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Biomedical subjects

W M Watkins

Publications and source records attributed to W M Watkins.

At least 91 records · Page 5Linked to original sources
PubMed1988

Activity of the human blood group ABO, Se, H, Le, and X gene-encoded glycosyltransferases in normal and malignant bladder urothelium.

Immunohistochemistry has led to the finding of an expression of ABO-related blood group antigens in normal and malignant bladder urothelium which is different from that found on erythrocytes from the same individual. This includes a loss of blood group ABO expression in malignant urothelium, and the expression of Leb antigens in normal and malignant cells from individuals with Le(a+b-) and Le(a-b-) erythrocytes. To elucidate the mechanism of this blood group antigen expression in urothelium we have analyzed the activity of the specific glycosyltransferases encoded by the ABO, Se, H, Le, and X blood group genes in normal and malignant urothelium. Biopsies of normal urothelium were obtained from 22 individuals and biopsies of urothelial tumors from 20 individuals. The tissue donors were typed for ABO, Lewis, and secretor status on erythrocytes and saliva. The biopsies were disaggregated to single cell suspensions, and the activity of the individual glycosyltransferases was determined as pmol of labeled sugar incorporated by oligosaccharide acceptors per 100,000 cells. The A (alpha-3-N-acetyl-D-galactosaminyl) and B (alpha-3-D-galactosyl) gene-specified transferases showed no activity in malignant cells, whereas all other enzymes examined were expressed in both normal and malignant cells. Secretors and nonsecretors showed the same alpha-2-L-fucosyltransferase activity in both normal and malignant cells, whereas the alpha-3-L-fucosyltransferase was reduced (P less than 0.02) in malignant cells from Lewis positive individuals. The Lewis gene-encoded alpha-4-L-fucosyltransferase showed a similar activity in Lewis positive and negative individuals. These results indicate that the disappearance of A and B blood group antigens in bladder tumors and the expression of Leb antigens in normal and malignant cells from individuals with Le(a+b-) and Le(a-b-) erythrocytes are due to corresponding differences in glycosyltransferases. The results indicate that the ABO, H, Se, and Le genes are subjected to a tissue-dependent differential expression.

ABO Blood-Group System↗
PubMed1988

Efficacy of multiple-dose halofantrine in treatment of chloroquine-resistant falciparum malaria in children in Kenya.

Halofantrine hydrochloride given to 46 Kenyan children with falciparum malaria at 10 mg/kg for two doses, and to 60 other children at 8 mg/kg for three doses, resulted in rapid parasite clearance, mean parasite clearance times being 45.4 h and 54.8 h, respectively. In-vitro chemosensitivity tests showed that most infections were due to chloroquine-resistant parasites, and that parasite maturation was inhibited by considerably lower concentrations of halofantrine than of chloroquine.

Administration, Oral↗
PubMed1988

Significance of altered alpha-2-L-fucosyltransferase levels in serum of leukemic patients.

Serum alpha-2-L-fucosyltransferase levels were measured in 20 patients with leukemia. Lower than normal levels were found in patients with acute leukemia and higher than normal activity was demonstrated in patients with chronic granulocytic leukemia. alpha-2-L-Fucosyltransferase activity is expressed in platelets, and in both groups of leukemic patients this enzyme activity in serum was found to correlate directly with the platelet count. Assays on platelets from normal donors and from leukemic patients showed that the changes in level of the enzyme in serum result from changes in platelet numbers and not from alterations in the cellular expression of the transferase in leukemia. alpha-2-L-Fucosyltransferase levels in serum are therefore not per se diagnostic markers of leukemia.

ABO Blood-Group System↗
PubMed1988

Chloroquine treatment of falciparum malaria in an area of Kenya of intermediate chloroquine resistance.

