PubMed Health⌕ Search

Biomedical subjects

F Lawrence

Publications and source records attributed to F Lawrence.

At least 19 recordsLinked to original sources
PubMed1992

Leishmania donovani: antagonistic effect of S-adenosyl methionine on ultrastructural changes and growth inhibition induced by sinefungin.

Sinefungin, an antifungal and antiparasitic nucleoside antibiotic, is a very potent antileishmanial agent in vitro and in vivo (Bachrach et al. 1980, FEBS Letters 121, 287-291; Neal et al. 1985, Transactions of the Royal Society of Tropical Medicine and Hygiene 79, 85-122). It was previously shown that this molecule is a competitive inhibitor of AdoMet for transmethylases (Paolantonacci et al. 1986, Molecular and Biochemical Parasitology 21, 47-54; Avila et al. 1987, Molecular and Biochemical Parasitology 26, 69-76) and that it induces shape changes of Leishmania donovani promastigotes as observed by light microscopy (Lawrence and Robert-Gero 1990; Bulletin de la Societé Française de Parasitologie 8, 13-18). In the present work the effect of the antibiotic on the ultrastructure was analyzed by electron microscopy. The main changes induced at sublethal concentrations (0.26 microM sinefungin for 16 hr) were progressive rounding, decreased motility, enlargement of the flagellar pocket, and shortening and loss of the external part of the flagellum. The comparison with control cells showed shorter Golgi saccules and fragmentation of the trans-Golgi network into vesicles, indicating a stimulated Golgi apparatus activity. This result, associated with the enlarged flagellar pocket, suggests an unbalanced cytoplasmic exchange between exocytosis and endocytosis. These effects are quite different from those induced by tunicamycin (Dagger et al. 1984, Biology of the Cell 50; 173-180) or paromomycin. In addition, other nucleoside and nonnucleoside growth inhibitors failed to induce similar changes. AdoMet antagonized the sinefungin-induced shape changes and ultrastructural modifications but had no effect with respect to other growth inhibitors. This suggests that the sinefungin activity at the cellular level is specifically related to competition with AdoMet. A comparative study of N-methylation and carboxylmethylation of proteins in sinefungin-treated promastigotes showed that the antibiotic preferentially inhibits the latter, catalyzed by protein-O-methyltransferases. These enzymes are known to regulate the function of various proteins involved in secretion. Overall the results suggest that one of the main targets of sinefungin in exponentially growing cells is the protein carboxylmethylation involved in membrane transport.

Adenosine↗
PubMed1992

Total synthesis of uracil analogues of sinefungin.

Analogues of sinefungin derivatives 18a and 18b have been prepared from uridine and L-aspartic acid. The key step in the synthesis was the coupling of the radical derived from 14 with the unsaturated amide 13. The latter was produced from the known N-hydroxy-2-thiopyridone ester of L-aspartic acid 12 with the olefin 11. Thus, the essential carbon skeleton was constructed by way of two radical coupling reactions. These analogues as well as 1a and 1b synthesized previously were tested for their antileishmanial effect in vivo and for their inhibitory activity of protein carboxymethylase (protein methylase II). The replacement of the adenine moiety by uracil or dihydrouracil considerably decreases the antiparasitic activity and the affinity for protein methylase II. The synthetic (S)-sinefungin was as active as the natural one. Interestingly, the C-6' epimer 1b was 50% less active in vitro than the natural sinefungin, but both had identical affinities for the target enzyme.

Adenosine↗
PubMed1991

Synthesis and biological activity of sinefungin analogues.

A series of nucleosides (2-4) that derive from adenosine by chain extension at the 5'-end have been synthesized starting from the known phosphonate 7. The latter was first combined with 4-pentenal to give 8, which underwent chemical manipulations to provide triacetate 11, which was found suitable for the adenylation step. Further transformations, among them the Hofmann degradation of the amide group of compound 13, and final deprotection gave nucleosides 2-4. They were considered as analogues of sinefungin (1) and tested for their antileishmanial activity together with compounds 5 and 6, which were obtained independently. All the modifications with respect to sinefungin resulted in nearly complete loss of growth inhibitory activity. These results indicate that the 9' terminal amino and carboxyl groups are necessary for the activity and that the presence of the amino group at C-6' is not sufficient to maintain the antileishmanial effect. Some of the analogues however could antagonize or reverse the inhibitory activity of sinefungin (1).

