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Biomedical subjects

C S Smith

Publications and source records attributed to C S Smith.

At least 19 recordsLinked to original sources
PubMed2000

Effects of arsenic, cadmium, chromium, and lead on gene expression regulated by a battery of 13 different promoters in recombinant HepG2 cells.

Toxic metals occur naturally at low concentrations throughout the environment, but are found in higher concentrations at many of the hazardous waste sites on the EPA Superfund list. As part of the Agency for Toxic Substances and Disease Registry (ATSDR) mandate to evaluate the toxicity of metals and mixtures, we chose four of the high-priority metal pollutants from ATSDR's HAZDAT list, including arsenic, cadmium, chromium, and lead, to test in a commercially developed assay system, CAT-Tox(L) (Xenometrix). This assay employs a battery of recombinant HepG2 cell lines to test the transcriptional activation capacity of xenobiotics in any of 13 different signal transduction pathways. Our specific aims were to identify metal-responsive promoters and determine whether the pattern of gene expression changed with a mixture of metals. Humic acid was used in all assays as a carrier to help solubilize the metals and, in all cases, the cells were exposed to the humic acid-metal mixture for 48 h. Humic acid alone, at 50-100 microM, showed moderate activation of the XRE promoter, but little other notable activity. As(V), at doses of 50-250 microM, produced a complex profile of activity showing significant dose-dependent induction of the hMTIIA, GST Ya, HSP70, FOS, XRE, NFkappaBRE, GADD153, p53RE, and CRE promoters. Pb(II) showed dose-related induction of the GST Ya, XRE, hMTIIA, GRP78, and CYP IA1 promoters at doses in the range of 12-100 microM. Cd(II), at 1.25-15 microM, yielded significant dose-dependent induction of hMTIIA, XRE, CYP IA1, GST Ya, HSP70, NFkappaBRE, and FOS. Whereas Cr(III) yielded small, though significant inductions of the CRE, FOS, GADD153, and XRE promoters only at the highest dose (750 microM), Cr(VI) produced significant dose-related inductions of the p53RE, FOS, NFkappaBRE, XRE, GADD45, HSP70, and CRE promoters at much lower doses, in the range of 5-10 microM. Assays testing serial dilutions of a mixture comprising 7.5 microM Cd(II), 750 microM Cr(III), and 100 microM Pb(II) (the combination of metals most frequently found at National Priority List sites) showed significant dose-dependent induction of the hMTIIA promoter, but failed to show dose-related induction of any other promoter and showed no evidence of synergistic activation of gene expression by the metals in this mixture. Our results thus show metal activation of gene expression through several previously unreported signal transduction pathways, including As(V) induction of GST Ya, FOS, XRE, NFkBRE, GADD153, p53RE, and CRE; Pb(II) induction of GST Ya, XRE, Cyp IA1, and GADD153; Cd(II) induction of NFkBRE, Cyp IA1, XRE, and GST Ya; and Cr(VI) induction of p53RE, XRE, GADD45, HSP70, and CRE promoters, and thus suggest new insights into the biochemical mechanisms of toxicity and carcinogenicity of metals. It is also an important finding that no evidence of synergistic activity was detected with the mixture of Cd(II), Cr(III), and Pb(II) tested in these assays.

Arsenic↗
PubMed2000

Pilot test of an organizational culture model in a medical setting.

The authors conducted a pilot test of the organizational culture model in a health care setting. The study was based on a questionnaire with mixed quantitative and qualitative analysis. Quantitative analysis confirmed the expected distribution of responses among the subcultures for all three questions, with significant differences in two of the three. Qualitative analysis further strengthened these results. The authors believe the organizational culture model may be a useful tool for making subcultural differences explicit, showing opportunities for better information exchange and opening dialogue between groups. These data should be confirmed with larger studies using psychometrically sound outcome instruments.

Attitude of Health Personnel↗
PubMed1999

CC-chemokine receptor 6 is expressed on diverse memory subsets of T cells and determines responsiveness to macrophage inflammatory protein 3 alpha.

