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Biomedical subjects

S E Moore

Publications and source records attributed to S E Moore.

At least 19 recordsLinked to original sources
PubMed2005

Early programming of adult diseases in resource poor countries.

Considerable evidence now exists to suggest that early exposure to nutritional deprivation can have long term consequences to health, with low birth weight now considered a risk factor for later health outcomes such as coronary heart disease, stroke, type 2 diabetes, and the metabolic syndrome. Of importance, such effects are most exaggerated when faced with over-nutrition in later life, forming the basis for the "thrifty phenotype" hypothesis. The evidence in support of these associations comes largely from retrospective cohort studies in which adult outcomes were correlated with birth weight records. Relatively little data is available from developing countries, where long term record keeping of birth weight data has not been a high priority. Arguably however, such countries are at the greatest risk from the mismatch of early nutritional deprivation and later nutritional affluence. This paper explores the importance of the "developmental origins of health and disease" hypothesis in resource poor countries.

Adult↗
PubMed2004

Ethnic differences in the relationship between fasting leptin and BMI in children.

OBJECTIVE: To compare the relationship between fasting serum leptin levels and body mass index (BMI) in children from different ethnic groups. SUBJECTS: Children aged 6-10 y from rural Gambia (n=471) and central Italy (n=839). MEASUREMENTS: Anthropometry (z-score of BMI) and fasting serum leptin concentrations. RESULTS: The Italian children had significantly higher mean BMI z-scores than the Gambian children (males: Italy 1.58, Gambia -1.44, P< or =0.0001; females: Italy 1.33, Gambia -1.42, P< or =0.0001) and significantly higher serum leptin concentrations (males: Italy 8.86 ng ml(-1), Gambia 1.78 ng ml(-1), P< or =0.0001; females: Italy 11.31 ng ml(-1), Gambia 2.22 ng ml(-1), P< or =0.0001). A significantly different relationship was observed between z-score of BMI and serum leptin levels in the Gambian and the Italian children for both boys and girls. CONCLUSION: A different relationship exists between z-score of BMI and leptin levels in these two groups of children from very diverse ethnic backgrounds. Future studies using detailed measures of body composition and energy balance are needed to help understand this relationship.

Body Composition↗
PubMed2004

Nogo A expression in the adult enteric nervous system.

Neuronal plasticity plays an important role in physiological and pathological processes within the gastrointestinal (GI) tract. Nogo A is a major contributor to the negative effect central nervous system (CNS) myelin has on neurite outgrowth after injury and may also play a role in maintaining synaptic connections in the healthy CNS. Nogo A is highly expressed during neuronal development but in the CNS declines postnatally concomitantly with a loss of regenerative potential while ganglia of the Peripheral Nervous System (PNS) retain Nogo A. The enteric nervous system shares a number of features in common with the CNS, thus the peripheral distribution of factors affecting plasticity is of interest. We have investigated the distribution of Nogo in the adult mammalian gastrointestinal tract. Nogo A mRNA and protein are detectable in the adult rat GI tract. Nogo A is expressed heterogeneously in enteric neurons throughout the GI tract though expression levels appear not to be correlated with neuronal sub-type. The pattern of expression is maintained in cultured myenteric plexus from the guinea-pig small intestine. As is seen in developing neurons of the CNS, enteric Nogo A is present in both neuronal cell bodies and axons. Our results point to a hitherto unsuspected role for Nogo A in enteric neuronal physiology.

Animals↗
PubMed2003

Impact of nutritional status on antibody responses to different vaccines in undernourished Gambian children.

