Biomedical subjects
R A Long
Publications and source records attributed to R A Long.
Antagonistic interactions among marine pelagic bacteria.
Recent studies suggest that bacterial abundance and species diversity in the ocean's water column are variable at the millimeter scale, apparently in response to the small-scale heterogeneity in the distribution of organic matter. We hypothesized that bacterium-bacterium antagonistic interactions may contribute to variations in community structure at the microscale. We examined each of the 86 isolates for their inhibition of growth of the remaining 85 isolates by the Burkholder agar diffusion assay. More than one-half of the isolates expressed antagonistic activity, and this trait was more common with particle-associated bacteria than with free-living bacteria. This was exemplified by members of the alpha subclass of the class Proteobacteria (alpha-proteobacteria), in which production of antagonistic molecules was dominated by attached bacteria. We found that gamma-proteobacteria (members of the orders Alteromonadales and Vibrionales) are the most prolific producers of inhibitory materials and also the most resilient to them, while members of the Bacteriodetes were the organisms that were least productive and most sensitive to antagonistic interactions. Widespread interspecies growth inhibition is consistent with the role of this phenomenon in structuring bacterial communities at the microscale. Furthermore, our results suggest that bacteria from pelagic marine particles may be an underutilized source of novel antibiotics.
Pharmacokinetics and pharmacodynamics of a new cardiotonic vasodilator agent, 349U85, in normal subjects.
OBJECTIVE: To assess the pharmacodynamics and pharmacokinetics of single oral doses of a new vasodilator-cardiotonic agent, 349U85 hydrochloride [6-piperidino-2(1H)-quinolinone hydrochloride], in healthy male subjects. METHODS: This randomized, parallel, double-blind, placebo-controlled, dose escalation trial was conducted at a university-based clinical research center among 27 healthy male subjects. Data measurements used in the study included cardiac index, supine and standing blood pressure, 24-hour ambulatory electrocardiography, and 12-lead electrocardiography. RESULTS: Doses from 2 mg to 250 mg were well tolerated. Cardiac index, supine heart rate, and orthostatic hypotension, indicators of inotropic, chronotropic, and vasodilator effects, respectively, correlated to plasma concentrations of 349U85 and of its metabolite, 661U88. Results suggest that 349U85 may be more responsible for inotropic effects, whereas 661U88 may be more responsible for vasodilatory and chronotropic effects. These results are consistent with the preclinical pharmacologic profile for these two compounds. Headache, orthostatic dizziness, and hypotension tended to occur more frequently at higher doses and were temporally related to drug administration. Pharmacokinetic analyses indicate nonlinearity of 349U85 and 661U88, suggestive of saturation of metabolism and large interindividual variability in maximum plasma drug concentration and area under the plasma concentration-time curve. The source of the variability is not known. The time to maximum distribution was approximately 0.7 hours for both 349U85 and 661U88; the terminal elimination half-life was 1 hour for 349U85 and 3 hours for 661U88. Holter monitoring revealed asymptomatic increases in ventricular and supraventricular ectopic activity in some volunteers; ectopy appeared to be related to the dose of 349U85 and generally occurred at higher doses.
Effect of emulsion concentration on biodistribution of perflubron in tumor-bearing mice.
Perflubron (perfluoroocytlbromide, PFOB) emulsion concentrations of 100%, 90%, or 60% w/v were administered to mice with and without 3 types of murine malignant tumor implants, and the distribution in blood, tumor, lung, liver and spleen were studied 48 hours after a dose of 10 or 3 g/Kg of PFOB. The most important changes were seen in the blood where the PFOB concentration [PFOB] was decreased in tumor bearing mice (TBM). Blood [PFOB] was also decreased in TBM and normal mice (NM) that received the 60% emulsion. Liver [PFOB] was increased in TBM. Lung [PFOB] was directly proportional to the emulsion concentration with the 10g/Kg dose. No major differences were seen in the biodistribution between the 100% and 90% emulsions using 10g/Kg, in spite of differences in composition and manufacturing history.
Cyclooxygenase inhibition with ibuprofen: effect on biodistribution of perflubron emulsions in mice with mammary tumor.