CC-chemokine receptor (CCR) 6 is the only known receptor for macrophage inflammatory protein (MIP)-3alpha, a CC chemokine chemotactic for lymphocytes and dendritic cells. Using anti-serum that we raised against the N-terminal residues of CCR6, we have characterized the surface expression of CCR6 on peripheral blood leukocytes and we have correlated CCR6 expression with responses to MIP-3alpha. We found that CCR6 was expressed only on memory T cells, including most alpha4beta7 memory cells and cutaneous lymphocyte-associated Ag-expressing cells, and on B cells. Accordingly, chemotaxis of T cells to MIP-3alpha was limited to memory cells. Moreover, calcium signals on T cells in response to MIP-3a were confined to CCR6-expressing cells, consistent with CCR6 being the only MIP-3alpha receptor on peripheral blood T cells. Unlike many CC chemokines, MIP-3alpha produced a calcium signal on freshly isolated T cells, and CCR6 expression was not increased by up to 5 days of treatment with IL-2 or by cross-linking CD3. Despite their surface expression of CCR6, freshly isolated B cells did not respond to MIP-3alpha. In addition to staining peripheral blood leukocytes, our anti-serum detected CCR6 on CD34+ bone marrow cell-derived dendritic cells. Our data are the first to analyze surface expression of CCR6, demonstrating receptor expression on differentiated, resting memory T cells, indicating differences in receptor signaling on T cells and B cells and suggesting that CCR6 and MIP-3alpha may play a role in the physiology of resting memory T cells and in the interactions of memory T cells, B cells, and dendritic cells.

Cell Line↗
PubMed1999

A process model of shiftwork and health.

The authors developed and tested a process model of adaptation to shiftwork, which hypothesizes that various individual and situational variables influence the development of sleep and social and domestic disturbances. Both types of disturbances trigger various types of coping behavior, leading to several proximal outcomes. The end result is the development of chronic health problems in the form of digestive and cardiovascular symptoms. The model was tested with survey data collected from 2 samples of nurses (N = 1,532) in the United Kingdom and was cross-validated against a 3rd sample of industrial workers (N = 370). Results indicate support for the model across the 3 samples, although some sample-specific and subgroup effects were found. Results have direct implications for the development of shiftwork theory and interventions.

Adaptation, Psychological↗
PubMed1999

Urinary excretion of pyridinium crosslinks in healthy 4-10 year olds.

Urinary pyridinoline and deoxypyridinoline, pyridinium crosslinks released during breakdown of mature collagen, might serve as useful markers of bone resorption. Before their role can be identified, reference values must be established. In this study, free pyridinoline (f-Pyr), free deoxypyridinoline (f-DPyr), and creatinine (Cr) were measured in first morning void urine samples from 250 girls and 265 boys between the ages of 4 and 10 years. Overall, there was a decrease in f-Pyr:Cr and f-DPyr:Cr ratios with increasing age in both sexes, but there was a wide range of values for individuals of similar ages. Further studies are required to assess whether urinary pyridinium crosslink excretion is sufficiently deranged in conditions affecting bone metabolism for the measurement of these compounds to be of clinical value.

Age Factors↗
PubMed1998

Nitric oxide induces cell death in a catecholaminergic cell line derived from the central nervous system.

The nitric oxide (NO) donors, sodium nitroprusside (SNP), 1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium+ ++-1,2-diolate] (DETA NONOate), and S-nitroso-N-acetyl-D,L-penicillamine (SNAP) produce a dose-dependent increase in cell death in a catecholaminergic cell line (CATH.a) derived from the central nervous system. Cell death is associated with a decrease in mitochondrial membrane potential. Dopamine also induced cell death of CATH.a cells and this was potentiated by concentrations of SNP which alone did not produce cell death. Hemoglobin, a scavenger of NO radicals, blocked SNP- and SNAP-induced cell death. Catalase and superoxide dismutase, enzymes that metabolize H2O2 and superoxide, respectively, did not inhibit SNP- or SNAP-induced cell death. These data indicate that NO donors produce cell death in CATH.a cells through a mechanism related to the production of NO and the loss of the mitochondrial membrane potential but unrelated to the production of H2O2.

Catalase↗
PubMed1998

Analysis of alpha2u-globulin in rat urine and kidneys by liquid chromatography-electrospray ionization mass spectrometry.

