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Biomedical subjects

R A Clark

Publications and source records attributed to R A Clark.

At least 325 records · Page 18Linked to original sources
PubMed1985

Granulocytic sarcoma (chloroma): CT manifestations.

Nests of granulocytic tumor cells in patients who have myelogenous leukemia are termed chloromas. Eight cases of chloroma seen on CT were reviewed. Lymph nodes, subcutaneous tissues, peritoneum, pleural space, pelvis, and portal hepatis were involved. Two patients exhibited chloroma as the sole manifestation of their disease during bone marrow remission. The extracranial appearance of chloroma on CT is that of small, nonenhancing, nodular densities that resemble lymphoma. Cranial involvement is characteristically in the orbit. The central nervous system appearance is variable, however, and high attenuation masses may occur that mimic lymphoma, hematoma, and metastatic neuroblastoma. The recognition of these lesions is important, since radiation, not chemotherapy, is often the preferred treatment for localized chloroma.

Adolescent↗
PubMed1985

Aluminon: its limited application as a reagent for the detection of aluminum species.

The triammonium salt of aurin tricarboxylic acid, commonly referred to as aluminon, forms a dye that has been used for the colorimetric determination of Al(III) species. We have reviewed the pertinent literature on the reaction of aluminon with respect to the metallic species that form colored aluminon complexes. The effects of experimental variables, such as time, temperature, and pH, upon the color development of the aluminon complex are also presented. Organic and inorganic species, particularly Be(II) and Fe(III), which can affect color formation, are described. The use of aluminon as a histochemical staining agent for the detection of aluminum requires verification by atomic absorption spectrophotometric analysis or other quantitative techniques.

Aluminum↗
PubMed1985

Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin.

Although many trials have evaluated the severity and treatment of nausea and vomiting immediately after cisplatin administration, no studies have focused on vomiting occurring more than 24 hours after chemotherapy--delayed emesis. Two consecutive trials were undertaken to evaluate the incidence, course (trial 1), and severity (trial 2) of delayed nausea and emesis and to develop methods to study these conditions. Eighty-six patients receiving cisplatin (120 mg/m2) for the first time were entered. On the day of cisplatin treatment, all received intravenous (IV) metoclopramide (3 mg/kg X 2 doses) plus dexamethasone (20 mg IV X 1 dose) with either diphenhydramine (50 mg IV) or lorazepam (1.0 to 1.5 mg/m2). Sixty-two percent of patients experienced no vomiting during the 24 hours immediately after administration of cisplatin. Overall, 93% of studied patients experienced some degree of delayed nausea or vomiting from 24 to 120 hours after cisplatin. In trial 1, the incidence of delayed vomiting ranged from 21% to 61% and delayed nausea from 24% to 78% in 58 patients. The highest incidence of both delayed nausea and emesis occurred during the period from 48 to 72 hours after administration of cisplatin. Patients who had no emesis during the initial 24 hours after cisplatin were less likely to experience delayed emesis. The severity of delayed nausea and vomiting was evaluated in 28 patients in trial 2. The amount of delayed nausea and vomiting was assessed daily by patients using a visual analogue scale and by an observer rating. The highest nausea and vomiting scores were seen during the period from 48 to 72 hours after administration of cisplatin, with acceptable correlation between patient scores and observer ratings. Although the nausea and vomiting occurring 24 or more hours after cisplatin administration is not as severe as that seen during the initial 24 hours after administration of cisplatin in patients not receiving antiemetics, it is a common condition that merits both further study and specific treatment.

Adult↗
PubMed1985

Lorazepam in cancer patients treated with cisplatin: a drug having antiemetic, amnesic, and anxiolytic effects.

