Biomedical subjects

D Cox

Publications and source records attributed to D Cox.

At least 73 records · Page 4Linked to original sources

PubMed1998

Abnormal uptake of Tc-99m MIBI, a novel myocardial imaging agent, in the lungs of patients with systemic sclerosis.

OBJECTIVE: Fibrosing alveolitis is a prominent feature of systemic sclerosis (SSc), and accounts for much of the morbidity and mortality of this disease. Sensitive techniques for the detection and monitoring of fibrosing alveolitis could target patients for early therapeutic intervention. The objective of this small pilot study was to assess the frequency and clinical significance of abnormal lung uptake of Tc-99m MIBI, a novel radionuclide imaging agent that selectively accumulates in cells rich in mitochondria. METHODS: Sixteen patients with SSc and evidence of pulmonary involvement were studied. The uptake of radionuclide in the lungs, and the ratio of pulmonary to cardiac uptake were evaluated after intravenous injection of Tc-99m MIBI. Results were correlated with clinical and laboratory parameters. RESULTS: Lung uptake of Tc-99m MIBI was increased in all 16 SSc patients compared to control patients with coronary heart disease but no evidence of pulmonary abnormality. The degree of isotope uptake in the lungs was correlated with the extent of maximal skin induration and with radiologic evidence of interstitial lung disease, but not with other clinical or laboratory parameters of disease activity or extent of pulmonary involvement. The ratio of pulmonary to cardiac uptake of isotope was also increased in patients with SSc compared to controls. CONCLUSION: Accumulation of Tc-99m MIBI is abnormally elevated in the lungs of SSc patients with pulmonary involvement. Isotope accumulation in the lungs may be related to activation of fibroblasts or endothelial cells. The specificity and sensitivity of Tc-99m MIBI scanning in the detection and monitoring of pulmonary involvement, and its potential role in the management of SSc, deserve further investigation.

Coronary Disease↗

PubMed1998

The impact of formalization, role conflict, role ambiguity, and communication quality on perceived organizational innovativeness in the Cancer Information Service.

Organizational members' levels of perceived innovativeness represent an insider's viewpoint of the organization's overall approach to innovation. This study tested a model of the impact of formalization, role ambiguity, role conflict, and communication quality on perceived organizational innovativeness in the Cancer Information Service. Data were gathered from self-report questionnaires completed by organizational members (n = 86) within the Cancer Information Service, a geographically dispersed federal government health information program that was implementing innovative intervention strategies related to disseminating health information to the public. Results indicated that although the predicted model provided a good overall fit to the data, there were some problematic paths. A revised model is offered to reconceptualize the relationships among role conflict, role ambiguity, and communication quality. These results are discussed in terms of their implications for managers and scholars who hope to understand the factors that contribute to perceptions of innovativeness in the new organizational forms emerging in the health service arena. These data suggest that formalization makes an important contribution to innovation in the highly uncertain world of new organizational forms.

Attitude of Health Personnel↗

PubMed1998

Components of variance: a miscellany.

Some general issues connected with components of variance are reviewed. These include matters of definition, of formal inference in a normal-theory context, of goodness of fit, and of simple methods for unbalanced data.

Analysis of Variance↗

PubMed1998

Transmission of vancomycin-resistant enterococcus among family members: a case study.

Enterococci are persistent organisms naturally occurring in the digestive tract, able to persist on environmental surfaces for days or weeks, surviving heat and desiccation. They are the second most common bacterial cause of nosocomial infection. Recent strains of enterococci resistant to vancomycin pose a serious health hazard to hospitalized, institutionalized, and immunocompromised patients. This article presents a case study of community-acquired vancomycin-resistant enterococcus in an otherwise healthy child and suggests strategies for management and containment in the community.

Community-Acquired Infections↗

PubMed1998

Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies.

This combined analysis investigated the effect of marimastat, a specific inhibitor of matrix metalloproteinases, on markers of tumor progression measured in patients with advanced cancer. By defining the tolerability and biological activity of the drug, it aimed to establish an appropriate dose range for use in Phase III trials. Patients with advanced, serologically progressive ovarian, prostatic, pancreatic, and colorectal cancer were recruited into six nonrandomized, dose ranging, multicenter clinical trials in North America and Europe. The biological activity of marimastat was assessed by serial measurements of the serum tumor markers carcinoembryonic antigen, CA125, CA19-9, and prostate-specific antigen. Patients were recruited with tumor markers rising by more than 25% averaged over a 4-week screening period. A biological effect was defined as a level of tumor marker at the end of treatment no greater than at study entry; a partial biological effect was defined as a rise in the level of tumor marker over the treatment period of 0-25% per 4 weeks. Pharmacokinetic and safety data were collected and assessed as the studies progressed. All patients were followed up for survival.