A quantitative method was developed for determination of alpha2u-globulin in urine and kidney samples collected from male rats using liquid chromatography-electrospray ionization mass spectrometry (LC-ESI/MS). Samples prepared from urine and kidney homogenates using size exclusion filters were subject to reversed-phase liquid chromatography and the effluent passed into an electrospray ionization source. Quantitative analysis using external standard calibration was based upon selected ion monitoring of protonated molecular ions by the mass spectrometer. Linear calibration curves were developed over the range of approximately 4. 6-370 microg of alpha2u-globulin/microL for spiked urine standards and over the range of approximately 4.6-550 microg of alpha2u-globulin/microL for spiked kidney standards. The precision (relative standard deviation) for repeated injection (using urine samples) and intra-assay precision (using both urine and kidney samples) were within +/-10.4% and +/-13.2%, respectively. Using spiked urine standards, inter-assay precision, intra-assay accuracy, and inter-assay accuracy were within +/-20%, +/-20%, and +/-15%, respectively. Using spiked kidney standards, intra-assay accuracy was within +/-15%. The limits of detection (LOD) for the determination of alpha2u-globulin in urine and kidney samples were approximately 0.41 pg/nL (1.0 fmol injected) and 25 pg/nL ( approximately 13 fmol injected), respectively. The limits of quantitation (LOQ) for determination of alpha2u-globulin in urine and kidney samples were calculated as 1.4 pg/nL (3.7 fmol injected) and 83 pg/nL (45 fmol injected), respectively. Applicability of the LC-ESI/MS method was demonstrated by determination of alpha2u-globulin in both urine and kidney samples collected from male Fischer 344/N rats dosed intravenously with cis-Decalin at concentrations of 0, 2.5, 5.0, 10, and 20 mg/kg. A dose-dependent relationship was found between the amount of cis-Decalin administered and alpha2u-globulin accumulation in kidney samples, whereas no significant change in the urinary levels of alpha2u-globulin occurred. These observations are consistent with excessive accumulation of alpha2u-globulin occurring in protein droplets in renal proximal tubule epithelial cells as a result of decreased catabolic activity due to formation of ligand-protein complexs with Decalin and its metabolite(s). This report demonstrates that LC-ESI/MS may be routinely applied for quantitative analysis of alpha2u-globulin in rat urine and kidney samples to address alpha2u-globulin accumulation and its role in the development of nephrotoxicity associated with chemical exposures.

Alpha-Globulins↗
PubMed1998

A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1.

Autoimmune polyendocrinopathy type 1 (APS1) is an autosomal recessive disorder characterized by autoimmune hypoparathyroidism, autoimmune adrenocortical failure, and mucocutaneous candidiasis. Recently, an autoimmune regulator gene (AIRE-1), which is located on chromosome 21q22.3, has been identified, and mutations in European kindreds with APS1 have been described. We used SSCP analysis and direct DNA sequencing to screen the entire 1,635-bp coding region of AIRE-1 in 12 British families with APS1. A 13-bp deletion (964del13) was found to account for 17 of the 24 possible mutant AIRE-1 alleles, in our kindreds. This mutation was found to occur de novo in one affected subject. A common haplotype spanning the AIRE-1 locus was found in chromosomes that carried the 964del13 mutation, suggesting a founder effect in our population. One of 576 normal subjects was also a heterozygous carrier of the 964del13 mutation. Six other point mutations were found in AIRE-1, including two 1-bp deletions, three missense mutations (R15L, L28P, and Y90C), and a nonsense mutation (R257*). The high frequency of the 964del13 allele and the clustering of the other AIRE-1 mutations may allow rapid molecular screening for APS1 in British kindreds. Furthermore, the prevalence of the 964del13 AIRE-1 mutation may have implications in the pathogenesis of the more common autoimmune endocrinopathies in our population.

Alleles↗
PubMed1998

Causes and characteristics of the street child phenomenon: a global perspective.

The street child phenomenon is an alarming and escalating worldwide problem. Street children are maltreated, imprisoned and, in some countries, killed. Street children, as the offspring of complex contemporary urban environments, represent one of our most serious global challenges. This article investigates the causes of this phenomenon, as well as the characteristics of street children throughout the world. In addition, the specific circumstances of street children in Nepal, Indonesia, India, Latin America, and the Philippines are discussed.

Child↗
PubMed1998

Psychological characteristics of South African street children.

Millions of children worldwide are subjected to poverty, abuse, and neglect, yet only a minority choose to abandon their homes in search of a supposedly better life on the street. This article seeks to identify the psychological characteristics that predispose certain children to run away and to survive, often for long periods, on the streets of South Africa. Vulnerability and resilience are examined, as well as social conditions that mediate the psychological predisposition to become a street child.

Adolescent↗
PubMed1998

Public perceptions of, and reactions to, street children.

Research has shown that no treatment program designed for street children can succeed unless the community is prepared to respect, protect, and provide opportunities for them (Tacon, cited in Schurink & Rip, 1993). Unfortunately, these children are abused in many parts of the world (Aptekar, 1994). This paper investigates why the general public, as well as those charged with enforcing the law, often treat street children with scorn and hostility.

