Biomedical subjects
Publications and source records attributed to J S Robinson.
Growth of the placenta is influenced by events before and during early pregnancy. Some of these events set the growth trajectory of the placenta and the fetus for the remainder of the pregnancy. Maternal size and nutrition, and the local metabolic, cytokine and hormonal environment of the embryo all affect growth of the placenta.
We have investigated the impact of chronic restriction of placental function on circulating catecholamine concentrations and responses to the indirectly acting, sympathomimetic amine, tyramine, in the fetal sheep in late gestation. In 10 ewes, endometrial caruncles or placental placentation sites were removed before conception (placental restriction (PR) group). Fetal sheep in the PR group were hypoxemic throughout late gestation and growth-restricted (3.02 +/- 0.35 kg) when compared with control fetal sheep (4.30 +/- 0.29 kg; n = 8) at 140 d of gestation. Fetal plasma concentrations of noradrenaline and adrenaline were higher (p < 0.05) in the PR (7.06 +/- 3.17 pmol/mL and 2.89 +/- 2.01 pmol/mL, respectively) than in the control group (3.55 +/- 0.54 pmol/mL and 1.30 +/- 0.48 pmol/mL, respectively) throughout late gestation. Plasma noradrenaline, but not adrenaline concentrations, increased significantly between 110 and 140 d of gestation in both the PR and control group, and there was a significant inverse relationship between plasma noradrenaline and arterial PO2 in the PR and control groups (plasma noradrenaline = 12.34 - 0.40 PO2). In the PR group, plasma noradrenaline increased (p < 0.05) after tyramine infusion from 4.51 +/- 1.28 pmol/mL to a peak of 19.40 +/- 3.56 pmol/mL. In the control group, noradrenaline increased from 2.08 +/- 0.30 pmol/mL to a peak of 12.23 +/- 1.67 pmol/mL after tyramine infusion. There was no difference, however, in the maximal proportional changes in plasma noradrenaline concentrations in the PR (319 +/- 55%) and control (449 +/- 100%) groups after tyramine. We conclude that the most likely source of the increased plasma catecholamines in the PR group is enhanced catecholamine synthesis and secretion from developing sympathetic neurons.
OBJECTIVE: The Australian Collaborative Trial of Antenatal Thyrotropin-Releasing Hormone (ACTOBAT) assessed the efficacy of 200 microg of thyrotropin-releasing hormone (TRH) in combination with glucocorticoids in the prevention of neonatal lung disease. This paper reports the 12-month follow-up of the infants from the trial completed in 1994. DESIGN: This was a double-blinded randomized controlled trial. SETTING: Women were recruited from level 3 perinatal centers throughout Australia. PARTICIPANTS: Mothers who had not withdrawn from treatment and whose infants were discharged alive (1262 infants). Extensive efforts were made to trace this entire cohort. OUTCOME MEASURES: A questionnaire was mailed to parents for self-completion immediately before their baby's/babies' first birthday. The questionnaire included a checklist to assess sensory, motor, language, and social development, and use of health services. RESULTS: Milestone scores were developed from items on the follow-up form. Treatment with TRH was associated with an increased risk of motor delay, social delay, fine motor delay, sensory impairment, and early language impairment. No differences were seen between treatment and placebo groups for motor impairment. Multivariate analyses were performed, adjusting for chronological age, duration of gestation at randomization, time from randomization to delivery, parity, history of perinatal death, history of preterm rupture of the membranes, infant sex, singleton or twin status, maternal age, and maternal blood pressure (systolic and diastolic) at randomization. For the total cohort (N = 1022), treatment with TRH was associated with motor delay (odds ratio [OR], 1.51; 95% confidence interval [CI] 1.11 to 2.05); social delay (OR 1.40; 95% CI 1.01 to 1.95); sensory impairment (OR, 2.00; 95% CI 1.06 to 3.74); severe impairment (OR, 1.75; 95% CI 1.07 to 2.87); and a trend toward motor impairment (OR, 1.50; 95% CI .97 to 2.33), early language impairment (OR, 1.27, 95% CI .90 to 1.79), and fine motor delay (OR, 1.15; 95% CI .83 to 1.60). There were no differences between the treatment groups in hospital admissions (OR, 1.08; 95% CI .83 to 1.42), doctors' visits (general practitioner OR adj, 1.09; 95% CI .79 to 1.50 or specialist OR adj 1.15; 95% CI .87 to 1.49), respiratory symptoms (OR adj, 1.16; 95% CI .88 to 1.53), or behavioral disturbances (OR adj, .93; 95% CI .71 to 1.21). CONCLUSIONS: Because antenatal administration of TRH is associated with small, consistent deficits in major milestone achievements at 12 months of age, it is essential that additional planned trials make provision for long-term follow-up. Antenatal TRH should only be used in the context of a clinical trial.