106 children aged 1-10 years who had pure Plasmodium falciparum infections and temperatures greater than or equal to 38 degrees C were treated with chloroquine base, 25 mg/kg body weight. 29% of the infections were sensitive in vivo, 41% recurred within 4 weeks (RI), 26% were RII resistant, and 4% were RII resistant. Rieckmann micro in vitro tests were successful in 64% of isolates obtained from these children; 63% were resistant to chloroquine. In 58 paired isolates obtained before and after treatment, the level of chloroquine sensitivity was lower in the parasites persisting or recurring after treatment. All children except 2 of the 4 with RIII resistance became afebrile an average of 1.4 d after starting treatment and their other symptoms resolved in an average of 1.8 d. By day 28, 57% of the children with RI resistance and 78% of those with RII resistance had recurrence of fever and other symptoms, compared with 19% of children with sensitive infections. No relationship was observed between the clinical or parasitological response and age, nutritional status, haematocrit, splenomegaly, presence of sickle-cell trait, or seropositivity to malaria by enzyme-linked immunosorbent assay. The study demonstrates that, in most children with malaria in an area of intermediate chloroquine resistance, fever and other symptoms resolve at least temporarily when treated with chloroquine.

Animals↗
PubMed1988

Failure of erythromycin to improve chloroquine treatment of Plasmodium falciparum malaria in Kenya.

58 children aged 1 to 10 years who had pure Plasmodium falciparum infections acquired on the coast of Kenya were treated with chloroquine 25 mg/kg given over 3 d and erythromycin 10 mg/kg 4 times a day given for 7 d. After 4 weeks follow-up, 62% had recurrent infections and 11% failed to clear their parasitaemia (1 had an RIII pattern of resistance). Of 38 children treated with chloroquine 25 mg/kg alone, 55% had recurrences and 21% failed to clear (including 1 RIII). In vitro microtests classified 74% of isolates from initial infections and 91% of isolates from recurrent infections as resistant. Erythromycin does not improve chloroquine treatment in children with infections due to P. falciparum having low to moderate levels of chloroquine resistance.

Animals↗
PubMed1988

Chlorproguanil/dapsone for the treatment of non-severe Plasmodium falciparum malaria in Kenya: a pilot study.

Chlorocycloguanil, the active metabolite of chlorproguanil, was synergistic in vitro with dapsone against 2 culture-adapted Plasmodium falciparum isolates from Kenya; maximal synergy occurred at lower concentrations that it did with pyrimethamine and sulfadoxine. 48 children with asymptomatic P. falciparum infections were treated with chlorproguanil (at a target dose of 1.2 mg/kg) and dapsone (target dose of 1.2 or 2.4 mg/kg); all were free of parasitaemia by day 7. The following numbers had recurrences on days 14, 21, and 28, respectively: 1 of 48, 7 of 47, and 7 of 40. All 39 children treated with pyrimethamine (target dose 1.2 mg/kg) and sulfadoxine (target dose 24 mg/kg) were cleared of infection, while the following had recurrences on days 14, 21, and 28: 1 of 39, 2 of 38, and 2 of 36. The rate of decrease in parasitaemia was the same in the 2 groups, and there was no change in haematocrit or haemoglobin during the follow-up. The rate of recurrence in the children receiving chlorporguanil/dapsone was higher, probably because these drugs have a much shorter clearance time than pyrimethamine/sulfadoxine. Chlorproguanil/dapsone is an effective combination for treating P. falciparum malaria and deserves further study.

Animals↗
PubMed1988

The changing response of Plasmodium falciparum to antimalarial drugs in east Africa.

For the past 20 years, chloroquine chemotherapy has been the single most effective malaria control measure in East Africa. The advent of chloroquine-resistant Plasmodium falciparum has reduced the clinical effectiveness of chloroquine and this trend is likely to continue. Combinations of antifol drugs are at present effective inhibitors of most P. falciparum infections in the region, in spite of widespread resistance to pyrimethamine. The development of (i) sensitive methods for monitoring changes in sensitivity to antifol combinations, (ii) more effective and less costly alternatives to commercially available combinations, and (iii) investigation of host and parasite factors leading to drug treatment failure in P. falciparum infections has been the primary goal of the Wellcome Trust Research Laboratories in Kenya (directed by Dr W.M. Watkins) within the malaria programme of the Kenya Medical Research Institute, and collaborating laboratories at the School of Tropical Medicine and the University of Liverpool.

Africa, Eastern↗
PubMed1988

Regulation of expression of carbohydrate blood group antigens.

