Biomedical subjects
Publications and source records attributed to D A Clark.
A new series of thiazolidine-2,4-diones was obtained by replacing the ether function of englitazone with various functional groups, i.e., a ketone, alcohol, or olefin moiety. These compounds lower blood glucose levels in the genetically obese and insulin-resistant ob/ob mouse. Appending an oxazole-based group at the terminus of the chain provided highly potent compounds.
Postimplantation murine decidual tissue from allopregnant C3H mice has been shown to release in vitro a potent immunosuppressive factor closely related to transforming growth factor (TGF)-beta 2 but slightly lower in apparent molecular weight. Decidual suppressor factor (DSF) activity was first detected in decidual tissue supernatant at day 9.5 of gestation and reached a plateau by day 10.5 to 12.5. By Northern analysis of decidual and placental tissue with a simian TGF-beta 2 probe, two characteristic TGF-beta 2 mRNA transcripts were detected in decidual tissue. In situ hybridization analysis of C3H implant sites, with the simian (pGEM-G1G2) TGF-beta 2 riboprobe, revealed a small population of TGF-beta 2+ cells localized to postimplantation decidua basalis and metrial gland cell area after day 8.5. On and before day 8.5, when DSF was not detectable, few TGF-beta 2 mRNA+ cells were detected. To test for TGF-beta release in situ, sections of uterine tissue were stained with antibody specific for TGF-beta 2, that identified DSF in Western blots. In postimplantation tissues (day 9.5, 12.5) patchy anti-TGF-beta 2 staining was seen over decidual tissue. Before day 9.5, slight and diffuse staining over decidual tissue was present with more marked staining of extradecidual tissue. Very little staining was noted over day 9.5 decidual tissue by using anti-TGF-beta 1 antibody as a control; however, some staining was seen over postimplantation fetal trophoblast and myometrial tissue. Fractionation of disaggregated postimplantation decidua by velocity sedimentation revealed that TGF-beta 2 mRNA+ cells were predominantly small and sedimented in the same fraction(s) as those cells previously shown to release DSF in vitro. Thus, the release of TGF-beta 2 related DSF correlates with the in situ detection of TGF-beta 2 mRNA and the in situ release of TGF-beta 2 peptide. These studies suggest that DSF may be a form of TGF-beta 2 released by a population of small lymphocytic decidual suppressor cells.
Involvement of the larynx by mycosis fungoides is extremely rare with only three reported clinical cases in the English-language literature. We present two patients with laryngeal mycosis fungoides, one of whom presented with vocal cord paresis (progressing to paralysis) as the initial clinical manifestation of laryngeal involvement. Our clinical findings and the observations from the three previous case reports suggest that laryngeal mycosis fungoides has a predilection for the arytenoids, aryepiglottic folds, and the laryngeal surface of the epiglottis. Laryngeal involvement, like other forms of visceral dissemination, appears to manifest clinically in the terminal stages of the disease. The natural history, clinical features, histopathology, and treatment of mycosis fungoides are reviewed and the etiopathology of the vocal cord paralysis is described.
Cardiac catheterization and angiography is a safe procedure performed on patients with suspected or potentially serious cardiovascular disorders. Complications of the procedure are related both to heart disease itself and to elements of the procedure. For a variety of social and financial reasons, the performance of cardiac catheterization and coronary angiography on an outpatient basis has increased recently. The purpose of this paper is to state the guidelines of The Society for Cardiac Angiography and Interventions regarding the performance of outpatient catheterization in a hospital setting.
A revised form of the Distressing Thoughts Questionnaire as well as standardized self-report measures of depression, anxiety and obsessionality were administered to a large sample of psychiatric inpatients, outpatients and non-clinical controls. A subsample of the clinical subjects completed the questionnaire battery after 3 months. Factor analysis identified three distinct dimensions of negative thinking which corresponded to anxious, depressive and intrusive thoughts. Further analysis revealed that the intrusive thoughts differed from the anxious and depressive negative automatic thoughts in terms of their reduced association with psychopathology, increased temporal stability and nonspecific association with negative affect in general. These findings suggest that by adopting a more specific focus on obsessive-like ego-dystonic intrusive thoughts, researchers will be in a better position to investigate the role of this phenomena in the development of clinical obsessions.