OBJECTIVE: To examine relationships between blood pressure during childhood and both placental weight and body size at birth, in an Australian population. DESIGN: A follow up study of a birth cohort, undertaken when cohort members were aged 8 years. SETTING: Adelaide, South Australia. SUBJECTS: 830 children born in the Queen Victoria Hospital in Adelaide, South Australia, during 1975-6. MAIN OUTCOME MEASURES: Systolic and diastolic blood pressure measured when the children were aged 8 years. RESULTS: Blood pressure at 8 years was positively related to placental weight and inversely related to birth weight, after adjusting for the child's current weight. For diastolic pressure there was a decrease of 1.0 mm Hg for each 1 kg increase in birth weight (95% confidence interval (CI) = -0.4 to 2.4) and an increase of 0.7 mm Hg for each 100 g increase in placental weight (95% CI = 0.1 to 1.3). Diastolic pressure was also inversely related to chest circumference at birth, independently of placental weight, with a decrease of 0.3 mm Hg for each 1 cm increase in chest circumference (95% CI = 0.2 to 0.5). CONCLUSIONS: These findings are further evidence that birth characteristics, indicative of fetal growth patterns, are related to blood pressure in later life.
Insulin-like growth factor I (IGF-I) is required for normal fetal growth and skeletal maturation in late gestation, because null mutations of the IGF-I gene in mice reduce fetal weight and retard ossification of bones. To determine if, conversely, increased abundance of IGF-I promotes fetal growth and skeletal maturation, fetal sheep were infused intravascularly with recombinant human IGF-I (n = 7) (26 +/- 3 micrograms. h-1.kg-1) from 120 to 130 days gestation and compared with controls (n = 15). IGF-I infusion increased plasma IGF-I concentrations by 140% (P = 0.002) and weights of fetal liver, lungs, heart, kidneys, spleen, pituitary, and adrenal glands by 16-50% (P < 0.05). Weights and/or lengths of the fetus, placenta, gastrointestinal tract, individual skeletal muscles, and long bones were unchanged by IGF-I. However, IGF-I increased the percentage of proximal epiphyses of long bones present (P < 0.05) and their cross-sectional areas by 15 to 38% (P < 0.05). These results show that IGF-I promotes growth of major fetal organs, endocrine glands, and skeletal maturation in vivo, consistent with IGF-I actively controlling and not merely facilitating fetal growth. The variable response of different tissues may partly reflect tissue specificity in growth requirements for additional factors.
Liver contains the highest concentrations of insulin-like growth factor (IGF) I mRNA in adult rats and sheep and is a major source of circulating IGF-I. In rats, inhibition of hepatic IGF-I production by exogenous IGF-I has been reported. In fetal sheep, skeletal muscle and liver are major sites of IGF-I synthesis and potential sources of circulating IGF-I. To determine whether feedback inhibition of IGF gene expression in fetal liver or muscle by IGF-I occurs, IGF-I and IGF-II mRNAs were measured in these tissues after intravenous infusion of recombinant human IGF-I into fetal sheep. Infusion of IGF-I (26 +/- 4 micrograms.h-1.kg-1; n = 6) or saline (n = 6) commenced on day 120 of pregnancy (term = 150 days) and continued for 10 days. Plasma concentrations of IGF-I were threefold higher in infused fetuses at 130 days of gestation (P < 0.0003), whereas those of IGF-II were unchanged. IGF-I infusion reduced the relative abundance of IGF-I mRNA (P < 0.0002) and IGF-II mRNA (P < 0.01) in fetal liver by approximately 50% but did not alter IGF-I or IGF-II mRNA in skeletal muscle. These results indicate that IGF-I inhibits the expression of both IGF-I and IGF-II genes in fetal liver and that IGF gene expression in fetal liver and muscle is differentially regulated by IGF-I.
