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Biomedical subjects

J Castle

Publications and source records attributed to J Castle.

At least 19 recordsLinked to original sources
PubMed2006

Dwarfism and cytochrome P450-mediated C-6 oxidation of plant steroid hormones.

BRs (brassinosteroids) are plant steroid hormones that are essential for normal plant development. The dramatic dwarfism exhibited by mutants in the CYP (cytochrome P450) enzymes involved in BR biosynthesis indicates a role for these hormones in plant growth and development. Since the mid-1990s, collaborative research has been geared towards developing a better understanding of the CYP85 class of CYPs involved in BR biosynthesis in both Arabidopsis and tomato. Some of the most recent observations include the fact that certain CYP85 CYPs catalyse the synthesis of the most bioactive BR, BL (brassinolide). Current evidence suggests that evolution of this function may have occurred independently in different dicotyledonous species. Interestingly, BL accumulates in tomato fruits, highlighting a key role for this hormone in fruit development. At the same time as developing a better understanding of the enzymatic function of these CYPs, we have also carried out experiments towards characterizing where and when these genes are expressed and mechanisms of their regulation. As expected for a hormone involved in growth and development, biosynthetic gene promoter activity is associated with young rapidly growing cells and with fruit development.

Arabidopsis↗
PubMed2004

Detection of novel splice forms in human and mouse using cross-species approach.

Millions of transcript sequences have become available for characterizing the transcriptome of human and mouse. Transcript databases have been extensively mined for extracting alternative splicing information within the same species; but they also represent a potentially valuable resource for the discovery of alternative splice variants in another species. In this study, we have performed analysis of alternative splicing patterns for 7,475 pairs of human and mouse genes. We found that cross-species transcript analysis could accomplish the same level of sensitivity in detecting constitutive splice patterns as EST resource from the same species. In contrast, identifying alternative splice patterns in human genes, mouse transcripts achieved only 50% of the sensitivity of human EST and 70% of the sensitivity of human mRNA. While identifying alternative splice patterns in mouse genes, human transcripts are 38% more sensitive than mouse mRNA, and reach 60% of the sensitivity of mouse EST. Furthermore, using the cross-species approach, we predicted novel alternative splice patterns for 42% of human genes and 51% of mouse genes. Splice site motif analysis suggests that the majority of predicted novel splice patterns are expressed in human. EST-based frequency analysis shows that novel splice patterns are expressed at lower frequency than alternative splice patterns present in the transcript data from both species, possibly explaining why they remain undetected in the transcript data of the same species.

Alternative Splicing↗
PubMed2002

Importance of plasma leptin in predicting future weight gain in obese children: a two-and-a-half-year longitudinal study.

OBJECTIVE: To determine whether relatively low leptin levels predict changes in adiposity in prepubertal and pubertal obese children. RESEARCH METHODS AND PROCEDURES: In a biracial cohort of 68 obese children (33 male and 35 female; 46 Caucasians and 22 African-Americans, age range 7-18 y), we measured at baseline fasting insulin and leptin levels, height and weight and calculated body mass index (kg/m(2)) and expressed body mass index as (BMI) Z-score. After a 2.5-y follow-up, anthropometric measurements were repeated and changes in weight gain were calculated as changes in BMI Z-score. RESULTS: At baseline obese preadolescent boys and girls had similar age and BMI Z-score, fasting insulin and leptin levels. After an average follow-up of 2.5 y, mean weight change calculated by changes in BMI Z-score from baseline was similar in both groups. In obese adolescent boys and girls at baseline, no significant gender differences were observed for BMI Z-score and insulin levels. In contrast, plasma leptin levels were significantly higher in obese girls compared with obese adolescent boys. At follow-up, there was no significant difference in change in BMI Z-score between obese boys and girls. Multiple linear regression analysis revealed that high basal leptin levels were positively associated with greater changes in BMI Z-score only in girls (r(2)=0.18, P<0.02), after adjusting for basal BMI Z-score, Tanner stage, years of follow-up and basal insulin. High basal leptin levels in girls explained 18% of the weight gain. CONCLUSION: High leptin levels are associated with excessive future weight gain only in girls.

Adolescent↗
PubMed2001

Experimental annotation of the human genome using microarray technology.

The most important product of the sequencing of a genome is a complete, accurate catalogue of genes and their products, primarily messenger RNA transcripts and their cognate proteins. Such a catalogue cannot be constructed by computational annotation alone; it requires experimental validation on a genome scale. Using 'exon' and 'tiling' arrays fabricated by ink-jet oligonucleotide synthesis, we devised an experimental approach to validate and refine computational gene predictions and define full-length transcripts on the basis of co-regulated expression of their exons. These methods can provide more accurate gene numbers and allow the detection of mRNA splice variants and identification of the tissue- and disease-specific conditions under which genes are expressed. We apply our technique to chromosome 22q under 69 experimental condition pairs, and to the entire human genome under two experimental conditions. We discuss implications for more comprehensive, consistent and reliable genome annotation, more efficient, full-length complementary DNA cloning strategies and application to complex diseases.