There currently is no pharmacologic approach to the problem of anticipatory nausea and vomiting (ANV). Lorazepam (Ativan, Wyeth Laboratories, Philadelphia) is an interesting candidate drug if it could block the recall of the unpleasant events associated with chemotherapy, especially if it also has antiemetic properties. Since ANV is a conditioned (learned) response, it may well depend on a memory imprint of the stimulus. This pilot study was designed to use intravenous lorazepam given before and after cisplatin infusion in 32 patients, and to make detailed measurements of nausea, vomiting, recent memory, anxiety, and sedation as well as toxicity. Satisfactory responses occurred in about 70%, as rated separately both by investigator and patient. Forty-six percent did not even recall receiving chemotherapy, regardless of whether or not they vomited; 80% had no significant anxiety after chemotherapy. Adverse reactions included some cases of perceptual disturbance, urinary incontinence, diarrhea, hypotension, and one case of severe transient amnesia. No long-term adverse effects were noted.

Adult↗
PubMed1985

Increased dermal mast cell populations in progressive systemic sclerosis: a link in chronic fibrosis?

Dermal collagen deposition is the hallmark of the early indurative phase of progressive systemic sclerosis (scleroderma). This process, however, tends to remit in late stages of the disease. Because mast cells are believed to participate in the development of fibrotic processes, we measured the density of the cutaneous mast cell population in clinically involved and uninvolved skin of a group of patients with scleroderma. Mast cell counts in clinically involved skin of patients with early stages of scleroderma (111 +/- 28 [SD] cells/mm2) were significantly greater than those in clinically uninvolved skin of the same patients (58 +/- 26 cells/mm2) and also greater than those of normal controls (50 +/- 14 cells/mm2). Mast cell counts in clinically involved and uninvolved skin of patients with late scleroderma were normal. When mast cell density was analyzed by depth of dermis, an 85% increase was noted in involved papillary dermis and a 152% increase in involved reticular dermis in patients with early scleroderma when compared with densities in controls. These results suggest that mast cells may be important in the pathogenesis of the early cutaneous lesions of progressive systemic sclerosis, perhaps by promoting fibrosis.

Adult↗
PubMed1985

Neutrophils autoinactivate secretory products by myeloperoxidase-catalyzed oxidation.

The neutrophil response to inflammatory stimuli involves the formation of reactive oxygen species and secretion of granule enzymes. In studying secretion of vitamin B12 binding protein by human neutrophils, we noted a major decrease in total recoverable activity from the extracellular fluid plus the stimulated cells (54% of resting cells). Recovery of B12 binding protein from neutrophils exposed to phorbol myristate acetate or opsonized zymosan was significantly enhanced on addition of heme enzyme inhibitors (azide, cyanide) or catalase or when halide-free medium was used. The changes in B12 binding protein recovery were attributable entirely to increases in extracellular fluid levels, and cell pellet content was unaffected. These data indicate extracellular destruction of functional B12 binding protein by the halide-dependent heme enzyme myeloperoxidase and H2O2. Kinetic studies demonstrated rapid secretion of B12 binding protein in the first two to five minutes, followed by its inactivation over the next 20 to 30 minutes. A cell-free extract of vitamin B12 binding protein was readily inactivated on exposure to purified myeloperoxidase, H2O2, and a halide. These findings document a functional interaction among products of the neutrophil specific granules (B12 binding protein), azurophil granules (myeloperoxidase), and metabolic burst (H2O2). They provide an interesting model for the modulation of the inflammatory response by oxidation of secretory products of neutrophils.

Catalysis↗
PubMed1985

Oxidant membrane injury by the neutrophil myeloperoxidase system. I. Characterization of a liposome model and injury by myeloperoxidase, hydrogen peroxide, and halides.

