DOPET. Nerve growth factor-induced differentiation of PC12 cells markedly potentiated DOPAL and DOPET accumulation in response to metabolic stress. DOPAL was toxic to differentiated PC12 as well as to SK-N-SH cell lines. Because complex I dysfunction has been implicated in the pathogenesis of Parkinson's disease, the accumulation of DOPAL may explain the vulnerability of the dopaminergic system to complex I inhibition. The rapid appearance of DOPAL and DOPET after inhibition of complex I may be a useful early index of oxidative stress in DA-forming neurons.
3,4-Dihydroxyphenylacetic Acid↗
Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum.
Throughout the latter half of this century, the development and spread of resistance to most front-line antimalarial compounds used in the prevention and treatment of the most severe form of human malaria has given cause for grave clinical concern. Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologue 1 (Pgh1) protein of Plasmodium falciparum, have been linked to chloroquine resistance; Pgh1 has also been implicated in resistance to mefloquine and halofantrine. However, conclusive evidence of a direct causal association between pfmdr1 and resistance to these antimalarials has remained elusive, and a single genetic cross has suggested that Pgh1 is not involved in resistance to chloroquine and mefloquine. Here we provide direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine. The same mutations influence parasite resistance towards chloroquine in a strain-specific manner and the level of sensitivity to the structurally unrelated compound, artemisinin. This has important implications for the development and efficacy of future antimalarial agents.
ATP-Binding Cassette Transporters↗
Increased permeability of the malaria-infected erythrocyte to organic cations.
The human malaria parasite, Plasmodium falciparum, induces in the plasma membrane of its host red blood cell new permeation pathways (NPP) that allow the influx of a variety of low molecular weight solutes. In this study we have demonstrated that the NPP confer upon the parasitised erythrocyte a substantial permeability to a range of monovalent organic (quaternary ammonium) cations, the largest having an estimated minimum cross-sectional diameter of 11-12 A. The rate of permeation of these cations showed a marked dependence on the nature of the anion present, increasing with the lyotropicity of the anion. There was no clear relationship between the permeation rate and either the size or the hydrophobicity of these solutes. However, the data were consistent with the rate of permeation being influenced by a combination of these two factors, with the pathways showing a marked preference for the relatively small and hydrophobic phenyltrimethylammonium ion over larger or less hydrophobic solutes. Large quaternary ammonium cations inhibited flux via the NPP, as did long-chain n-alkanols. For both classes of compound the inhibitory potency increased with the size and hydrophobicity of the solute. This study extends the range of solutes known to permeate the NPP of malaria-infected erythrocytes as well as providing some insight into the factors governing the rate of permeation.
Animals↗
Studying the telomerase RNA in Tetrahymena.
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Animals↗
Hexose transport in asexual stages of Plasmodium falciparum and kinetoplastidae.
The hexose sugar, glucose, is a vital energy source for most organisms and an essential nutrient for asexual stages of Plasmodium falciparum. Kinetoplastid organisms (e.g. Trypanosoma and Leishmania spp) also require glucose at certain critical stages of their life cycles. Although phylogenetically unrelated, these organisms share many common challenges during the mammalian stages of a parasitic life cycle, and possess hexose uptake mechanisms that are amenable to study using similar methods. Defining hexose permeation pathways into parasites might expose an Achilles' heel at which both antidisease and antiparasite measures can be aimed. Understanding the mode of entry of glucose also presents a good general model for substrate acquisition in multicompartment systems. In this review, Sanjeev Krishna and colleagues summarize current understanding of hexose transport processes in P. falciparum and provide a comparison with data obtained from kinetoplastids.
Animals↗
Organic osmolyte channels: a comparative view.
Cells respond to osmotic swelling by releasing inorganic ions and small organic molecules (organic osmolytes). In many cell-types, osmotic swelling results in the activation of an outwardly-rectifying anion-selective current. The channel underlying this current has a significant permeability to a number of organic osmolytes and may play a role in the hypoosmotically-activated efflux of these compounds. However, there is also evidence that the volume-regulatory efflux of organic osmolytes involves other pathways which may be selective for neutral osmolytes over anions.
Animals↗
pH regulation in the intracellular malaria parasite, Plasmodium falciparum. H(+) extrusion via a V-type H(+)-ATPase.
