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Biomedical subjects

R A Gibson

Publications and source records attributed to R A Gibson.

At least 55 records · Page 3Linked to original sources
PubMed1997

The genomic organization of the Fanconi anemia group A (FAA) gene.

Fanconi anemia (FA) is a genetically heterogenous disease involving at least five genes on the basis of complementation analysis (FAA to FAE). The FAA gene has been recently isolated by two independent approaches, positional and functional cloning. In the present study we describe the genomic structure of the FAA gene. The gene contains 43 exons spanning approximately 80 kb as determined by the alignment of four cosmids and the fine localization of the first and the last exons in restriction fragments of these clones. Exons range from 34 to 188 bp. All but three of the splice sites were consistent with the ag-gt rule. We also describe three alternative splicing events in cDNA clones that result in the loss of exon 37, a 23-bp deletion at the 5' end of exon 41, and a GCAG insertion at the 3' portion also in exon 41. Sequence analysis of the 5' region upstream of the putative transcription start site showed no obvious TATA and CAAT boxes, but did show a GC-rich region, typical of housekeeping genes. Knowledge of the structure of the FAA gene will provide an invaluable resource for the discovery of mutations in the gene that accounts for about 60-66% of FA patients.

Alternative Splicing↗
PubMed1997

VACTERL with hydrocephalus in twins due to Fanconi anemia (FA): mutation in the FAC gene.

We present a dizygotic twin pair each with ventriculomegaly, a radial ray defect and multiple malformations in keeping with the VACTERL association. Molecular studies demonstrated that both are homozygous for IVS4 + 4 A-->T, a mutation in the Fanconi anemia complementation group C gene. This is the first molecular proof that VACTERL with hydrocephalus may be the result of severe Fanconi anemia.

Abnormalities, Multiple↗
PubMed1997

Effect of increasing breast milk docosahexaenoic acid on plasma and erythrocyte phospholipid fatty acids and neural indices of exclusively breast fed infants.

OBJECTIVES: To determine the effect of increasing docosahexaenoic acid (DHA, 22:6 n-3) in breast milk on infant fatty acid profiles. A secondary aim was to examine aspects of neural development. DESIGN AND SETTING: Double blind, placebo controlled study of infants recruited from postnatal wards at Flinders Medical Centre. SUBJECTS: Fifty-two healthy term infants who were breast fed for at least 12 weeks and were from middle class families. INTERVENTION: Breast milk with DHA concentrations that ranged from 0.1-1.7% of total fatty acids. This was achieved by supplementation of the maternal diet for the first 12 weeks post partum. RESULTS: Breast milk with DHA was related to infant plasma (r = 0.89, P < 0.001) and erythrocyte (r = 88, P < 0.001) phospholipids in a saturable curvilinear manner so that breast milk DHA above 0.8% of total fatty acids resulted in little further increase in infant plasma or erythrocyte DHA levels. The rise in plasma and erythrocyte DHA was approximated by a fall in total n-6 polyunsaturated fatty acids. We could detect no relationship between visual evoked potential acuity (measured at 12 and 16 weeks) of infants by either the dietary grouping or the DHA status of individuals. A stepwise multiple regression showed that infant erythrocyte DHA at 12 weeks and home stimulation were the only independent factors associated with Bayley's MDI at 1 y (adjusted model r2 = 0.18, P < 0.005); while at 2 y gender and social score of the spouse were the only significant predictors of Bayley's MDI (adjusted model r2 = 0.22, P < 0.005). CONCLUSIONS: Increasing breast milk DHA levels caused a dose dependent saturable increase in infant plasma and erythrocyte phospholipid DHA. There were no long-term effects of infant DHA status on indices of neurodevelopment.

Breast Feeding↗
PubMed1996

Schizophrenia, tardive dyskinesia and essential fatty acids.

Several reports have indicated that people suffering from schizophrenia show an associated abnormality in levels of certain essential fatty acids (EFAs) in blood cells. Similar abnormalities have also been noted in association with the presence of tardive dyskinesia (TD). In order to study this further, 72 patients with the diagnosis of schizophrenia or schizoaffective disorder were examined to assess the relationship between psychiatric status, movement disorder (TD) and relative levels of the n-3 and n-6 essential fatty acids in red blood cell membranes and plasma. Patients were followed up over the next 4.5 years to determine whether or not changes in clinical state showed any systematic relationship to changes in essential fatty acid levels. We hypothesised that patients with schizophrenia would show persistently lowered levels of n-6 and n-3 series essential fatty acids, compared with normal controls. We further hypothesised that this abnormality would be greater in the presence versus absence of TD and the dominance of negative rather than positive symptoms. The only consistent findings were that lower levels of linoleic acid and higher levels of dihomogamma-linolenic acid characterised the patient population compared with control subjects but there was considerable variability in patients' EFA profile.

