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Biomedical subjects

A K Sullivan

Publications and source records attributed to A K Sullivan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Characterization of an acquired IgG inhibitor of coagulation factor XIII in a patient with systemic lupus erythematosus.

An acquired IgG inhibitor to factor XIII was identified in a 30-year-old Vietnamese woman with systemic lupus erythematosus. The IgG fraction was isolated from plasma by chromatography on an agarose gel column and by protein G adsorption. The anti-factor XIII activity, identified within the IgG fraction, inhibited factor XIII from both normal plasma (a2b2) and platelets (a2). A normal level of the b subunit was measured by immunoelectrophoresis of the patient's plasma, but the a subunit was not detected. These results suggested the presence of an IgG immunoglobulin which recognized the a subunit and interfered with its activity.

Adult↗
PubMed1996

Recombinant human bone morphogenetic protein-2 induces a hematopoietic microenvironment in the rat that supports the growth of stem cells.

In the mammalian bone marrow, stromal components support the growth and differentiation of blood cells. To study this complex system, we used a rat model in which ectopic hematopoietic tissue was induced to form after subcutaneous implantation of recombinant human bone morphogenetic protein (rhBMP-2). We showed that this organoid contained clonogenic precursors of both erythroid and myeloid lineages and progenitors competent to regenerate splenic lymphopoiesis. Furthermore, stem cells derived from ectopic foci conferred both short-term (30 day) and long-term (>6-month) protection in vivo against radiation-induced marrow aplasia. Lead shielding of the ectopic marrow in situ also permitted endogenous recovery of hematopoiesis after sublethal irradiation. Extending previous observations that most fibroblastoid cells of the marrow stain with the anti-ST3 antibody (but minimally with anti-ST4), whereas those growing from nonhematopoietic tissues react with anti-ST4, we found that analogous cells of the ectopic foci stained predominantly with anti-ST3. The ability to induce formation of a hematopoietic microenvironment from mesenchymal precursors may make possible the development of new strategies for the treatment of primary disorders of stem cells and irreversible stromal injury.

Animals↗
PubMed1995

Acute effect of oestrogen replacement therapy on treadmill performance in postmenopausal women with coronary artery disease.

The significant reduction in cardiovascular morbidity and mortality following oestrogen replacement therapy in postmenopausal women is only partly explained by an improved lipid profile. Given acutely, oestradiol causes vasodilatation and increases coronary blood flow and, in large doses, improves treadmill performance in postmenopausal women with coronary artery disease. However, the significance of oestrogen-mediated vasodilatation is unknown since the acute effects of oestradiol in doses and preparations commonly used clinically have not been tested. The aim of this study was to evaluate the acute effects of conventional replacement therapy with 17 beta-oestradiol on treadmill performance in 16 postmenopausal women with angina in a randomized, double-blind, placebo-controlled cross-over trial. Following baseline treadmill testing a transdermal oestrogen patch releasing 50 micrograms oestradiol. 24 h-1 or matching placebo was applied and the exercise test repeated 24 h later. The patch was then removed. Seven to 14 days later the sequence was repeated using the alternative patch. The changes in time to angina, time to 1 mm ST segment depression and total exercise time for each treatment compared with the corresponding baseline test were calculated. Plasma 17 beta-oestradiol increased with active therapy from 56 +/- 30 pmol.l-1 to 204 +/- 90 pmol.l-1, indicating adequate replacement. Compared with their respective baseline exercise tests there were no differences between active and placebo patches for time to angina (active: 13 +/- 55 s vs placebo: 10 +/- 47 s), time to 1 mm ST segment depression (active: -30 +/- 52 s vs placebo: 24 +/- 71 s) or total exercise time (active: 14 +/- 45 s vs placebo: 13 +/- 35 s). Despite the recognized acute vasodilator action of larger doses of oestrogen, doses conventionally used in hormone replacement therapy had no acute effect on treadmill performance in this group of postmenopausal women with coronary artery disease.

Administration, Cutaneous↗
PubMed1994

Chest pain in women: clinical, investigative, and prognostic features.