Neutrophils and other phagocytes can injure cells by means of oxygen-dependent mechanisms, particularly the myeloperoxidase (MPO)-H2O2-halide system. The extent of such damage depends in part on the antioxidant defenses of the target cell. To facilitate the study of this phenomenon, we developed a model system in which we employed liposomes as targets for the myeloperoxidase system. The most useful species of liposomes employed 51Cr as the aqueous space marker and phosphatidyl choline with or without dicetyl phosphate and cholesterol as the structural lipid. Marker entrapment was established on the basis of 1) resolution of free from lipid-associated 51Cr by gel exclusion chromatography, 2) latency of 51Cr on rechromatography of detergent-treated liposomes, and 3) a correlation between entrapment and surface charge density. Exposure of liposomes to the complete MPO system resulted in release of 50 to 75% of the entrapped 51Cr. Release was abrogated by omission of myeloperoxidase or H2O2, heating of MPO, or addition of azide, cyanide, or catalase. Reagent H2O2 could be replaced by glucose plus glucose oxidase. Kinetic studies indicated a rapid process, lysis reaching half-maximal levels in less than 2 min. The addition of cyanide at various times interrupted lysis at once, indicating a requirement for ongoing myeloperoxidase-dependent reactions. Liposome disruption by the MPO system was pH dependent, increasing dramatically as pH was decreased from neutrality to 6.0. In the absence of halides, no lysis was observed. Maximum lysis was found with chloride at 10 to 100 mM, although at 1 mM concentrations, iodide, bromide, and thiocyanate were more active than chloride. Fluoride was inactive. Antagonism between halide species was demonstrated in that low concentrations of iodide or bromide inhibited the effect of optimal concentrations of chloride. Using 125I, we found that exposure of liposomes to the MPO system resulted in an association between iodide and liposomes; moreover, there was a close correspondence between this phenomenon and 51Cr release, suggesting that halogenation may be one mechanism of injury. These studies establish the usefulness of the liposome as a model of oxidant injury by a physiologically relevant system. They bear a striking parallel to work being done on MPO-mediated injury to eukaryotic and prokaryotic cells. By using this simplified model system, it should be possible to explore a number of determinants of target cell injury at a biochemical and molecular level.

Animals↗
PubMed1985

Oxidant membrane injury by the neutrophil myeloperoxidase system. II. Injury by stimulated neutrophils and protection by lipid-soluble antioxidants.

The stimulated human neutrophil can damage a variety of target cells, and in some models, a mechanism involving secretion of myeloperoxidase and H2O2 has been demonstrated. We explored the characteristics of this cell-cell interaction by using neutrophils and our recently described liposome model target cell system. Exposure of 51Cr-labeled liposomes to phorbol myristate acetate-stimulated human neutrophils resulted in release of 25 to 30% of the radioactivity. 51Cr release was abrogated by omission of the neutrophils, the phorbol ester or halide (iodide), replacement of the phorbol by an inactive congener, or addition of azide, cyanide, or catalase. Neutrophils from patients with hereditary absence of myeloperoxidase (MPO) or a failure of H2O2 formation (chronic granulomatous disease) did not cause liposome lysis unless purified MPO or a source of H2O2, respectively, was added. These data indicate that 51Cr release from liposomes is a consequence of the secretion of MPO and H2O2, which combine with extracellular halides to form a membrane lytic system. The influence of liposome composition on injury was then examined, with a focus on physiologically relevant lipid soluble antioxidants. Liposomes containing either alpha-tocopherol (0.33 to 1.67% of molar fraction of lipid) or beta-carotene (1.67% of molar fraction of lipid) were markedly resistant to lysis by the cellfree MPO-H2O2-chloride system. When the major structural lipid phosphatidyl choline was replaced by dipalmitoyl phosphatidyl choline, a synthetic phospholipid with no oxidizable double bonds, the resultant liposomes were totally resistant to lysis by the MPO-H2O2-chloride system. The addition of iodide to this system (i.e., both chloride and iodide present) changed the pattern of protection dramatically in that alpha-tocopherol and beta-carotene were no longer protective and the resistance of dipalmitoyl phosphatidyl choline liposomes was partial rather than complete. In contrast to iodide, the addition of bromide or thiocyanate did not have a major effect on the protection by antioxidants. Finally, we demonstrated protection by alpha-tocopherol or dipalmitoyl phosphatidyl choline against liposome lysis by phorbol-activated neutrophils. These studies illustrate the use of model phospholipid membranes in the characterization of oxygen-dependent cell-mediated cytotoxicity. Activated neutrophils lyse liposome targets through a MPO-dependent mechanism. Target properties, especially the content of lipid-soluble antioxidants, have a marked influence on susceptibility to lysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Antioxidants↗
PubMed1985

Myeloperoxidase-induced inactivation of alpha 1-antiprotease in hamsters.