The mechanism by which the intra-erythrocytic form of the human malaria parasite, Plasmodium falciparum, extrudes H(+) ions and thereby regulates its cytosolic pH (pH(i)), was investigated using saponin-permeabilized parasitized erythrocytes. The parasite was able both to maintain its resting pH(i) and to recover from an imposed intracellular acidification in the absence of extracellular Na(+), thus ruling out the involvement of a Na(+)/H(+) exchanger in both processes. Both phenomena were ATP-dependent. Amiloride and the related compound ethylisopropylamiloride caused a substantial reduction in the resting pH(i) of the parasite, whereas EMD 96785, a potent and allegedly selective inhibitor of Na(+)/H(+) exchange, had relatively little effect. The resting pH(i) of the parasite was also reduced by the sulfhydryl reagent N-ethylmaleimide, by the carboxyl group blocker N,N'-dicyclohexylcarbodiimide, and by bafilomycin A(1), a potent inhibitor of V-type H(+)-ATPases. Bafilomycin A(1) blocked pH(i) recovery in parasites subjected to an intracellular acidification and reduced the rate of acidification of a weakly buffered solution by parasites under resting conditions. The data are consistent with the hypothesis that the malaria parasite, like other parasitic protozoa, has in its plasma membrane a V-type H(+)-ATPase, which serves as the major route for the efflux of H(+) ions.
Adenosine Triphosphate↗
Passive Ca(2+) transport and Ca(2+)-dependent K(+) transport in Plasmodium falciparum-infected red cells.
Previous reports have indicated that Plasmodium falciparum-infected red cells (pRBC) have an increased Ca(2+) permeability. The magnitude of the increase is greater than that normally required to activate the Ca(2+)-dependent K(+) channel (K(Ca) channel) of the red cell membrane. However, there is evidence that this channel remains inactive in pRBC. To clarify this discrepancy, we have reassessed both the functional status of the K(Ca) channel and the Ca(2+) permeability properties of pRBC. For pRBC suspended in media containing Ca(2+), K(Ca) channel activation was elicited by treatment with the Ca(2+) ionophore A23187. In the absence of ionophore the channel remained inactive. In contrast to previous claims, the unidirectional influx of Ca(2+) into pRBC in which the Ca(2+) pump was inhibited by vanadate was found to be within the normal range (30-55 micromol (10(13) cells. hr)(-1)), provided the cells were suspended in glucose-containing media. However, for pRBC in glucose-free media the Ca(2+) influx increased to over 1 mmol (10(13) cells. hr)(-1), almost an order of magnitude higher than that seen in uninfected erythrocytes under equivalent conditions. The pathway responsible for the enhanced influx of Ca(2+) into glucose-deprived pRBC was expressed at approximately 30 hr post-invasion, and was inhibited by Ni(2+). Possible roles for this pathway in pRBC are considered.
Animals↗
Identification of an essential proximal sequence element in the promoter of the telomerase RNA gene of Tetrahymena thermophila.
Telomerase is a ribonucleoprotein reverse transcriptase that synthesizes and maintains telomeric DNA. Studies of telomeres and telomerase are facilitated by the large number of linear DNA molecules found in ciliated protozoa, such as Tetrahymena thermophila. To examine the expression of telomerase, we investigated the transcription of the RNA polymerase III-directed gene encoding the RNA subunit (TER1) of this enzyme. A chimeric gene containing the Glaucoma chattoni TER1 transcribed region flanked by 5' and 3' Tetrahymena regions was used to identify promoter elements following transformation of Tetrahymena cells. Disruption of a conserved proximal sequence element (PSE) located at -55 in the Tetrahymena TER1 5' flanking region eliminated expression of the chimeric gene. In addition, mutation of an A/T-rich element at -25 decreased expression markedly. A gel mobility shift assay and protein-DNA cross-linking identified a PSE-binding polypeptide of 50-60 kDa in Tetrahymena extracts. Gel filtration analysis revealed a native molecular mass of approximately 160 kDa for this binding activity. Our results point to a similar architecture between ciliate telomerase RNA and metazoan U6 small nuclear RNA promoters.
Animals↗
Transport properties of the host cell membrane.
The malaria-infected erythrocyte shows an increased permeability to a wide range of solutes. The increase is mediated in part by parasite-induced new permeation pathways (NPP) and in part (for some solutes, under some conditions) by increased activity of endogenous transporters. The NPP provide the major route for the influx into the infected cell of a number of essential nutrients, but although the functional characteristics of these pathways are understood in some detail, they are yet to be identified at a molecular level. Lucifer yellow, a fluorescent anion, is taken up by malaria-infected erythrocytes to a much greater extent than uninfected erythrocytes via a pathway that differs in its pharmacological characteristics from the NPP. The nature, origin and location of this pathway remain to be established.
Animals↗
Transport and trafficking in the malaria-infected erythrocyte.
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Animals↗
Unique genetic and environmental determinants of prolonged fatigue: a twin study.
