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Biomedical subjects

D E Chadwick

Publications and source records attributed to D E Chadwick.

13 recordsLinked to original sources
PubMed1994

Trypsin-like activity levels of Treponema denticola and Porphyromonas gingivalis in adults with periodontitis.

Treponema denticola (Td) and Porphyromonas gingivalis (Pg) are associated with human moderate and severe adult periodontal diseases. This study quantifies these two anaerobes and their trypsin-like (TL) activities in subgingival plaque collected from both clinically healthy and periodontally diseased sites of human periodontitis patients. Antigen levels of the microorganisms were determined by monoclonal antibodies and TL activities were measured by the fluorescent substrate Z-gly-gly-arg-AFC in a disc format. Significant positive correlations were observed between the antigen levels and the TL activities when the data were subjected to statistical analyses both on a site-specific and on a patient basis. Anaerobe synergism was found between Td and Pg in a continental US population, and positive correlations were found between anaerobe levels (individually and total) and clinical indicators of adult periodontitis.

Adult↗
PubMed1994

Longitudinal evaluation of elastase as a marker for the progression of periodontitis.

To determine whether elastase levels in gingival crevicular fluid (GCF) could serve as a marker for the progression of periodontitis, we monitored GCF elastase and periodontal status in selected sites in 32 periodontally healthy volunteers and 31 periodontitis patients at intervals over a 6-month period. Clinical measurements included plaque index, gingival index, bleeding on probing, suppuration, probing depth, clinical attachment level, and relative attachment level measured with an automated disk probe. GCF elastase, detected by reaction with a fluorescent substrate, was assessed visually against fluorescence standards and quantitatively with a fluorometer. Bone loss was detected by subtraction radiography of standardized vertical bite-wing radiographs at baseline and 6 months. Mean visual elastase scores (VES) and quantitative elastase measurements were significantly higher (P < 0.001) in sites from periodontitis patients than in sites from healthy volunteers. When bone loss was used as the criterion for disease progression, significantly higher (P < 0.001) visual and quantitative GCF elastase levels were found at progressing sites than in nonprogressing sites in the periodontitis patients. The odds ratios (OR) for the event of developing bone loss with positive 4-minute and 8-minute VES tests were 4.2 (P < 0.001) and 7.4 (P < 0.001), respectively. When corrected for the tendency of progressing sites to be clustered within a subpopulation of patients, the OR for developing bone loss with the 4-minute and 8-minute VES tests were 3.1 (P < 0.007) and 4.9 (P < 0.001), respectively. These data indicate that sites with high levels of elastase are at significantly greater risk for progressive bone loss as assessed by digital subtraction radiography.

Adult↗
PubMed1993

Differential sensitivity of human myeloma cell lines and normal bone marrow colony forming cells to a recombinant diphtheria toxin-interleukin 6 fusion protein.

The cytotoxicity of a recombinant interleukin 6 (IL-6)-diphtheria toxin (DT) fusion protein towards human myeloma cell lines was investigated. DAB389-IL-6 inhibited protein synthesis and methylcellulose colony formation by U266 myeloma cells. In the clonogenic assay, the fusion protein approached the level of cytotoxicity achieved by native DT. The specificity of killing by DAB389-IL-6 was demonstrated by inhibition of cytotoxicity by a molar excess of free rhIL-6. The effect of DAB389-IL-6 on colony formation by six OCI-My cell lines was assessed. Similar to U266 cells, colony growth by the OCI-My 5 and -My 2 cell lines was inhibited in a simple dose dependent manner. However, a biphasic effect was observed for the IL-6 dependent OCI-My 4 cells; DAB389-IL-6 stimulated colony formation at low (< or = 10(-11) M) concentrations, yet was inhibitory at higher doses. Three other cell lines whose growth was not altered by IL-6 were relatively unaffected by DAB389-IL-6, despite their sensitivity to native DT. Flow cytometric analysis for IL-6 receptor expression using phycoerythrin-conjugated IL-6 demonstrated specific binding sites on both DAB389-IL-6 sensitive and certain insensitive cell lines, suggesting that other factors in addition to the expression of IL-6 receptors are involved in killing by the fusion toxin. Despite evidence for a role of IL-6 in myeloid cell development, normal bone marrow was insensitive to the IL-6 fusion toxin. In cultures containing both normal bone marrow and U266 cells DAB389-IL-6 effectively inhibited the growth of U266 myeloma colonies but had little effect on normal bone marrow erythroid, granulocyte and mixed erythroid/granulocyte colony growth. From these experiments we conclude that DAB389-IL-6 is specifically cytotoxic towards a subset of IL-6-responsive human myeloma cell lines and may be useful, in some cases, in the selective elimination of tumour cells from mixed populations of normal and malignant cells.

