Search PubMed⌕ Search

Biomedical subjects

R A Clark

Publications and source records attributed to R A Clark.

At least 235 records · Page 13Linked to original sources
PubMed1989

Inactivation of transferrin iron binding capacity by the neutrophil myeloperoxidase system.

Human serum apotransferrin was exposed to the isolated myeloperoxidase-H2O2-halide system or to phorbol ester-activated human neutrophils. Such treatment resulted in a marked loss in transferrin iron binding capacity as well as concomitant iodination of transferrin. Each component of the cell-free system (myeloperoxidase, H2O2, iodide) or neutrophil system (neutrophils, phorbol ester, iodide) was required in order to observe these changes. In the cell-free system, the H2O2 requirement was fulfilled by either reagent H2O2 or the peroxide-generating system glucose oxidase plus glucose. Both loss of iron binding capacity and transferrin iodination by either the myeloperoxidase system or activated neutrophils were blocked by azide or catalase. The isolated peroxidase system had an acidic pH optimum, whereas the intact cell system was more efficient at neutral pH. The kinetics of changes in iron binding capacity and iodination closely paralleled one another, exhibiting t1/2 values of less than 1 min for the myeloperoxidase-H2O2 system, 3-4 min for the myeloperoxidase-glucose oxidase system, and 8 min for the neutrophil system. That the occupied binding site is protected from the myeloperoxidase system was suggested by 1) a failure to mobilize iron from iron-loaded transferrin, 2) an inverse correlation between initial iron saturation and myeloperoxidase-mediated loss of iron binding capacity, and 3) decreased myeloperoxidase-mediated iodination of iron-loaded versus apotransferrin. Since as little as 1 atom of iodide bound per molecule of transferrin was associated with substantial losses in iron binding capacity, there appears to be a high specificity of myeloperoxidase-catalyzed iodination for residues at or near the iron binding sites. Amino acid analysis of iodinated transferrin (approximately 2 atoms/molecule) demonstrated that iodotyrosine was the predominant iodinated species. These observations document the ability of neutrophils to inactivate transferrin iron binding capacity via the secretion of myeloperoxidase, formation of H2O2, and subsequent myeloperoxidase-catalyzed iodination. This sequence of events may help to explain the changes in iron metabolism associated with the in vivo inflammatory response.

Amino Acids↗
PubMed1989

Subcellular distribution and membrane association of human neutrophil substrates for ADP-ribosylation by pertussis toxin and cholera toxin.

Neutrophil guanine nucleotide-binding proteins are important components of receptor-mediated cellular responses such as degranulation, chemotaxis, and superoxide production. Because the cytoplasmic granules of neutrophils serve as an intracellular store of receptors and NADPH oxidase components, we investigated the subcellular distribution of substrates for ADP-ribosylation by both pertussis and cholera toxins. Cholera toxin substrates of Mr 43 and 52 kDa were present only in the plasma membrane fraction. A 39-kDa pertussis toxin substrate was present in the plasma membrane, cytosol, and a specific granule-enriched fraction. There were no substrates for either toxin in the primary granules. Quantitative GTP-gamma-5 binding was localized predominantly to the plasma membrane fraction (47%), but significant portions were found in the specific granule-enriched fractions (13%) and cytosol (34%) as well. Two-dimensional gel electrophoresis and chymotryptic digests of the pertussis toxin substrate from these three subcellular fractions suggested that they are highly homologous. Triton X-114 phase partitioning was used to investigate the hydrophobicity of the toxin substrates. The pertussis toxin substrates in the plasma membrane and granule fractions behaved like integral membrane proteins, whereas the cytosolic substrate partitioned into both lipophilic and aqueous fractions. ADP-ribosylation converted the substrates to a somewhat less lipophilic form. These data suggest that the specific granules or an organelle of similar density serve as an intracellular store of a G protein with a 39-kDa alpha-subunit and that the cytosolic fraction of neutrophils contains free alpha-subunits of the same size.

Adenosine Diphosphate Ribose↗
PubMed1989

Phase II trials of the serotonin antagonist GR38032F for the control of vomiting caused by cisplatin.