AIM: To test the efficacy of T-cell-dependent and T-cell-independent vaccines in rural Gambian children suffering from a range of energy/protein and micronutrient deficiencies. METHODS: Nutritional status (anthropometry, haemoglobin, plasma leptin and micronutrient status) and response to two vaccinations (23 valent pneumococcal capsular polysaccharide vaccine, Pneumovax and the Human Diploid-Cell Rabies Vaccine) were assessed in 472 children aged 6 1/2 h to 9 1/2 y. RESULTS: Anthropometry and micronutrient status (as z-scores against European reference values) indicated a range from moderate to severe levels of undernutrition [mean (interquartile range): weight-for-age z-score -1.58 (-2.18 to -0.95); height-for-age z-score -0.94 (-1.51 to -0.35); body-mass-index-for-age z-score -1.43 (-2.05 to -0.84); mid-upper arm circumference -1.41 (-1.72 to -1.13); leptin -1.06 (-1.10 to -1.03); haemoglobin (Hb) -0.30 (-1.18 to 0.79); zinc -1.29 (-2.42 to -0.55); vitamin C -0.01 (-1.18 to 1.15); retinol -1.33 (-1.97 to -0.77)]. A seasonal effect was observed in haemoglobin levels and in all micronutrients (with the exception of zinc and retinol) and in the response to vaccination. After adjusting for seasonality, age and gender, no consistent associations were found between any of the measures of nutritional status and the effectiveness of seroconversion to either of the vaccines. CONCLUSION: The successful short-term seroconversion to whole inactivated viral and bacterial polysaccharide vaccines indicates that the processes leading to antibody secretion remain intact over a wide range of single and combined nutrient deficiencies.

Antibody Formation↗
PubMed2003

Birth season and environmental influences on patterns of thymic growth in rural Gambian infants.

AIM: In rural Gambia, birth season predicts infection-related adult mortality. Seasonal factors in early life may programme the immune system, possibly via an effect on thymic development. This study tested whether thymus size in rural Gambian infants is affected by birth season, defined as January-June (harvest, few infections) versus July-December (hungry, high infectious load). METHODS: Thymic volume (thymic index) was assessed sonographically at 1, 8, 24 and 52 wk in 138 singleton infants born over 14 consecutive months. Growth and morbidity were regularly assessed. RESULTS: Mean thymic index increased from 19.9 at 1 wk to 30.9 at 8 wk and 35.7 at 24 wk, then fell to 32.0 at 52 wk. Thymic index was associated with each preceding thymic index up to 24 wk. This tracking persisted after correcting for infant weight and month of measurement (p < 0.01). Thymic index at 1 wk was marginally but non-significantly lower in hungry season births (p = 0.06). Thymic index was lower in hungry season measurements; this effect persisted after adjusting for current weight and infection markers, and was strongest at 8 wk (p = 0.001). CONCLUSION: These results describe a pattern of thymic growth followed by diminution in size. An infant's thymic index tracks despite changes in body weight and season. Thymic index was lower in the hungry season. This appears not to be explained by infection or nutritional status. A possible influence of trophic factors in breast milk merits investigation.

Body Weight↗
PubMed2002

Leptin, malnutrition, and immune response in rural Gambian children.

BACKGROUND: The adipocyte derived hormone, leptin, has cytokine like function and may mediate the effects of starvation on immunity. Mice with congenital leptin deficiency (ob/ob) have small hypocellular thymuses and impaired cellular immunity. In humans leptin influences the differentiation of naïve and memory cells in vitro, and genetic leptin deficiency has been associated with an ill defined susceptibility to infection. AIMS: To describe the in vivo relation of leptin and immune function in children. METHODS: Fasting plasma leptin concentrations, immune function (T and B cell mediated vaccine responses and delayed type hypersensitivity), and mucosal function (dual sugar permeability test and salivary sIgA concentrations) were measured in a cohort of 472 moderately undernourished rural Gambian children. RESULTS: Leptin concentrations correlated with body fat assessed by mid upper arm circumference or BMI for age Z scores, and were very low compared to well nourished European norms (males 1.8 v 11.1 ng/ml; females 2.4 v 13.8 ng/ml). No detectable relations were found between leptin concentrations and any of the measures of immune or mucosal function. CONCLUSIONS: The data confirm that leptin acts as a peripheral signal of energy restriction, but do not support an association between fasting plasma leptin levels and immune function in children of this age.

Antibody Formation↗
PubMed2001

Myelin-associated glycoprotein interacts with ganglioside GT1b. A mechanism for neurite outgrowth inhibition.