Adolescent↗
PubMed1996

Novel mutations and polymorphisms in the Fanconi anemia group C gene.

Fanconi anemia (FA) is an autosomal recessive disorder associated with hypersensitivity to DNA cross-linking agents and bone marrow failure. At least four complementation groups have been defined, and the FA group C gene (FAC) has been cloned. We have screened 76 unrelated FA patients of diverse ethnic and geographic origins and from unknown complementation groups for mutations in the FAC gene either by chemical cleavage mismatch analysis or by single-strand conformational polymorphism (SSCP). Five mutations were detected in four patients (5.3%), including two novel mutations (W22X and L496R). Nine polymorphisms were detected, seven of which have not been described previously (663A-->G, L190F, IVS6 + 30C-->T, I312V, V449M, Q465R, and 1974G-->A). Six of the nine polymorphisms occurred in patients or controls from the Tswana or Sotho chiefdoms of South Africa and were not found in 50 unrelated European controls. Restriction site assays were established for all 8 pathogenic mutations identified in the FAC gene to date and used to screen a total of 94 unrelated FA patients. This identified only one other group C patient, who was homozygons for the mutation IVS4 + 4A-->T. This study indicates that the proportion of FA patients from complementation group C is generally likely to be less than 10%. Guidelines for the selection of FA patients for FAC mutation screening are proposed.

Cell Cycle Proteins↗
PubMed1996

Is dietary docosahexaenoic acid essential for term infants?

There is a need to determine whether there is a dietary requirement for docosahexaenoic acid (DHA, 22:6 omega 3) by term infants to achieve their full developmental potential. Studies of brain fatty acid composition have demonstrated that infants who were breast fed have greater levels of cerebral cortex DHA than infants who were formula fed, suggesting that DHA in the cerebrum is dependent on a supply in the diet. Some physiological studies report that electrophysiological and behavioral assessments of visual function are improved in breast-fed infants relative to those fed formula, and that this is related to the level of DHA in their erythrocytes, whereas other studies demonstrate equivalent visual function between breast- and formula-fed infants. However, randomized studies of DHA supplementation of infant formula demonstrate that the visual function of formula-fed infants can be improved to breast-fed levels by adding DHA to formula. Further work is necessary to establish if there are long-term benefits of dietary DHA to the term infant.

Brain↗
PubMed1996

Effect of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma lipid fractions and tissue phospholipids.

n-9 Eicosatrienoic acid (ETrA), also known as Mead acid, is a minor fatty acid in essential fatty acid (EFA)-sufficient healthy subjects but is found at increased levels in EFA deficiency. This study examined the influence of dietary ETrA from a biological source on plasma and tissue ETrA. A synthetic fat-free diet was prepared to which was added Mut 48 oil which contains 19% ETrA (wt%) as well as other n-9 fatty acids. Blends of vegetable oils were used to achieve overall diets with 5% fat (wt%) and varying amounts of ETrA at two different dietary levels of linoleic acid (LA), approximately 4.4 and 19% of total fatty acids. These diets were fed to 5-week-old Dark Agouti rats for four weeks. Plasma lipid fractions and liver, spleen, and peritoneal exudate (PE) cells were analyzed for fatty acid composition. ETrA was present at up to 20% total fatty acids in plasma triglyceride, cholesterol ester, and phospholipid fractions. ETrA also accumulated to substantial levels in phospholipids of liver and spleen (up to 15% of total fatty acids) and PE cells (up to 11%). ETrA was found in plasma and tissue phospholipids in proportion to the amount of ETrA present in the diet. The incorporation was reduced in diets with higher LA content compared to diets containing similar amounts of ETrA but lower LA. All rats remained apparently healthy, and histological survey of major organs revealed no abnormality. While the long-term implications for health of ingestion of diets rich in ETrA remain to be established, rats appear to tolerate high levels of dietary ETrA without adverse effects. Dietary enrichment with ETrA warrants further investigation for possible beneficial effects in models of inflammation and autoimmunity, as well as in other conditions in which mediators derived from n-6 fatty acids can affect homeostasis adversely.

