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Biomedical subjects

K Marsh

Publications and source records attributed to K Marsh.

At least 145 records · Page 8Linked to original sources
PubMed1993

Falciparum malaria: differential effects of antimalarial drugs on ex vivo parasite viability during the critical early phase of therapy.

A method of monitoring Plasmodium falciparum viability ex vivo was used to compare the ability of different antimalarial drugs to arrest the progression of young parasites to mature, potentially damaging stages. Neither pyrimethamine-sulfadoxine nor quinine, the treatment of choice for severe, life-threatening malaria, had a demonstrable effect on circulating parasites during the first 24 hr of therapy. In contrast, in vivo exposure to halofantrine for as little as six hours was sufficient to arrest parasite development. The method of assessing ex vivo parasite viability permits a comparison of antimalarial drug action at a time that may be critical for the therapy of life-threatening disease. If parenteral formulations of halofantrine prove to be safe and effective, they may have a role in the therapy of severe malaria.

Animals↗
PubMed1993

Low-level Plasmodium falciparum transmission and the incidence of severe malaria infections on the Kenyan coast.

The transmission of Plasmodium falciparum was studied in relation to the incidence of severe malaria infections at Sokoke and Kilifi town, Kilifi District, Kenya. Intensive mosquito sampling during a one-year period yielded Anopheles gambiae s.l., An. funestus, and An. coustani. Anopheles gambiae s.l. was the predominant vector, comprising 87.9% and 97.9% of the total anophelines collected in Sokoke and Kilifi town, respectively. The proportion of An. gambiae s.l. with P. falciparum sporozoite infections was 4.1% (20 of 491) in Sokoke and 2.2% (3 of 138) in Kilifi town; no infections were detected in An. funestus or in An. coustani. Entomologic inoculation rates indicated that residents were exposed to only 8.0 infective bites per year in Sokoke and 1.5 in Kilifi town. Transmission was detected during only six months in Sokoke and three months in Kilifi town despite low-level, year-round vector activity. The yearly incidence of severe P. falciparum infections in children, 1-4 years of age was 24.1 per 1,000 in Sokoke and 4.2 per 1,000 in Kilifi town. Monthly patterns of transmission corresponded closely with the incidence of severe infections. At these sites on the coast of Kenya, the spatial and temporal incidence of severe malaria infections is associated with low-level P. falciparum transmission by vector populations.

Animals↗
PubMed1992

Childhood deaths in Africa: uses and limitations of verbal autopsies.

The verbal autopsy (VA) is an epidemiological tool that is widely used to ascribe causes of death by interviewing bereaved relatives of children who were not under medical supervision at the time of death. This technique was assessed by comparison with a prospective survey of 303 childhood deaths at a district hospital in Kenya where medically confirmed diagnoses were available. Common causes of death were detected by VA with specificities greater than 80%. Sensitivity of the VA technique was greater than 75% for measles, neonatal tetanus, malnutrition, and trauma-related deaths; however, malaria, anaemia, acute respiratory-tract infection, gastroenteritis, and meningitis were detected with sensitivities of less than 50%. There may have been unwarranted optimism in the ability of VAs to detect some of the major causes of death, such as malaria, in African children. VA used in malaria-specific intervention trials should be interpreted with caution and only in the light of known sensitivities and specificities.

Cause of Death↗
PubMed1992

Rapid switching to multiple antigenic and adhesive phenotypes in malaria.

Adhesion of parasitized erythrocytes to post-capillary venular endothelium or uninfected red cells is strongly implicated in the pathogenesis of severe Plasmodium falciparum malaria. Neoantigens at the infected red-cell surface adhere to a variety of host receptors, demonstrate serological diversity in field isolates and may also be a target of the host-protective immune response. Here we use sequential cloning of P. falciparum by micromanipulation to investigate the ability of a parasite to switch antigenic and cytoadherence phenotypes. Our data show that antigens at the parasitized cell surface undergo clonal variation in vitro in the absence of immune pressure at the rate of 2% per generation with concomitant modulations of the adhesive phenotype. A clone has the potential to switch at high frequency to a variety of antigenic and adhesive phenotypes, including a new type of cytoadherence behaviour, 'auto-agglutination' of infected erythrocytes. This rapid appearance of antigenic and functional heterogeneity has important implications for pathogenesis and acquired immunity.

Animals↗
PubMed1992

Rheological analysis of the adhesive interactions of red blood cells parasitized by Plasmodium falciparum.

