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Biomedical subjects

L McCabe

Publications and source records attributed to L McCabe.

At least 19 recordsLinked to original sources
PubMed2005

Central regulation of the hypothalamic-pituitary-adrenal axis during fetal development in the Guinea-pig.

We have previously shown that the foetal guinea-pig hypothalamic-pituitary-adrenal (HPA) axis is activated near the time of parturition and that this is associated with changes in limbic glucocorticoid receptors (GR) and mineralocorticoid receptors. In the present study, we hypothesized that the foetal hypothalamic paraventricular nucleus (PVN) and pituitary contribute significantly to foetal HPA drive but that these areas remain sensitive to negative feedback by circulating glucocorticoids in late gestation. However, we observed decreased corticotrophin-releasing hormone mRNA expression in the PVN and decreased pro-opiomelanocortin (POMC) mRNA levels in the anterior pituitary with advanced gestational age. The reduction in POMC mRNA expression was likely the result of negative feedback via circulating glucocorticoids because GR mRNA was unchanged during development in the foetal pituitary. Furthermore, we found that maternally administered glucocorticoids significantly decreased foetal pituitary POMC mRNA expression in a dose-dependent manner at gestational day (gd) 62 with male foetuses being more sensitive to these effects. These findings show that the foetal HPA axis remains highly sensitive to glucocorticoid feedback even as plasma adrenocorticotropic hormone and cortisol levels are elevated at the end of gestation.

Animals↗
PubMed2001

Effect of the hydroxyl radical scavenger, dimethylthiourea, on peripheral nerve tissue perfusion, conduction velocity and nociception in experimental diabetes.

AIMS/HYPOTHESIS: Increased oxidative stress has been linked to diabetic neurovascular complications, which are reduced by antioxidants. Our aim was to assess the contribution of hydroxyl radicals to early neuropathic changes by examining the effects of treatment with the specific scavenger, dimethylthiourea, on nerve function and neural tissue blood flow in diabetic rats. METHODS: Diabetes was induced by streptozotocin. Measurements comprised sciatic nerve motor and saphenous nerve sensory conduction velocity. Responses to noxious mechanical and thermal stimuli were estimated by Randall-Sellito and Hargreaves tests respectively. Sciatic nerve and superior cervical ganglion blood flow were measured by hydrogen clearance microelectrode polarography. RESULTS: Eight weeks of diabetes reduced motor and sensory conduction velocity by 19.9% and 15.7% respectively, and these were completely corrected by 2 weeks of dimethylthiourea treatment. The ED50 for motor conduction was 9 mg kg(-1) x day(-1). Mechanical and thermal nociceptive sensitivities were 18.9% and 25.0% increased by diabetes, respectively, indicating hyperalgesia which was 70% reduced by dimethylthiourea. Sciatic endoneurial and superior cervical ganglion blood flows were 51.2% and 52.4% reduced by diabetes and there was an approximately 80% improvement with treatment. CONCLUSION/INTERPRETATION: Hydroxyl radicals seem to make a major contribution to neuropathy and vasculopathy in diabetic rats. Treatment with the hydroxyl scavenger, dimethylthiourea, was highly effective. The data suggest that the development of potent hydroxyl radical scavengers suitable for use in man could markedly enhance the potential therapeutic value of an antioxidant approach to the treatment of diabetic neuropathy and vascular disease.

Animals↗
PubMed2001

Repeated antenatal glucocorticoid treatment decreases hypothalamic corticotropin releasing hormone mRNA but not corticosteroid receptor mRNA expression in the fetal guinea-pig brain.