Adult↗

PubMed1997

Requirements for both Rac1 and Cdc42 in membrane ruffling and phagocytosis in leukocytes.

Specific pathways linking heterotrimeric G proteins and Fcgamma receptors to the actin-based cytoskeleton are poorly understood. To test a requirement for Rho family members in cytoskeletal events mediated by structurally diverse receptors in leukocytes, we transfected the full-length human chemotactic peptide receptor in RAW 264.7 cells and examined cytoskeletal alterations in response to the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP), colony stimulating factor-1 (CSF-1), IgG-coated particles, and phorbol 12-myristate 13-acetate (PMA). Expression of Rac1 N17, Cdc42 N17, or the GAP domain of n-chimaerin inhibited cytoskeletal responses to FMLP and CSF-1, and blocked phagocytosis. Accumulation of F-actin- rich "phagocytic cups" was partially inhibited by expression of Rac1 N17 or Cdc42 N17. In contrast, PMA-induced ruffling was not inhibited by expression of Rac1 N17, but was blocked by expression of Cdc42 N17, indicating that cytoskeletal inhibition by these constructs was nonoverlapping. These results demonstrate differential requirements for Rho family GTPases in leukocyte motility, and indicate that both Rac1 and Cdc42 are required for Fcgamma receptor- mediated phagocytosis and for membrane ruffling mediated by structurally distinct receptors in macrophages.

Animals↗

PubMed1997

The role of immunoglobulin G and fibrinogen in platelet aggregation by Streptococcus sanguis.

Previous work has shown that the type strain of Streptococcus sanguis, NCTC 7863, induces aggregation of normal platelets by a complement-dependent mechanism. We investigated the roles of IgG and fibrinogen in the aggregation process. Plasma depleted of IgG by passage through protein A-sepharose failed to support platelet aggregation, as did plasma absorbed at 0 degrees C with whole bacteria. However, absorption of plasma with a non-aggregating strain of S. sanguis, SK96, did not remove aggregating activity for NCTC 7863. Supplementing 0 degrees C-absorbed plasma with purified IgG restored the aggregation supporting activity. A monoclonal antibody to the Fc gammaRII receptor inhibited platelet aggregation by the bacteria, indicating a requirement for bacteria-IgG complexes interacting with the Fc receptor in platelet aggregation. There was a lag time to the onset of platelet aggregation of 7-19 min depending upon the platelet donor, but the length of this lag did not correlate with either total IgG concentration recognizing NCTC 7863 in subjects' plasma, or the concentration any of the four IgG subclasses or with IgG avidity levels. Fibrinogen was shown to bind rapidly to the bacterial cell surface. Monoclonal antibody to GPIIb/IIIa, RGDS peptide, and a specific antagonist for the platelet fibrinogen receptor, GPIIb/IIIa, FK633, inhibited platelet aggregation by NCTC 7863, indicating that platelet aggregation is fibrinogen dependent. These data suggest that platelet aggregation by some strains of S. sanguis requires multiple stimuli/agonists, including IgG-Fc receptor interaction, complement and fibrinogen.

Complement System Proteins↗

PubMed1997

The vulnerability of Asian women migrant workers to a lack of protection and to violence.

"The paper argues that women moving abroad as domestic workers are, in many instances, unprepared, unprotected, and therefore open to exploitation and violent treatment. It suggests that the factors resulting in this common outcome are clear, and that an examination of the situation and the relevant factors leads us to a set of intervention strategies which are feasible. Six areas of intervention are identified: conventions, legislation, government control of processes, supervision, preparation and empowerment of the women, and support NGOs [nongovernmental organizations] including self-help groups."

Asia↗

PubMed1997

The psychosocial impact of severe hypoglycemic episodes on spouses of patients with IDDM.

