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K Kirk

Publications and source records attributed to K Kirk.

At least 55 records · Page 3Linked to original sources
PubMed1998

Increased choline transport in erythrocytes from mice infected with the malaria parasite Plasmodium vinckei vinckei.

Parasitized erythrocytes from mice infected with the murine malaria parasite Plasmodium vinckei vinckei showed a marked increase in the rate of influx of choline compared with erythrocytes from uninfected mice. In contrast, uninfected erythrocytes from P. vinckei-infected animals transported choline at the same rate as those from uninfected mice. The increased influx of choline into parasitized cells was via two discrete routes. One was a saturable pathway with a Km similar to that of the choline carrier of normal erythrocytes but a Vmax approx. 20-fold higher than that observed in uninfected cells. The other was a non-saturable pathway inhibited by furosemide. At choline concentrations within the normal physiological plasma concentration range, the former pathway contributed approx. two-thirds and the latter approx. one-third of the influx of choline into parasitized cells. The characteristics of the furosemide-sensitive pathway were similar to those of a broad-specificity pathway that is induced in human erythrocytes infected in vitro with Plasmodium falciparum. The results of this study rule out the possibility that the induced transport pathway of P. falciparum-infected erythrocytes is an artifact arising in vitro from the long-term culture of parasitized cells and provide evidence that this pathway makes a significant contribution to the uptake of choline into the parasitized cells of malaria-infected animals.

Animals↗
PubMed1998

Transport and metabolism of the essential vitamin pantothenic acid in human erythrocytes infected with the malaria parasite Plasmodium falciparum.

The growth of the human malaria parasite, Plasmodium falciparum, within its host erythrocyte is reliant on the uptake of a number of essential nutrients from the extracellular medium. One of these is pantothenic acid, a water-soluble vitamin that is a precursor of coenzyme A. In this study we show that normal uninfected erythrocytes are impermeable to pantothenate but that the vitamin is taken up rapidly into malaria-infected cells via a transport pathway that has the characteristics (furosemide sensitivity, nonsaturability) of previously characterized, broad specificity permeation pathways induced by the intracellular parasite in the host cell membrane. The transport of pantothenate therefore constitutes a critical physiological role for these pathways. Inside the parasitized cell pantothenate undergoes phosphorylation, the first step in its conversion to coenzyme A. Parasites within saponin-permeabilized erythrocytes were shown to take up and phosphorylate pantothenate, consistent with the intracellular parasite having both a pantothenate transporter and a pantothenate kinase. Comparisons of the rate of phosphorylation of pantothenate by lysates prepared from uninfected and infected erythrocytes revealed that the pantothenate kinase activity of the P. falciparum trophozoite is some 10-fold higher than that of its host cell and that most, if not all, of the phosphorylation of pantothenate within the malaria-infected cell occurs within the intracellular parasite. These results contrast with those of previous studies in which it was proposed that the avian malaria parasite Plasmodium lophurae lacks pantothenate kinase (as well as the other enzymes for the synthesis of coenzyme A) and is reliant upon the uptake of preformed coenzyme A from the host cell cytosol.

Animals↗
PubMed1998

Hemispheric organization of local- and global-level visuospatial processes in deaf signers and its relation to sign language aphasia.

Previous work has shown that deficits in the production and perception of signed language are linked to left hemisphere damage but not right hemisphere damage in deaf lifelong signers, whereas severe deficits in nonlinguistic visuospatial abilities are more frequent following right hemisphere damage than left hemisphere damage in this population. In the present study we investigated the extent to which sign language deficits in deaf individuals can be dissociated from more subtle visuospatial deficits commonly associated with left hemisphere damage in the hearing/speaking population. A group of left- or right-lesioned deaf signers were asked to reproduce (1) two line drawings (a house and an elephant) and (2) four hierarchical figures. Drawings were scored separately for the presence of local vs global features. Consistent with data from hearing patients, left hemisphere-damaged deaf subjects were significantly better at reproducing global-level features, whereas right hemisphere-damaged deaf subjects were significantly better at reproducing local-level features. This effect held for both types of stimuli. Local-level performance in the LHD group did not correlate with performance on sign language tasks, suggesting that language deficits in LHD deaf signers are in fact linguistic specific.