Ascitic fluid from human ovarian carcinoma (AF) has been shown to inhibit IL-2-induced lymphokine-activated killer (LAK) cell generation from peripheral blood mononuclear cells (PBMC) resulting from the presence of biologically active transforming growth factor-beta (TGF-beta). A 50% concentration of AF completely suppressed the LAK response to 100 units IL-2/ml and only partial reversal (less than 50%) could be achieved by increasing the IL-2 concentration to 1000 units/ml. We evaluated the ability of tumor necrosis factor-alpha (TNF-alpha, 1-1000 ng/ml) and anti-CD3 antibody (alpha-CD3, 1-100 ng/ml) to reverse AF-mediated suppression of IL-2-stimulated LAK generation. TNF-alpha alone did not generate significant LAK activity, but in the presence of suboptimal concentrations of IL-2 (10 and 100 units/ml), TNF-alpha significantly boosted the generation of LAK, but was unable to significantly reverse AF-mediated suppression of the IL-2 response (even at 1000 units/ml). In contrast, alpha-CD3 alone generated LAK activity at concentrations as low as 1 ng/ml and markedly enhanced generation of LAK activity when added to suboptimal concentrations of IL-2. alpha-CD3 combined with IL-2 significantly reversed AF suppression at 100 units IL-2/ml and at 1000 units/ml completely reversed suppression by two of three highly suppressive samples of AF. Significant reversal occurred with the third AF sample. It may be possible to overcome TGF-beta-mediated suppression by measures other than by increasing the IL-2 concentration.
Granulocyte-derived chlorinated amines and bacterial formyl peptides are thought to enhance epithelial permeability. In the current study, gut permeability to [51Cr]ethylenediaminetetraacetic acid (EDTA) was monitored in response to luminal formyl-methionyl-leucyl-phenylalanine (fMLP) and histamine monochloramine and dichloramine. Responses were determined in rabbits during states of basal and elevated permeability. Luminal fMLP had minimal effects of gut permeability in control and injured states. Histamine monochloramine or dichloramine enhanced epithelial permeability under basal conditions; this effect was exaggerated by a pre-existing injury. Both histamine monochloramine and dichloramine retained full histamine agonist properties, and a combination of antioxidant and antihistamine therapy was required to block this increase in gut permeability. Whereas histamine chloramines caused a dose-dependent cytotoxicity in rat-cultured enterocytes, marked histological changes to the mucosa were not evident, nor were mucosal glutathione levels depleted. As histamine chloramines retain the histaminergic and oxidizing potential of their precursors, they represent a unique form of inflammatory mediator, although their highly reactive nature precludes in vivo confirmation of their formation.
Rapid isolation of tumor cells growing in clumps from the ascitic fluid of patients with ovarian carcinoma was achieved by harvesting cells from ascitic fluid and subsequently passing them over a 30-microns nylon mesh filter. Single cells and small cell aggregates passed through the mesh, and large cell clumps that had not passed through the filter were isolated by backwashing. Morphologically, the cells in the clumps consisted almost entirely of tumor cells. The clumps were analyzed by immunocytochemistry and only a small proportion of cells (3.1 +/- 0.5% to 8.3 +/- 0.8%) stained with anti-CD45 monoclonal antibody (a panleukocyte marker for cells of hematopoietic origin). Most of the cells in clumps stained positively (90.6 +/- 1.7% to 97.5 +/- 0.5%) with 2G3 (a monoclonal antibody binding to a high-molecular-weight carcinoma-associated antigen). Unfiltered cell populations, however, contained up to 34.4 +/- 2.1% contaminating CD45+ non-tumor cells. This method should be useful for rapidly and easily obtained highly enriched fresh ovarian carcinoma cells from ascitic fluid in a form in which they grow naturally.