Adenosine↗
PubMed1991

Relationships between steps taken in selecting a nursing home and consumers' satisfaction.

Analysis of data related to selection of a nursing home by 411 families of nursing home residents led to the conclusion that steps selected and taken by consumers in the selection of a home were associated with their subsequent satisfaction with the home. Satisfaction was greater (a) for families in agreement about the home selected and (b) for families who investigated all homes in an area before selecting one. Less satisfied were families (a) who were forced to make an immediate decision about placement following illness of a patient, (b) who felt they lacked sufficient time to investigate homes, and (c) who chose the first home with space available.

Consumer Behavior↗
PubMed1991

A comparison of physical activity in Gambian and UK children aged 6-18 months.

The activity patterns of 81 Gambian and 53 UK children aged six, 12 or 18 months were compared by means of an activity diary technique. Major differences between communities were observed in the duration of play (2-3 times longer in UK compared to Gambian children) and in the duration of vigorous activities such as crawling, walking and running (2-4 times longer duration in the UK compared to the The Gambia). To investigate whether the lower activity of Gambian children could be explained by differences in nutritional or health status, subgroups of Gambian children were compared. Only small differences in activity pattern were found between Gambian children above and below 80% weight for age and between Gambian children who were or were not diagnosed ill within 10 days of study, suggesting that other factors (e.g. socio-cultural differences or the absence of conventional toys) may explain the lower activity of Gambian compared to UK children.

Analysis of Variance↗
PubMed1990

Bilateral uveal metastases from small-cell carcinoma of the lung.

Metastasis from small-cell carcinoma of the lung (SCCL) has most frequently been found in the lymph nodes, bones, brain, and liver. We have reported a case of metastatic SCCL located in the uveal layer of both eyes (choroidal in one and iridic in the other), an extremely rare occurrence.

Carcinoma, Small Cell↗
PubMed1987

Energy requirements of pregnancy in The Gambia.

At most times of the year adjustments in maternal energy expenditure and energy balance in rural Gambian women can provide sufficient energy to sustain reasonable rates of fetal growth without an increase in food intake, although this study suggests that the overall level of energy intake has been substantially underestimated in the past. At certain times of year, however, pre-harvest food shortages and the energy demands of subsistence farming did substantially reduce maternal fat stores and fetal growth. Dietary supplementation, already known to increase birthweight, also had measurable effects on the mothers' physiology, resulting in increased energy expenditure on basal metabolism and improving maternal fat deposition. These findings suggest that the precise energy cost of pregnancy varies as a function of the additional energy intake consumed at this crucial period.

Activities of Daily Living↗
PubMed1987

Inhibition of leishmanial DNA synthesis by sinefungin.

RNA, DNA and protein biosynthesis were studied in Leishmania donovani and L. tropica promastigotes cultured with or without sinefungin. Thymidine incorporation was significantly impaired by this compound. Neither the uptake of thymidine nor its phosphorylation were inhibited. Furthermore the ratios of deoxyribonucleotide to the corresponding ribonucleotide were not significantly affected by sinefungin. Analysis of the DNA indicates that the inhibition of thymidine incorporation affects mostly nuclear DNA, kDNA being less affected by this drug. No such effect on thymidine incorporation was observed in macrophages, the host cells of these parasites.

Adenosine↗
PubMed1987

Fat gain during pregnancy in rural African women: the effect of season and dietary status.