Adhesion of parasitized red blood cells (RBCs) to vascular endothelium is thought to be a key factor in the pathology of falciparum malaria. However, quantitative analyses of the intercellular forces and of the effects of flow on adhesion have been lacking. We have characterized cytoadhesion of RBCs parasitized by the strains ITO4 (which can bind to receptors ICAM-1 or CD36) and FCR3A2 (which can bind to CD36 only) using micropipette manipulation and flow chamber techniques. Target cells were unfixed or glutaraldehyde-fixed human umbilical vein endothelial cells (HUVEC, bearing ICAM-1 only) or human amelanotic melanoma cells (C32, bearing CD36 and ICAM-1). In the static, micropipette assay, 60% to 70% of parasitized cells would adhere when tested at up to three successive sites. The percentage of cells adhering and the force required for their detachment (approximately 10(-10) N) were similar for each combination of parasite strain and adhesion target (ITO4/HUVEC, ITO4/C32, FCR3A2/C32). In the flow chamber, efficiency of initial adhesion of parasitized cells was essentially constant (at about 1%) up to a stress of 0.1 Pa, and then decreased rapidly with increasing stress. Either receptor (ICAM-1 or CD36) could immobilize flowing cells at a physiologic flow stress (0.1 Pa), but the numbers of cells adhering varied for the different combinations (ITO4/C32 greater than ITO4/HUVEC greater than FCR3A2/C32). When flow was increased in steps, adhered cells were gradually washed off but many could withstand stresses at which they would not initially adhere. The force for detachment estimated in this way was similar to the pipette value, and again, was similar for the different combinations of strains and targets. Adhesion from flow depends on the affinity between surfaces being above a critical level, and once adhesion is established, the fracture energy determines resistance to disruption of adhesion. The results show that the fracture energy is greater than the affinity (ie, that adhesion becomes stabilized after it is initially established) and that the ratio of affinity to fracture energy is different for different receptor/ligand pairs, with ICAM-1 appearing to be the more efficient immobilizing receptor. Also, static and flow-based assays of adhesion clearly differ; the affinity is less critical in the static situation, so that most parasitized cells were capable of adhering in a static assay, but fewer did so under flow. Adhesiveness varied markedly from cell to cell, both for targets and parasitized cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

The binding site on ICAM-1 for Plasmodium falciparum-infected erythrocytes overlaps, but is distinct from, the LFA-1-binding site.

The intercellular adhesion molecule-1 (ICAM-1, CD54) is one of three putative endothelial receptors that mediate in vitro cytoadherence of P. falciparum-infected erythrocytes. Since cytoadherence to postcapillary venular endothelium is thought to be a major factor in the virulence of P. falciparum malaria, we have examined the interaction between ICAM-1 and the P. falciparum-infected cell, and have compared it with the interaction to the physiological counter receptor, the leukocyte integrin LFA-1. Our results demonstrate that the malaria-binding site resides in the first two domains of the ICAM-1 molecule and overlaps, but is distinct from, the LFA-1 site.

Amino Acid Sequence↗
PubMed1992

Plasmodium falciparum: the human agglutinating antibody response to the infected red cell surface is predominantly variant specific.

There is mounting evidence that an important component of the host-protective immune response to Plasmodium falciparum is the antibody response to the altered surface of the infected erythrocyte. The nature of these surface changes and the responses to them have been difficult to analyse because of the diverse nature of the parasite-derived neoantigens (PDN) expressed, because of the additional presence of modified host determinants, and because of the lack of monospecific reagents. We have studied the reactivity of field isolates and laboratory clones with pooled or individual sera using a novel approach which obviates the need for specific antibody. We see marked diversity in PDN but in contrast to previous studies, we also find that the predominant agglutinating antibody response in humans is variant specific. Antibodies which cross-react between different serotypes are rare and react only with a subset of PDN types. These results have implications for mechanisms underlying the development of acquired immunity to P. falciparum.

Agglutination↗
PubMed1992

Malaria--a neglected disease?

In situations where malaria eradication is not an option in the foreseeable future the emphasis must be on the control of morbidity and mortality due to malaria. Under such circumstances drawing a distinction between malarial parasitization and malarial disease may be important for workers in both field and laboratory. This concept is explored from the points of view of the epidemiological picture of malaria in endemic populations, the factors which may influence progression to disease and the processes which mediate disease.

Africa↗
PubMed1992

Surveying University of Arizona students' health.