Aged↗
PubMed1998

A variety of cytokines and immunologically relevant surface molecules are expressed by normal human skeletal muscle cells under proinflammatory stimuli.

Muscle is an attractive target for gene therapy and for immunization with DNA vaccines and is also the target of immunological injury in myositis. It is important therefore to understand the immunologic capabilities of muscle cells themselves. In this study, we show that proinflammatory stimuli induce the expression of other cytokines such as IL-6, transforming growth factor-beta (TGF-beta), and granulocyte-macrophage colony-stimulating factor (GM-CSF) by muscle cells themselves, as well as the up-regulation of human leucocyte antigen (HLA) class I, class II and intercellular adhesion molecule-1 (ICAM-1). Thus, muscle cells have an inherent ability to express and respond to a variety of cytokines and chemokines. The levels of HLA class I, class II and ICAM-1 in inflamed muscle may be affected by the secreted products of the stimulation.

Animals↗
PubMed1998

Functional properties and physiological roles of organic solute channels.

Membrane channels provide routes for the rapid, passive movement of solutes across plasma and intracellular membranes. It is generally assumed that the major physiological role of membrane channels is to transport inorganic ions for processes such as transepithelial salt absorption and secretion, cell volume regulation, signal transduction, and control of membrane electrical properties. Increasing evidence indicates, however, that channels play an important role in organic solute transport in a wide variety of cell types and organisms. Some of the major physiological roles of organic solute channels include uptake of nutrients, excretion of metabolic waste products, volume-regulatory organic osmolyte transport, and control of mitochondrial metabolism. This article reviews the functions and characteristics of channels that participate in the transport and regulation of both charged and electroneutral organic solutes.

Animals↗
PubMed1997

The telomere and telomerase: how do they interact?

The tandemly repeated DNA sequence of telomeres is typically specified by the ribonucleoprotein enzyme telomerase. Telomerase copies part of its intrinsic RNA moiety to make one strand of the telomeric repeat DNA. Recent work has led to the concept of a telomere homeostasis system. We have been studying two key physical components of this system: the telomere itself and telomerase. Mutating the template sequence of telomerase RNA caused various phenotypes: (1) mutating specific residues in the ciliate Tetrahymena and two yeasts showed that they are required for critical aspects of telomerase action; (2) certain mutated telomeric sequences caused a previously unreported phenotype, i.e. a strong anaphase block in Tetrahymena micronuclei; and (3) certain template mutations in the telomerase RNA gene of the yeast Kluyveromyces lactis led to unregulated telomere elongation, which in some cases was directly related to loss of binding to K. lactis Rap1p. Using K. lactis carrying alterations in the genes for Rap1p and other silencing components, we proposed a general model for telomere length homeostasis: namely, that the structure and DNA length of the DNA-protein complex that comprises the telomere are key determinants of telomerase access, and hence the frequency of action of telomerase, at the telomere.

Anaphase↗
PubMed1997

Angiotensin-converting enzyme inhibitor therapy affects left ventricular mass in patients with ejection fraction > 40% after acute myocardial infarction.

OBJECTIVES: We tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitor therapy decreases left ventricular (LV) mass in patients with a left ventricular ejection fraction (LVEF) > 40% and no evidence of heart failure after their first acute Q wave myocardial infarction (MI). BACKGROUND: Recently, ACE inhibitor therapy has been shown to have an early mortality benefit in unselected patients with acute MI, including patients without heart failure and a LVEF > 35%. However, the effects on LV mass and volume in this patient population have not been studied. METHODS: Thirty-five patients with a LVEF > 40% after their first acute Q wave MI were randomized to titrated oral ramipril (n = 20) or conventional therapy (control, n = 15). Magnetic resonance imaging (MRI) performed an average of 7 days and 3 months after MI provided LV volumes and mass from summated serial short-axis slices. RESULTS: Left ventricular end-diastolic volume index did not change in ramipril-treated patients (62 +/- 16 [SD] to 66 +/- 17 ml/m2) or in control patients (62 +/- 16 to 68 +/- 17 ml/m2), and stroke volume index increased significantly in both groups. However, LV mass index decreased in ramipril-treated patients (82 +/- 18 to 73 +/- 19 g/m2, p = 0.0002) but not in the control patients (77 +/- 15 to 79 +/- 23 g/m2). Systolic arterial pressure did not change in either group at 3-month follow-up. CONCLUSIONS: In patients with a LVEF > 40% after acute MI, ramipril decreased LV mass, and blood pressure and LV function were unchanged after 3 months of therapy. Whether the decrease in mass represents a sustained effect that is associated with a decrease in morbid events requires further investigation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Glucose uptake in Plasmodium falciparum-infected erythrocytes is an equilibrative not an active process.