Three phase II studies of the serotonin antagonist GR38032F were conducted. In trial 1, 20 patients given initial chemotherapy with cisplatin at doses greater than or equal to 100 mg/m2 were randomized to receive three GR38032F doses (0.18 mg/kg) on an every-2-hour or every-4-hour schedule. In trial 2, eight similar patients were given three 0.04-mg/kg doses every 2 hours. In trial 3, 12 previously treated patients receiving cisplatin at 20-25 mg/m2 on 4 or 5 consecutive days each received three daily GR38032F doses (0.15 mg/kg) every 2 hours. In trial 1, 35% of the patients had no emesis [95% confidence interval (CI), 16%-58%] and 55% had one or two emetic episodes (95% CI, 32%-76%). Results were similar between the every-2-hour and every-4-hour schedules. In trial 2, only one of eight patients (13%) had no vomiting (95% CI, 1%-50%). In trial 3, in which previously treated patients were studied, complete control ranged from 75% on day 1 to 33% on day 3. Mild sedation, headache, and transient elevations of serum SGOT (AST) were observed. No extrapyramidal symptoms occurred. A dose of 0.15-0.18 mg/kg every 2 hours for three iv doses is recommended. Further comparison and combination studies of GR38032F are warranted.

Adult↗
PubMed1989

The biochemical effects of high-dose inhaled salbutamol in patients with asthma.

We have studied the biochemical effects of high doses of inhaled salbutamol in 14 asthmatic patients age 38 years, FEV1 62%. Cumulative doubling doses of inhaled salbutamol were given every 20 min as follows: 100 micrograms, 200 micrograms, 500 micrograms, 1000 micrograms, 2000 micrograms, 4000 micrograms. Plasma glucose, potassium, and magnesium were measured at each step of the dose-response curve. Salbutamol produced significant hypokalaemic and hyperglycaemic effects, but no significant change in magnesium. There were linear log-dose responses for both glucose (r = 0.58) and potassium (r = -0.46). There were wide individual variations in maximum responses to salbutamol 4000 micrograms (as means and 95% confidence intervals): delta glucose 1.46 (0.83 to 2.09) mmol/l, delta potassium -0.38 (-0.64 to -0.12) mmol/l. Thus, hypokalaemic and hyperglycaemic effects may occur with doses of salbutamol similar to those currently used for nebulizer therapy (2.5-5 mg). We postulate that during acute exacerbations of airflow obstruction these changes may be accentuated and become clinically relevant.

Administration, Inhalation↗
PubMed1989

Pharmacokinetics, efficacy and adverse effects of sublingual salbutamol in patients with asthma.

Administration of drugs by the sublingual route provides rapid systemic absorption and avoids first-pass metabolism. The purpose of the present study was to assess the pharmacokinetics, efficacy and adverse effects of standard salbutamol tablets given by this route to patients with asthma. Seven asthmatic patients were given either sublingual salbutamol tablet 2 mg (SL), swallowed tablet 2 mg (O), metered dose inhaler 200 micrograms (MDI) or placebo (PL), in a randomized single-blind cross-over design. Airways responses (FEV1, FVC, PEFR), finger tremor (Tr), heart rate (HR), plasma potassium (K) and plasma salbutamol were measured over a 6 h period following drug administration. There were highly significant changes in FEV1 with MDI, O and SL routes compared with PL, although the response to MDI was greater and more rapid than with O or SL. There were similar findings for FVC and PEFR responses. There were no adverse effects with MDI, whereas both 0 and SL produced significant tremor responses. There were no differences between O and SL for any of the pharmacodynamic parameters. In addition, pharmacokinetic profiles for O and SL were also similar apart from an initial delay in absorption with SL. There were however, no significant differences in any of the pharmacokinetic parameters, between O and SL. This suggest that buccal absorption of salbutamol was negligible, and that systemic absorption occurred after swallowing of the dissolved sublingual tablet. These results show that sublingual administration of salbutamol tablet has no clinical benefit over the oral route.

Administration, Inhalation↗
PubMed1989

Single dose and steady-state pharmacokinetics of 4 mg and 8 mg oral salbutamol controlled-release in patients with bronchial asthma.