Approximately 10% of pregnant women are treated with synthetic glucocorticoids in late gestation, to promote fetal lung maturation. The effectiveness of this treatment has led to the use of repeated dose regimens, with little knowledge of the impact on neuroendocrine development. Animal studies have recently shown that repeated fetal glucocorticoid exposure can lead to permanent changes in hypothalamic-pituitary-adrenal (HPA) function in offspring. In this study, we hypothesized that such treatment modifies corticotropin releasing hormone (CRH), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) systems in the developing limbic system and hypothalamus. Pregnant guinea-pigs were treated with dexamethasone, betamethasone or vehicle on days 40,41,50,51,60 and 61 of gestation (birth = 68 days). On day 62, guinea-pigs were killed and the fetuses rapidly removed. Glucocorticoid treatment resulted in a dose-dependent reduction in plasma cortisol concentrations in both male and female fetuses. There was also a significant reduction in CRH mRNA expression in the hypothalamic paraventricular nucleus. In contrast, exposure to glucocorticoid increased MR mRNA expression in the hippocampus (CA1/2 and CA3) and dentate gyrus of female fetuses. There was a small but significant increase in GR mRNA expression in limbic structures in male fetuses following treatment with 1 mg/kg dexamethasone. However, there was no significant effect of glucocorticoid exposure on hippocampal GR mRNA expression in female fetuses, or hypothalamic GR mRNA in either males or females. In conclusion, repeated maternal glucocorticoid treatment inhibits fetal HPA function. The fact that CRH mRNA levels were reduced indicates that synthetic glucocorticoids enter the fetal brain. By contrast, fetal glucocorticoid exposure does not downregulate GR mRNA, and increases MR mRNA expression. The latter likely reflects removal of circulating endogenous ligand (cortisol). These alterations may form the basis for permanently modified HPA activity in later life.

Animals↗
PubMed2001

Using research to improve infection control practice.

Research into nurses' knowledge of infection control provided the basis for a hospital training programme. A combined approach by occupational health and infection control specialists developed an appropriate needs-based programme.

Education, Nursing, Continuing↗
PubMed1999

AP-1 and vitamin D receptor (VDR) signaling pathways converge at the rat osteocalcin VDR element: requirement for the internal activating protein-1 site for vitamin D-mediated trans-activation.

Responsiveness of genes to steroid hormones is a complex process involving synergistic and/or antagonistic interactions between specific receptors and other nonreceptor transcription factors. Thus, DNA recognition elements for steroid hormone receptors are often located among binding sites for other trans-acting factors. The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3, stimulates transcription of the tissue-specific osteocalcin (OC) gene in osteoblastic cells. The rat OC vitamin D response element contains an internal acitvating protein-1 (AP-1) site. Here, we report for the first time that this AP-1 site is critical for the transcriptional enhancement of rat osteocalcin gene expression mediated by vitamin D. Precise mutations were introduced either in the steroid half-elements or in the internal AP-1 sequences. One mutation within the internal AP-1 site retained vitamin D receptor/retinoid X receptor binding equivalent to that of the wild-type sequence, but resulted in complete loss of vitamin D inducibility of the OC promoter. These results suggest a functional interaction between the hormone receptor and nuclear oncoproteins at the rat OC vitamin D response element. This cooperation of activities may have important consequences in physiological regulation of osteocalcin transcription during osteoblast differentiation and bone tissue development in vivo.

Animals↗
PubMed1998

DAX1 mutations map to putative structural domains in a deduced three-dimensional model.

The DAX1 protein is an orphan nuclear hormone receptor based on sequence similarity in the putative ligand-binding domain (LBD). DAX1 mutations result in X-linked adrenal hypoplasia congenita (AHC). Our objective was to identify DAX1 mutations in a series of families, to determine the types of mutations resulting in AHC and to locate single-amino-acid changes in a DAX1 structural model. The 14 new mutations identified among our 17 families with AHC brought the total number of families with AHC to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and six missense mutations and one single-codon deletion. We mapped the seven single-amino-acid changes to a homology model constructed by use of the three-dimensional crystal structures of the thyroid-hormone receptor and retinoid X receptor alpha. All single-amino-acid changes mapped to the C-terminal half of the DAX1 protein, in the conserved hydrophobic core of the putative LBD, and none affected residues expected to interact directly with a ligand. We conclude that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculate that the codon deletion and missense mutations give insight into the structure and function of DAX1.