While numerous studies have demonstrated that the myeloperoxidase system found in neutrophils can oxidize and functionally inactivate alpha 1-proteinase inhibitor in vitro, there is little direct evidence that this phenomenon is relevant in vivo. Using incubation with tritiated porcine pancreatic elastase followed by column chromatography to quantitate binding, we demonstrated recovery of microgram amounts of functional alpha 1-protease inhibitor from bronchoalveolar lavage of hamster lungs. When exposed to the myeloperoxidase system in vitro, hamster alpha 1-protease inhibitor was 97% inactivated. Functional alpha 1-protease inhibitor recovered by bronchoalveolar lavage 20 minutes after hamsters were given intratracheal injections with myeloperoxidase and either hydrogen peroxide or glucose plus glucose oxidase was only half that recovered from control animals. These studies suggest that the myeloperoxidase system is effective in oxidizing alpha 1-protease inhibitor in vivo. They support the concept that oxidation of alpha 1-protease inhibitor by myeloperoxidase from neutrophil granules in the presence of H2O2 and halide may produce elastase-antielastase imbalance in vivo and contribute to the development of acute lung injury and emphysema in humans.

Animals↗
PubMed1985

Consecutive dose-finding trials adding lorazepam to the combination of metoclopramide plus dexamethasone: improved subjective effectiveness over the combination of diphenhydramine plus metoclopramide plus dexamethasone.

Four consecutive trials were undertaken to study lorazepam at each of three dosage levels and diphenhydramine when used in combination with iv metoclopramide and dexamethasone in patients receiving cisplatin at 120 mg/m2. The combination containing diphenhydramine had been the most effective treatment identified in prior trials. Earlier studies have found lorazepam to be a useful adjunct to other antiemetic agents. Sixty-five patients who had never received chemotherapy or antiemetics were directly observed in the hospital for 24 hours following cisplatin. Overall, 56% of the patients experienced no emesis and 78.5% of the patients had two or fewer vomiting episodes during the study period. No significant differences were noted in the number of patients who experienced no emesis or two or fewer episodes among the four trials. More sedation was seen with the lorazepam-containing regimens; other side effects were similar in type and severity. The trial using the highest dose of lorazepam (1.5 mg/m2) demonstrated significantly greater patient satisfaction (P = 0.039) and less anxiety during therapy (P = 0.02) when compared with the diphenhydramine combination. We conclude that combinations of iv metoclopramide plus dexamethasone with either diphenhydramine or lorazepam are well tolerated and effective in controlling cisplatin-induced emesis. The regimens containing lorazepam produced better subjective evaluations, and the combination using the highest lorazepam dose tested showed superior patient satisfaction and less anxiety during therapy.

Adult↗
PubMed1984

Psittacosis.

Explore the source record for details and available documents.

Humans↗
PubMed1984

In vivo co-distribution of fibronectin and actin fibers in granulation tissue: immunofluorescence and electron microscope studies of the fibronexus at the myofibroblast surface.

The fibronexus ( FNX ), a very close transmembrane association of individual extracellular fibronectin fibers and actin microfilaments, was found previously at the substrate-binding surface of fibroblasts in tissue culture (Singer, 1. 1., 1979, Cell, 16:675-685). To determine whether the fibronexus might be involved in fibroblast adhesion during wound healing in vivo, we looked for co-localization of actin and fibronectin in granulation tissue formed within full-thickness guinea pig skin wounds. At 7-9 d, most of the actin fibers were observed to be coincident with congruent fibronectin fibers using double-label immunofluorescence microscopy. These fibronectin and actin fibers were co-localized at the myofibroblast surface surrounding the nucleus, and along attenuated myofibroblast processes which extended deeply into the extracellular matrix. This conspicuous co-distribution of fibronectin and actin fibers prompted us to look for fibronexuses at the myofibroblast surface with electron microscopy. We observed three kinds of FNXs : (a) tandem associations between the termini of individual extracellular fibronectin fibers and actin microfilament bundles at the tips of elongate myofibroblast processes, (b) plaque-like and, (c) track-like FNXs , in which parallel fibronectin and actin fibers were connected by perpendicular transmembranous fibrils. Goniometric studies on the external and internal components of these cross-linking fibrils showed that their membrane-associated ends are probably co-axial. Using immunoelectron microscopy on ultrathin cryosections, we confirmed that the densely staining external portion of these various FNXs does indeed contain fibronectin. The finding that these FNXs appear to connect collagen fibers to intracellular bundles of actin microfilaments is particularly significant. Our studies strongly suggest that the fibronexus is an important in vivo cell surface adhesion site functioning in wound repair, and perhaps within fibronectin-rich tissues during embryogenesis, tumor growth, and inflammation.