Fifteen patients with asthma were given salbutamol controlled-release (SCR) 4 mg or 8 mg twice daily for seven days, in a randomised double-blind cross-over design. Plasma salbutamol levels were measured after the first and fifteenth doses for a 12 h period following drug ingestion. At steady-state the geometric mean values for Cmax were 8.2 ng/ml for 4 mg, and 16.1 ng/ml for 8 mg. Median tmax values were 300 and 240 min respectively. The geometric mean AUC (0-12) were 4507 ng.min.ml-1 and 8980 ng.min/ml. Peak to trough fluctuation ratios were 0.577 and 0.572. There were no significant differences between 4 mg or 8 mg formulations, for any of the parameters measured, after appropriate corrections for dose. The concentration-time profiles at steady-state showed little fluctuation in plasma salbutamol levels over the twelve hour dosing interval. These results show that 4 mg and 8 mg formulations of SCR provide smooth plasma profiles at steady-state with a twice daily dosing regime.

Adult↗
PubMed1989

The relationship between positive aeroallergen patch test reactions and aeroallergen exacerbations of atopic dermatitis.

Previously we have demonstrated that patient contact with specific aeroallergens can cause flares of atopic dermatitis. In this study we report six additional cases that further document the relationship between positive aeroallergen patch test reactions and aeroallergen exacerbation of atopic dermatitis. In total, we have seen 18 patients (8 male, 10 female; ages 1-54 years) who have noted marked improvement in their skin symptomatology when antigen elimination (or moderation) was instituted as part of their general management. Delineation of inciting allergen was accomplished by a combination of prick tests and patch tests to aeroallergens. On prick testing all patients had markedly positive immediate wheal and flare reactions to a variety of aeroallergen extracts (tree, grass, and weed pollen, house dust mite, animal protein, and mold spores). The same patients were subsequently patch tested on uninvolved, nonabraded skin with allergen extracts at the same concentrations that had given positive prick tests. Patch tests were applied for 48 hr, removed, and interpreted at 48 and 72 hr. Patients reacted to specific aeroallergens with an eczematous eruption at 48 or 72 hr or at both time points. Positive delayed cutaneous reactions correlated strongly with aeroallergens identified in the patient's environment and/or suspected by the patients as inducers of dermatitis. Delayed cutaneous reactions were negative to allergens not historically relevant. Avoidance of aeroallergens that elicited an eczematous reaction at patch test sites resulted in marked improvement or resolution of dermatitis in all patients. Environmental rechallenge with incriminated allergens resulted in flares of dermatitis. We conclude that aeroallergen contact plays an important role in select patients with atopic dermatitis and that the responsible allergens can be elucidated by a combination of prick and patch tests.

Aerosols↗
PubMed1989

Antiemetic therapy: management of chemotherapy-induced nausea and vomiting.

Physicians and nurses involved in the care of oncology patients share the responsibility for proper management of chemotherapy-induced nausea and vomiting. Oncology nurses have taken an active part in the research and investigation of new antiemetic agents and the sharing of this knowledge with others. Identifying patient characteristics, using specific guidelines for antiemetic selection, and a knowledge of the antiemetic agents that are active singly or in combination can mean the difference between success and failure in preventing or controlling vomiting induced by chemotherapy. Proper dosing and scheduling of antiemetics using recommendations that have proved efficacious can further decrease a patient's discomfort during a most difficult time in his or her life.

Antiemetics↗
PubMed1989

Clinical and radiographic correlates of femoral artery visualization on bone scan.

In order to determine if the linear pattern of thigh uptake medial to the femur often seen on a 99mTc diphosphonate bone scan (DiP) is caused by calcification of the femoral artery, 42 patients with and without this pattern were studied by a combination of conventional radiographs, radioisotope angiography and/or computed tomography. Risk factors for arteriosclerotic disease were recorded for all patients. These techniques identified the postulated femoral artery pattern on bone scan as always corresponding to calcified femoral arteries. The prevalence of diabetes, cigarette use, hypertension and a family or clinical history of arteriosclerotic vascular disease was the same in the groups with or without DiP uptake.

Adult↗
PubMed1989

Wound repair.

Explore the source record for details and available documents.

Animals↗
PubMed1989

Aeroallergen contact can exacerbate atopic dermatitis: patch tests as a diagnostic tool.