The carbohydrate antigens associated with the human ABO and Lewis blood group systems are excellent models for the study of the genetic regulation of glycoconjugate biosynthesis because their expression on erythrocytes and in saliva has been thoroughly investigated in terms of classical genetics and the chemical structures and pathways for the formation of the antigens are now well understood. The primary protein products of the blood group genes are believed to be the glycosyltransferase enzymes that complete the biosynthesis of the determinants. The important controlling factors still to be elucidated are the genetic and environmental influences leading to the tissue specific expression of these antigens. The 3 types of regulation mechanisms discussed in this review are those arising: 1) from the specificity requirements of the glycosyltransferases encoded by the blood group genes; 2) from the competition or co-operation of glycosyltransferases encoded by genes at the same or independent loci; and 3) from the existence and tissue distribution of glycosyltransferases with related, but not identical, substrate specificities.

ABO Blood-Group System↗
PubMed1988

Zulu XX/XX dispermic chimaera from Natal with two populations of red blood cells and patchy skin pigmentation.

The chimaera is female and has two children. Her blood contains 99% group O, type AcP:BA, Pep-A:8-2 and 1% group A2B, type AcP:RA, Pep-A:1 red cells. H-, A- and B-transferase activities were demonstrated in her serum. The level of the H enzyme activity is low but is at the lower end of the normal range for group O persons. The levels of the A and B enzymes are also low but are higher than expected in a person with 1% A2B red cells in the blood. The levels of the A and B enzymes indicate that tissues other than the chimaera's haemopoietic tissue carry her genetically A2B cell line and are contributing the corresponding transferases to her plasma. Gross patchy skin pigmentation is present on the upper part of her body. The chimaera has evidently inherited two dissimilar germ nuclei from each parent.

Blood Group Antigens↗
PubMed1988

Immunolocalization of blood group A gene specified alpha 1,3N-acetylgalactosaminyltransferase and blood group A substance in the trans-tubular network of the Golgi apparatus and mucus of intestinal goblet cells.

The subcellular distribution of blood group A gene specified alpha 1,3N-acetylgalactosaminyltransferase and its product was studied in human intestinal goblet cells by immunoelectron microscopy. The O-glycosylation step yielding blood group A-active glycoconjugates occurred in the trans region of the Golgi apparatus as indicated by the presence of immunolabel for both antigens. In the Golgi apparatus, immunoreactive alpha 1,3N-acetylgalactosaminyltransferase was detectable in trans cisternae and in the trans-tubular network which was found to be continuous with the cisternal stack and exhibited acid phosphatase activity. This demonstrates that in intestinal goblet cells (i) the trans-tubular network does not constitute a compartment distinct from trans cisternae, and (ii) structures corresponding to GERL are structurally and functionally part of the Golgi apparatus. In addition to immunolabel for transferase at the inner surface of the cisternal membranes, luminally located immunolabel indicating the presence of free, not membrane-associated transferase became first detectable in the trans-tubular network and early forming mucus droplets contained therein. Further, the content of mature mucus droplets as well as the extracellular mucus layer were labeled. Absence of immunolabel in blood group 0 subjects lacking the blood group A gene specified transferase and the apparent non-reactivity of the antibodies with carbohydrate epitopes indicates that free alpha 1,3N-acetylgalactosaminyltransferase is present in mucus droplets and becomes secreted by intestinal goblet cells.

ABO Blood-Group System↗
PubMed1987

Inadequacy of chlorproguanil 20 mg per week as chemoprophylaxis for falciparum malaria in Kenya.

After treatment with chloroquine and pyrimethamine/sulfadoxine, 118 school children aged 6 to 10 years living near the Kenyan coast were enrolled in a malaria chemoprophylaxis study and followed up for 20 weeks. Children were randomly assigned to receive either chlorproguanil 20 mg weekly (n = 78) or placebo (n = 37). The attack rate of Plasmodium falciparum infection was 42% in chlorproguanil recipients (39.8 episodes per 1000 person-weeks of prophylaxis) and 73% in placebo recipients (69.2 episodes per 1000 person-weeks, p less than 0.02). Sensitivity tests on 36 isolates successfully cultured in vitro showed that all 21 isolates from chloroproguanil recipients were resistant to dihydrofolate-reductase inhibitors, whereas only 3 of 15 isolates from the placebo group were resistant (p less than 10(-6)). Chlorproguanil in a weekly adult dose of 40 mg does not provide adequate prophylaxis against P falciparum in Kenya, probably because drug levels between doses fall below those required to suppress parasites resistant to dihydrofolate-reductase inhibitors.