Adolescent↗
PubMed1998

Is the street child phenomenon synonymous with deviant behavior?

The police, court officials, social workers, and the public, in general, perceive street children negatively--their behavior is deemed deviant. This paper examines the concept of deviance as a label placed on the powerless by those in positions of power.

Adolescent↗
PubMed1997

Normal MR appearances of the posterior pituitary in central diabetes insipidus associated with septo-optic dysplasia.

Magnetic resonance (MR) imaging of the pituitary in children with central diabetes insipidus usually shows absence of the normal high signal within the posterior gland. The high signal of the normal posterior pituitary is thought to be due to the presence of intra- cellular storage granules of vasopressin. MR imaging has been advocated as a useful investigation to aid in the distinction between central diabetes insipidus and other causes of thirst and polydipsia. We report the case of an infant with central diabetes insipidus in association with septo-optic dysplasia in whom MR imaging showed normal appearances of the posterior pituitary. The mechanism of central diabetes insipidus in this case may be related to a failure of hypothalamic function affecting osmoreception, rather than to a deficiency of vasopressin. Normal MR appearances of the pituitary do not exclude central diabetes insipidus in infants with midline cerebral malformations.

Abnormalities, Multiple↗
PubMed1997

Bone mineral density in Turner's syndrome--a longitudinal study.

OBJECTIVE: Osteoporosis is a recognized problem in adult women with Turner's syndrome, the aetiology of which is unclear. The aim of this study was to examine bone mineralization longitudinally in a group of girls with Turner's syndrome and to study the effect of different treatments on bone mineral density. DESIGN: A prospective observational study. PATIENTS: Eighteen girls with Turner's syndrome aged 4-17 years attending a paediatric endocrine clinic. MEASUREMENTS: Bone mineral density of the lumbar spine was assessed using dual energy X-ray absorptiometry at several time points over a 2.5-year period. RESULTS: Only one girl had evidence of a significant reduction in bone density when comparisons were made with control data related to body weight and pubertal status. No advantage was found for any form of treatment in optimizing bone mineralization. CONCLUSIONS: As there is little evidence of reduced bone mineral density in girls with Turner's syndrome there is no justification for an early introduction of oestrogen replacement during the prepubertal years.

Adolescent↗
PubMed1997

The roles of experience and reflection in ambulatory care education.

While ambulatory care education typically does not provide much direct instruction, supervision, or feedback, experiential learning occurs. Using experiential learning theory, the authors describe how this process of learning works. the process is characterized by a cycle of having a concrete experience (e.g., an encounter with a patient), reflecting on that experience as it unfolds, formulating conceptualizations and generalizations from the experience, and testing those generalizations and concepts in other situations. With this model in mind, the authors make four recommendations for improving ambulatory care education for both medical students and residents: (1) plan for experiences in carefully selected ambulatory care settings; (2) facilitate reflective observation; (3) encourage conceptual thinking and inquiry; and (4) promote feedback and testing of insights from experiences. The authors discuss the rationale behind each recommendation and offer guidelines for how each might be implemented.

Ambulatory Care↗
PubMed1996

Strong hydrogen bonding interactions involving a buried glutamic acid in the transmembrane sequence of the neu/erbB-2 receptor.

The receptor tyrosine kinase encoded by the neu/erbB-2 proto-oncogene is constitutively activated by a single valine to glutamic acid substitution at position 664 in the predicted membrane-spanning sequence of the receptor. We have explored the structural changes involved in receptor activation with polarized FTIR and magic angle spinning NMR spectroscopy. The hydrophobic transmembrane sequence folds into a well-defined alpha-helical structure spanning the membrane bilayer. Measurements of the pKa and 13C chemical shift anisotropy of Glu 664 reveal that the side chain carboxyl group is protonated and strongly hydrogen bonded. These studies provide direct evidence for glutamate hydrogen-bonding interactions in the mechanism of receptor dimerization and activation.

Amino Acid Sequence↗
PubMed1996

A theoretical model for nursing systems outcomes research.

Nursing research on patient and administrative outcomes has typically examined the relationships between selected structural characteristics and outcomes, without taking into account the organization's context. In contrast, health services research has focused on the relationships between the organization's context and outcomes, most often mortality, without taking into account structural characteristics. Although widely used, both approaches develop fragmented knowledge. This article describes a comprehensive theoretical model that takes into account the relationships among the organization's context, its structure, and both patient and nursing administrative outcomes.

Humans↗