Cells, Cultured↗
PubMed1993

Cytotoxicity of a recombinant diphtheria toxin-granulocyte colony-stimulating factor fusion protein on human leukemic blast cells.

Granulocyte colony-stimulating factor (G-CSF) is a potent stimulator of the growth of normal and malignant hematopoietic cells and synergizes with other factors such as interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The action of G-CSF is mediated through a specific membrane receptor, however it is not clear if all of the effects of G-CSF are direct or indirect. As a step towards addressing this problem, a recombinant diphtheria toxin (DT)-related human G-CSF fusion protein has been constructed and purified from E. coli. The 70,000 dalton chimeric protein has immunologic determinants characteristic of both DT and G-CSF. At high concentrations, DAB486-G-CSF is cytotoxic towards G-CSF-dependent OCI/AML1 cells, but not factor independent OCI/AML3 cells; colony formation by G-CSF-responsive leukemic blasts from a patient with acute myeloblastic leukemia (AML) was also inhibited. The G-CSF fusion toxin displayed ADP-ribosyltransferase activity in a cell-free system. Genetic conjugation of G-CSF to an enzymatically inactive DT mutant, CRM197, resulted in a 200-fold reduction in the ability of G-CSF to stimulate normal bone marrow colony formation. These results suggest that fusion of G-CSF to DT sequences interferes with some of the activity but not the specificity of the ligand binding domain of the molecule. Nevertheless, DAB486-G-CSF may be included with the increasing number of other toxin-hormone fusion proteins whose toxicity is directed towards specific receptor-bearing cells, and may represent a novel approach towards the study and treatment of leukemia.

ADP Ribose Transferases↗
PubMed1992

Elastase as an indicator of periodontal disease progression.

THIS STUDY SOUGHT TO EVALUATE the ability of gingival crevicular fluid (GCF) elastase to predict attachment and bone loss in human periodontitis. Thirty subjects who were medically healthy and had a history of progressive periodontitis were studied with an automated probe. Five sites in each patient were monitored bi-monthly for a 6-month period for attachment loss. Subtraction radiography was utilized at the beginning and end of the study to monitor bone loss. GCF elastase was measured at 0 month and then bi-monthly by collecting GCF on paper strips impregnated with PMN leukocyte elastase substrate inserted into the gingival crevice for 15 seconds. After 8 minutes of reaction time, the strips were scored relative to fluorescent standards in an ultraviolet view box. Strips were then eluted in methanol and total elastase measured by spectrofluorometry. Total elastase was significantly higher in sites demonstrating progressive attachment loss than in inactive sites (2.81 +/- .29 versus 2.03 +/- .07, P less than 0.0005) and sites demonstrating bone loss (2.32 +/- .17 versus 2.01 +/- .08 P less than 0.05). When considering the joint presence of bone loss and attachment loss of 1.0 mm or greater in the 6-month period following a visual elastase kit score of 2 or greater, the test kit shows a sensitivity and specificity of 82% and 66%, respectively. This study demonstrated that GCF elastase levels are significantly higher in sites demonstrating progressive periodontal attachment and bone loss assessed 6 months later and may serve as a predictor of future bone and attachment loss.

Adult↗
PubMed1988

Coincidental acquisition of growth autonomy and metastatic potential during the malignant transformation of factor-dependent CCL39 lung fibroblasts.