Myelin-associated glycoprotein (MAG) is expressed on myelinating glia and inhibits neurite outgrowth from post-natal neurons. MAG has a sialic acid binding site in its N-terminal domain and binds to specific sialylated glycans and gangliosides present on the surface of neurons, but the significance of these interactions in the effect of MAG on neurite outgrowth is unclear. Here we present evidence to suggest that recognition of sialylated glycans is essential for inhibition of neurite outgrowth by MAG. Arginine 118 on MAG is known to make a key contact with sialic acid. We show that mutation of this residue reduces the potency of MAG inhibitory activity but that residual activity is also a result of carbohydrate recognition. We then go on to investigate gangliosides GT1b and GD1a as candidate MAG receptors. We show that MAG specifically binds both gangliosides and that both are expressed on the surface of MAG-responsive neurons. Furthermore, antibody cross-linking of cell surface GT1b, but not GD1a, mimics the effect of MAG, in that neurite outgrowth is inhibited through activation of Rho kinase. These data strongly suggest that interaction with GT1b on the neuronal cell surface is a potential mechanism for inhibition of neurite outgrowth by MAG.

Animals↗
PubMed2001

Cell signalling cascades regulating neuronal growth-promoting and inhibitory cues.

During development of the nervous system, neurons extend axons over considerable distances in a highly stereospecific fashion in order to innervate their targets in an appropriate manner. This involves the recognition, by the axonal growth cone, of guidance cues that determine the pathway taken by the axons. These guidance cues can act to promote and/or repel growth cone advance, and they can act either locally or at a distance from their place of synthesis. The directed growth of axons is partly governed by cell adhesion molecules (CAMs) on the neuronal growth cone that bind to CAMs on the surface of other axons or non-neuronal cells. In vitro assays have established the importance of the CAMs (N-CAM, N-cadherin and the L1 glycoprotein) in promoting axonal growth over cells, such as Schwann cells, astrocytes and muscle cells. Strong evidence now exists implicating the fibroblast growth factor receptor tyrosine kinase as the primary signal transduction molecule in the CAM pathway. Cell adhesion molecules are important constituents of synapses, and CAMs appear to play important and diverse roles in regulating synaptic plasticity associated with learning and memory. Negative extracellular signals which physically direct neurite growth have also been described. The latter include the neuronal growth inhibitory proteins Nogo and myelin-associated glycoprotein, as well as the growth cone collapsing Semaphorins/neuropilins. Although less well characterised, evidence is now beginning to emerge describing a role for Rho kinase-mediated signalling in inhibition of neurite outgrowth. This review focuses on some of the major themes and ideas associated with this fast-moving field of neuroscience.

Animals↗
PubMed2001

Glucose, insulin and lipid metabolism in rural Gambians exposed to early malnutrition.

AIMS: There is now substantial evidence to suggest that susceptibility to certain non-communicable diseases may be increased by early undernutrition. In rural Gambia, an annual hungry season reduces birth weight by 200-300 g and increases the prevalence of low birth weight (< 2500 g) from 11% to 24%. The aim of this study was to investigate whether fetal nutritional stress (using season of birth as a proxy measure for prenatal growth retardation) or early childhood malnutrition (using historical anthropometric records) had a residual influence on risk factors for cardiovascular disease in a cohort of rural Gambian adults. METHODS: Two hundred and nineteen adults (mean age = 35.8 years; mean body mass index = 21.3 kg/m2; women = 181) for whom month of birth and infant anthropometric records were available participated in this study. Risk factors for cardiovascular disease were measured. RESULTS: No differences were found between season of birth groups (hungry vs. harvest) and fasting measures of glucose, insulin, lipids, fibrinogen or cortisol, or against 30 and 120 min glucose and insulin levels following an oral glucose tolerance test, or blood pressure. Similarly, these risk factors for adult disease were not related to the subjects' weight-for-age as children. CONCLUSIONS: Moderate-to-severe fetal and childhood malnutrition in rural Gambia caused no detectable impairment of the glucose/insulin axis, or of other cardiovascular disease risk factors in adults remaining lean and fit on a low-fat diet.

Adult↗
PubMed2001

Immune function in rural Gambian children is not related to season of birth, birth size, or maternal supplementation status.