The biodistribution of Perflubron (perfluorocytylbromide, PFOB) was studied by infusing 10 or 3 g/Kg doses of 90% and 100% w/v emulsions into Balb C mice with and without malignant mammary tumor implants. PFOB concentrations were measured in blood, liver, spleen, lung and tumor, and X-rays were taken 48 hours after infusion. Ibuprofen (IBU) was given intraperitoneally 10 mg/Kg dialy for 3 days to study the effects of cyclooxygenase blockade. The results showed that the blood [PFOB] in tumor-bearing mice (TBM) was only 3.6% of that measured in normal mice (NM), and the liver [PFOB] was increased by 59%. The lung [PFOB] increase with IBU therapy in NM was highly significant. IBU therapy resulted in a 98% and 468% increase in blood [PFOB] in normal and TBM, respectively. Smaller but statistically significant changes occurred in blood [PFOB] with saline and sham injections. Tumor [PFOB] was lower by 17% (P = .028) in mice treated with IBU. Smaller decreases were seen with saline and sham injections but did not achieve statistical significance. In conclusion, the presence of this malignant tumor resulted in changes that might influence the usefulness of PFOB as a contrast agent and as an adjuvant for radiation and chemotherapy. This study shows that cyclooxygenase inhibition significantly modified the pharmacodynamics of PFOB emulsions in blood, tumor and lung. The changes seen in the saline placebo and sham category were attributed to stress from procedures.
An overview of perfluoroctylbromide--application as a synthetic oxygen carrier and imaging agent for X-ray, ultrasound and nuclear magnetic resonance.
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A spontaneously produced lipopolysaccharide biosynthetic defect which causes both pleiotropic phage resistance and mucoid colony morphology in Salmonella anatum.
A spontaneously derived mutant of the smooth bacterial strain, Salmonella anatum A1, specifically blocks the DNA ejection function of bacteriophage E15 during infection. The mutant, AE15R-5, exhibits mucoid colony morphology but no evidence of colanic acid biosynthesis. It is resistant not only to bacteriophage E15, but also to all other smooth- and rough-specific phages which have been tested. Chemical, immunological and gel electrophoretic analyses indicate that its lipopolysaccharide (LPS) molecules fall into two categories: they are either highly truncated (probably heptoseless) or extremely large (complete LPS molecules with O-polysaccharides containing 80 or more repeat units). The antibiotic resistance pattern of AE15R-5 is roughly intermediate between that of a known heptoseless mutant, S. anatum MG4, and that of the parent strain, S. anatum A-1.
Meobentine sulfate: antiarrhythmic and electrophysiologic effects assessed by programmed electrical stimulation and ambulatory monitoring in patients with complex ventricular tachyarrhythmia. Report of a multicenter evaluation.
Five cardiology centers conducted open-label prospective trials of meobentine sulfate, an intravenously and orally available analog of bethanidine, to assess its potential for treatment of recurrent, drug refractory ventricular tachycardia (VT) or fibrillation (VF), and complex ventricular arrhythmias. The study population comprised 26 patients (mean age, 61 years); 18 were men. Coronary artery disease was present in 15, cardiomyopathy in six, and valvular heart disease in three. Patients presented with both VT and VF (seven), sustained VT alone (12), or frequent ventricular ectopy (PVCs) and nonsustained VT (seven). Of the 26 patients, 5 were enrolled in antiarrhythmic studies (chronic PVC suppression) and 21 were enrolled in programmed electrical stimulation (PES) studies. Two of five in the chronic PVC study showed greater than 75% arrhythmia suppression. Among 21 patients in PES studies, there were eight intravenous (16 mg/kg) and 19 oral trials (400 to 1000 mg every 6 hours, 3 days/dose interval). Five of 22 patients showed efficacy at repeat PES study (neither VT nor VF), one showed partial efficacy, and four were not restudied because of clinical arrhythmia (three) and/or adverse effects (two). Overall, three patients (12%) were continued on the drug for an extended period of time. Adverse experience included hypotension in 50% and gastrointestinal effects (nausea, vomiting, or diarrhea) in 56% (oral trials only). Adverse reactions led to drug discontinuation in six and dosage reduction in eight patients. Thus, meobentine may prevent induction of VT or VF or reduce frequency of complex PVCs in selected patients refractory to other antiarrhythmic agents, but the response rate is relatively low. Symptomatic hypotension or gastrointestinal adverse effects are common and may limit utility of meobentine as a chronic oral antiarrhythmic agent.
Effect of tamoxifen on H-Y antigen expression and gonadal development in chicken embryos.