Actins↗
PubMed1984

Inactivation of Clostridium difficile cytotoxin by the neutrophil myeloperoxidase system.

The cytotoxin of Clostridium difficile was examined for sensitivity to oxidant secretory products of neutrophils. Exposure to myeloperoxidase, H2O2, and a halide resulted in loss of toxin activity measured by tissue-culture cytotoxicity. The peroxide requirement was provided by reagent H2O2, a peroxide-generating enzyme (glucose oxidase), or a peroxide-producing intestinal microorganism, Lactobacillus acidophilus. Human neutrophils stimulated by phorbol myristate acetate caused similar toxin inactivation. In both the cell-free and the neutrophil systems, inactivation of toxin required halides and was abrogated by azide, cyanide, or catalase. Neutrophils from patients with lack of myeloperoxidase or failure to produce H2O2 were impaired in toxin inactivation unless myeloperoxidase or H2O2, respectively, was added. The reducing agent 2-mercaptoethanol enhanced toxin activity. These data suggest a similarity between C difficile cytotoxin and the classic thiol-activated cytolysins. Moreover, they raise the possibility that neutrophils are involved in oxidative detoxification of microbial products.

Bacterial Proteins↗
PubMed1984

Fibronectin in basal cell epithelioma: sources and significance.

Nodular basal cell epitheliomas (BCE) contain fibronectin both within tumor nodules and at the nodule-stroma interface (basement membrane zone). Fibronectin within or at the periphery of tumor nodules could be derived from the tumor cells, from entrapped stroma, or from plasma. The present study was designed to elucidate the source(s) of fibronectin within BCE nodules. If stromal entrapment occurred to any great extent, von Willebrand factor VIII:Ag-stained blood vessels within tumor nodules should be evident by immunofluorescence techniques. Likewise, if plasma proteins were deposited in BCE, the tumor nodules should stain with fluorescein-conjugated antifibrinogen antibodies. Therefore, 6 basal cell epitheliomas were double labeled with rhodamine-conjugated antihuman fibronectin and fluorescein-conjugated antihuman factor VIII:Ag or fluorescein-labeled antihuman fibrinogen. Fibronectin was present in a linear disposition along the margin of tumor lobules and as a fine filamentous deposit in the central portions of tumor tissue. There was no evidence of fibrinogen or factor VIII:Ag in any of the tumor lobules. Factor VIII:Ag was present in a granular pattern within blood vessel walls that coursed between tumor nests. An indirect immunoperoxidase technique using rabbit antihuman fibronectin and peroxidase-labeled goat antirabbit IgG demonstrated that fibronectin within the central portion of the tumor lobules was closely associated with the tumor cells. The absence of fibrinogen and factor VIII:Ag within the tumor tissue indicates that the fibronectin is probably not plasma- or stroma-derived while immunoperoxidase data suggest that fibronectin may be a product of BCE cells.

Antigens↗
PubMed1984

Human keratinocytes synthesize, secrete, and deposit fibronectin in the pericellular matrix.

Fibronectin production by human keratinocytes cultured in serum-free, low-calcium medium without a fibroblast feeder layer was examined using several techniques. Immunohistochemical examination confirmed that the cultures were not contaminated with fibroblasts or Langerhans cells. By indirect immunofluorescence, fibronectin appeared as intracellular granules within all cells and as short radial fibrils between the cells and the substratum, and in the pericellular matrix. Conditioned media taken from 4-, 6-, 8-, 10-, and 12-day cultures contained fibronectin as measured by enzyme-linked immunosorbent assay in proportion to the cell number in cultures. Synthesis of fibronectin by 7-day keratinocyte cultures was determined by 18-h [35S]methionine metabolic labeling followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and autoradiography. Fibronectin accounted for 12% of the secreted protein under these culture conditions. Our results indicate that human keratinocytes under conditions that prevent terminal differentiation in vitro can synthesize, secrete, and deposit fibronectin in the extracellular matrix.

