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Biomedical subjects

L McCabe

Publications and source records attributed to L McCabe.

At least 19 recordsLinked to original sources
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↗
PubMed1987

Evaluation of a phenylalanine-free product for treatment of phenylketonuria.

Ten children with classic phenylketonuria (PKU) participated in a controlled study of a phenylalanine-free formula recently released in the United States (PKU-2). Control data were obtained in the clinic while the children were receiving their baseline formula. The children were given the study formula and returned to the clinic for follow-up after they had been receiving the new formula for 4, 8, and 12 months. Serum phenylalanine and tyrosine concentrations, other hematologic measurements, urine analysis, growth, electroencephalogram, and physical findings remained similar to baseline values throughout the study. Nutrient intakes were comparable with the exception of a decrease in several micronutrients relative to baseline levels. We found that PKU-2 is appropriate for children with PKU who are over 3 years of age and may prove beneficial for the overweight child with PKU.

Child↗
PubMed1987

Histamine release and circulating cells after antigen inhalation in allergic dogs.

Histamine can be recovered from the blood of ragweed-sensitized dogs after aerosol antigen challenge, although its source is unknown. Neutrophils and eosinophils have been recovered from bronchoalveolar lavage fluid (BALF) obtained under identical conditions. We investigated the time course of changes in histamine levels in plasma and BALF taken from ragweed-sensitized dogs after aerosol challenge. Changes in the numbers of circulating neutrophils, eosinophils, lymphocytes, monocytes, and platelets were also studied. After 3 min, total pulmonary resistance (RL) was maximally increased and systolic blood pressure was maximally decreased. Histamine levels in plasma and BALF were increased and circulating eosinophils and neutrophils were decreased. After 15 min, platelet numbers were reduced. By 90 min, changes in RL, blood pressure, plasma and BALF histamine concentrations, and circulating neutrophils and eosinophils had returned to base-line values, but platelet numbers remained significantly decreased. Sham challenge caused no significant changes in any of these variables. Intravenous administration of histamine in doses large enough to attain plasma levels comparable with those achieved after aerosol antigen challenge resulted in no concomitant rise in BALF histamine levels. We conclude that antigen challenge in sensitized dogs causes increases in BALF and plasma histamine levels and is associated with a reduction in circulating neutrophils, eosinophils, and platelets. It is likely that antigen causes airway mast cells to release mediators that move down a concentration gradient from the airways to the pulmonary circulation.

Administration, Inhalation↗
PubMed1986

Issues in the dietary management of phenylketonuria: breast-feeding and trace-metal nutriture.

We have reviewed our experience with supplemental breast-feeding of the infant with PKU. Our results indicate no harmful nutritional effects of breast-feeding the child with PKU, in comparison with the traditional approach using formula or cow's milk for supplementation. In addition, breast-feeding may provide a source of emotional support for the mother during this difficult period of initial diagnosis and management. It is hoped that this may improve the family's adjustment to this chronic illness. Our work with breast-feeding led us to a consideration of trace-metal nutriture in children treated with these synthetic and semi-synthetic formulas. The results of these investigations suggest that there is a biochemically significant decrease in the bioavailability of zinc when these artificial formulas are used. While no clinical trace-metal deficiency has been described in treated PKU patients, we suggest that these nutritional deficits may relate to subtle abnormalities exhibited by these patients.

Biological Availability↗
PubMed1983

Newborn screening for phenylketonuria: predictive validity as a function of age.

Data from questionnaires were assembled for 109 infants with phenylketonuria (PKU) and 114 control infants to assess the predictive validity of newborn screening for PKU as a function of age. Patients with PKU had values of less than 4 mg/dL in cord blood and in samples from days 1, 2, and 4 through 7. The proportion of patients with PKU expected to fall below screening cutoffs of 2, 4, and 6 mg/dL was predicted for each age range. Using a cutoff of 4 mg/dL, approximately one third of patients with PKU would be missed by a sample taken from the neonate in the first 12 hours of life, and nearly 10% would be missed with a sample from the second 12 hours of life. This study shows that not all patients with PKU will be detected by newborn screening, and that the phenomenon of early nursery discharges must be considered in developing appropriate screening strategies.

Age Factors↗