Avian species follow the ZW/ZZ system of sex determination, which the female is heterogametic and expresses H-Y (or, more appropriately, 'H-W') antigen. We present the results of an investigation into the effects of the antiestrogen, tamoxifen, on gonadal differentiation and H-Y antigen expression in chickens. When given at doses of 0.25-2 mg per egg immediately before incubation, tamoxifen blocked regression of the right gonad in a significant number of 14-day-old female embryos. The nonregressed right gonad had a testis-like external appearance and, in some cases, contained what appeared to be spermatogenic tubules. Tamoxifen had no histologically detectable effect on the differentiation of the left ovary or the testes. In spite of tamoxifen's histological effects on right female gonads, it did not masculinize the steroidogenic capabilities of these gonads. Whether obtained from drug- or vehicle-treated embryos, the left and right female gonads always contained appreciable amounts of estrogen. In contrast, testes obtained from either drug- or vehicle-treated embryos did not contain detectable amounts of estrogen. Tamoxifen reduced the H-Y antigen levels in female liver and gonads. In both left and right female gonads, the reduction was to male levels. In female livers, tamoxifen reduced H-Y antigen to levels intermediate between those of normal males and females. Thus, the expression of H-Y antigen in both gonadal and nongonadal tissue is estrogen dependent, but the dependency appears to be more stringent for gonadal tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Purification and properties of chicken growth hormone and the development of a homologous radioimmunoassay.
Highly purified growth hormone (GH) has been isolated from pituitary glands of chicken (Gallus domesticus), and a specific homologous radioimmunoassay (RIA) has also been developed. The purified chicken GH was active in the rat tibia bioassay and it gave a dose-dependent response which paralleled that of the bovine GH standard. High pressure liquid chromatography revealed that the purified chicken GH was homogenous. Chicken GH had an Rf value of 0.2 in disc electrophoresis, and a MW of 26,000 from sodium dodecyl sulfate-gel electrophoresis. The isoelectric point was estimated to be 7.6 by gel isoelectric focusing. The amino acid composition of chicken GH was found to be similar to that of mammalian GH, and the NH2-terminal amino acid was threonine. Partial sequencing (114 amino acids) of the chicken GH showed 79% homology with bovine GH. An antiserum was developed to the purified chicken GH in a rabbit, and it was used to develop a homologous RIA using 125I-labeled chicken GH as the ligand. The purified chicken GH was iodinated via the lactoperoxidase method to a specific activity of approximately 100 microCi/micrograms. Plasma from chickens, medium from incubation of pituitary glands, and homogenates of pituitary glands gave parallel dilution-response curves with the chicken GH standard. Mammalian GH, prolactin (PRL), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) showed no cross-reaction with the 125I-labeled chicken GH. Purified turkey GH showed parallel dose response with the chicken GH, but purified turkey PRL did not cross-react. Chicken FSH and LH also showed no inhibition of binding. The minimum detectable concentration of the assay was 0.93 ng/tube, and the intraassay and interassay coefficients of variation were 9 and 16%, respectively. The specific binding of 125I-labeled chicken GH to a microsomal fraction isolated from chicken liver was identified, and the specific binding was generally low (1-4%). Turkey PRL, and chicken LH and FSH showed no inhibition of the 125I-labeled chicken GH hepatic binding and the ontogeny of the hepatic GH receptor binding sites in male and female chickens was examined.
The antifertility and antiadrenergic actions of thiocarbamate fungicides in laying hens.
The effects of the thiocarbamate fungicides, thiram, ziram, ferbam, maneb, and zineb, on norepinephrine synthesis by laying hens were investigated. Inhibition experiments with dopamine beta-hydroxylase purified from chicken adrenals indicated that thiram, ziram, and ferbam are potent competitive inhibitors with the substrate the substrate ascorbate. Maneb and zineb were without effect at comparable concentrations. Experiments investigating the interaction of thiram, ziram, and ferbam with cupric ions suggested that these compounds probably inhibit the enzyme by complexing the fully oxidized copper at its active site. Maneb and zineb also complexed cupric ions in solution and thus their failure to inhibit is not due to their inability to complex copper. When tested in vivo, thiram, ziram, and ferbam at po doses of 2.5 mg/kg or greater significantly reduced the conversion of radioactive dopa, given systemically, to brain norepinephrine. Since they did not affect the uptake of radioactive dopa by the brain or its subsequent decarboxylation within the brain to yield dopamine, these three compounds inhibit cerebral dopamine beta-hydroxylase in vivo. In contrast maneb and zineb at a po dose of 20 mg/kg had no significant effect on brain norepinephrine synthesis. Previously published results (Weppelman et al., Biol. Reprod. 23, 40-46, 1980) demonstrated that thiram, ziram, and ferbam (but not maneb or zineb) have antifertility action in laying hens. The correlation between this action and inhibition of dopamine beta-hydroxylase suggests that the antifertility effects of thiram, ziram, and ferbam might result from their antiadrenergic action. The observation that all doses of thiram in the diet which caused significant antigonadal action when fed to laying hens for 1 week also significantly decreased central and peripheral stores of norepinephrine supports this conclusion.