Previous studies have documented that atopic dermatitis can worsen when patients ingest specific foods to which they are sensitive. In this article we demonstrate that patient contact with specific aeroallergens can cause flares of atopic dermatitis. Marked improvement in skin symptoms was noted when 12 patients (eight males and four females; ages, 1 to 54 years) were removed from their unusual environment. In response to prick tests, these patient had markedly positive, immediate wheel-and-flare reactions to a variety of aeroallergen extracts (tree, grass, and weed pollen; house dust mite; animal protein; and mold spores). The same patients were subsequently patch tested on uninvolved, nonabraded skin with the allergen extracts that had yielded positive prick tests. Patch tests were applied for 48 hours, removed, and interpreted 24 hours later. The patients reacted to specific aeroallergens with an eczematous eruption at 48 and 72 hours. Positive delayed cutaneous reactions correlated strongly with aeroallergens identified in the patient's environment or suspected by the patients as provocateurs of their atopic dermatitis. Delayed cutaneous reactions were negative to allergens not historically relevant. Continued avoidance of aeroallergens that elicited an eczematous reaction at patch test sites resulted in marked improvement or resolution of dermatitis in all patients. We conclude that aeroallergen contact plays an important role in select patients with atopic dermatitis.

Adult↗
PubMed1989

Cloning of the cDNA and functional expression of the 47-kilodalton cytosolic component of human neutrophil respiratory burst oxidase.

Neutrophil NADPH oxidase is a multicomponent enzyme that is activated to generate superoxide anion and is defective in the cells of patients with chronic granulomatous disease. It requires both membrane and cytosolic components, the latter including 47- and 67-kDa proteins recognized by the polyclonal antiserum B-1. Immunoscreening of an induced HL-60 lambda ZAP cDNA library yielded seven cross-hybridizing cDNAs encoding the 47-kDa component. Fusion proteins of 22-50 kDa were recognized by B-1. Antiserum against a fusion protein recognized a 47-kDa protein in normal neutrophils but not in those from patients with autosomal chronic granulomatous disease who lack the 47-kDa cytosolic oxidase component. In a cell-free NADPH oxidase system full-length and C-terminal fusion proteins augmented superoxide generation and reconstituted the cytosolic defect of a patient missing the 47-kDa protein. The cDNA hybridized with a 1.4-kilobase mRNA from induced HL-60 cells. The longest cDNA contained an open reading frame encoding a protein of 41,440 Da with a calculated pI of 10.4, an N-terminal glycine, sites favorable for phosphorylation, a nucleotide binding domain, and a region of homology to the src protein kinases, phospholipase C, and alpha-fodrin. These structural features are pertinent to proposed functional roles of the protein in the respiratory burst oxidase.

Amino Acid Sequence↗
PubMed1989

Dose-ranging antiemetic trial of high-dose oral metoclopramide.

The present trial with high oral doses of metoclopramide was undertaken to (a) determine a well-tolerated dosage of oral metoclopramide; (b) measure the blood levels achieved with these oral doses; (c) determine the side effects of high doses; and (d) observe for antiemetic efficacy. Thirty-six patients receiving emesis-producing chemotherapy consisting primarily of high intravenous (i.v.) doses of cyclophosphamide plus adriamycin or cisplatin received 48 courses of oral metoclopramide. The metoclopramide dosage was escalated in six steps from 0.5 to 3.0 mg/kg and was given 1/2 h before chemotherapy, then 1 1/2, 3 1/2, 7 1/2, 11 1/2, and 15 1/2 after chemotherapy. Diphenhydramine (50 mg orally) was given with the first, third, and fifth dosages. Toxicity was generally mild, not dose related, and similar to that observed with the i.v. drug with the exception of an increased incidence of acute dystonic reactions. Antiemetic effects were observed at each dose level. In patients receiving oral metoclopramide doses of 2 or 3 mg/kg, all achieved serum levels greater than 1,000 ng/ml. High-dose oral metoclopramide was well tolerated and demonstrated antiemetic effects at the dose levels explored. We recommend 2-3 mg/kg oral metoclopramide doses with 50 mg diphenhydramine for use in future trials.

Administration, Oral↗
PubMed1989

Complications of esophageal prostheses: roentgenologic manifestations.

We reviewed the roentgenographic findings in 15 patients who had endoscopic placement of a new type of esophageal prosthesis for obstruction caused by a malignant neoplasm. Each patient was evaluated with an esophagogram. Chest roentgenography and computerized tomography were used to confirm abnormalities seen on esophagography. The complication rate was 74% (11 cases), and included five cases of migration or malposition, two cases of perforation, and one case of obstruction. The recognition of postprocedural complications is paramount to their successful management. The complications associated with this new esophageal prosthesis are no different from those reported with the Celestin tube, though the frequency may be higher.