Antibody responses to ingested antigens can be inhibited by a mechanism known as oral tolerance which acts to prevent excessive stimulation from luminal contents. Local IgA responses can be induced in this non-responsive environment and during intestinal inflammation, mucosal IgG responses can also be increased. The purpose of this study was to compare a panel of cytokines to factors from macrophage-T cell co-culture supernatants for their ability to enhance isotype and sheep red blood cell (SRBC)-specific plaque-forming cell responses in an in vitro model of oral tolerance. IL-2, IL-4, IL-5, and IL-6, which have been implicated in IgA regulation of lipopolysaccharide-stimulated B cells, were not capable of enhancing responses in tolerized cultures; however, transforming growth factor (TGF)-beta 1 had a dose-dependent ability to enhance responses to the T cell-dependent antigen SRBCs in this system. The enhancement was only seen when antigen was present and was neutralized by specific rabbit antiserum but not normal rabbit IgG. Similar treatment of soluble factors from the macrophage-T cell co-cultures did not inhibit their ability to enhance responses suggesting at least two distinct molecular mechanisms could augment responses in tolerized cultures. This was substantiated further by showing that TGF-beta 1 was not isotype-specific. In contrast, adsorption of the macrophage-T cell co-culture supernatants against monoclonal IgA or IgG removed isotype-specific binding factors which were necessary for the enhancement of IgA and IgG respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
To examine the immune response to retroviral gag sequences in autoimmune disease, we measured antibody levels to synthetic peptides representing the major epitopes on HTLV-1 p19 gag and a homologous sequence on the endogenous retrovirus, HRES-1, in sera from 121 patients with autoimmune disease and 52 healthy controls. In the absence of HTLV-1 antibodies, using a conventional diagnostic assay, significantly elevated levels of antibodies to the HTLV-1 peptide were found in 23% of multiple sclerosis and 20% of anti-Sm antibody positive systemic lupus erythematosus patients. Elevated antibody levels to HRES-1 were found in 32% of Sjögren's syndrome and 19% of multiple sclerosis patients. Evidence of reactivity with both HTLV-1 and HRES-1 was found in human sera and cross-reactivity demonstrated with affinity purified rabbit anti-peptide antibodies. Expression of HRES-1, detected by antibodies and Northern blots, was found in lymphoblastoid cells, salivary gland biopsy sections and salivary gland epithelial cells in culture. This study confirms previous reports of low levels of anti-retroviral gag antibodies in autoimmune disease. The cross-reactions support the concept that reports of elevated HTLV-1 antibodies may be due to an endogenous agent such as HRES-1. The expression of HRES-1 salivary gland may explain its antigenicity in a small proportion of Sjögren's syndrome patients as well as suggesting mechanisms whereby it may contribute to the chronic inflammation of autoimmune disease.
To examine the possible involvement of retroviruses in Sjögren's syndrome (SS), labial salivary gland sections from 99 individuals were probed with three MoAbs to core (gag) proteins of human T cell leukaemia virus-1 (HTLV-1) and two MoAbs to HIV-1. Sections from 31% of 39 patients with primary SS (pSS) contained an epithelial cytoplasmic protein reactive with a MoAb (197) to the p19 group specific antigen (gag) of HTLV-1. The antigen was also detected in samples from 24% of 17 patients with rheumatoid arthritis (RA) and SS, 21% of 14 patients with sicca symptoms and 12.5% of 16 patients with other connective tissue diseases. It was not found in the salivary glands of 13 normal controls. A second MoAb to p19 gag, a MoAb to the p24 gag of HTLV-1 and MoAbs to HIV-1 p17 and p24 gags gave negative reactions. Serum antibodies to HTLV-1 were negative, confirming that the antigen was not part of HTLV-1. The antigen showed properties consistent with an endogenous retrovirus in that it was absent in healthy tissues or resting cells but inducible by stimulation with phytohaemagglutinin (PHA) or interferon-gamma (IFN-gamma). It appeared to be distinct from the endogenous retroviral sequence HRES-1. These data suggest the presence of an endogenous retrovirus in salivary gland epithelium which could contribute to the chronic inflammation of SS.
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Transforming growth factor beta (TGF beta) is a multifunctional protein which has been suggested to play a central role in the pathogenesis of chronic inflammation and fibrosis. Nasal polyposis is a condition affecting the upper airways characterized by the presence of chronic inflammation and varying degrees of fibrosis. To examine the potential role of TGF beta in the pathogenesis of this condition, we investigated gene expression and cytokine production in nasal polyp tissues as well as in the normal nasal mucosa. By Northern blot analysis using a porcine TGF beta 1 cDNA probe, we detected TGF beta 1-specific mRNA in nasal polyp tissues, as well as in the tissue from a patient with allergic rhinitis, but not in the normal nasal mucosa. By the combination of tissue section staining with chromotrope 2R with in situ hybridization using the same TGF beta 1 probe, we found that approximately 50% of the eosinophils infiltrating the polyp tissue express the TGF beta 1 gene. In addition, immunohistochemical localization of TGF beta 1 was detected associated with extracellular matrix as well as in cells in the stroma. These results suggest that in nasal polyposis where eosinophils are the most prevalent inflammatory cell, TGF beta 1 synthesized by these cells may contribute to the structural abnormalities such as stromal fibrosis and basement membrane thickening which characterize this disease.