OBJECTIVE: No previous studies have examined the psychosocial impact of severe hypoglycemic episodes in IDDM patients on their spouses. This study compared spouses of IDDM patients with and without a history of recent severe hypoglycemia (SH) using traditional measures of psychosocial status and marital conflict, as well as diabetes-specific measures. RESEARCH DESIGN AND METHODS: A total of 61 nondiabetic spouses (23 wives and 38 husbands) of IDDM patients participated in the study. Spouses completed a battery of traditional psychometric measures (depression, anxiety, marital conflict) and diabetes-specific measures (fear of hypoglycemia, marital conflict over diabetes, sleep disturbance caused by hypoglycemia). Scores of spouses of IDDM patients with and without a recent history of SH were compared with t tests. RESULTS: Spouses of IDDM patients with and without a recent history of SH showed no differences on traditional psychometric measures of depression, anxiety, and marital conflict. However, spouses of patients with a recent history of SH showed significantly more fear of hypoglycemia, marital conflict about diabetes management, and sleep disturbances caused by hypoglycemia. Exploratory analyses of variance (ANOVAs) found no differences on psychometric measures between wives and husbands, with the exception that husbands of SH patients reported more sleep disturbance. Nondiabetic spouses, on average, showed greater fear of hypoglycemia than their diabetic partners. CONCLUSIONS: Although SH in IDDM patients can have a significant impact on the psychosocial status of their spouses, in this study the negative impact was restricted to areas of life that are directly related to diabetes and its management. Thus, SH per se is not necessarily associated with significant increases in spousal anxiety, depression, or marital conflict, but may be associated with types of diabetes-specific psychosocial distress that are not easily identified by traditional psychometric measures.

Adult↗

PubMed1997

A biopsychobehavioral model of risk of severe hypoglycemia.

Severe hypoglycemia (SH) is a significant problem for many patients with type I diabetes and presents a major barrier to optimal diabetes control. A critical task facing diabetes research is to understand, predict, and reduce the risk of SH in insulin-treated patients. The purpose of this article is to propose a biopsychobehavioral model of SH risk that integrates and extends previously proposed models. Current biological and psychological models of SH risk, which focus on hormonal counterregulation and symptom awareness, are reviewed. The limitations of these models are also discussed, including their failure to recognize important psychological and behavioral processes that contribute to SH risk. Specifically, the biopsychobehavioral model includes patients' decision-making, judgment, and behavioral responses as significant predictors of SH risk. The proposed model is comprised of seven steps: 1) physiological and behavioral precursors to low blood glucose (BG), 2) low BG occurrence, 3) hormonal and neurological responses to low BG, 4) awareness of symptoms caused by hormonal and neurological changes, 5) detection of low BG, 6) decision-making and judgment, and 7) behavioral response. The model has several advantages, including the ability to mathematically calculate the transitional probabilities from each step to the next as well as the ability to describe SH risk in both hypoglycemia-aware and hypoglycemia-unaware patients. Research findings supporting the biopsychobehavioral model are presented, and its empirical and clinical implications are discussed.

Behavior↗

PubMed1997

Recombinant human transforming growth factor beta 3 accelerates gastric ulcer healing in rats.

BACKGROUND: Gastric ulcer healing is mediated by various endogenous growth factors. In this experimental study effect of locally and systemically applied recombinant human transforming growth factor beta 3 (rhTGF-beta 3) on gastric ulcer healing was investigated in the rat. METHODS AND RESULTS: Gastric ulcers were induced with a cryoprobe, and ulcer healing was evaluated 7 days after local infiltration (0.5 micrograms, 1.0 microgram, 2.5 micrograms, and 50 micrograms) or systemic (intravenous) application of TGF-beta 3 (500 micrograms/kg body weight). Compared with controls, a dose-dependent stimulation of ulcer healing (as evidenced by a reduction in ulcer size) was observed 7 days after local infiltration of TGF-beta 3 (1.0 microgram, 2.5 micrograms, and 50 micrograms). Corresponding increases in the levels of proliferating cell nuclear antigen (PCNA) and intracellular TGF-beta 3 expression and a downregulation of the TGF-beta type-II receptor expression were also observed in the granulation tissue of the ulcer margins. Systemic application of TGF-beta 3 produced effects similar to those observed after local treatment with 50 micrograms of the compound. CONCLUSION: Local and systemic TGF-beta 3 treatment accelerates gastric ulcer healing in rats.

Animals↗

PubMed1997

Biomonitoring of possible human exposure to environmental genotoxic chemicals: lessons from a study following the wreck of the oil tanker Braer.