Body-fat gain during pregnancy (weight--total body water/0.73) was measured in 50 rural Gambian women exposed to seasonal energy demands of subsistence farming and to annual preharvest food shortages. Twenty-eight women received dietary supplements in amounts previously shown to increase birth weight. In unsupplemented women, fat gain was profoundly affected by the seasons through which the pregnancy progressed, ranging from an estimated loss of 4.7 kg to a net gain of 3 kg at various times of the year. Adjustment for season revealed, however, that pregnancy per se was without effect on body fat content. Supplementation increased fat gain during pregnancy by approximately 2 kg (p less than 0.05) and gave protection against the worst effects of season on energy balance. These findings contribute to our understanding of the consequences of low food intake during pregnancy and the effects of dietary supplementation on birth weight.

Adipose Tissue↗
PubMed1987

[Effect of 5'-deoxy-5'-S-isobutyl adenosine (SIBA) on the synthesis of polyoma virus constituents in infected mouse cells].

At 100 microM 5'-S-isobutyladenosine (SIBA) inhibits polyoma virus production in infected mouse embryo fibroblasts and in mouse kidney cells, as measured by plaque formation and by haemagglutination assays. SIBA has no significant effect on the synthesis of T and V antigens as well as on viral DNA synthesized in infected cells. Analysis of virus production on CsCl gradients on CsCl gradients showed that in the presence of SIBA reduced amount of heavy viral particles is produced and that part of these particles are pseudovirions containing low density DNA instead of supercoiled viral DNA.

Animals↗
PubMed1986

Protein methylation and protein methylases in Leishmania donovani and Leishmania tropica promastigotes.

We studied the content of acid-stable methylated amino acids of soluble proteins in promastigotes of Leishmania donovani and L. tropica. epsilon-N-Trimethyllysine and NG,NG-dimethylarginine were found in both Leishmania species after culture in the presence of [methyl-14C]methionine. In addition, 3-N-methylhistidine was found only in L. tropica and epsilon-N-dimethyllysine only in proteins of L. donovani. As sinefungin, an antileishmanial nucleoside antibiotic, is a known transmethylase inhibitor, its effect on protein methylation was studied, in whole cells and in vitro. In the first case the drug had no effect on the content of methylated amino acid residues of soluble proteins. In vitro, histone methylation by crude extracts was studied at pH 7.2 and 9.0, known in other organisms as optimum pH values for arginine and lysine methylation, respectively. Surprisingly, arginine methylation by extracts of L. donovani was the same at both pH values while lysine residues were more efficiently methylated at pH 7.2 than at pH 9 by the extracts of the two species. These results indicate that the properties of protein methylases I and III of these parasites are different from those of other organisms hitherto studied. The inhibition constants of sinefungin for the leishmanial protein methylases were weak in comparison with those for enzymes from other sources, with the exception of the constant of L. donovani enzyme at pH 9.

Adenosine↗
PubMed1985

A quantification of child care and infant-caregiver interaction in a West-African village.

We have investigated infant-caregiver interactions in an isolated African subsistence farming community where women perform arduous agricultural tasks in addition to their normal domestic duties which include child care. 49 babies aged 3-18 months were studied on one or two occasions. Detailed observations were made of the level of care and of positive and negative stimulation offered to the child. Children were left in the charge of young nursemaids for up to 40% of the day while the mothers tended the crops. Despite this the total amount of positive and negative stimulation and care were similar whether or not the mother was engaged in fieldwork on the day of study. Grandmothers and fathers were both relatively unimportant caregivers. Total positive stimulation did not increase with age; on the contrary, young babies (3-9 months of age) were offered more positive stimulation and less negative stimulation than older ones (12-18 months). A positive correlation was found between total positive stimulation and developmental quotient (assessed by the Griffiths test). Similar amounts of care were given at all ages and there was no difference in the treatment of the two sexes.

Age Factors↗
PubMed1985

Induction of heat shock and stress proteins in promastigotes of three Leishmania species.