The uptake of glucose into human erythrocytes infected with Plasmodium falciparum was investigated using a number of different glucose analogues. In short time-courses with cells suspended in media containing 5 mM glucose, 2-deoxy-D-glucose equilibrated rapidly between the intracellular and extracellular compartments. Its transport into the infected cell was primarily via the host cell (cytochalasin B-sensitive) transporter. 2-Deoxy-D-glucose did permeate the broad-specificity pathway that is induced in infected cells by the intracellular parasite. However, this pathway made little contribution to the total uptake of 2-deoxy-D-glucose under physiological conditions. In parasitised cells incubated with [14C]2-deoxy-D-glucose for prolonged periods the intracellular concentration of radiolabel increased to values higher than that in the external medium; it reached a maximum value three to six times higher than the extracellular concentration before falling back to a concentration similar to that outside the cells. This transient intracellular accumulation of radiolabel was due entirely to the phosphorylation of the [14C]2-deoxy-D-glucose and its consequent trapping within the cell. The specific characteristics of the 2-deoxy-D-glucose uptake time courses measured under different conditions were accounted for by the kinetics of the phosphorylation process and the energy status of the cell. The data indicate that 2-deoxy-D-glucose (as well as the non-phosphorylated compounds 3-O-methyl-D-glucose and L-glucose) enter the intracellular parasite via a passive (i.e. equilibrative) rather than an active (i.e. concentrative) transport process.

3-O-Methylglucose↗
PubMed1996

Anion-selectivity of the swelling-activated osmolyte channel in eel erythrocytes.

Osmotic swelling of fish erythrocytes activates a broad-specificity permeation pathway that mediates the volume-regulatory efflux of taurine and other intracellular osmolytes. This pathway is blocked by inhibitors of the erythrocyte band 3 anion exchanger, raising the possibility that band 3 is involved in the volume-regulatory response. In this study of eel erythrocytes, a quantitative comparison of the pharmacology of swelling-activated taurine transport with that of band 3-mediated SO4(2-) transport showed there to be significant differences between them. N-ethylmaleimide and quinine were effective inhibitors of swelling-activated taurine transport but caused little, if any, inhibition of band 3. Conversely, DIDS was a more potent inhibitor of band 3-mediated SO4(2-) flux than of swelling-activated taurine transport. In cells in isotonic medium, pretreated then co-incubated with 0.1 mM DIDS, the band 3-mediated transport of SO4(2-) and Cl- was reduced to a low level. Exposure of these cells to a hypotonic medium containing 0.1 mM DIDS was followed by the activation of a Cl- permeation pathway showing the same inhibitor sensitivity as swelling-activated taurine transport. The data are consistent with swelling-activated transport of taurine and Cl- being via a common pathway. A comparison of the swelling-activated transport rates for taurine and Cl- with those for several other solutes was consistent with the hypothesis that this pathway is an anion-selective channel, similar to those that mediate the volume-regulatory efflux of Cl- and organic osmolytes from mammalian cells.

Animals↗
PubMed1996

Volume-regulatory amino acid release from the protozoan parasite Crithidia luciliae.

