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Biomedical subjects

R Harrison

Publications and source records attributed to R Harrison.

At least 73 records · Page 4Linked to original sources
PubMed1993

RANTES is a chemotactic and activating factor for human eosinophils.

RANTES is a member of the 8-kDa cytokine family that has been shown to possess chemotactic activity for monocytes and CD4 T cells. In this study, we investigated whether RANTES could affect eosinophil chemotaxis and function. Peripheral blood eosinophils from blood donors were isolated on Percoll gradients to > 98% purity and then used for chemotaxis, flow cytometry, eosinophil cationic protein release assay, and survival assay. We found that RANTES is chemotactic for eosinophils at 10(-9) to 10(-8) M concentrations. RANTES elicited 65% of the chemotactic response to 10(-7) M platelet-activating factor in all experiments. The mechanism of chemotaxis was investigated by studying the expression of adhesion molecules on eosinophils by flow cytometry. We found that RANTES up-regulated the expression of CD11b/CD18 on eosinophils in a dose-dependent manner. In another set of experiments, purified eosinophils incubated with various concentrations of RANTES released eosinophil cationic protein as measured by a RIA. We also investigated the effect of RANTES on eosinophil density. Leukocytes were incubated in the presence or absence of RANTES, and the distribution of eosinophils on discontinuous Percoll gradients was then examined. We found that eosinophils became hypodense (< 1.085) when incubated in RANTES. However, unlike IL-3, RANTES did not affect the survival of eosinophils in a 4-day culture system. Thus, we established that RANTES is a chemotactic and activating factor for eosinophils.

Chemokine CCL5↗
PubMed1993

Argon laser trabeculoplasty in pigmentary glaucoma.

PURPOSE: To evaluate the long-term effect of argon laser trabeculoplasty (ALT) in pigmentary glaucoma. METHODS: The authors retrospectively analyzed results of ALT in 32 eyes of 32 patients with medically uncontrolled pigmentary glaucoma. Data were longitudinally adjusted to normalize the disparity in time of follow-up and evaluated by life-table analysis. RESULTS: Mean age (+/- standard deviation) was 45.1 +/- 13.1 years (range, 23-72 years) (males, 46.3 +/- 13.7 years; females, 42.9 +/- 12.2 years). Mean baseline intraocular pressure (IOP) was 27.8 +/- 5.3 mmHg. Mean follow-up time was 33.0 +/- 5.0 months (range, 1 week [immediate failures] to 96 months). Three eyes were lost to follow-up at 3 months. Eleven eyes required trabeculectomy between 1 week (2 eyes) and 37 months after laser treatment. Life-table analysis indicated a cumulative success for all eyes of 80% at 1 year, 62% at 2 years, and 45% at 6 years. Mean IOP was significantly reduced (P < 0.001; paired Student's t test) for male and female eyes at all intervals calculated. Age was a significant factor in determining time to failure. CONCLUSION: Argon laser trabeculoplasty is effective in pigmentary glaucoma. Younger patients had a greater chance of success than older patients at all intervals. This became highly significant (P < 0.001) after 3 years.

Adult↗
PubMed1993

Hepatitis C virus antibody positive blood donors.

In an analysis of 15 blood donors referred from the Blood Transfusion Service to the Queen Elizabeth Hospital, Birmingham, more than 50% of anti-hepatitis C virus (HCV) positive patients had a parenteral risk factor. Most were serum HCV-RNA positive, and all were liver HCV-RNA positive. Although no physical signs of liver disease were apparent, all anti-HCV positive donors had abnormal liver histology.

Adult↗
PubMed1992

Helical model of nucleation and propagation to account for the growth of type I collagen fibrils from symmetrical pointed tips: a special example of self-assembly of rod-like monomers.

A model was developed to account for the recent observations indicating that type I collagen fibrils assembled in vivo grow from symmetrical pointed tips. The essential features of the model are (i) a distinctive structural nucleus forms at each end of a growing fibril and growth of the fibril then proceeds by propagation of the two structural nuclei, (ii) the two structural nuclei have similar spiral or helical conformations, and (iii) assembly of each structural nucleus requires two kinds of specific binding steps defined as 3.4 D-period and 0.4 D-period overlaps, but propagation of the nucleus requires only the 3.4 D-period binding step.

Collagen↗
PubMed1992

The immunosuppressive and toxic effects of FK-506 are mechanistically related: pharmacology of a novel antagonist of FK-506 and rapamycin.