In January 1993 the oil tanker Braer ran aground in the Shetland Islands, Scotland. Approximately 80,000 tons of crude oil were released. Exceptionally high winds caused extensive pollution and exposure of the local population to crude oil. We describe the study which was immediately set in place to examine the exposed population for evidence of genotoxic exposure. Blood samples were taken and primary DNA damage was measured in the mononuclear cell fraction by the butanol modification of the 32P-postlabelling method. Mutation was measured at the hprt locus in T lymphocytes. No evidence of genotoxicity was obtained for either end point, but nevertheless, we believe that useful lessons were learnt, which should be incorporated into the design of future studies: (1) A rapid response is essential, and even if sufficient funds are not immediately available, it is still worth attempting to obtain samples quickly and use cryopreservation, also to attempt to estimate exposure. (2) Adequate numbers of volunteers must be sought, together with enough controls, not just to allow meaningful analysis but to overcome loss of samples and failure of things to go according to plan. (3) Points concerning laboratory practice include: (i) samples should be coded, (ii) clearly defined and proven protocols should be used, (iii) irreplaceable samples should not be used for method development, (iv) should a problem become apparent during the study, work on such samples should cease immediately until the problem is solved, (v) all critical experimental components should be pretested against a laboratory standard. (4) The study design should include replicate experiments to monitor experimental variability and reproducibility, as well as internal standards and cryopreserved "in house" samples. Care must be taken that samples from any one exposure group are spread between a number of independent experiments and that each experiment includes samples from a number of exposure groups. (5) A computerised data base should be maintained with full details of experimental variables, donor attributes, and raw data so that any contribution of experimental artefacts to "outlier" results can be monitored. (6) Because of the nature of the statistical variation for many environmental genotoxicity end points, only a large-scale study is likely to be capable of yielding useful information.

Accidents, Occupational↗

PubMed1996

Syk tyrosine kinase is required for immunoreceptor tyrosine activation motif-dependent actin assembly.

Clustering of several multisubunit receptors on hematopoetic cells results in a signaling cascade involving the phosphorylation of immunoreceptor tyrosine activation motifs, or "ITAMs," and actin polymerization. Recent experiments indicate that direct clustering of the ITAM-binding protein, p72(syk) (Syk), is capable of transmitting a phagocytic signal in COS cells (Greenberg, S., Chang, P., Wang, D., Xavier, R., and Seed, B.(1996) Proc. Natl. Acad. Sci. U. S. A. 93, 1103-1107). However, the possibility of redundant signaling pathways makes it difficult to test the requirement for Syk in ITAM-dependent actin polymerization in hematopoetic cells. We developed a model system to study ITAM-dependent actin assembly. DT40 lymphocytes were transfected with fusion proteins encoding the transmembrane and cytosolic domains of the ITAM-containing gamma subunit of Fc receptors. Clustering the gamma-containing fusion proteins with IgG-coated erythrocytes triggered submembranous actin assembly. This response depended on an intact ITAM, was absent in cell lines that had been engineered to lack Syk, and was augmented in cell lines that stably overexpressed Syk. These experiments demonstrate an absolute requirement for Syk tyrosine kinase in ITAM-dependent actin assembly in transfected lymphocytes.

Actins↗

PubMed1996

The anti-platelet and anti-thrombotic effects of FK633, a peptide-mimetic GPIIB/IIIA antagonist.

The anti-platelet and anti-thrombotic properties of FK633, a peptide mimetic GPIIb/IIIa antagonist were studied. In human platelet rich plasma, FK633 inhibited ADP-, collagen-, thrombin-, and PAF-induced platelet aggregation with IC50 values of 103, 87, 98, and 239 nM, respectively. RGDS acted similarly, but it's potency was about 1,000 times weaker than FK633, FK633 inhibited 125I-fibrinogen binding to human washed platelet with an IC50 of 88 nM. FK633 did not inhibit alphavbeta3, alpha5beta1, and alphavbeta1 integrin-mediated cellular adhesion up to 1.0mM, while RGDS inhibited all these interactions. In dogs, bolus injection of FK633 at 0.1 mg/kg significantly suppressed ex vivo ADP-induced platelet aggregation (>40% inhibition) and thrombus formation at stenosed and injured coronary artery, but did not prolong template bleeding time. However, FK633 inhibited >90% ADP-induced aggregation at 0.32 mg/kg, causing significant prolongation of the bleeding time. Thus, FK633 is a specific GPIIb/IIIa antagonist with potent anti-thrombotic effect in vivo, but careful dosing study might be necessary to avoid the bleeding complications in the clinic.

Animals↗

PubMed1996

11 beta-hydroxysteroid dehydrogenases of the choriocarcinoma cell line JEG-3 and their inhibition by glycyrrhetinic acid and other natural substances.