We have experimentally restricted placental growth in the sheep to investigate the impact of reduced substrate delivery on fetal pituitary proopiomelanocortin (POMC) mRNA levels and on circulating ACTH 1-39, immunoreactive ACTH, and cortisol concentrations during late gestation. Endometrial caruncles were removed in nine ewes before mating to reduce the number of placentomes formed [placental restriction group (PR)]. Fetal arterial PO2 and O2 saturation were reduced in the PR group (2.0 +/- 0.1 kPa and 42.8 +/- 1.1%, n = 9) when compared with control fetuses (3.1 +/- 0.1 kPa and 66.4 +/- 0.9%, n = 10). The ratio of anterior pituitary POMC mRNA:18 S ribosomal RNA was also lower (p < 0.05) in the PR group (0.49 +/- 0.05) when compared with the control group (0.80 +/- 0.12) after 140 d of gestation. In contrast, plasma concentrations of ACTH 1-39 and immunoreactive ACTH were similar in the PR and control groups throughout late gestation. Plasma ACTH 1-39 concentrations increased (p < 0.006) between 128 and 134 d of gestation, in both the PR (122-128 d: 2.70 +/- 0.34 pmol/L: 134-141 d; 7.07 +/- 1.57 pmol/L) and control (122-128 d; 3.36 +/- 0.56 pmol/L: 134-141 d; 10.78 +/- 2.88 pmol/L) groups. Combined adrenal weight was higher (p < 0.005) in the PR group (130 +/- 10 mg/kg) compared with controls (80 +/- 1 mg/kg) at 140 d of gestation, and plasma cortisol concentrations were also higher (p < 0.02) in PR than control fetuses between 127 and 141 d of gestation. These changes imply that the fetal hypothalamopituitary-adrenal axis is operating at a new central set point in the growth-restricted fetus.
Residual Postsurgical Back Pain (RPP) is a complex problem, involving considerable etiologic and diagnostic confusion. About two-thirds of all patients enrolled in chronic pain centers in the United States suffer from RPP. More than 50 billion dollars are spent on the diagnosis and treatment of back pain in this country. In most cases, the etiology of the patient's complaints is multifactorial. Treatment is difficult and frequently involves surgical as well as non-surgical modalities. Surgical treatment is of value in a carefully selected group of patients, either those in whom the original procedure failed to correct the underlying abnormality or those who show evidence of compression of neural elements, or instability of vertebral column. Because extensive co-morbidity is often present, discrete operative intervention may not fully arrest the compete etiology of the patient's distress, and, indeed; may sometimes worsen the patient's complaints. Possible coexisting problems like degenerative disease or depression should be addressed in all patients prior to surgical intervention, so that the corrected variable is the preponderant cause of the patient's difficulty.