The unicellular protozoan parasite, Crithidia luciliae, responded to osmotic swelling by undergoing a regulatory volume decrease. This process was accompanied by the efflux of amino acids (predominantly alanine, proline and glycine). The relative loss of the electroneutral amino acids proline, valine, alanine and glycine was greater than that for the anionic amino acid, glutamate; there was negligible loss of the cationic amino acids, lysine, arginine and ornithine. The characteristics of amino acid release were investigated using a radiolabeled form of the nonmetabolized alanine analogue alpha-aminoisobutyrate. alpha-Aminoisobutyrate efflux was activated within a few seconds of a reduction of the osmolality, and inactivated rapidly (again within a few seconds) on restoration of isotonicity. The initial rate of efflux of alpha-aminoisobutyrate from cells in hypotonic medium was unaffected by the extracellular amino acid concentration. Hypotonically activated alpha-aminoisobutyrate efflux (as well as the associated regulatory volume decrease) was inhibited by the sulfhydryl reagent N-ethylmaleimide but was not inhibited by a range of anion transport blockers. As in the efflux experiments, unidirectional influx rates for alpha-aminoisobutyrate increased markedly following reduction of the osmolality, consistent with the swelling-activated amino acid release mechanism allowing the flux of solutes in both directions. Hypotonically activated alpha-aminoisobutyrate influx showed no tendency to saturate up to an extracellular concentration of 50 mM. The functional characteristics of the amino acid release mechanism are those of a channel, with a preference for electroneutral and anionic amino acids over cationic amino acids. However, the pharmacology of the system differs from that of the anion-selective channels that are thought to mediate the volume-regulatory efflux of organic osmolytes from vertebrate cells.

Amino Acids↗
PubMed1996

Anion channel blockers inhibit swelling-activated anion, cation, and nonelectrolyte transport in HeLa cells.

The effect of osmotic cell swelling on the permeability of HeLa cells to a range of structurally unrelated solutes including taurine, sorbitol, thymidine, choline, and K+ (96Rb+) was investigated. For each solute tested, reduction in the osmolality of the medium from 300 to 200 mosmol/kgH2O caused a significant increase in the unidirectional influx rate. In each case, the osmotically activated transport component was nonsaturable up to external substrate concentrations of 50 mM. Inhibitors of the swelling-activated anion channel of HeLa cells [quinine, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, niflumate, 1,9-dideoxyforskolin, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), and tamoxifen] blocked the osmotically activated influx of each of the different substrates tested, as well as the osmotically activated efflux of taurine and I-. Tamoxifen and NPPB were similarly effective at blocking the osmotically activated efflux of 96Rb+. The simplest of several hypotheses consistent with the data is that the osmotically activated transport of the different solutes tested here is via a swelling-activated anion-selective channel that has a significant cation permeability and a minimum pore diameter of 8-9 A.

Anions↗
PubMed1996

Swelling-activated K+ transport via two functionally distinct pathways in eel erythrocytes.

Following osmotic swelling, erythrocytes from the European eel, Anguilla anguilla, underwent a regulatory volume decrease. This was prevented by replacement of Na+ with K+ in the suspending medium, consistent with a role for the (normally outward) electrochemical K+ gradient in the volume-regulatory response. The effect of cell swelling on K- transport in these cells was investigated using 86Rb+ as a tracer for K+. Osmotic swelling resulted in an increase in ouabain-insensitive K+ transport that was highest for cells in Cl- and Br- media but which was also significant in I- and NO3- media. Treatment of eel erythrocytes suspended in isotonic Cl- or Br- (but not I- or NO3-) media with the sulfhydryl reagent N-ethylmaleimide (NEM) resulted in a large increase in K+ transport. A quantitative comparison of the pharmacological properties of the "Cl(-)-dependent" NEM-activated pathway with those of the "Cl(-)-independent" pathway mediating swelling-activated K+ transport in cells in Cl(-)-free (NO3- containing) media showed there to be significant differences between them. By contrast, the pharmacological properties of the Cl(-)-independent swelling-activated K+ pathway were indistinguishable from those of the pathway responsible for the swelling-activated transport of taurine, the major organic osmolyte in these cells. A pharmacological analysis of ouabain-insensitive K+ transport in cells swollen in a hypotonic Cl(-)-containing medium showed there to be two components, one with the characteristics of the NEM-activated system, the other showing the characteristics of the Cl(-)-independent swelling-activated pathway. The data are consistent with the presence of two functionally distinct swelling-activated K+ transport mechanisms in eel erythrocytes: a KCl cotransporter that is activated under isotonic conditions by NEM and a Cl(-)-independent, broad-specificity channel that accommodates a diverse range of organic and inorganic solutes.

Anguilla↗
PubMed1995

In search of a selective inhibitor of the induced transport of small solutes in Plasmodium falciparum-infected erythrocytes: effects of arylaminobenzoates.