Adrenal Glands↗
PubMed1997

Patient, visitor, and nurse evaluations of visitation for adult postanesthesia care unit patients.

Although PACU visitation for children is sometimes encouraged, most families of adult postoperative patients continue to be excluded from PACUs in this country. At an academic medical center, an open visitation policy for adult postoperative patients was evaluated by eliciting patient, visitor, and nurse evaluations of visitation for adult patients from 181 families. Commonly cited reasons for restricting PACU visitation were not identified as problems by the vast majority of respondents. Even when some aspect of a PACU visit was disturbing, patients and families expressed a desire for visitation. The results of this evaluation of a change in practice led to permanent implementation of an open visitation policy in this PACU.

Adult↗
PubMed1997

Weight gain and longitudinal changes in lung function in steel workers.

Associations among dust exposure, smoking habits, and demographic factors and longitudinal changes of lung function were assessed among male steel workers. Cohort descriptive data analysis was conducted in 541 steel workers who had performed spirometry at least twice between 1982 and 1991 (mean follow-up, 6.1 years). The annual change (slope) in FVC, FEV1, FEV1/FVC%, and in body weight was determined by simple linear regression. The Pearson correlation coefficient between weight change and spirometry changes was calculated. Comparisons were also done in 75 pairs of steel workers matched by age, height, initial FEV1, and smoking status, but whose FEV1 declines differed by > or = 60 mL/yr. The FEV1 and FVC declined an average of 44 and 50 mL/yr, respectively, for the cohort as a whole. The FEV1 and FVC declined 52 and 54 mL/yr for current smokers, 43 and 53 mL/yr for ex-smokers, and 36 and 43 mL/yr for nonsmokers, respectively. Increasing weight was highly correlated with accelerated decline in lung function (p<0.0001). In the matched pairs, mean slopes for FVC, FEV1, and FEV1/FVC ratio were -96 mL/yr, -95 mL/yr, and -0.40%/yr for the rapid decliners; and +5 mL/yr, +10 mL/yr, and +0.10%/yr for their partners (p<0.0001). Matched pair comparisons showed that the rapid decliners averaged a 4.313 kg weight gain, while their partners gained 1.044 kg during the follow-up period. The slope of weight gain was 0.708 kg/yr for rapid decliners and 0.191 kg/yr for comparison workers (p<0.0036). Weight gain, in addition to aging and cigarette smoking, was found to be associated with the longitudinal rate of decline in FVC, FEV1, and FEV1/FVC ratio.

Adult↗
PubMed1996

Improvement in lung function measurements using a flow spirometer that emphasizes computer assessment of test quality.

We compared retrospective measurements of lung function from 101 steel workers using a commercially available spirometer to prospective lung function measurements performed, on average, 1.3 years later, with a newly developed spirometer. This spirometer was designed and developed to incorporate technology that provides immediate feedback on the quantitative and qualitative aspects of each forced expiratory effort. Of the 101 workers, 82 who had spirometry performed with each spirometer had at least two acceptable curves, and 51 workers tested with each spirometer had curves that met all American Thoracic Society (ATS) criteria for spirometry. No group showed the anticipated decline in forced expiratory volume in 1 second (FEV1) over time. The results showed an increased number of curves meeting ATS acceptability and reproducibility criteria, and a statistically significant increase in the FVC in all groups, and an increase in the FEV1 in the group encompassing all workers. Use of technology that strengthens the interaction between the spirometry technician, the data available to the technician on the computer, and the participant appears to represent true underlying lung function more accurately. Such an approach to the collection of lung function data should be considered by those evaluating spirometers for implementation in the workplace or pulmonary function laboratory as well as by those planning future spirometer development.

Humans↗
PubMed1996

Longitudinal and cross-sectional analyses of lung function in steelworkers.