BACKGROUND: We previously showed that mortality from infectious diseases among young adults in rural Gambia is strongly correlated with the season of their birth. This suggests that early life insults that involve fetal malnutrition, exposure to natural toxins, or highly seasonal infections affecting the infant or pregnant mother cause permanent damage to the immune system. Excess mortality begins after puberty and has a maximal odds ratio of >10 for deaths between ages 25 and 50 y. OBJECTIVE: We investigated the immune function of children according to birth weight, season of birth, and exposure to maternal dietary supplementation during pregnancy. DESIGN: Immune function was measured in 472 prepubertal children aged 6.5-9.5 y from 28 villages in rural Gambia. The mothers of these children had been randomly assigned to a high-energy prenatal supplementation program, which significantly increased birth weight. This permitted supplementation status, birth weight, and season of birth to be investigated as exposure variables. The outcome variables tested were naive responses to rabies and pneumococcus vaccines, delayed-type hypersensitivity skin reactions, and mucosal defense (secretory immunoglobulin A and dual-sugar permeability). RESULTS: Immune responses were strongly related to current age and sex, suggesting a high level of sensitivity, but were not consistently related to birth weight, season of birth, or maternal supplementation (control compared with intervention). CONCLUSION: Events in early life did not predict a measurable defect in immune response within this cohort of rural Gambian children. It is possible that the early programming of immune function may be mediated through a defect in immunologic memory or early senescence rather than through impairment of early responses.

Adult↗
PubMed2000

Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins.

Neuropilins are receptors for class 3 secreted semaphorins, most of which can function as potent repulsive axon guidance cues. We have generated mice with a targeted deletion in the neuropilin-2 (Npn-2) locus. Many Npn-2 mutant mice are viable into adulthood, allowing us to assess the role of Npn-2 in axon guidance events throughout neural development. Npn-2 is required for the organization and fasciculation of several cranial nerves and spinal nerves. In addition, several major fiber tracts in the brains of adult mutant mice are either severely disorganized or missing. Our results show that Npn-2 is a selective receptor for class 3 semaphorins in vivo and that Npn-1 and Npn-2 are required for development of an overlapping but distinct set of CNS and PNS projections.

Age Factors↗
PubMed2000

Human autoantibodies to carcinoembryonic antigen (CEA) induced by a vaccinia-CEA vaccine.

Carcinoembryonic antigen (CEA) is a well-characterized oncofetal glycoprotein whose overexpression by human adenocarcinomas has been a target for cancer immunotherapy. Limited information is available regarding the ability of patients to mount an antibody response to this self-antigen following vaccination. Recombinant vaccinia viruses encoding full-length or internally deleted cDNAs for human CEA were used to vaccinate 32 patients with CEA-expressing adenocarcinomas, predominantly of colorectal origin. CEA-specific autoantibodies were induced by vaccination in 7 of 32 patients. None of the patients had CEA antibodies detected before vaccination. CEA specificity of the antibodies initially identified by ELISA was confirmed by competitive inhibition analysis as well as recognition of recombinant CEA produced in baculovirus-infected insect cell cultures and human cell cultures by Western blot. The CEA autoantibodies were predominantly IgG1, with a minority of patients also demonstrating IgM autoantibodies. CEA antibodies were of low titer and low avidity, based on competitive inhibition assays. These autoantibodies did not affect clinical serum CEA protein quantitation. Furthermore, elevated serum CEA levels commonly encountered in patients with advanced adenocarcinoma did not hinder detection of low avidity polyclonal CEA antibodies. CEA antibodies such as those induced in these pilot trials are projected to have modest antitumor activity. Thus, additional Phase I/II trials of recombinant vaccinia-CEA with alternative prime-boost approaches and/or augmentation strategies are warranted in an effort to enhance the frequency and avidity of CEA-specific autoantibodies and cytolytic T cells before Phase III trials.

Adenocarcinoma↗
PubMed1999

Cytosol-to-lysosome transport of free polymannose-type oligosaccharides. Kinetic and specificity studies using rat liver lysosomes.