FK-506 inhibits Ca(2+)-dependent transcription of lymphokine genes in T cells, and thereby acts as a powerful immunosuppressant. However, its potential therapeutic applications may be seriously limited by several side effects, including nephrotoxicity and neurotoxicity. At present, it is unclear whether these immunosuppressive and toxic effects result from interference with related biochemical processes. FK-506 is known to interact with FK-binding protein-12 (FKBP-12), an abundant cytosolic protein with cis-trans peptidyl-prolyl isomerase activity (PPIase) activity. Because rapamycin (RAP) similarly binds to FKBP-12, although it acts in a manner different from FK-506, by inhibiting T cell responses to lymphokines, such an interaction with FKBP-12 is not sufficient to mediate immunosuppression. Recently, it was found that the complex of FKBP-12 with FK-506, but not with RAP, inhibits the phosphatase activity of calcineurin. Here, we used L-685,818, the C18-hydroxy, C21-ethyl derivative of FK-506, to explore further the role of FKBP-12 in the immunosuppressive and toxic actions of FK-506. Although L-685,818 bound with high affinity to FKBP-12 and inhibited its PPIase activity, it did not suppress T cell activation, and, when complexed with FKBP-12, did not affect calcineurin phosphatase activity. However, L-685,818 was a potent antagonist of the immunosuppressive activity of both FK-506 and RAP. Moreover, L-685,818 did not induce any toxicity in dogs and rats or in a mouse model of acute FK-506 nephrotoxicity, but it blocked the effect of FK-506 in this model. Therefore, FK-506 toxicity involves the disruption of biochemical mechanisms related to those implicated in T cell activation. Like immunosuppression, this toxicity is not due to the inhibition of the PPIase activity of FKBP-12, but may be linked to the inhibition of the phosphatase activity of calcineurin by the drug FKBP-12 complex.

Amino Acid Isomerases↗
PubMed1992

Purification and partial characterization of xanthine oxidase from human milk.

Xanthine oxidase was purified from human milk in yields comparable with those obtained from bovine milk. The freshly purified enzyme appeared homogeneous in gel permeation FPLC and SDS-PAGE, consistent with its being a homodimer with total M(r) 290,000 +/- 6000. The ultraviolet/visible absorption spectrum differed only slightly from that of bovine milk enzyme and showed an A280/A450 ratio of 5.13 +/- 0.29, indicating a high degree of purity. Xanthine oxidase activities of purified enzyme varied with batches of milk, ranging between 3 and 46 mU/mg protein; values that are some two to three orders of magnitude smaller than those shown by the most highly purified samples of bovine milk enzyme. Direct comparison with commercially-available bovine milk enzyme showed that activities involving xanthine as reducing substrate were 1-6% that of the bovine enzyme, whereas those involving NADH, in contrast, were of the same order for the two enzymes. Anaerobic bleaching experiments indicated that less than 2% of the human enzyme was present as a form active with xanthine. These findings, together with the activity data, are consistent with a very high content, possibly greater than 98%, of demolybdo- and/or desulpho-forms of human enzyme, both of which occur, to a lesser extent, in bovine xanthine oxidase. Molybdenum assay indicated that demolybdo-enzyme could only account for some 26% of this inactive component, suggesting that desulpho-enzyme may account for the remainder.

Animals↗
PubMed1992

Trafficking of glucose transporters in 3T3-L1 cells. Inhibition of trafficking by phenylarsine oxide implicates a slow dissociation of transporters from trafficking proteins.

We have compared the rates of insulin stimulation of cell-surface availability of glucose-transporter isoforms (GLUT1 and GLUT4) and the stimulation of 2-deoxy-D-glucose transport in 3T3-L1 cells. The levels of cell-surface transporters have been assessed by using the bismannose compound 2-N-[4-(1-azi-2,2,2-trifluoroethyl)benzoyl]-1,3-bis(D-mannos -4-yloxy) propyl-2-amine (ATB-BMPA). At 27 degrees C the half-times for the appearance of GLUT1 and GLUT4 at the cell surface were 5.7 and 5.4 min respectively and were slightly shorter than that for the observed stimulation of transport activity (t 1/2 8.6 min). This lag may be due to a slow dissociation of surface transporters from trafficking proteins responsible for translocation. When fully-insulin-stimulated cells were subjected to a low-pH washing procedure to remove insulin at 37 degrees C, the cell-surface levels of GLUT1 and GLUT4 decreased, with half-times of 9.2 and 6.8 min respectively. These times correlated well with decrease in 2-deoxy-D-glucose transport activity that occurred during this washing procedure (t1/2 6.5 min). When fully-insulin-stimulated cells were treated with phenylarsine oxide (PAO), a similar decrease in transport activity occurred (t1/2 9.8 min). However, surface labelling showed that this corresponded with a decrease in GLUT4 only (t1/2 7.8 min). The cell-surface level of GLUT1 remained high throughout the PAO treatment. Light-microsome membranes were isolated from cells which had been cell-surface-labelled with ATB-BMPA. Internalization of both transporter isoforms to this pool occurred when cells were maintained in the presence of insulin for 60 min. In contrast with the surface-labelling results, we have shown that the transfer to the light-microsome pool of both transporters occurred in cells treated with insulin and PAO. These results suggest that both transporters are recycled by fluid-phase endocytosis and exocytosis. PAO may inhibit this recycling at a stage which involves the re-emergence of internalized transporters at the plasma membrane. The GLUT1 transporters that are recycled to the surface in insulin- and PAO-treated cells appear to have low transport activity. This may be because of a failure to dissociate fully from trafficking proteins at the cell surface. GLUT4 transporters appear to have a greater tendency to remain internalized if the normal mechanisms that commit transporters to the cell surface, such as dissociation from trafficking proteins, are uncoupled.