The induction of heat shock proteins in three species of Leishmania, L. tropica, L. enrietti, and L. donovani is reported. When cultures of promastigotes are shifted from 26 degrees C to 37 degrees C or 40 degrees C, the synthesis of proteins with apparent molecular weights of 88,000, 74,000, and 54,000 is stimulated. Actinomycin D added just prior to the shift prevented the appearance of these proteins but had no effect when present 30 min after the transfer onward, suggesting that the regulation of leishmanial heat shock proteins occurs at the transcriptional level. Exposure of L. tropica promastigotes to sodium arsenite elicits the synthesis of three major and four minor polypeptides. Their apparent molecular weights are, respectively, 94,000, 78,000, and 56,000 and 70,000, 45,000, 22,000, and 18,000. The response of Leishmania organisms to heat shock and to sodium arsenite is similar to that of other organisms, but some of the proteins identified as stress proteins in the parasite differ in size. The heat shock proteins might play a role in cytodifferentiation during the life cycle of the parasite and also in cellular adaptation to higher temperatures.

Animals↗
PubMed1985

The energy cost of common daily activities in African women: increased expenditure in pregnancy?

We have performed, by open-circuit indirect calorimetry, a total of 1546 measurements of energy expenditure on 142 nonpregnant, pregnant, or lactating Gambian village women. Of the 47 common daily activities measured, only 7 would be classified as moderate according to internationally accepted standards, the remainder being light (ie requiring less than 3.5 kcal/min). This was unexpected since many of the tasks, judged subjectively, appeared quite demanding. Furthermore there was no increase towards the end of pregnancy in the energy cost of a range of activities requiring 1-5 kcal/min and involving a variety of body movements, despite the substantial weight gains observed. Only for walking was there the expected increase in energy expenditure. Although in the past it has been assumed that the heavier pregnant women would require additional energy for activity, no special allowance for this is included in current dietary recommendations. The present results indicate that, for women from the developing world, no allowance is necessary. The finding that most activities were light is also of relevance to total energy requirements in this community.

Adolescent↗
PubMed1985

Differential effect of sinefungin and its analogs on the multiplication of three Leishmania species.

Sinefungin and seven analogs were evaluated in vitro for activity against promastigote multiplication of Leishmania donovani, L. tropica, and L. enrietti. Of these compounds, sinefungin, the cyclic derivative, and A9145C were leishmanicidal at concentrations ranging from 0.13 to 2.6 microM. Sinefungin was the most active of these three compounds against L. donovani, and A9145C was most active against L. enrietti. None of the remaining derivatives exhibited significant activity against any one of the three species at the highest dose tested. All agents were assayed for activity against protein methylases I and III. The results of these tests showed that there is no relationship between the inhibition of growth and inhibition of protein methylases I and III.

Adenosine↗
PubMed1985

[Decrease in the transforming action of Rous sarcoma virus produced by avian cells grown in the presence of 5'-deoxy-5'-S-isobutyladenosine (SIBA)].

Treatment of Rous Sarcoma virus transformed chick embryo fibroblasts with 1 mM 5'-deoxy-5'-S-isobutyladenosine for 24 hrs. leads to the inhibition of transforming virus production. A kinetic analysis of the inhibition of active virion production revealed that the effect of the drug was time and concentration dependent. After 24 hrs. with 1 mM SIBA, the production of transforming virus was inhibited 165 fold. However, under these conditions there was only a 2 fold inhibition in viral particle production. Thus, these viral particles were either non infective (non adsorbed on cell membrane) or non transforming. The majority of viral particles produced by cells cultured with the drug have a decreased density. Analysis of these virions showed a decrease of protein P19 and an accumulation of proteins with high molecular weight.

Animals↗
PubMed1979

Relationship between inhibition of protein methylase I and inhibition of Rous sarcoma virus-induced cell transformation.

A correlation was found between inhibition of protein methylase I and inhibition of virus-induced cell transformation by structural analogs of S-adenosylhomocysteine; all good inhibitors of this enzyme are also good inhibitors of Rous sarcoma virus-induced chicke embryo fibroblast transformation. The inhibitory effect of these analogs was similar on enzymes from normal and transformed cells; no significant variation of the inhibition constants was observed after purification of protein methylase I. From the kinetic constants obtained, a structure-activity relationship can be established for protein methylase I.

Animals↗