STUDY DESIGN: An animal model of laminectomy in rats was used to study scar tissue formation around the spinal cord. Dexamethasone, in controlled-release form, was tested in this system for its ability to decrease fibrous tissue formation. OBJECTIVES: The results were evaluated to determine whether dexamethasone in a biodegradable controlled-release vehicle could be used to limit scar tissue formation around the spinal cord after laminectomy. SUMMARY OF BACKGROUND DATA: Steroids can delay the formation of scar tissue. Continued treatment with dexamethasone results in various unacceptable side effects. Use of biodegradable controlled-release vehicles to deliver drugs may allow for prolonged low-dose treatment, concentrated at the surgical site, thereby avoiding side effects. METHODS: Forty-four Sprague Dawley rats underwent laminectomies and were treated with dexamethasone in one of two controlled-release vehicles or with vehicle alone. After 4 weeks, the rats were killed and histologic sections prepared from the spines were examined and graded by a pathologist. In addition, the dexamethasone preparations were introduced into Hunt-Schilling wound chambers, which were implanted in rats. Four weeks after implantation, the wound chambers were removed and the tissue inside was assayed for DNA and protein content. RESULTS: Dexamethasone acetate (Decadron, MSD, West Point, PA) significantly reduced the density of the scar tissue undermining the laminas. Steroids embedded in polymer did not change the scar formation in the back, but did decrease protein and DNA values in wound chamber tissues. CONCLUSIONS: Long-term release of small amounts of steroid from the polymer poly-carboxy-phenoxypropane does not appear to reduce scar at laminectomy sites but does decrease the protein:DNA ratio in wound chambers. In contrast, Decadron does not significantly alter the biochemistry of wound chamber tissue but does reduce scar in the back.
The epidemiological observations that prenatal and perinatal events lead to adult disease are now well supported by animal data. The events in the periconceptual period, in early and late pregnancy and in infancy can effect programming of cardiovascular, endocrine and metabolic regulatory systems. However, the mechanisms underlying these pathological changes remain to be elucidated. Until this is addressed in experimental animals, clinical trials in human pregnancy are premature.
It is clear that the timing of parturition is dependent on a cascade of endocrine signals from an intact fetal hypothalamo-pituitary-adrenal axis. What is not known, however is the nature or source of the central neural stimulation which results in the stimulation of adrenocorticotrophic hormone (ACTH) synthesis and secretion in late gestation. The changes which occur in the synthesis and posttranslational processing of the ACTH precursor, proopiomelanocortin (POMC), in the fetal anterior pituitary before birth and the consequence of these changes for expression of the corticosteroidogenic enzymes in the fetal adrenal are described in this review. Evidence for the functional heterogeneity of corticotrophic cell types in the fetal sheep pituitary and the proposal that there is a maturational change in the populations of corticotrophic cells in late gestation are discussed. Finally, the development of cortisol negative feedback in the late gestation fetal hypothalamo-pituitary axis and the relevance of chronic stress to the timing of parturition are also discussed.
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To determine whether tissue production of the IGFs is altered when fetal growth is retarded, IGF-I and -II mRNAs were measured in tissues of fetal sheep subjected to placental restriction and the relationships between IGF gene expression, circulating IGF protein and fetal growth were examined. The majority of potential placental attachment sites were surgically removed from the uterus of 12 non-pregnant ewes to restrict placental size in a subsequent pregnancy. Blood and tissues were collected at 121 days of gestation (term = 150) in 12 fetuses with restricted placental size and eight normal fetuses. IGF-I and IGF-II mRNA was detected by solution hybridization/ribonuclease protection assay in placenta and all fetal tissues studied. IGF-I mRNA was most abundant in skeletal muscle and liver and IGF-II mRNA was highest in kidney and lung. Restriction of placental size reduced fetal weight by 17% and reduced the pO2 (18%) and glucose concentration (23%) of fetal blood. Placental restriction also reduced IGF-I mRNA in fetal muscle (P < 0.002), lung (P < 0.05) and kidney (P < 0.01) but had no significant effect on IGF-II mRNA in any tissue. IGF-I mRNA in fetal liver, kidney and skeletal muscle correlated positively with the concentration of IGF-I protein in fetal blood (P < 0.01). There was no relationship between the concentration of IGF-II protein in fetal blood and IGF-II mRNA in any fetal tissue examined. The concentration of IGF-binding protein-3 (IGFBP-3) in fetal arterial blood plasma measured by RIA correlated positively with fetal weight and with plasma IGF-I.(ABSTRACT TRUNCATED AT 250 WORDS)