In hepatocellular carcinoma HepG2 cells, free polymannose-type oligosaccharides appearing in the cytosol during the biosynthesis and quality control of glycoproteins are rapidly translocated into lysosomes by an as yet poorly defined process (Saint-Pol, A., Bauvy, C., Codogno, P., and Moore, S. E. H. (1997) J. Cell Biol. 136, 45-59). Here, we demonstrate an ATP-dependent association of [2-3H]mannose-labeled Man5GlcNAc with isolated rat liver lysosomes. This association was only observed in the presence of swainsonine, a mannosidase inhibitor, which was required for the protection of sedimentable, but not nonsedimentable, Man5GlcNAc from degradation, indicating that oligosaccharides were transported into lysosomes. Saturable high affinity transport (Kuptake, 22.3 microM, Vmax, 7.1 fmol/min/unit of beta-hexosaminidase) was dependent upon the hydrolysis of ATP but independent of vacuolar H+/ATPase activity. Transport was inhibited strongly by NEM and weakly by vanadate but not by sodium azide, and, in addition, the sugar transport inhibitors phloretin, phloridzin, and cytochalasin B were without effect on transport. Oligosaccharide import did not show absolute specificity but was selective toward partially demannosylated and dephosphorylated oligosaccharides, and, furthermore, inhibition studies revealed that the free reducing GlcNAc residue of the oligosaccharide was of critical importance for its interaction with the transporter. These results demonstrate the presence of a novel lysosomal free oligosaccharide transporter that must work in concert with cytosolic hydrolases in order to clear the cytosol of endoplasmic reticulum-generated free oligosaccharides.

Acetylglucosamine↗
PubMed1999

Alteration of mannose transport in fibroblasts from type I carbohydrate deficient glycoprotein syndrome patients.

The aim of the present study was to explore how mannose enters fibroblasts derived from a panel of children suffering from different subtypes of type I carbohydrate deficient glycoprotein syndrome: seven carbohydrate deficient glycoprotein syndrome subtype Ia (phosphomannomutase deficiency), two carbohydrate deficient glycoprotein syndrome subtype Ib (phosphomannose isomerase deficiency) and two carbohydrate deficient glycoprotein syndrome subtype Ix (not identified deficiency). We showed that a specific mannose transport system exists in all the cells tested but has different characteristics with respect to carbohydrate deficient glycoprotein syndrome subtypes. Subtype Ia fibroblasts presented a mannose uptake equivalent or higher (maximum 1.6-fold) than control cells with a D-[2-3H]-mannose incorporation in nascent N-glycoproteins decreased up to 7-fold. Compared to control cells, the mannose uptake was greatly stimulated in subtype Ib (4.0-fold), due to lower Kuptake and higher Vmax values. Subtype Ib cells showed an increased incorporation of D-[2-3H]-mannose into nascent N-glycoproteins. Subtype Ix fibroblasts presented an intermediary status with mannose uptake equivalent to the control but with an increased incorporation of D-[2-3H]-mannose in nascent N-glycoproteins. All together, our results demonstrate quantitative and/or qualitative modifications in mannose transport of all carbohydrate deficient glycoprotein syndrome fibroblasts in comparison to control cells, with a relative homogeneity within a considered subtype of carbohydrate deficient glycoprotein syndrome. These results are consistent with the possible use of mannose as a therapeutic agent in carbohydrate deficient glycoprotein syndrome Ib and Ix.

Biological Transport↗
PubMed1999

Oligosaccharide transport: pumping waste from the ER into lysosomes.

N-glycans play important roles during the folding and secretion of glycoproteins. Surprisingly, during the N-glycosylation of glycoproteins, considerable amounts of unconjugated polymannose-type oligosaccharides ('free OS') are generated. Although free oligosaccharides have no known function in mammalian cells, a sophisticated cellular machinery enables them to be cleared from the endoplasmic reticulum (ER) into the cytosol and then re-enter the endomembrane system at the level of the lysosome. One possible function of this pathway is to stop free OS from interfering with the carbohydrate-dependent aspects of glycoprotein folding and transport along the secretory pathway.

Biological Transport↗