After sc implantation into BALB/c nude mice, factor-dependent and premalignant Chinese hamster lung fibroblasts (CCL39) developed into tumors that occasionally disseminated and produced pulmonary metastases. Unlike CCL39 cells that required several growth factors (insulin, alpha-thrombin, epidermal growth factor) to proliferate in culture, metastatic tumor cells divided autonomously in serum-free medium. The re-implantation of independently isolated primary tumors revealed that they comprised factor-independent clones present at a variable frequency, as well as malignant clones that disseminated to the lungs after sc or iv inoculation. The resulting metastases invariably contained cells that were able to divide in serum-free medium and that presumably represented the progeny of autonomous variants populating the primary tumors. Among ten CCL39 variants selected in vitro for reduced growth factor requirements, two were metastatic upon sc and iv inoculation. These cell lines were the only ones that replicated rapidly in the absence of growth factors. Unlike myc transfectants, CCL39 fibroblasts that were transformed with an activated Harvey ras oncogene or that were infected with polyomavirus were both metastatic and autonomous. Taken together, these observations are consistent with the notion that the metastatic potential of CCL39 tumor cells coincides with their ability to obviate growth factor requirements and thus to divide in an autonomous fashion.

Animals↗
PubMed1983

Should beta-blockers be stopped if myocardial ischaemia occurs?

56 patients who were taking a long-term beta-blocker, and in whom myocardial ischaemia occurred, were randomised to stop or to continue the drug. Assessed in terms of deaths, heart failure, cardiogenic shock, further myocardial ischaemia and arrhythmias (except atrial fibrillation), the outcome did not differ significantly in the two groups. We found no evidence in this small series that either maintaining or stopping beta-blockers after an episode of myocardial ischaemia significantly alters the short-term prognosis of chronically beta-blocked patients.

Adrenergic beta-Antagonists↗
PubMed1983

Absorption and antiarrhythmic efficacy of sustained-release mexiletine.

Absorption of the antiarrhythmic agent mexiletine from conventional capsules (200 mg) and two sustained-release formulations (360 and 432 mg) was studied in four healthy volunteer subjects, and use of the 360-mg preparation was studied in nine patients who had been using conventional capsules. In the four volunteers, acute dosage with the 432-mg preparation produced a markedly lower peak mexiletine concentration and fewer side effects than did two 200-mg capsules. Chronic dosing in two volunteers, which indicated that the 360-mg preparation produced fewer side effects and lower predose and peak plasma mexiletine concentrations than did the 432-mg preparation, suggested the use of equivalent doses of the 360-mg preparation in the nine patients who had been using 100-, 200-, or 250-mg preparations. The arrhythmia control produced by the slow-release preparation, as measured by 24-hour ECGs, was comparable to that produced by the conventional forms of mexiletine; gastrointestinal side effects were less marked when patients took the slow-release preparation, despite higher mean predose plasma mexiletine concentrations associated with use of the 360-mg preparation. Reduced frequency of daily dosage as well as patient acceptance are clinical advantages of the slow-release preparation.

Absorption↗
PubMed1980

Inhibitors of RNA synthesis and passage of chick embryo fibroblasts through the G1 period.

Events that are essential for progression through the G1 period begin immediately or shortly after resting chick embryo cells are given fresh medium with serum. The following observations support the contention that the critical events include the production of non-ribosomal RNAs: (1) Addition to the "shift-up" medium of either of two inhibitors of RNA formation, camptothecin or 5, 6-dichloro--1-beta-D-ribofuranosylbenzimidazole, delays the onset of DNA replication by about the length of time the cells are exposed to the drugs. (2) Although entry into the S phase is delayed by the inhibitors, the slopes of the DNA response curves are identical to that of control cultures. (3) Neither drug reduces significantly the rate of overall protein synthesis. Observations (2) and (3) are taken to mean that expansion of the G1 period is not due to cell damage. (4) A third inhibitor of RNA synthesis, cordycepin, also delays passage of stimulated cells through the G1 phase, but, in this case, the length of the delay period is greater than that of the exposure period. (5) A low dose of actinomycin D does not impede movement towards the S phase, even though the synthesis of preribosomal RNA is considerably reduced. The possibility is considered that the essential G1 molecules are mRNAs.

Animals↗