The penultimate step in the biosynthesis of the human ABO blood group oligosaccharide antigens is catalyzed by alpha-(1,2)-fucosyltransferase(s) (GDP-L-fucose: beta-D-galactoside 2-alpha-L-fucosyltransferase, EC 2.4.1.69), whose expression is determined by the H and Secretor (SE) blood group loci (also known as FUT1 and FUT2, respectively). These enzymes construct Fuc alpha 1-->2Gal beta-linkages, known as H determinants, which are essential precursors to the A and B antigens. Erythrocytes from individuals with the rare Bombay and para-Bombay blood group phenotypes are deficient in H determinants, and thus A and B determinants, as a consequence of apparent homozygosity for null alleles at the H locus. We report a molecular analysis of a human alpha-(1,2)-fucosyltransferase gene, thought to correspond to the H blood group locus, in a Bombay pedigree and a para-Bombay pedigree. We find inactivating point mutations in the coding regions of both alleles of this gene in each H-deficient individual. These results define the molecular basis for H blood group antigen deficiency in Bombay and para-Bombay phenotypes, provide compelling evidence that this gene represents the human H blood group locus, and strongly support a hypothesis that the H and SE loci represent distinct alpha-(1,2)-fucosyltransferase genes. Candidate sequences for the human SE locus are identified by low-stringency Southern blot hybridization analyses, using a probe derived from the H alpha-(1,2)-fucosyltransferase gene.
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To determine the relationship between placental delivery of oxygen and glucose, circulating insulin-like growth factors (IGFs) and fetal growth, the effect of variable restriction of placental growth was determined in sheep in late gestation. Arterial blood was obtained via indwelling catheters at 120 and 127 days of gestation, prior to necropsy at 130 days to measure fetal and placental weights. Plasma was acidified and subjected to size-exclusion high-performance liquid chromatography at pH 2.8 to dissociate and separate IGFs from their binding proteins. The acid-dissociated IGF fraction was analysed by sensitive and highly specific radioligand assays for IGF-I and IGF-II, previously defined using ovine IGFs. Fetal weight and blood pO2 and glucose at 120 and 127 days of gestation correlated positively with placental weight. Plasma IGF-I was positively associated with fetal weight and fetal liver weight, and with blood pO2 and glucose at both ages. Plasma IGF-II levels also correlated positively with fetal weight, fetal liver weight and with blood glucose and pO2, but only at 127 days of gestation. In the most severely growth-retarded fetal sheep, blood glucose and pO2 and plasma IGF-I were significantly reduced when compared with normal fetuses at 120 days. All decreased further by 127 days of gestation as did plasma IGF-II in severely growth-retarded fetal sheep compared with normal fetuses. These observations are consistent with the hypothesis that both IGF-I and IGF-II are chronically regulated by oxygen and nutrition in utero and mediate part of the influence of placental supply of substrate over fetal growth.
Babies who are small at birth or during infancy have increased rates of cardiovascular disease and non-insulin-dependent diabetes as adults. Some of these babies have low birthweights, some are small in relation to the size of their placentas, some are thin at birth, and some are short at birth and fail to gain weight in infancy. This paper shows how fetal undernutrition at different stages of gestation can be linked to these patterns of early growth. The fetuses' adaptations to undernutrition are associated with changes in the concentrations of fetal and placental hormones. Persisting changes in the levels of hormone secretion, and in the sensitivity of tissues to them, may link fetal undernutrition with abnormal structure, function, and disease in adult life.
A Legionella-like organism (strain 214T [T = type strain]) was isolated from a cooling tower in Stratford-upon-Avon, England. This strain required L-cysteine and contained cellular branched-chain fatty acids that are typical of the genus Legionella. Strain 214T produced pink colonies on buffered charcoal-yeast extract agar. Ubiquinone Q-12 was the major quinone. Strain 214T was serologically distinct from other legionellae as determined by a slide agglutination test. The results of DNA hybridization studies showed that strain 214T (= ATCC 49655T) is a member of a new Legionella species, Legionella shakespearei.