We evaluated associations between dust exposure, demographic factors, and lung function by longitudinal and cross-sectional analyses in 475 steelworkers who participated in at least three spirometry tests over 5 yr between 1982 and 1991. Baseline and follow-up spirometry and changes between baseline and final follow-up assessment attributable to age, height, weight, weight gain, smoking status, pack-years, and years worked in dusty areas were examined using stepwise multiple linear regression techniques. Smoking, aging, being overweight, excessive weight gain, and dust exposure were related to a lower level and a steeper slope of decline of pulmonary function. Cigarette smoking was also an important risk factor. Dust exposure was related to the level of lung function, with a stronger effect at baseline than at follow-up. Estimated loss at baseline of FEV1, FVC, and FEV1/FVC% was 9.3, 6.4 ml, and 0.1 % per year of employment in a dusty area, respectively, whereas the association between dust exposure and longitudinal decline of lung function was weak. However, a strong relationship between weight gain and longitudinal decline of FEV1 and FVC was found. Estimated decreases in FEV1 and FVC attributable to weight gain were 4.7 and 6.3 ml per lb/yr, respectively. This work suggests that weight gain is an important determinant for longitudinal lung function decline. This large impact of weight gain in the decline of lung function in a middle-age and relatively overweight working population has not been previously reported. Additional work needs to be undertaken to show the strength of this relationship in other populations.

Adult↗
PubMed1996

The osteocalcin gene promoter provides a molecular blueprint for regulatory mechanisms controlling bone tissue formation: role of transcription factors involved in development.

Characterization of regulatory sequences and their cognate binding factors in the bone-specific osteocalcin (OC) gene promoter has provided insight into mechanisms that control expression of the gene under diverse biological conditions. We present evidence for AP-1 motifs and two multipartite conserved regulatory sequences, the OC Box I (nt-99 to-76) and a site designated OC Box II (nt-136 to-130) in contributing to developmental and tissue-specific expression of osteocalcin. OC Box I is characterized by a homeodomain binding site and OC Box II is a recognition sequence for AML-1 (also called PEBP2 alpha), a runt homology-related DNA binding protein. Functional activity of the elements was established in osseous and non-osseous cell lines and is in part related to the binding of osteoblast-specific complexes which enhance OC transcription. The contribution of several elements and binding of multiple classes of transcription factors to independent elements in both these domains serve to illustrate the complexity of control required for tissue-specific OC expression.

Animals↗
PubMed1994

Influence of DNA replication inhibition on expression of cell growth and tissue-specific genes in osteoblasts and osteosarcoma cells.

Interrelationships between proliferation and expression of cell growth as well as bone cell-related genes were examined from two standpoints. First, the consequence of downregulating proliferation by DNA synthesis inhibition on expression of a cell cycle-regulated histone gene and genes associated with development of the bone cell phenotype (type I collagen, alkaline phosphatase, osteopontin, and osteocalcin) was investigated. Second, the requirement for stringent growth control to support functional relationships between expression of proliferation and differentiation-related genes was explored. Parameters of cell growth and osteoblast-related gene expression in primary cultures of normal diploid osteoblasts, that initially express proliferation-dependent genes and subsequently postproliferative genes associated with mature bone cell phenotypic properties, were compared to those operative in ROS 17/2.8 osteosarcoma cells that concomitantly express cell growth and mature osteoblast phenotypic genes. Our findings indicate that in both normal diploid osteoblasts and osteosarcoma cells, expression of the cell cycle regulated histone genes is tightly coupled with DNA synthesis and controlled predominantly at a posttranscriptional level. Inhibition of proliferation by blocking DNA synthesis with hydroxyurea upregulates a subset of developmentally expressed genes that postproliferatively support progressive establishment of mature osteoblast phenotypic properties (e.g., alkaline phosphatase, type 1 collagen, and osteopontin). However, the osteocalcin gene, which is expressed during the final stage of osteoblast differentiation when extracellular matrix mineralization occurs, is not upregulated. Variations in the extent to which inhibition of proliferation in normal diploid osteoblasts and in ROS 17/2.8 osteosarcoma cells selectively affects transcription and cellular levels of mRNA transcripts from bone cell-related genes (e.g., osteocalcin) may reflect modifications in proliferation/differentiation interrelationships when stringent growth control is abrogated.