Algorithms↗
PubMed1999

Effects of qualities of early institutional care on cognitive attainment. E.R.A. Study Team. English and Romanian Adoptees.

The adoption of children reared in poor quality Romanian institutions provided a "natural experiment" to determine whether psychological privation is the cause of later deficits. Low IQ at six years was strongly related to the duration of institutional care, with malnutrition having a weaker effect. After taking both into account, there was an additional effect of a particularly marked lack of individualized care.

Child Care↗
PubMed1999

Administration of n-3 fatty acids in the diets of rats or directly to hepatocyte cultures results in different effects on hepatocellular ApoB metabolism and secretion.

Hepatocytes derived either from rats fed a diet enriched in n-3 fatty acids or from rats fed a low-fat diet and cultured with an n-3 fatty acid (eicosapentaenoic acid, EPA) in vitro were used to distinguish between the dietary effects and the direct effects of n-3 fatty acids on hepatocellular apolipoprotein (apo) B metabolism and secretion. ApoB-48 and apoB-100 synthesis, degradation, and secretion as large (d<1.006) and small (d>1.006) particles were determined after a pulse label with [35S]methionine. These effects were compared with changes in triacylglycerol (TAG) synthesis and secretion and with changes in de novo fatty acid synthesis (using 3H2O incorporation) under identical conditions. When n-3 fatty acid was given via the dietary route, apoB-48 very low density lipoprotein (VLDL) secretion was inhibited, but there was no effect on the secretion of apoB-100 VLDL. There was no effect on the secretion of either apoB-48 or apoB-100 as small, dense particles (d>1.006). Cellular TAG synthesis was significantly inhibited under these conditions, and fatty acid synthesis de novo was inhibited by 80%. By contrast, after direct addition of EPA to hepatocytes from normal rats, the secretion of both apoB-48 and apoB-100 VLDL was suppressed. The secretion of apoB-48, but not of apoB-100, as dense particles was also inhibited. However, there was little or no effect on TAG synthesis nor on fatty acid synthesis de novo. In addition, whereas dietary administration of n-3 fatty acid gave rise to decreased net synthesis and degradation of apoB-48, direct administration in vitro resulted in increased degradation with no effect on net synthesis. We conclude that the effects of n-3 fatty acids on hepatic lipid and apoB metabolism differ according to whether they are administered in vivo, via the dietary route, or in vitro, via direct addition to hepatocyte cultures.

Animals↗
PubMed1999

Quasi-autistic patterns following severe early global privation. English and Romanian Adoptees (ERA) Study Team.

Six per cent of child in a sample of 111 children who were adopted into U.K. families from Romania, and who were systematically assessed at the ages of 4 and 6 years, showed autistic-like patterns of behaviour. A further 6% showed milder (usually isolated) autistic features. Such autistic characteristics were not found in a similarly studied sample of 52 children adopted in the first 6 months of life within the U.K. The children from Romania with autistic patterns showed clinical features closely similar to "ordinary" autism at 4 years but they differed with respect to the improvement seen by age 6 years, to an equal sex ratio, and to a normal head circumference. The children from Romania with autistic features tended to differ from the other Romanian adoptees with respect to a greater degree of cognitive impairment and a longer duration of severe psychological privation.

Adoption↗
PubMed1999

Prosocial action in very early childhood.

We tested a model of prosocial development, which predicted that prosocial action might decline, not increase, throughout childhood, becoming increasingly selective, individual, gender-related, and linked to emotional dysregulation. Sixty-six focal children at 18, 24, or 30 months of age were observed at home with familiar peers and then again 6 months later. Episodes of peer interaction were analysed for instances of sharing. The predicted decline in sharing with age was qualified by cohort differences and many associations with gender. Most children shared less as they grew older, but the oldest girls slightly increased their rate of sharing over time. As peer relationships developed, girls were more likely to share with other girls; boys were more likely to show reciprocity in sharing. Individual differences in sharing were moderately stable over time and linked to another form of prosocial action, sensitivity to the peer's distress. As predicted, children who shared at higher rates were rated more negatively by their mothers. The positive relationship between prosocial action and mothers' ratings of negative personality traits was especially strong for boys.

Age Distribution↗
PubMed1997

Infant nutrition: implication for somatic growth, adult onset diseases, and oral health.

The gold standard for assessing the adequacy of nutrient intake in pediatrics is that diet which promotes optimal growth and development. Thus, it is crucial that our methods for measuring these outcomes be valid, reliable, and widely accepted. A review of the recent medical literature in the field of clinical nutrition indicates that both growth data and dietary standards continue to evolve as more data accrue concerning their applicability in both health and disease. In addition, oral nutrition is clearly a determinant of perhaps the most prevalent infectious disease in pediatrics: dental caries. Research in this field stresses the importance of oral fluoride intake in the prevention of caries, as well as the fact that current efforts at reducing milk-bottle tooth decay are inadequate.