OBJECTIVE: To characterise clinical, investigative, and prognostic features of women referred with chest pain who subsequently underwent coronary angiography. DESIGN: Analysis of all women with angina referred to one consultant during 1987-91 who subsequently underwent coronary angiography, with follow up to present day. SETTING: Cardiothoracic centre. SUBJECTS: Women with normal coronary arteries; women with coronary artery disease shown on angiography; men with coronary artery disease matched for age; men referred with chest pain during the same period subsequently found to have normal coronary arteries. MAIN OUTCOME MEASURES: Risk factor analysis; results of exercise testing and coronary angiography; intervention; morbidity and mortality. RESULTS: Women comprised 23% (202/886) of patients referred with chest pain who subsequently underwent angiography. 83/202 women had normal coronary angiograms compared with 55/684 men (41% v 8%, P < 0.01). Diabetes mellitus was the only risk factor more frequently encountered in women with coronary artery disease (P = 0.001). The specificity and positive predictive value of exercise testing before angiography were significantly lower in women than men (71% v 93%, P < 0.001 and 76% v 95%, P < 0.001, respectively). Revascularisation procedures were as common in women with coronary artery disease as in men (81 (68%) v 70 (59%)), and there was no difference in event rate during follow up. Many patients with normal coronary arteries, irrespective of sex, had symptoms during follow up (61 (73%) women, 36 (65%) men) and continued to take antianginal drugs (27 (33%) women, 14 (28%) men); 14 (17%) women and six (11%) men required hospital readmission for severe symptoms. CONCLUSIONS: In this series, although women comprised the minority of patients referred with chest pain, a diagnosis of normal coronary arteries was five times more common in women than men. Risk factor analysis and exercise testing were of limited value in predicting coronary artery disease in women. There was no sex bias regarding revascularisation procedures, and outcome was similar. A diagnosis of non-cardiac chest pain in patients with normal coronary arteries was of little benefit to the patient with regard to morbidity.

Angina Pectoris↗
PubMed1993

Lack of rebound during intermittent transdermal treatment with glyceryl trinitrate in patients with stable angina on background beta blocker.

OBJECTIVE: To assess whether intermittent transdermal treatment with glyceryl trinitrate causes clinically significant rebound in patients maintained on beta blockers for stable angina pectoris. DESIGN: Serial treadmill exercise testing in a double blind, randomised, placebo controlled cross over trial. Baseline exercise testing was performed at 0900 and 1100 at visit 1. Transdermal glyceryl trinitrate patches releasing 15 mg/24 h were applied at 2200 the evening before visits 2 and 3, and exercise testing was performed at 0900 the next morning. The patch was removed and replaced with either an identical patch or matching placebo and exercise tests were repeated two hours later. The alternative treatment was given at visit 3. SETTING: Tertiary referral centre. PATIENTS: 14 patients with stable angina pectoris maintained on beta blocker treatment alone. MAIN OUTCOME MEASURES: Time to angina, 1 mm ST segment depression, and total time, together with heart rate, systolic blood pressure, and rate-pressure product. RESULTS: Active treatment improved treadmill performance at 0900 and 1100. Time to angina, time to 1 mm ST segment depression, and total time fell significantly on placebo compared with the 0900 exercise test on active treatment, but were not significantly different to the baseline exercise test either. CONCLUSIONS: Intermittent transdermal treatment with glyceryl trinitrate is not associated with the rebound phenomenon in patients maintained on beta blockers for stable angina pectoris.

Administration, Cutaneous↗
PubMed1993

Inhibitors of hematopoietic colonies are produced by certain rat fibroblastoid cell lines and are modulated by corticosteroids.

Both stimulatory (CSA) and inhibitory (INH) factors may contribute to hematopoietic regulation, but little is known about how their physiologic balance is maintained. Previously we have shown that antigen-defined fibroblastoid cells cultured from rat lung (ST3-/ST4+) constitutively produce INH, and those derived from bone marrow (ST3+/ST4-) respond to macrophage cytokines to release both CSA and INH into their conditioned media (CM). Here we show that this pattern was maintained in cell strains ("ST3" and "ST4") propagated from the primary cultures, and that the presence of CSA was measured in "ST4" CM if the inhibitory > 100 kd fraction was removed. Two subclones of the "ST3" line, called 2A and 9D, were selected for high or low expression of the ST3 antigen, respectively. Both produced CSA, but only 9D produced the > 100 kd inhibitor. In the CM of cells cultured in the presence of hydrocortisone, there was less INH detected but CSA was not changed. From these data, however, we cannot assess how many individual cell products might be contributing to the INH activity. These results demonstrate that the appearance of inhibitory activity in the growth media differs among fibroblast subpopulations, and that it can be modified by natural regulators such as corticosteroids.

Adrenal Cortex Hormones↗
PubMed1992

Fibroblastoid cells derived from rat bone marrow and lung differ in their pattern of production of hemopoietic stimulators and inhibitors.