Enzyme-Linked Immunosorbent Assay↗
PubMed1984

Modulation of the late asthmatic response by antigen-specific immunoglobulin G in an animal model.

The late asthmatic response (LAR) occurs 4 to 12 h after antigenic challenge and has been related to the severity of asthma. In addition, improvement of asthmatic symptoms after immunotherapy has also been related to loss of the LAR. Because the LAR seems to be a critical component of asthma, we employed an animal model of the LAR to study its immunopathogenesis, concentrating on the role of antigen-specific rabbit homocytotropic (IgE) and heterocytotropic (IgG) antibodies to Alternaria tenuis. Serum samples from rabbits previously immunized with Alternaria extract were infused into age-matched previously nonimmunized recipients. Groups of recipients were categorized according to the immune status of the transfused serum: E-only, E/G, subdivided into E/low G (1:256 to 1:512) and E/high G 1:2,048), G (serum heat-treated to minimize IgE), and Control (transfused with serum from nonimmunized rabbits). Subsequently, pulmonary function was measured before and for 6 h after challenge with aerosolized Alternaria tenuis by recording pulmonary resistance, functional residual capacity by helium dilution, specific conductance, and dynamic compliance. The E-only recipients showed an immediate asthmatic response followed by a marked LAR comparable in magnitude to actively immunized animals. The E/G recipients showed blunting of the LAR in a dose-dependent fashion, with increasing titers of IgG antibody. The G recipients showed no immediate or late responses. Immunofluorescent studies in selected animals from each group failed to show any granular deposition of immunoglobulin or C3 in either the airways or blood vessels of the lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Fibronectin deposition in delayed-type hypersensitivity. Reactions of normals and a patient with afibrinogenemia.

During development of delayed hypersensitivity (DH) skin reactions, fibronectin accumulates in two distinct sites: (a) the dermal interstitium in a pattern similar to fibrin and with a time course similar to that of fibrin deposition and mononuclear cell infiltration, and (b) blood vessel walls in a pattern suggestive of basement membrane staining and with a time course similar to that of endothelial cell proliferation. In vitro fibronectin can bind to monocytes or endothelial cells and simultaneously bind to fibrin or collagen matrices; by such interaction in vivo it may affect cell migration or proliferation. Thus, fibronectin deposition in DH reactions may facilitate cell-matrix interactions; however, the possibility exists that extravascular fibronectin accumulation may be only secondary to interstitial fibrin clot formation, and that blood vessel-associated fibronectin may be only a function of adsorption onto basement membrane (type IV) collagen. To address these possibilities, we investigated the association of fibronectin with fibrin, type IV collagen, and mononuclear cell infiltrates in DH reactions. Skin sites of DH reactions in normal volunteers were biopsied at 24, 48, and 72 h after intradermal challenge and examined by immunofluorescence technique. At all time points most of the interstitial fibronectin coincided with fibrin; however, some interstitial fibronectin was coincident with mononuclear cells positive for HLA-DR or monocyte-specific antigen. The coincidence of fibronectin with mononuclear cells was more apparent in a 48-h DH reaction from a patient with congenital afibrinogenemia. Vessel wall fibronectin was increased by 48 h after challenge and appeared as a fine linear band on the luminal side of a much thicker band of type IV collagen. Thus, the coincidence of extravascular fibronectin with mononuclear cells, its appearance without fibrin in the site from a patient with afibrinogenemia, and incomplete correspondence of vessel wall fibronectin with type IV collagen suggest that fibronectin localization in DH reactions involves endothelial cell and mononuclear cell binding as well as adsorption to fibrin and/or type IV collagen.

Afibrinogenemia↗