Purification and characterization of avian dopamine beta-hydroxylase.
Dopamine beta-hydroxylase (EC 1.14.17.1) has been purified from the chromaffin granules of avian adrenals. The enzyme has a molecular mass of approximately 320K daltons and consists of four apparently identical subunits joined in pairs by disulfide bonds. Analysis of the products formed from dopamine tritiated in the beta position indicated that 1.72 times as much tritium was retained in norepinephrine as was released as water. Ferrocyanide could serve as a reductant, but ascorbate at equal concentrations afforded higher rates. The enzyme had a pH optimum of 5-6 and was activated by either fumarate or acetate, with fumarate being far more effective. Kinetic experiments varying the concentrations of the substrates ascorbate and dopamine and those of the products dehydroascorbate and norepinephrine suggested that the mechanism was un-uni bi-uni ping pong. By this mechanism, the enzyme released dehydroascorbate after being irreversibly reduced by ascorbate and then sequentially bound oxygen and dopamine and released the product norepinephrine. The enzyme was inhibited by high but probably physiological concentrations of the substrate ascorbate and was activated by low concentrations of the product dehydroascorbate. Ascorbate inhibition was noncompetitive with dopamine, and dehydroascorbate activation was due to an increase in the enzyme's affinity for ascorbate with little or no change in its Vmax. Substrate inhibition by ascorbate and product activation by dehydroascorbate might together ensure that the rate of norepinephrine synthesis in vivo remains relatively unaffected by changes in the ratio of ascorbate to dehydroascorbate within chromaffin granules.
Digital plethysmography for assessing erythrityl tetranitrate bioavailability.
The bioavailability or oral, sublingual, and chewable tablets or erythrityl tetranitrate (ETN) was evaluated in 15 normal men. In a randomized, complete crossover investigation with nitroglycerin and placebo controls, drug-induced changes in the diastolic amplitude response intensity were measured with a digital plethysmogram. Values for area under the response intensity curve (AUC), maximum response intensity (Imax), and time lapse from dosing to peak response (tmax) were obtained by computer processing and converted to intensity values and AUC segments for specific time intervals. Sublingual nitroglycerin induced a response (p less than 0.05) from placebo within the first hour. Although somewhat slower in reaching peak intensity, all forms of ETN induced significant responses over placebo (p less than 0.05) for 2 hr, with oral (swallowed) ETN different 6 hr. Our results indicate that all the ETN dosage forms were bioavailable, with the longest duration of effect by the oral form.
Antifertility effects of dithiocarbamates in laying hens.
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A resonance Raman and electronic absorption probe of membrane energization. Quinaldine red in cells of Streptococcus faecalis.
Resonance Raman and electronic absorption spectra were used to show that the state of an amphiphilic cation, relative to dilute aqueous solution, changes when it is accumulated by cells of Streptococcus faecalis when they are energized. The general characteristics of the cation employed, quinaldine red, closely paralleled those of other amphiphilic cations which have been used to measure membrane potential. A major aspect of the change is that in sodium-loaded cells, essentially all of the quinaldine red accumulated as the result of energization forms a strong bond with an anionic group. This binding is similar to that which occurs for the basal level of quinaldine red taken up in nonenergized cells. Ionic binding was detected using resonance Raman spectroscopy through shifts associated with a N+ parallel C--C parallel C stretching vibration to lower frequency on uptake. Another aspect of the change in state is that the cell-localized probe cation can aggregate while ionically bonded in a card pack fashion, the transition dipoles being parallel. A combination of resonance Raman and electronic absorption spectroscopy was used to characterize this aggregation. The aggregates were estimated to contain at least five quinaldine red cations at or near van der Waals contact, and the presence of other molecules, such as phospholipids, could not be excluded. Aggregation effects are complex depending on the ratio of cells to probe cation, and on energization. The site of binding is suggested to be the lipid bilayer region of the plasma membrane on the basis of experiments with liposomes and other model systems. In addition, some quinaldine red may be present in the cytoplasm in an aggregated, ionically bound form. The change in state on uptake following energization seems to be associated with a membrane potential, similar spectral and uptake effects being produced by an artificially generated membrane potential in cells and liposomes. The results show that membrane potential cannot be computed in a simple manner from the distribution of quinaldine red between cells and medium, assuming that the thermodynamic activity coefficient of cell-localized material is identical with that in dilute aqueous solution. However, uptake as well as subsequent ionic binding of quinaldine red seems to be related to potential in an as yet undefined manner.