Blood cells develop in the bone marrow, controlled by a complex network of regulatory factors, some of which originate in the non-hemopoietic stroma. Previously we found that the predominant fibroblastoid (FB) cell growing in primary cultures of rat marrow bears surface antigens different from similar cells derived from certain other tissues. As determined by two monoclonal antibodies, the 'marrow type' is ST3+/ST4-, and the 'peripheral type' is ST3-/ST4+. Here we describe some of the functional differences between these two cell types. After primary cultures were depleted of hemopoietic elements and 'other' type FB, colony-stimulating activity was detected in the conditioned media (CM) of cells derived from marrow (ST3+), but not from lung (ST4+). Conversely, lung FB produced a CM that inhibited the clonogenic growth of normal marrow precursors. This substance (or substances) was produced by lung cells in the absence of exogenous stimulation, but by marrow cells only after they had been cultured in the presence of macrophage-derived products. The inhibitory activity did not have any measurable effect on murine blood cell precursors. We conclude that these isolated antibody-defined fibroblast subpopulations from different organs differ in their capacity to stimulate or inhibit normal hemopoietic precursors.

Animals↗
PubMed1992

The use of monoclonal antibodies against primary myeloid granules in normal and leukemic cells.

Three monoclonal antibodies, K101, D46, and H36/71 (CD15), reactive with membrane components of primary granules of human promyelocytes, were studied to assess their binding to normal and leukemic cells. Using the alkaline phosphatase antialkaline phosphatase technique, these antibodies were applied to sections of normal organs and to peripheral blood and bone marrow films from hematologically normal individuals and patients with hematologic malignancies. In control experiments, antibodies showed reactivity with cytoplasmic constituents of granulocytes from the promyelocytic to the neutrophilic stage. In acute myeloid leukemia, antibody K101 was positive (more than 20% of blasts) in 13 of 21 (62%) cases, while antibody D46 was positive in 11 of 17 (65%) cases. Antibody H36/71 was positive in only 4 of 24 (17%) cases of acute myeloid leukemia. At least one marker was present in 6 of 8 (75%) cases of acute lymphoblastic leukemia with myeloid antigen-positive blasts and was negative in 20 cases of acute lymphoblastic leukemia with myeloid antigen-negative blasts. These results support the view that abnormal granules (with defective expression of the D46, K101, and H36/71 antigens) form in blastic and leukemic cells of patients with acute myeloid leukemia. Data also suggest that membrane components of myeloid granules are made in the cytoplasm of cells from some acute lymphoblastic leukemia patients with myeloid antigen-positive blasts.

Antibodies, Monoclonal↗
PubMed1991

Expression of a marrow stroma and thymus-associated antigen (ST3) in the rat brain: comparison with Thy-1.

Cells of the immunohemopoietic and nervous systems express certain molecules that generally are not found in other tissues. One example is the 'ST3' antigen, which is present on the major population of fibroblastoid cells grown from rat bone marrow, but is not detected on adherent cells from most peripheral organs (e.g. lung). An immunohistological survey revealed ST3 also in the thymic cortex, the glomerular mesangial area, and the brain. Because this pattern of distribution is similar to that described for Thy-1, we compared the localization of the two antigens in the adult rat brain and found that there were areas where it was congruent and others where it was distinct. Staining for ST3 was absent from the white matter, but was especially notable in discrete layers of the frontal, orbital, parietal, and cingulate cortices, the substantia nigra, the inferior olivary nuclei, and the deep molecular layer of the cerebellum, as well as other scattered regions in the gray matter. This is in contrast to Thy-1, which stained more diffusely throughout the gray zones. In further experiments using primary brain cell cultures, ST3 was demonstrated on neurons, but not on oligodendrocytes or astrocytes. Similarly, it was found on the surface of cells of the PC12 neuronal line, but not on the C6 astrocytoma. This restricted distribution on a subpopulation of neurons raises the possibility that the ST3 epitope might be part of a cell interaction molecule of the marrow stroma, thymus, and brain.

Animals↗
PubMed1991

Clonal succession and deletion of bcr/abl sequences in chronic myelogenous leukemia with recurrent lymphoid blast crisis.