Mineralocorticoid receptor (MR) selectivity for aldosterone is thought to be exerted by enzymes which inactivate competing glucocorticoids before they bind the receptor. Two different 11 beta-hydroxysteroid dehydrogenases (11 beta-HSD) have been described. 11 beta-HSD-1 is NADP(+)-dependent and has a Km in the micromolar range and bidirectional activity. 11 beta-HSD-2 is NAD(+)-dependent, has a Km in the nanomolar range, exhibits only oxidase activity, and colocalizes with the MR in the kidney, so is likely to serve as the gatekeeper for the MR. We have further characterized 11 beta-HSD activity in JEG-3 cells, a cell line derived from a human choriocarcinoma which was reported to have only the high affinity, NAD(+)-dependent 11 beta-HSD-2. We found that the Km for the conversion of corticosterone to 11-dehydrocorticosterone in intact cells and homogenates was about 16 nM. NAD(+)-dependent corticosterone conversion was equal in the nuclear and mitochondrial fractions and less, but significant, in the microsomal fraction. A high affinity, Km = 40 nM, NADP(+)-dependent enzyme was also found in homogenates. The subcellular distribution of this high affinity activity was greatest in the mitochondria, less in the nuclei, and even less, but still significant, in microsomes. Because of its cofactor dependency, high affinity, and different subcellular distribution, we suggest that this enzyme is neither the 11 beta-HSD-1 nor the 11 beta-HSD-2 and have named it 11 beta-HSD-3. Conversion of 11-dehydrocorticosterone to corticosterone did not occur in intact cells or in homogenates incubated with NADH or NADPH. Enzyme activity in intact cells was inhibited by glycyrrhetinic acid, carbenoxolone, progesterone, 5 beta-dihydroprogesterone, and 5 alpha-dihydroprogesterone, but not bile acids.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1996

Ascertaining dementia by expert panel in epidemiologic studies of nursing home residents.

A new method for ascertaining dementia in epidemiologic research and the results of a study to evaluate it are described. The method relies on an expert panel of clinicians reviewing clinically relevant information collected by lay evaluators to arrive at a diagnosis based on DSM-III-R criteria. The approach was developed to study dementia in a statewide sample of over 2400 new admissions to 59 nursing homes in Maryland. Expert panel ascertainment of dementia was compared to that obtained by direct clinical evaluation for 100 nursing home residents. Agreement between the panel and direct assessment was 76% (kappa = 0.59) using a three-category classification of dementia, no dementia, and indeterminate. This ascertainment strategy provides an alternative to methods currently in use and is particularly well-suited for populations with a high prevalence, in those dispersed over large geographic areas, and when timely, cost-effective evaluations are required.

Aged↗

PubMed1996

Re-expression of ABP-120 rescues cytoskeletal, motility, and phagocytosis defects of ABP-120- Dictyostelium mutants.

The actin binding protein ABP-120 has been proposed to cross-link actin filaments in nascent pseudopods, in a step required for normal pseudopod extension in motile Dictyostelium amoebae. To test this hypothesis, cell lines that lack ABP-120 were created independently either by chemical mutagenesis or homologous recombination. Different phenotypes were reported in these two studies. The chemical mutant shows only a subtle defect in actin cross-linking, while the homologous recombinant mutants show profound defects in actin cross-linking, cytoskeletal structure, pseudopod number and size, cell motility and chemotaxis and, as shown here, phagocytosis. To resolve the controversy as to what the ABP-120- phenotype is, ABP-120 was re-expressed in an ABP-120- cell line created by homologous recombination. Two independently "rescued" cell lines that express wild-type levels of ABP-120 were analyzed. In both rescued cell lines, actin incorporation into the cytoskeleton, pseudopod formation, cell morphology, instantaneous velocity, phagocytosis, and chemotaxis were restored to wild-type levels. There is no alteration in the expression levels of several related actin binding proteins in either the original ABP-120- cell line or in the rescued cell lines, leading to the conclusion that neither the aberrant phenotype observed in ABP-120- cells nor the normal phenotype reasserted in rescued cells can be attributed to alterations in the levels of other abundant and related actin binding proteins. Re-expression of ABP-120 in ABP-120- cells reestablishes normal structural and behavioral parameters, demonstrating that the severity and properties of the structural and behavioral defects of ABP-120- cell lines produced by homologous recombination are the direct result of the absence of ABP-120.

Actins↗

PubMed1996

P2T purinoceptor antagonists. A QSAR study of some 2-substituted ATP analogues.

FPL67085MX represents the first in a class of novel, highly potent and selective P2T purinoceptor antagonists which are inhibitors of adenosine diphosphate (ADP)-induced platelet aggregation in-vitro. In an early series of compounds we studied the effect of variation of the adenine 2-substituent on potency and derived quantitative structure-activity relationships (QSARs) between the properties of the molecules and their biological activity. This work has recently been revisited using comparative molecular-field analysis (CoMFA) and the comparison of the predictions from the two methods is discussed along with their relative merits in terms of compound design. The model suggests that the receptor for these molecules has a narrow lipophilic cleft, which is occupied by the adenine 2-substituent.

Adenosine Triphosphate↗