The resonance Raman spectrum of carotenoids as an intrinsic probe for membrane potential. Oscillatory changes in the spectrum of neurosporene in the chromatophores of Rhodopseudomonas sphaeroides.
The resonance Raman spectrum of the carotenoid neurosporene is shown to be a sensitive monitor of absorption shifts, and thus changes in membrane potential, in chromatophores of the GlC mutant of Rhodopseudomonas sphaeroides. For a Raman excitation wavelength at 472.7 nm, the intensities of the two most prominent resonance Raman features (v1 and v2) respond very differently to small shifts in the absorption maxima. Thus, the ratio intensity v1/intensity v2 is a sensitive probe for absorption shifts. Changes in this ratio of approximately 20% were observed during a valinomycin induced diffusion potential. At 5 degrees C changes in the average intensity ratio of +6, -4 and -14% were brought about by oligomycin, FCCP and sodium deoxycholate, respectively. The changes in intensity ratio were temperature dependent and, in addition, effects due to the laser beam acting as an actinic light could be detected. Oscillatory changes were observed in absolute Raman and Rayleigh scattering intensities for chromatophores at 5 degrees C and for intact cells under growing conditions.
Synthesis and antitumor and antiviral activities of 1-beta-D-arabinofuranosyl-2-amino-1,4(2H)-iminopyrimidine and its derivatives.
1-beta-D-Arabinofuranosyl-2-amino-1,4(2H)-imino-5-fluoropyrimidine (10), 1-beta-D-arabinofuranosyl-2-amino-1,4(2H)-imino-5-fluoropyrimidine 3'-phosphate (9), and 1-beta-D-arabinofuranosyl-2-amino-1,4(2H)-imino-5-chloropyrimidine (11) have been synthesized from 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine (5), 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine 3'-phosphate (4), and 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-chlorocytosine (6), respectively. 2,2'-Anhydro-1-beta-D-arabinofuranosylcytosine 3'-phosphate (7), 1-beta-D-arabinofuranosyl-2-amino-1,4-(2H)-iminopyrimidine (13), 1-beta-D-arabinofuranosyl-2-amino-1,3(2H)-iminopyrimidine 3'-phosphate (12), and compounds 4, 5, and 9 showed significant in vitro activity against a number of DNA viruses. Compounds 7 and 12 were also effective in vivo against type 1 herpes simplex virus. Compounds 7, 12, and 13 were extremely effective in the treatment of mice bearing leukemia L1210.
Physiological alterations secondary to perfusion and revascularization of canine intestine.
Our studies suggest that the perfusion rates of canine intestinal segments during extracorporeal perfusion are directly related to the quality of preservation; namely, better preserved specimens exhibit higher perfusion rates and vice versa. Production of intraluminal fluid (ILF) during preservation and following revascularization is related to the quality of preservation. Poorly preserved intestine seems generally to produce more fluid than well preserved specimens. Conversely, continuous pulsatile perfusion techniques resulted in more ILF production than specimens perfused with low-flow gravity-dependent systems. Ex vivo intestinal perfusion resulted in organ oedema inversely proportional to the quality of preservation. Poor preservation is also associated with washout of potassium, lactic dehydrogenase, and tissue acidosis both during preservation and revascularization. Perfusion with a high concentration of potassium ions results in poor preservation presumably owing to vasoconstriction. Mucosal malperfusion as demonstrated by the Microfil technique is the circulatory abnormality most closely associated with inadequate preservation. Smooth-muscle function, as measured by electrical activity recordings, is well preserved by pulsatile flow methods, whereas gravity perfusion results in disorganized and spastic muscular activity. The best preservation appeared to be obtained by the use of pulsatile flow with cryoprecipitated plasma as the perfusate.