Alkaline Phosphatase↗
PubMed1994

TGF beta alters growth and differentiation related gene expression in proliferating osteoblasts in vitro, preventing development of the mature bone phenotype.

This study examines the mechanism by which TGF-beta 1, an important mediator of cell growth and differentiation, blocks the differentiation of normal rat diploid fetal osteoblasts in vitro. We have established that the inability for pre-osteoblasts to differentiate is associated with changes in the expression of cell growth, matrix forming, and bone related genes. These include histone, jun B, c-fos, collagen, fibronectin, osteocalcin, alkaline phosphatase, and osteopontin. Morphologically, the TGF-beta 1-treated osteoblasts exhibit an elongated, spread shape as opposed to the characteristic cuboidal appearance during the early stages of growth. This is followed by a decrease in the number of bone nodules formed and the amount of calcium deposition. These effects on differentiation can occur without dramatic changes in cell growth if TGF-beta 1 is given for a short time early in the proliferative phase. However, continuous exposure to TGF-beta 1 leads to a bifunctional growth response from a negative effect during the proliferative phase to a positive growth effect during the later matrix maturation and mineralization phases of the osteoblast developmental sequence. Extracellular matrix genes, fibronectin, osteopontin and alpha 1(I) collagen, are altered in their expression pattern which may provide an aberrant matrix environment for mineralization and osteoblast maturation and potentiate the TGF-beta 1 response throughout the course of osteoblast differentiation. The initiation of a TGF-beta 1 effect on cell growth and differentiation is restricted to the proliferative phase of the culture before the cells express the mature osteoblastic phenotype. Second passage cells that are accelerated to differentiate by the addition of dexamethasone or by seeding cultures at a high density are refractory to TGF-beta 1. These in vitro results indicate that TGF-beta 1 exerts irreversible effects at a specific stage of osteoblast phenotype development resulting in a potent inhibition of osteoblast differentiation at concentrations from 0.1 ng/ml.

Animals↗
PubMed1990

Overo lethal white foal syndrome: equine model of aganglionic megacolon (Hirschsprung disease).

The lethal white foal syndrome (LWFS) is a congenital abnormality of overo spotted horses which is a model for human aganglionic megacolon or Hirschsprung disease. Foals with LWFS have an all white, or nearly all white, coat. They also present clinically with an intestinal obstruction that proves fatal within the first few days of life. The LWFS involves both melanocytes and intestinal ganglion cells, and appears to result from a genetic defect involving neural crest cells. This report describes pathologic studies of two recent cases of LWFS. Two different hypothetical models of inheritance of LWFS are presented and discussed.

Animals↗
PubMed1989

The management of breast feeding among infants with phenylketonuria.

Treatment for phenylketonuria (PKU) involves using low phenylalanine-free or phenylalanine-free formulas and supplementation with sufficient phenylalanine for normal growth and development. Eighteen infants with phenylketonuria who received breast milk as their primary phenylalanine source were compared with ten other infants with PKU who received their phenylalanine primarily from infant formulas. There were no significant differences between breast-fed and formula-fed infants for serum phenylalanine, serum tyrosine, length, weight, head circumference, haematocrit, haemoglobin, serum iron, total iron binding capacity, percentage iron saturation, ferritin, plasma zinc and total calorie intake. Breast-fed infants did show lower mean corpuscular volume at 3 months and 6 months of age. Breast-fed infants had lower phenylalanine intake at 2, 4, 5 and 6 months of age. Breast-fed infants at 1, 2, 3, 4, 5 and 6 months of age had lower protein intake. Breast feeding may be continued in the newly diagnosed phenylketonuric infant without any apparent adverse nutritional consequences.

Breast Feeding↗