Esophageal Neoplasms↗
PubMed1989

Compartmentation of Nucleotides in Corn Root Tips Studied by P-NMR and HPLC.

Corn (Zea mays L.) root tips were subjected to different conditions so that nucleotide levels varied over a wide range. Levels of nucleotides in corn root tips were measured using (31)P nuclear magnetic resonance (NMR) spectroscopy and high performance liquid chromatography. Results indicate: (a) Similar amounts of NTP and sugar nucleotides were observed by in vivo NMR and in extracts. In contrast, a significant amount of NDP observed in root tip extracts was not detected by in vivo NMR. Thus, for a given sample, [NTP]/[NDP] ratios determined in vivo by (31)P-NMR are always higher than ratios observed in extracts, deviating by approximately 4-fold at the highest ratios. The NMR-invisible pool of NDP appeared quite metabolically inert, barely changing in size as total cell NDP changed. We conclude that NDP in corn root tips is compartmented with respect to NMR visibility, and that it is the NMR-visible pool which responds dynamically to metabolic state. The NMR-invisible NDP could either be immobilized (and so have broad, undetectable NMR signals), or be complexed with species that cause the chemical shift of NDP to change (so it does not contribute to the NMR signal of free NDP), or both. (b) (31)P-NMR cannot distinguish between bases (A, U, C, and G) of nucleotides. HPLC analysis of root tip extracts showed that the relative amount of each base in the NTP and NDP pools was quite constant in the different samples. (c) In extracts, for each of the nonadenylate nucleotides, [NTP]/[NDP] was linearly proportional to [ATP]/[ADP], indicating near equilibrium in the nucleoside diphosphokinase (NDPK) reaction. However, the apparent equilibrium constants for the phosphorylation of GDP and UDP by ATP were significantly lower than 1, the true equilibrium constant for the NDPK reaction. Thus, for a given sample, [ATP]/[ADP] approximately [CTP]/[CDP] > [UTP]/[UDP] > [GTP]/[GDP]. This result suggests that the different NDPs in corn root tips do not have equal access to NDPK.

Journal Article↗
PubMed1989

Mammography registry: considerations and options.

Radiologists are being urged to provide high-quality low-cost screening mammography to all women over 40 years of age. A mammography registry coupled with existing cancer registries would permit the quality and effectiveness of screening efforts to be evaluated. Standards of care would be determined that would permit quality assessment at individual centers and that could enhance medicolegal defense. The organizing group should consist of physician users, experts in mammography, statisticians, and administrators. Data regarding the number and type of studies, findings, interpretations, and recommendations could be collected and reported easily and cheaply with a standardized form. The registry could be financed by federal, state, or private funds; the latter are most preferable, but a combination of the three is most feasible. Screening mammography presents a serious public health challenge that is best addressed by the organization and support of a registry by radiologists.

Costs and Cost Analysis↗
PubMed1989

Platelet isoforms of platelet-derived growth factor stimulate fibroblasts to contract collagen matrices.

Fibroplasia and angiogenesis are essential components of tissue repair when substantial tissue has been lost at a site of injury. Platelets and monocyte/macrophages accumulate at these sites and release a variety of growth factors that are thought to initiate and sustain the repair. Often the involved tissue contracts, a process that can markedly reduce the amount of fibroplasia and angiogenesis necessary for the reestablishment of organ integrity. Such tissue contraction occurs over hours or days, a much slower time course than the rapid, reversible contraction of muscle tissue. Fibroblasts, which are rich in f-actin bundles, appear to be responsible for wound contraction. However, the signals that stimulate contraction are not known. Using cultured fibroblasts, which are also rich in f-actin bundles, we demonstrate the platelet and monocyte isoforms of platelet-derived growth factor (PDGF; AB and BB) but not PDGF-AA, can stimulate fibroblasts to contract collagen matrix in a time course similar to that of wound contraction. In addition, PDGF appears to be the predominant fibroblast/collagen gel contraction activity released from platelets. Vasoactive agonists known to stimulate smooth and striated muscle contraction do not stimulate fibroblast-driven collagen gel contraction.

Actin Cytoskeleton↗