8,11,14-Eicosatrienoic Acid↗
PubMed1996

Effect of dietary docosahexaenoic acid on brain composition and neural function in term infants.

There is a need to determine whether there is a dietary requirement for docosahexaenoic acid (DHA, 22:6n-3) by term infants to achieve their full developmental potential. Studies of brain fatty acid composition demonstrated that infants who were breast fed had greater levels of cerebral cortex DHA than did infants who were formula fed, suggesting that DHA in the cerebrum is dependent on a supply in the diet. Some physiological studies reported that electrophysiological and behavioral assessments of visual function were improved in breast-fed infants relative to those fed formula and that this was related to the length of breast feeding. While some randomized studies of DHA supplementation of infant formula to term infants demonstrated that the visual function of formula-fed infants could be improved to breast-fed levels by adding DHA to formula, others failed to demonstrate an effect. Variations in dietary treatments and methods of assessment make comparison of the studies difficult. Further work is necessary to rigorously establish if there are long-term benefits of dietary DHA to the term infant.

Brain↗
PubMed1996

Fanconi's anaemia presenting as acute myeloid leukaemia in adulthood.

We describe a 28-year-old male patient who presented with apparently de novo acute myeloid leukaemia (AML) who was subsequently found to have Fanconi's anaemia (FA). The gene for complementation group A (FAA) has recently been localized to chromosome 16q24.3 and utilizing genetic markers closely linked to this locus we were able to conclude that this patient was likely to belong to complementation group A. FA presenting as AML is an exceptionally rare event and all previously described cases have occurred in patients less than 21 years of age. We conclude that the diagnosis of FA should always be considered in younger patients presenting with AML. It is important that the correct diagnosis is made in these individuals because the administration of conventional chemotherapy may well have devastating consequences for them. Correlations between the specific mutations causing FA and clinical phenotypes are likely to become apparent as more genetic analyses are performed in this group of patients.

Adult↗
PubMed1996

The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil.

The effect of a flaxseed oil-based diet on tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta) synthesis was examined in healthy volunteers. Use of flaxseed oil in domestic food preparation for 4 wk inhibited TNF alpha and IL-1 beta production by approximately 30%. Fish-oil supplementation (9 g/d) continued for a further 4 wk; TNF alpha and IL-1 beta synthesis were inhibited by 74% and 80%, respectively. There was a significant inverse exponential relation between TNF alpha or IL-1 beta synthesis and mononuclear cell content of eicosapentaenoic acid (EPA), an n--3 fatty acid derived from ingested EPA (fish oil) or metabolism of ingested alpha-linolenic acid (flaxseed oil). Cytokine production decreased as cellular EPA increased to approximately 1% of total fatty acids. Further increases in EPA content did not result in further decreases in cytokine production. The results indicate that vegetable oils rich in n--3 fatty acids inhibit TNF alpha and IL-1 beta synthesis.

Adult↗
PubMed1996

Dietary (n-9) eicosatrienoic acid from a cultured fungus inhibits leukotriene B4 synthesis in rats and the effect is modified by dietary linoleic acid.

Eicosatrienoic acid (ETrA) is the (n-9) homologue of (n-6) arachidonic acid (AA) and (n-3) eicosapentaenoic acid (EPA). ETrA can be synthesized endogeneously, but tissue levels are normally undetectable except in essential fatty acid (EFA) deficiency. An ETrA-rich oil extracted from a cultured fungus was used to prepare diets which had varying levels of ETrA (0-8 g/kg diet) in combination with one of two levels of linoleic acid (LA, 2.2 or 9.5 g/kg diet). All diets were sufficient in essential fatty acids. Groups of rats were fed these diets for 4 wk after which leucocyte fatty acid content and leukotriene B4 (LTB4) synthesis were measured. The influence of dietary LA on ETrA accumulation in cells was studied and correlations with LTB4 synthesis determined. ETrA was efficiently incorporated into peritoneal exudate cell (PEC) phospholipids with no evident saturation being observed with levels up to 10 mol/100 mol total fatty acids in peritoneal exudate cells. Cellular ETrA levels were lower (P < 0.001) in rats fed the higher level of LA. ETrA accumulation in peritoneal exudate cells correlated (r(2) = 0.63, P < 0.05) with reduced LTB4 synthesis which was attributable to LTA hydrolase inhibition. Thus, dietary ETrA from a biological source can accumulate in leucocytes and suppress inflammatory eicosanoid synthesis. The findings justify further studies into the biochemical and anti-inflammatory effects of dietary ETrA, which could be incorporated into palatable food additives.