The development of cancer is generally believed to occur by a multistep process in which critical genetic defects accumulate in a clone of cells, confer a growth advantage, and result in the emergence of more malignant subclones. This paper describes the clonal origin of cells in a patient with Philadelphia-chromosome negative, M-bcr rearrangement-positive chronic myelogenous leukemia, observed in two episodes of lymphoid blast crisis (BC), the intervening chronic phases (CP), and following allogeneic bone marrow transplantation. Serial analysis of immunoglobulin heavy and kappa light chain (IgJH, IgCK), beta-T-cell receptor (beta-TcR) and bcr major breakpoint cluster region (M-bcr) gene rearrangements was performed. Clonal IgJH rearrangements present in cells of the first lymphoblastic crisis (BC1) were altered during the chronic phase post-treatment (CP1), and were again altered in recurrent blast crisis (BC2). In addition, the M-bcr gene rearrangement present in BC1 and CP1 was absent from cells in BC2. These observations suggest that the course of clinical neoplastic disorders may not always be characterized simply by a hierarchical process of clonal evolution, but may also involve clonal succession of malignant cells. Moreover, the deletion of M-bcr in recurrent BC suggests that bcr/abl may not be essential for the maintenance of cell growth in established BC.

Adult↗
PubMed1990

Establishment of an osseous cell line from fetal rat calvaria using an immunocytolytic method of cell selection: characterization of the cell line and of derived clones.

Using selective media and complement-mediated lysis of primary cultures of a fetal rat calvarial cell population, we have developed a cell line (OBCK6) that exhibits osteoblastic characteristics. OBCK6 cells demonstrated enhanced parathyroid hormone (PTH)-stimulated adenylate cyclase activity relative to the primary calvarial population, production of alkaline phosphatase activity and type 1 collagen, and the capacity to form mineralized nodules in unsupplemented medium after prolonged (22-26 day) culture. Two sublines, CFK1 and CFK2, which were isolated by dilution cloning, differed morphologically and with respect to growth rate. CFK1 cells demonstrated high PTH and prostaglandin E2-stimulated adenylate cyclase activity, whereas only low PTH-stimulated activity was observed in CFK2 cells. Retinoic acid and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] each reduced PTH-stimulated adenylate cyclase activity in both the cell types. Retinoic acid and dexamethasone reduced and 1,25(OH)2D3 enhanced alkaline phosphatase activity in these cells. PTH significantly augmented alkaline phosphatase activity to a much greater extent in CFK1 than in CFK2 cells. Both CFK1 and CFK2 cells expressed type I but type III collagen, and neither expressed osteocalcin. Strong Alcian blue staining of CFK2 cells was suggestive of a cartilaginous phenotype. These three cell lines, therefore, demonstrated discrete characteristics of skeletal cell function and should provide important models for evaluation of mechanisms of mineralization and for control of skeletal cell growth and mesenchymal differentiation in vitro.

Adenylyl Cyclases↗
PubMed1989

New CD4(+) cell line susceptible to infection by HIV-1.

Infection of a newly described human T lymphoid cell line, CEM-CL10, with three different variants of HIV-1 resulted in cytopathic effects followed by cell lysis. Following primary lytic infection, proviral DNA could not be detected by Southern blot analysis in the outgrowth of the surviving CEM-CL 10 cells 60 days after initial exposure to HIV-1. These surviving cells could be further grown as a separate line, derived from CEM-CL10, and were found to be resistant to subsequent infection by HIV-1. A marked decrease in CD4 antigen expression was observed in these latter cells but not of the CD3 and transferrin receptor antigens. This decline in cell surface CD4 expression was correlated with both an absence of specific CD4 mRNA and with changes in structure of the CD4 gene. Both the HIV-1-sensitive CEM-CL10 cell line and its CD4(-), HIV-1-resistant derivative line, will be made available to interested investigators.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Cellular composition of rat bone marrow stroma. Antigen-defined subpopulations.

Although stromal cells establish the architecture of mammalian bone marrow and organize hemopoiesis, the interrelationships among their macrophage, fibroblastic, endothelial, and adipocyte-like components are not wholly understood. Using murine monoclonal antibodies to cultured adherent cells of rat bone marrow, we observed that the predominant fibroblastoid cells grown from marrow differed from those of non-hemopoietic organs. The marrow type bore a detectable quantity of the ST3 but not ST4 antigen, whereas those from lung, diaphragm, and epididymal fat pad, bore more ST4 than ST3. Those from spleen were an equal mix of both types. Although the tissue distribution of the ST3 antigen was similar to that of Thy-1, it was not identical, and in the brain, the two structures were localized in different areas. While none of the ST3, ST4 (fibroblast directed), or BN(MB)35 (myeloid directed) antibodies recognized fat cells cultured from marrow, the ST10 antibody, selected for binding to marrow derived fat cells, stained peripheral adipose cells, unidentified aglobular cells in areas of fat cell formation, and macrophages, but not fibroblasts. On the basis of these observations, we suggest that the fibroblastoid cells of the marrow are different from those of non-hemopoietic tissues.

Adipose Tissue↗