BACKGROUND: Prolonged fatigue syndromes have been proposed as prevalent and disabling forms of distress that occur independently of conventional notions of anxiety and depression. METHODS: To investigate the genetic and environmental antecedents of common forms of psychological and somatic distress, we measured fatigue, anxiety, depression and psychological distress in 1004 normal adult twin pairs (533 monozygotic (MZ), 471 dizygotic (DZ)) over 50 years of age. RESULTS: Familial aggregation of psychological distress, anxiety and fatigue appeared to be due largely to additive genetic factors (MZ:DZ ratios of 2.12-2.69). The phenotypic correlations between the psychological measures (distress, anxiety and depression) were moderate (0.67-0.79) and higher than that between fatigue and psychological distress (0.38). Multivariate genetic modelling revealed a common genetic factor contributing to the development of all the observed phenotypes (though most strongly for the psychological forms), a second independent genetic factor also influenced anxiety and depression and a third independent genetic factor made a major contribution to fatigue alone. In total, 44% (95% CI 25-60%) of the genetic variance for fatigue was not shared by the other forms of distress. Similarly, the environmental factor determining psychological distress made negligible contributions to fatigue, which was underpinned largely by its own independent environmental factor. CONCLUSION: This study supports the aetiological independence of prolonged fatigue and, therefore, argues strongly for its inclusion in classification systems in psychiatry.
Anxiety Disorders↗
Discriminant analysis of event-related potential curves using smoothed principal components.
Principal component analysis enhanced by the use of smoothing is used in conjunction with discriminant analysis techniques to devise a statistical classification method for the analysis of event-related potential data. A training set of premedication potentials collected from adolescents with attention-deficit hyperactive disorder (ADHD) is used to predict whether adolescents from an independent subject group will respond to long-term medication. Comparison of outcome prediction rates demonstrates that this method, which uses information from the whole ERP curve, is superior to the classification technique currently used by clinicians, which is based on a single ERP curve feature. The need to administer an initial dose of medication to classify patients is also eliminated.
Adolescent↗
A controlled clinical study of the effect of nasal immunization with a Streptococcus mutans antigen alone or incorporated into liposomes on induction of immune responses.
Recent attention to mucosal immunization strategies has been focused on the nasal route for vaccine delivery. This study was designed to determine the effectiveness of a liposome-protein vaccine compared to that of a protein-only vaccine in inducing immune responses in humans. Healthy subjects were randomly assigned to two groups and immunized intranasally with a crude antigen preparation rich in glucosyltransferase (C-GTF) from Streptococcus mutans, alone or in liposomes. Parotid saliva, nasal wash, and serum were collected prior to and at weekly intervals following immunization and were analyzed for anti-C-GTF activity by enzyme-linked immunosorbent assay. The levels of immunoglobulin A (IgA) anti-C-GTF activity in the nasal wash from both groups after immunization increased to a mean peak of fivefold over the baseline level on day 28. Salivary IgA anti-C-GTF responses were induced to a lesser extent. IgG and IgA anti-C-GTF responses in serum were detected on day 14. The IgA responses were predominantly of the IgA1 subclass. These results show that C-GTF vaccines were more effective in inducing a local secretory IgA antibody response than a salivary or serum response when they were given intranasally. The IgA1 anti-C-GTF response in nasal wash samples for liposomal antigen versus antigen only was the only response which was significantly different (P < 0.04). This suggests that the form of the antigen affects the magnitude of the local mucosal response but not that of a disseminated response. These results provide evidence for the effective use of a nasal protein vaccine in humans for the induction of mucosal and systemic responses.
Administration, Intranasal↗
Comparing the biological and cultural inheritance of personality and social attitudes in the Virginia 30,000 study of twins and their relatives.
Measures of four dimensions of personality (Psychoticism, Extraversion, Neuroticism, and Lie scores) and six aspects of social attitudes (to sex, taxation, militarism, politics, religion and a general conservatism scale) were obtained by mailed questionnaire from 29,691 US subjects including adult twins (n = 14,761) their parents (n = 2360), their spouses (n = 4391), siblings (n = 3184) and adult children (n = 4800). After correction for the average effects of age, sex and source of sample, familial correlations were computed for 80 distinct biological and social relationships. The data allow for the estimation of the additive and non-additive effects of genes, assortative mating, vertical cultural inheritance and other non-parental effects of the shared environment on differences in personality and social attitudes. The interaction of genetic and environmental effects with sex may also be analyzed. Model-fitting analyses show that personality and social attitude measures differ markedly in major features of family resemblance. Additive and dominant genetic effects contribute to differences in both personality and attitudes, but the effects of the family environment, including vertical cultural transmission from parent to child, are much more marked for social attitudes than for personality. There is substantial assortative mating for social attitudes and almost none for personality. The causes of family resemblance depend significantly on sex for almost every variable studied. These findings clarify and extend the more tentative findings derived from previous twin, family and adoption studies.
Adult↗
Advance directives in a pediatric emergency department.
Parents of children with terminal illnesses are not always present when a life-threatening event occurs. For many of these children, an advance directive specifying alternate code orders has been written by the parent or legal guardian (hereafter the use of parent is to be interpreted as parent/legal guardian) and the patient's attending physician. Implementing a pediatric advanced directive presents significant problems for emergency personnel if the parent is not present to identify the existence of the directive and interpret the contents in the context of the current medical crisis.
Advance Directives↗