3T3 Cells↗
PubMed1992

Hospital records as a data source for occupational disease surveillance: a feasibility study.

To assess the feasibility of using hospital records for occupational disease surveillance and to evaluate the quality of the industry/occupation (I/O) information available in these records, the computer file of all discharge diagnoses from a large health maintenance organization during 1985 was reviewed. The frequencies of discharge diagnoses previously listed as Sentinel Health Events (Occupational), or SHE (O), were calculated and three possible SHE(O) diagnoses--lung cancer, bladder cancer, and toxic hepatitis--were selected for further review. Outpatient charts of patients discharged for each diagnosis were abstracted with regard to I/O information and the discharged patients were interviewed by telephone to obtain a lifetime occupational history. The accuracy of the I/O information obtained from the hospital chart was compared to that obtained by patient interview by number of digits matched on standard classification codes. The frequencies of matches for occupation and industry were greater for "usual" than for "last" categories with both cancer diagnoses, but were similar for "usual" and "last" categories with toxic hepatitis. To assess the proportion of each possible SHE(O) diagnosis that was related to workplace exposures, the I/O information obtained by interview was rated in a blinded fashion by an experienced occupational medicine physician. The highest probability ratings for work-relatedness were noted for lung cancer, primarily due to asbestos exposure. The results of this study suggest that hospital records can be used to identify possible SHE(O); if adequate I/O information is available, then work-relatedness can be assessed. However, the accuracy of I/O obtained from hospital charts is relatively low. The efficient and accurate collection of I/O information from hospital records will require the use of a simple, easily coded instrument to be routinely administered on admission.

Asbestos↗
PubMed1992

Compliance with hormone replacement therapy (HRT) after screening for post menopausal osteoporosis.

OBJECTIVE: To assess compliance with recommendations for hormone replacement therapy (HRT) in postmenopausal women following screening for osteoporosis. DESIGN: A postal questionnaire sent to women an average of 8 months (range 6-12) following measurement of their bone mineral density (BMD), and recommendations regarding HRT given to the referring general practitioner. SETTING: Referrals from local general practitioners. Mixed social class. SUBJECTS: 400 postmenopausal women aged 40-69 years (average age 52). MAIN OUTCOME MEASURES: Compliance with advice and if failing to comply, reasons for not doing so. RESULTS: Replies were received from 352 women (88%) and 74% of respondents followed advice to start, continue, or refrain from starting or continuing HRT with regard to protecting their skeleton. Those who rejected advice to take HRT mostly had concern over side effects or the efficacy or safety of treatment. Of the women who started HRT 28% subsequently stopped, the principal reasons being withdrawal bleeding and weight gain. Of the women recommended to take HRT, 39% were not taking treatment by 8 months after referral, either because they ignored advice given (22%) or because of side effects (17%). CONCLUSIONS: Screening leads to increased usage of HRT among women at most risk for osteoporosis. However, almost 40% of women with low bone mineral density were not taking HRT 8 months after referral, and therefore until improved compliance has been demonstrated screening cannot be widely recommended.

Aged↗
PubMed1991

Human fibroblast stromelysin catalytic domain: expression, purification, and characterization of a C-terminally truncated form.

Stromelysin-1 is a member of a tissue metalloproteinase family whose members are all capable of degrading extracellular matrix components. A truncated form of human fibroblast prostromelysin 1 lacking the C-terminal, hemopexin-like domain has been expressed in Escherichia coli and purified to homogeneity. Treatment of this short form of prostromelysin with (aminophenyl)mercuric acetate resulted in activation and loss of the propeptide in a manner identical with the wild-type, full-length protein. Kinetic comparisons using Nle11-substance P as a substrate showed that the wild-type stromelysin and the truncated form of the enzyme had similar kcat and Km values. Likewise, both enzymes displayed similar Ki values for a hydroxamate-containing peptide inhibitor. Taken together, these results indicate that the C-terminal portion of stromelysin is not required for proper folding of the catalytic domain, maintenance of the enzyme in a latent form, activation with an organomercurial, cleavage of a peptide substrate, or interaction with an inhibitor. Moreover, the active short form of stromelysin displayed a reduction in the C-terminal heterogeneity, a characteristic degradation of the full-length stromelysin, and thereby provides a more suitable protein for future structural studies.

Amino Acid Sequence↗