8,11,14-Eicosatrienoic Acid↗
PubMed1996

Effect of maternal docosahexaenoic acid (DHA) supplementation on breast milk composition.

OBJECTIVE: To assess the effect of varying maternal intake of docosahexaenoic acid (DHA, 22 : 6n-3), in the absence of other dietary polyunsaturates, on breast milk fatty acids. DESIGN AND INTERVENTION: Lactating mothers were randomised on day 5 post-partum to groups consuming equal numbers of capsules but containing either placebo or an oil containing DHA (43%) as its only polyunsaturate to receive 0, 0.2, 0.4, 0.9, 1.3 g DHA/day. Breast milk fatty acids as well as maternal plasma and erythrocyte phospholipids were assessed at 12 weeks post partum by capillary gas chromatography. RESULTS: Breast milk DHA levels ranged from 0.2 to 1.7% of total fatty acids and increased in a dose dependent manner (r2 = 0.89, P < 0.01). Maternal plasma (r2 = 0.71, P < 0.01) and erythrocyte (r2 = 0.77, P < 0.01) phospholipid DHA levels increased and were also strongly associated with dietary dose of DHA. Increasing maternal dietary doses of DHA did not affect breast milk arachidonic acid (AA, 20 : 4n-6) levels or antioxidant status as measured by plasma vitamin A or E levels. CONCLUSIONS: Our results have demonstrated that DHA in the diet has a strong, specific and dose-dependent effect on breast milk DHA.

Antioxidants↗
PubMed1995

Erythrocyte fatty acids of term infants fed either breast milk, standard formula, or formula supplemented with long-chain polyunsaturates.

The purpose of our study was to assess whether a supplement of fish oil (FO) and evening primrose oil (EPO) for formula-fed infants was capable of avoiding reductions in erythrocyte docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) associated with standard formula feeding. Healthy, term infants, whose mothers chose to formula feed, were randomized to either a placebo or supplemented formula for their first 30 wk of life. A reference group of beast-fed infants also was enrolled. Erythrocyte fatty acids were measured by capillary gas chromatography on day 5 and in weeks 6, 16, and 30. Supplementation of formula with 0.36% of total fatty acids as DHA resulted in erythrocyte DHA being maintained at or above breast-fed levels for the entire 30-wk study period, and breast feeding (0.21% DHA) resulted in a modest fall in erythrocyte DHA relative to baseline (day 5) values. The level of erythrocyte DHA in placebo formula-fed infants was halved by week 16. AA levels decreased in all infants in the first six weeks, but the levels in breast- and placebo formula-fed infants increased with age and returned to approximate baseline (day 5) values by 16 and 30 wk of age, respectively. Erythrocyte AA in FO+EPO-supplemented infants remained low and below breast- and placebo formula-fed levels. Our data suggest that dietary supplementation with DHA at 0.36% total fatty acids results in erythrocyte DHA levels above those found in breast-fed infants. EPO supplementation was not effective at maintaining erythrocyte AA when given with FO.

Aging↗
PubMed1995

Differences in fatty acid composition of immature and mature articular cartilage in humans and sheep.

Chondrocytes are imbedded in an avascular, highly charged extracellular matrix which could form a barrier to the transfer of dietary essential fatty acids (EFA) to chondrocytes. A study was designed to assess the composition of immature and mature joint cartilage with respect to essential and nonessential fatty acids relevant to EFA deficiency. Cartilage and muscle samples were obtained from human fetus, infant and adult cadavers, and from fetal and mature sheep. Lipid extracts were prepared and the fatty acid composition determined. In human and sheep joint cartilage, linoleic acid (LA; 18:2n-6) content was lower, and n-9 eicosatrienoic acid (ETrA; 20:3n-9) and arachidonic acid (AA; 20:4n-6) were higher in fetuses compared to mature subjects. An intermediate pattern was seen in infant cartilage. n-3 Fatty acids tended to be higher in fetal than in mature cartilage in humans and in sheep. In human muscle (and in other noncartilaginous comparison tissues), similar differences between fetuses and adults were seen in LA and AA, but not in ETrA. In fetal sheep muscle, very low LA, reduced AA and raised ETrA levels compared to mature sheep muscle were seen. However, although the pattern is characteristic of EFA deficiency, the abundance of n-6 EFA in liver and spleen of human fetuses and of n-3 EFA in liver and spleen of fetal sheep suggests that placental transfer of EFA is not likely to be limiting. During fetal development, the metabolism of fatty acids is distinctive and differs between the species. ETrA appears to be a readily measurable component of some tissues at certain stages of development when its presence in tissues does not indicate EFA deficiency.