Following invasion of the human erythrocyte by the malaria parasite, Plasmodium falciparum, there appear in the parasitized cell new, high-capacity permeation pathways that transport a diverse range of low-molecular-mass solutes. In this study a series of 16 arylaminobenzoates, analogues of the Cl- channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), were tested for their effects on the transport of choline, a univalent cation, into malaria-infected cells. A number of the arylaminobenzoates were found to be potent inhibitors of malaria-induced choline transport and to be similarly effective at blocking the induced transport of the uncharged pyrimidine nucleoside thymidine and the univalent anion lactate. The data are consistent with the hypothesis that much of the induced transport of cations, anions and non-electrolytes into parasitized cells is via broad-specificity, anion-selective pathways of a single type. A comparison of the effects of the arylaminobenzoates on malaria-induced transport with their effects on a number of representative anion transport systems in normal mammalian cells suggests that it is possible to identify pharmacological agents that block the malaria-induced pathway while not significantly affecting important transport mechanisms in host tissues. The most potent of the induced-transport inhibitors identified were shown to inhibit [3H]hypoxanthine incorporation in in vitro parasite growth assays. These data support the view that the induced-transport pathway may be a viable pharmacological target.

Aminobenzoates↗
PubMed1995

Novel anion dependence of induced cation transport in malaria-infected erythrocytes.

Following invasion by the malaria parasite there appear in the parasitized erythrocyte new ("induced") permeation pathways that mediate the transport of a wide variety of small solutes. Although anion-selective, these pathways have a significant cation permeability and cause a substantial increase in the basal leak of cations into and out of the infected cell. In this study of human erythrocytes infected in vitro with Plasmodium falciparum it was shown that the transport of monovalent cations (Rb+ and choline), but not that of a nonelectrolyte (sorbitol) or a monovalent anion (lactate), via the malaria-induced pathways is strongly dependent on the nature of the anion in the suspending medium. Substitution of NO3- for Cl- resulted in a 4-6-fold increase in the unidirectional influx and efflux of Rb+, and a 2-3-fold increase in the influx of choline via the induced pathways. By contrast, replacement of Cl- with NO3- caused a slight (although not significant) decrease in the malaria-induced influx of sorbitol and lactate. Hemolysis experiments with a range of K+ salts revealed that the net influx of K+ into infected cells showed the same novel anion dependence as seen for the unidirectional flux of Rb+ and choline, with hemolysis occurring much faster in iso-osmotic KNO3 and KSCN solutions than in KCl, KBr, or KI solutions. Hemolysis in the corresponding Na+ salt solutions was very much slower, consistent with the induced pathways being selective for K+ over Na+, and raising the possibility that the efflux of cell K+ via these pathways may play a role in host cell volume regulation. A number of models that would account for the anion dependence of malaria-induced cation transport are considered.

Animals↗
PubMed1995

Association between carriage of oral yeasts and malnutrition among Tanzanian infants aged 6-24 months.

OBJECTIVE: To determine if there is an association between carriage of oral yeasts and malnutrition in infants. DESIGN: A case-control study within a cross-sectional study. The dependent variable was carriage of oral yeasts. The exposure variable was malnutrition and confounders to be adjusted for were age, sex, and breast-feeding. SETTING: A maternal and child health clinic in Dar-es-Salaam, Tanzania that offers routine medical check-ups to all expectant mothers and children aged between 0 and 5 years in its catchment areas. SUBJECTS AND METHODS: 972 infants aged 6-24 months participated. Smears from the tongue and cheek mucosa were examined for candidal hyphae and blastospores. Malnutrition was categorized according to Tanzanian standards (weight-for-age) and World Health Organization (WHO) standards (weight-for-height and height-for-age). MAIN OUTCOME MEASURE: Carriage of oral yeasts (hyphae and blastospores). RESULTS: Carriage of oral yeasts was significantly higher in the 227 malnourished compared with the 745 well nourished adjusted for confounders. Odds ratio for presence of hyphae in smears from the severely malnourished (weight-for-age) was 4.5 (90% CI: 2.0-10.0). Odds ratio for presence of hyphae was 2.3 (90% CI: 1.1-4.8) when weight-for-height were used to categorize for malnutrition. CONCLUSION: The study tends to confirm the generally held view that malnutrition may predispose to carriage of oral yeasts and subsequent oral candidiasis.

Candida↗