OBJECTIVE: This study sought to determine the short- and long-term effects of focused cognitive therapy for panic disorder. METHOD: Thirty-three psychiatric outpatients with the DSM-III diagnosis of panic disorder were randomly assigned to either 12 weeks of individual, focused cognitive therapy or 8 weeks of brief supportive psychotherapy based on principles of client-centered therapy. The patients who received supportive psychotherapy were subsequently given the opportunity to cross over to cognitive therapy for 12 weeks. Patients were rated for panic and depression before therapy, after 4 and 8 weeks of therapy, and at 6-month and 1-year follow-up. RESULTS: Clinician ratings and self-ratings of panic frequency and intensity indicated that the focused cognitive therapy group achieved significantly greater reductions in panic symptoms and general anxiety after 8 weeks of treatment than did the group that received brief supportive psychotherapy. At 8 weeks, 71% of the cognitive therapy group were panic free, compared to 25% of the psychotherapy group. Moreover, 94% of the psychotherapy patients elected to cross over to 12 weeks of cognitive therapy. At 1-year follow-up, 87% of the group that received cognitive therapy only and 79% of the group that crossed over into cognitive therapy remained free of panic attacks. CONCLUSIONS: Focused cognitive therapy offers a promising nonpharmacological alternative for the treatment of panic disorder.
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GM-CSF decreases the hematopoietic toxicity of both nonablative and marrow ablative intensive chemotherapy regimens. Data are limited at this time, particularly in regard to optimal schedules and GM-CSF dosing regimens with particular chemotherapy programs. The importance of GM-CSF scheduling in relationship to chemotherapy is becoming more clear. The dose-intensive regimens supported by GM-CSF produce a high complete remission rate in several types of malignancy. Evidence that these remissions will be durable is still lacking. Future directions will include filling some of these voids in our knowledge, as well as exploring various cytokine combinations for improved hematopoietic recovery and other chemotherapeutic regimens for improved antitumor effect. The near complete cytoreduction produced by these dose-intensive regimens may also create a better setting for attempts at therapeutic immunomodulation. Yet another, but more difficult, task will be to identify those situations where progenitor cell replacement is beneficial and appropriate.
This report presents the first year's experience of a totally computerized cardiac catheterization laboratory reporting system, including the results and complications of invasive and interventional procedures. Sixty-three laboratories reported a total of 71,916 patients studied between January 1 through December 31, 1990. Two previous registry reports have been published. Compared with data acquired by previous methods, in spite of an older and sicker population, the mortality for diagnostic procedures has remained remarkably constant (0.11%). The computerized format facilitates data collection and analysis, helps resolve new issues as they arise and serves as a method of monitoring quality of laboratories and individuals.
The effect of cell-free ascitic fluid from patients with epithelial ovarian carcinoma on the generation of lymphokine-activated killer cells (LAK) was compared to the activity generated in control medium containing 10% fetal bovine serum, using Daudi target cells. Samples of ascitic fluid from nine different patients tested inhibited LAK generation. Suppressive activity was evident as early as 24 h of incubation in the presence of ascitic fluid and increasing suppression developed with prolonged exposure. Suppression was concentration-dependent, present at 10%-20% and increasing with concentrations up to 80%. The suppressive effect of ascitic fluid was only partially reversed on increasing the concentration of interleukin-2 (IL-2) from 10 units to 1000 units/ml. Activated LAK appeared to maintain the majority of their activity on further culture in ascitic fluid in the presence of IL-2 but further enhancement of lytic activity was prevented. Fractionation of a suppressive sample by HPLC, using 0.1 M KCl/acetic acid buffer pH 2.6, revealed that the dominant peak of suppressive activity eluted at 25 kDa; with pH 7.0 TRIS-buffered saline, most of the activity was lost on the column. Antibody neutralization studies of the 25-kDa suppressive peak as well as on whole ascitic fluid have revealed that transforming growth factor beta (TGF beta) is the major suppressive factor present in ascitic fluid. Factors that suppress LAK generation in vitro were present in all samples tested. The effect on the lytic activity of activated LAK cells was minimal. This suggests that, in the clinical setting, the greatest impact would be achieved by activating LAK cells ex vivo and subsequently transferring them to the peritoneal cavity in the presence of IL-2 rather than by attempting to generate them in situ by injecting IL-2 into the peritoneal cavity. However, reversal of TGF beta-mediated suppression in situ may be necessary to allow local proliferation of LAK cells to achieve an effective killer-to-target ratio.