8,11,14-Eicosatrienoic Acid↗
PubMed1995

Localisation of the Fanconi anaemia complementation group A gene to chromosome 16q24.3.

Fanconi anaemia (FA) is an autosomal recessive disorder associated with diverse developmental abnormalities, bone-marrow failure and predisposition to cancer. FA cells show increased chromosome breakage and hypersensitivity to DNA cross-linking agents such as diepoxybutane and mitomycin C. Somatic-cell hybridisation analysis of FA cell lines has demonstrated the existence of at least five complementation groups (FA-A to FA-E), the most common of which is FA-A. This genetic heterogeneity has been a major obstacle to the positional cloning of FA genes by classical linkage analysis. The FAC gene was cloned by functional complementation, and localised to chromosome 9q22.3 (ref. 2), but this approach has thus far failed to yield the genes for the other complementation groups. We have established a panel of families classified as FA-A by complementation analysis, and used them to search for the FAA gene by linkage analysis. We excluded the previous assignment by linkage of an FA gene to chromosome 20q, and obtained conclusive evidence for linkage of FAA to microsatellite markers on chromosome 16q24.3. Strong evidence of allelic association with the disease was detected with the marker D16S303 in the Afrikaner population of South Africa, indicating the presence of a founder effect.

Chromosome Mapping↗
PubMed1995

Differences exist in the relationships between dietary linoleic and alpha-linolenic acids and their respective long-chain metabolites.

Increased concentrations of cellular eicosapentaenoic acid (EPA) have been shown to be beneficial in coronary heart disease, hypertension, and inflammatory disorders. Successful long-term strategies for increasing cellular EPA concentrations require information on the relationships between cellular concentrations of EPA and dietary amounts of alpha-linolenic acid (alpha-LA), a precursor of EPA, and dietary amounts of linoleic acid (LA), an antagonist of alpha-LA conversion to EPA. A dietary intervention study with healthy human volunteers that incorporated alpha-LA-rich vegetable oil (flaxseed oil), against a background diet low in LA, allowed us to examine these relationships. Linear relationships were found between dietary alpha-LA and EPA in plasma fractions and in cellular phospholipids. By contrast there was no relationship observed between dietary LA and tissue concentrations of its metabolite, arachidonic acid (AA). There was an inverse relationship between dietary alpha-LA and docosahexaenoic acid concentrations in the phospholipids of plasma, neutrophils, mononuclear cells, and platelets. The results indicate that increasing dietary alpha-LA will elevate tissue EPA concentrations in a predictable manner. This insight will facilitate the rational planning of practical dietary strategies for the long-term elevation of EPA concentrations in tissues.

Adult↗
PubMed1995

Sudden infant death syndrome: effect of breast and formula feeding on frontal cortex and brainstem lipid composition.

METHODOLOGY: Docosahexaenoic acid levels were measured by gas chromatography in samples of frontal lobe and brainstem taken from 28 and 26 infants, respectively, who had died of sudden infant death syndrome (SIDS). RESULTS: Significantly higher levels of docosahexaenoic acid were present in the frontal lobe tissues derived from the 13 breast fed infants (age range = 3.3-36.3 weeks; mean 15.9 +/- 11.3 weeks) compared to the 15 formula fed infants (age range = 6.9-47.7 weeks; mean 19.3 +/- 10.6 weeks); mean (+/- s.d.) levels were 8.5 +/- 1.1% and 7.6 +/- 0.8% of total fatty acids (P = 0.019). There was, however, no significant difference in brainstem docosahexaenoic acid levels between breast and formula fed infants. CONCLUSIONS: Given these variable findings, further investigation of the relationship between dietary fatty acid intake and cerebral lipid levels may help to clarify whether different modes of feeding have a role in the pathogenesis of SIDS.

Autopsy↗