Adolescent↗
PubMed1987

Epidemiology of chloroquine-associated pruritus in Saradidi, Kenya.

The association of pruritus and ingestion of chloroquine phosphate in Saradidi, Kenya, was determined by randomly giving 437 children (less than 18 years) and 182 adults either 10 mg base kg-1 of regular chloroquine, 10 mg base kg-1 of enteric-coated chloroquine, 10 mg base kg-1 of amodiaquine, or one 300 mg tablet of enteric-coated ferrous sulphate. Before treatment, a blood smear was taken. Paired urine samples were tested for 4-aminoquinolines to exclude prior drug ingestion, to document drug absorption, and to exclude chloroquine or amodiaquine intake in persons who received iron. The following day, the incidence of itching was ascertained. More adults (20.3%) reported itching than did children (12.8%) (P less than 0.05); no significant difference between males and females was noted. A history of itching 24 hours after treatment was not significantly more common in persons with malaria parasitaemia. Pruritus was more frequent in those receiving regular chloroquine (21.5% of 186) and enteric-coated chloroquine (17.8% of 118) than after amodiaquine (11.6% of 173) or iron (8.5% of 142) (P less than 0.005). Amodiaquine which is a 4-aminoquinoline like chloroquine did not appear to cause significant pruritus in this population. These results demonstrate that chloroquine-associated pruritus is experienced frequently in Saradidi. This side effect of malaria treatment could influence usage of chloroquine phosphate provided by village health workers.

Adolescent↗
PubMed1987

A preliminary pharmacokinetic study of the antimalarial drugs, proguanil and chlorproguanil.

Pharmacokinetic parameters for cycloguanil and chlorcycloguanil, the active metabolites of proguanil (Paludrine] and chlorproguanil (Lapudrine) have been measured in a bioassay which assesses the in-vitro growth inhibition of a cycloguanil- and chlorcycloguanil-sensitive strain of Plasmodium falciparum produced by dilutions of plasma collected after oral administration of the pro-drugs. A single compartment model is applicable for cycloguanil with mean rate constants of elimination of 0.0624 h-1 and availability of 0.2398 h-1. The elimination profile for chlorcycloguanil indicates partition of drug into more than one compartment. In 2 of 10 subjects dosed with proguanil and 1 of 11 subjects dosed with chlorproguanil, the active metabolite levels were significantly lower than the mean for the other subjects. Abnormally low cycloguanil or chlorcycloguanil plasma levels may be of importance in relation to effective prophylaxis against malaria.

Adult↗
PubMed1987

In vitro susceptibility of Plasmodium falciparum isolates from Jilore, Kenya, to antimalarial drugs.

Twenty-six Plasmodium falciparum isolates obtained during a prophylaxis study at Jilore primary school, Malindi, Kenya, were adapted to in vitro culture and their susceptibility to 13 antimalarial drugs was tested by a modified radioisotopic method. Pyrimethamine, chloroquine, amodiaquine, cycloguanil, chlorcycloguanil, quinine, quinidine and sulfadoxine, and the experimental compounds MB 35769, mefloquine, WR 184806, parvoquone, and menoctone were used. The isolates could be divided into two groups with significantly different susceptibility to pyrimethamine, shown by a 755-fold difference in the mean ID50 values (2.77 +/- 1.98 x 10(-10) mol/l and 2.09 +/- 1.64 x 10(-7) mol/l). The mean susceptibility of the two groups differed 7.7-fold for chlorcycloguanil and 14.6-fold for cycloguanil, but were not significantly different for the other drugs. All isolates were more sensitive to amodiaquine than to chloroquine in vitro. The ratio of the geometric mean ID50 values of chloroquine to amodiaquine was 3.13. The ratio for the chemically related compounds parvoquone to menoctone was 5.63, quinine to quinidine was 5.58, and mefloquine to WR 184806 was 12.16.

Animals↗