Adult↗
PubMed1988

Active cytomegalovirus particles in the eyes of an AIDS patient being treated with 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine (Ganciclovir).

The eyes of an AIDS patient with cytomegalovirus (CMV) retinitis and pneumonitis who died while receiving maintenance therapy with the antiviral agent 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine (Ganciclovir) were obtained for pathological examination. While under treatment the patient had significant improvement but not complete regression of retinitis. Electron microscopic and immunofluorescent techniques revealed cytomegalovirus particles in the retina, sclera, iris, and ciliary body. These findings are consistent with a virostatic type of inhibition of CMV by this agent. They also suggest that CMV involvement in the eye and other organs may be more widespread than is clinically apparent in AIDS patients.

Acquired Immunodeficiency Syndrome↗
PubMed1982

Calcifications of cerebral medullary veins associated with carotid-jugular fistula.

Unusual calcification of the cerebral medullary veins is noted in a 34-year-old mentally retarded female who had a right carotid-jugular anastomosis 30 years earlier. The patient was hospitalized because of a right neck mass, proptosis, and the recent onset of left flaccid hemiplegia. Arch aortography and CT of the head and neck were performed. Surgery to oblate the fistula provided dramatic relief of venous engorgement in the orbits and face. The finding of medullary vein calcification is emphasized because it is a hitherto unreported entity.

Adult↗
PubMed1977

Extrathyroidal conversion of thyroxine to 3,3',5'-triiodothyronine (reverse-T3) and to 3,5,3'-triiodothyronine (T3) in humans.

In order to estimate the relative magnitude of the two alternative pathways of monodeiodination of thyroxine (T4) in adult humans, the metabolic clearance rates (MCR) and production rates (PR) of 3,3',5'-triiodothyronine (reverse-T3,rT3) and of 3,5,3'-triiodothyronine (T3) were determined in six euthyroid control subjects (C) and in five hypothyroid patients (H) receiving L-T4 as replacement therapy (0.15-0.3 mg/day). MCR was computed by a non-compartmental method of analysis from the plasma disappearance of 125I rT3 and 131I T3 during 72 h following simultaneous injection of tracers. PR was calculated from MCR and the serum concentration of rT3 and T3, respectively, determined by radioimmunoassay. In the H subjects, rT3 MCR averaged 97.1 +/- 12.8 (SD) 1/day and rT3 PR, 34.3 +/- 12.8 microng/day; T3 MCR was 28.7 +/- 6.1 1/day and T3 PR, 20.3 +/- 6.6 microng/day (all corrected to 70 kg body weight). These results were not significantly different from those in the control group; rT3 MCR 104 +/- 24 1/day, rT3 PR 33.0 +/- 9.2 microng/day; T3 MCR 24.0 +/- 5.9, T3 PR 24.2 +/- 4.1. The proportionof total triiodothyronine (rT3 averaged 62% in H patients and was similar (57%) in the C group. The results obtained in the H subjects indicate that the production of rT3 is a major route of T4 metabolism, equal to or exceeding that of T3. From the close agreement between the mean values for rT3 PR in the C and H groups it is concluded that most, if not all of the rT3 produced in normal humans is derived by extrathyroidal conversion from T4.

Aged↗
PubMedDate not supplied

Microarray-based compendium of hepatic gene expression profiles for prototypical ADME gene-inducing compounds in rats and mice in vivo.

To examine species-specific aspects of the induction of absorption, distribution, metabolism and excretion (ADME)-related genes, we used 25 000 gene oligonucleotide microarrays to construct a rodent gene-response compendium that compared hepatic gene expression profiles and developed consensus aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X-receptor (PXR) ligand signatures relevant to drug clearance. Twenty-six inducer compounds were chosen from the literature. Rats and mice received one of six dose levels (log2 dose escalation, 32-fold dose range) of each compound daily for 3 days. Animals were necropsied 6-9 h after the last dose, and tissues were collected for RNA analysis. Hepatic gene expression profiles were obtained using Rosetta Resolver expression analysis system, and ADME-related genes were extracted. Cross-talk among nuclear receptors or hepatoxicity at high dose levels resulted in large signatures (usually >1000 genes at p < 0.01) for most compounds. After ADME gene transcript enrichment, agglomerative clustering separated AhR ligands from CAR/PXR ligands, but it was difficult to distinguish CAR from PXR ligands. Consensus signatures were derived from groups of AhR, CAR and PXR ligands; and cross-talk among responding genes was determined. Many compounds had distinct log dose-response profiles, and relative potencies for ligands were established. Robust responses by CYP1A1, CYP2B10 (CAR responsive in mice) and CYP2B15 (CAR responsive in rats) and CYP3A1 (PXR responsive in rats) were used to benchmark the relative potency of different ligands and to determine the relative selectivity for AhR, CAR or PXR. By using a compendium of gene expression profiles, we defined species-specific induction patterns across the ADME transcriptome.

Animals↗