The authors sampled more than 600 University of Arizona students to determine how student attitudes, beliefs, and practices should be considered by healthcare personnel in planning campus health education programs. The survey found that students worried more about diet, exercise, and weight than they did about more serious health problems and that, although generally positive and optimistic, the students frequently felt anxious and overwhelmed. Two thirds of the students were sexually active, 74% of those who were active used various contraceptive methods. More than three quarters of those surveyed indicated they currently drank alcoholic beverages; one quarter of the drinkers said they frequently downed three or more drinks on one occasion, and 44% of the drinkers reported driving while under the influence of alcohol.

Arizona↗
PubMed1992

The disposition of oral and intramuscular pyrimethamine/sulphadoxine in Kenyan children with high parasitaemia but clinically non-severe falciparum malaria.

1. H.p.l.c. methods are described for the measurement of pyrimethamine and sulphadoxine in small volumes of plasma dried on filter paper strips. 2. Pyrimethamine/sulphadoxine (Fansidar, Hoffman LaRoche) was given by mouth and by intramuscular injection to children with uncomplicated falciparum malaria but with high parasitaemia (n = 8 for both routes; pyrimethamine 1.25 mg kg-1, sulphadoxine 25 mg kg-1). 3. Plasma concentrations of pyrimethamine and sulphadoxine associated with synergistic effects against pyrimethamine-resistant strains of Plasmodium falciparum in vitro were achieved within 1 h of administration and were maintained beyond the end of sampling. 4. After both oral and parenteral administration the plasma concentrations of both compounds were lower than those predicted by data from healthy subjects. 5. Areas under the plasma concentration-time curves of sulphadoxine after oral and i.m. administration did not differ significantly, although maximum plasma drug concentrations were higher after the i.m. route (P = 0.03). 6. The AUC values of pyrimethamine did not differ significantly between the two routes of administration. However, after i.m. administration AUC(0,24 h) values were smaller (P = 0.03), and the time to maximum plasma drug concentration (tmax) was longer (P = 0.004) than when the drug was given orally.

Administration, Oral↗
PubMed1992

Prophylactic phenobarbitone in young children with severe falciparum malaria: pharmacokinetics and clinical effects.

1. A method is described for the measurement of phenobarbitone (PB) by reversed phase high performance liquid chromatography (h.p.l.c.) from small samples of whole blood dried onto filter paper strips. 2. The disposition of PB given prophylactically to young children with severe malaria on parenteral quinine is contrasted with that in aparasitaemic Kenyan children on no antimalarial drugs. There were no differences in the disposition of PB between the two groups. 3. Peak blood PB concentrations were equal to or greater than 15 mg l-1 in 27% of the patients on quinine and 23% of those not on quinine; a concentration of 10 mg l-1 was achieved or exceeded by 100% and 92% of each group, respectively, and was maintained for 39 +/- 24 h (mean +/- s.d.), and 33 +/- 21 h, respectively. 4. In an open, dose-finding study, the progress of young children with cerebral malaria given prophylactic PB (10 mg kg-1), was contrasted with that of controls given no seizure prophylaxis. 5. The drug had no apparent effect on depth or duration of coma, but neither was the incidence of seizures reduced. 6. A controlled trial of prophylactic PB in young children with cerebral malaria is needed, but a larger dose than 10 mg kg-1 should be studied.

Child↗
PubMed1992

Differential tissue regulation of the insulin-like growth factors in rats bearing the MStT/W15 pituitary tumor.

The content of insulin-like growth factors, IGF-I and IGF-II, was measured in tissues of rats bearing a transplantable mammosomatotrophic tumor, MStT/W15. Serum IGF-I was elevated in tumor-implanted rats [2,557 +/- (SE) 419 vs. 891 +/- 100 ng/ml], and tumor tissue concentrations of IGF-I were increased (321 +/- 16 ng/g) in comparison to control liver tissue (160 +/- 5 ng/g) or control pituitary (80 +/- 3 ng/g). The IGF-I levels were significantly increased in most peripheral tissues in the tumor-bearing rats with the exception of the liver. In support of this finding, messenger RNA for prepro IGF-I was likewise not increased in the livers of tumor-bearing rats, nor was there an increase in the growth hormone-dependent IGF-binding protein, BP-3, in the liver or serum of these animals. All tumors had detectable levels of prepro IGF-I mRNA which was, however, less than 50% of that noted in normal control liver. The tumors also expressed an IGF-BP which was identified as IGF-BP-2 by immunoblotting. Serum concentrations of IGF-II were similar in control and tumor-bearing animals (approximately 70 ng/ml). IGF-II levels in the tumor (90 +/- 5 ng/g) were significantly higher than levels in control liver (34 +/- 2 ng/g), but similar to those found in normal pituitary (165 +/- 24 ng/g). In peripheral tissues, IGF-II concentrations were selectively increased in skeletal muscle and heart of tumor-bearing rats. These data demonstrate tissue-specific regulation of IGF-I and IGF-II. Paradoxically, the liver does not appear to be stimulated over control levels by high serum growth hormone levels, since neither IGF-I peptide, IGF-I mRNA, nor IGF-BP-3 levels are increased in livers of tumor-bearing rats. This suggests that the increase in serum IGF-I in these animals is due to increased production of IGF-I by the tumors themselves and by nonhepatic peripheral tissues and further that hepatic responsiveness to growth hormone is diminished in these tumor-bearing animals.

Animals↗
PubMed1992

Differential tissue regulation of insulin-like growth factor binding proteins in experimental diabetes mellitus in the rat.

The expression and regulation of IGF-I is tissue-specific in diabetes mellitus in the rat. These studies were designed to examine if similar tissue specificity exists for IGF-BPs in the diabetic milieu. Diabetes mellitus was induced by a single i.p. injection of STZ (100 mg/kg body weight). Rats were treated with either vehicle--insulin, vanadate, or phlorizin for 7-14 days. Tissues were analyzed for IGF-BPs by ligand blotting and by affinity cross-linking and immunoprecipitation. In liver tissue from nondiabetic control rats, multiple forms of IGF-BPs were noted, ranging from 48,000 to 25,000 M(r). In diabetic rat liver tissue, the 25,000-M(r) form was unchanged, whereas the higher M(r) forms (48,000-42,000 M(r)) were decreased, and the 30,000-M(r) form was increased. Insulin therapy of diabetic rats decreased all forms to below control levels. In the kidney tissue of control rats, faint IGF-BP bands were seen at 30,000 and 25,000 M(r). In diabetic rat kidney tissue, the 30,000-M(r) form again was increased (as in liver) and restored to control levels with insulin therapy. In contrast, only a 30,000-M(r) band was seen in control pituitary tissue, which was slightly increased in the diabetic rats and also was decreased below control levels by insulin. In hypothalamus and cerebral cortex tissue, bands at 30,000 and 25,000 M(r) were noted, and neither was altered by diabetes or insulin treatment. Treatment of diabetic rats with vanadate and phlorizin resulted in comparable blood glucose levels, which were only slightly higher than those achieved with insulin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Case-control studies of severe malaria.

The majority of children infected with Plasmodium falciparum in areas of stable endemicity do not develop severe, life-threatening disease. It is important to identify risk factors for the minority who do. Case-control studies in which children with severe disease are compared with children with non-severe disease and with community controls, avoid some of the ethical and logistical problems inherent in such an undertaking. This paper discusses methodological aspects of case-control studies of severe malaria including case and control definitions, selection of cases and controls, potential risk factors, sample size calculations and analysis. Although specifically concerned with malaria, many of these issues are equally relevant to case-control studies of other infectious and parasitic diseases in a tropical environment.

Case-Control Studies↗
PubMed1991

Characterization and localization of Plasmodium falciparum surface antigens on infected erythrocytes from west African patients.

The malaria-induced surface antigens on Plasmodium falciparum-infected erythrocytes from West African patients were characterized by agglutination of infected cells by human sera, surface immunofluorescence of live infected cells, inhibition of cytoadherence to C32 melanoma cells by human sera, immunoelectron microscopy (immunoEM), and immunoprecipitation. In a nonimmune individual, serum antibody reactivity to surface antigens of infected cells was acquired during convalescence, as tested by all five methods, and was generally parasite isolate-specific. By contrast, adult hyperimmune West African sera reacted with many isolates, including isolates from geographically distinct regions. A quantitative correlation was established between agglutination and surface immunofluorescence assay titers, and between surface immunofluorescence assay and immunoEM reactivity, suggesting that a single antigen or a set of coexpressed antigens is being detected. Surface iodination of infected cells identified trypsin-sensitive high M, antigens in the sodium dodecyl sulfate extract. All sera tested that agglutinated infected cells also immunoprecipitated these antigens. The same surface antigens were immunoprecipitated by the homologous convalescent serum as by adult sera. By immunoEM these antigens were localized exclusively at the knob-like protrusions of infected cells, where they may participate in adherence to vascular endothelium.

Africa, Western↗