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Biomedical subjects

D W Miller

Publications and source records attributed to D W Miller.

At least 145 records · Page 8Linked to original sources
PubMed1991

Age-dependent hyperresponsiveness of spontaneously hypertensive rats to the pressor effects of intravenous neuropeptide Y (NPY): role of mode of peptide administration and plasma NPY-like immunoreactivity.

The effects of various doses of intravenously (i.v.) infused (5-min duration, 0.1-3.2 nmol/kg/min) or bolus-injected (0.1-3.2 nmol/kg) porcine and/or rat/human neuropeptide Y (NPY) on mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of porcine NPY-like immunoreactivity (pNPYir) were examined in conscious, unrestrained spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats of various ages. When administered as an infusion to 12- to 17-week-old SHR, WKY, and SD rats, porcine NPY (pNPY) was more potent in increasing MAP in SHR than in either WKY or SD rats. Infusions of rat/human NPY instead of pNPY resulted in similar increases in potency in 12- to 17-week-old SHR as compared with WKY. This potency-associated hyperresponsiveness to infused pNPY was also observed when 36- to 41-week-old and 6-week-old SHR and WKY were examined, but infused NPY induced similar HR reductions in age-matched rats regardless of rat strain. Furthermore, doses of infused pNPY that elicited significantly greater pressor responses in SHR and WKY (0.32 nmol/kg/min in 12- to 17-week-old rats and 1.0 nmol/kg/min in 6-week-old rats) resulted in essentially identical plasma pNPYir concentrations in the two rat strains. In contrast, hyperresponsiveness to the MAP effects of bolus injections of pNPY in 12- to 17-week-old SHR was manifested as an increase in efficacy rather than potency, was associated with significantly smaller reductions in HR in SHR than in WKY and occurred at plasma pNPYir concentrations that were significantly larger than those required for infusion-associated hyperresponsiveness. These results are consistent with the hypothesis that NPY is an important contributor to the development and maintenance of essential hypertension.

Aging↗
PubMed1990

Stereoselective formation of a K-region dihydrodiol from phenanthrene by Streptomyces flavovirens.

The metabolism of phenanthrene, a polycyclic aromatic hydrocarbon (PAH), by Streptomyces flavovirens was investigated. When grown for 72 h in tryptone yeast extract broth saturated with phenanthrene, the actinomycete oxidized 21.3% of the hydrocarbon at the K-region to form trans-9,10-dihydroxy-9,10-dihydrophenanthrene (phenanthrene trans-9,10-dihydrodiol). A trace of 9-phenanthrol was also detected. Metabolites isolated by thin-layer and high performance liquid chromatography were identified by comparing chromatographic, mass spectral, and nuclear magnetic resonance properties with those of authentic compounds. Experiments using [9-14C]phenanthrene showed that the trans-9,10-dihydrodiol had 62.8% of the radioactivity found in the metabolites. Circular dichroism spectra of the phenanthrene trans-9,10-dihydrodiol indicated that the absolute configuration of the predominant enantiomer was (-)-9S,10S, the same as that of the principal enantiomer produced by mammalian enzymes. Incubation of S. flavovirens with phenanthrene is an atmosphere of 18O2, followed by gas chromatographic/mass spectral analysis of the metabolites, indicated that one atom from molecular oxygen was incorporated into each molecule of the phenanthrene trans-9,10-dihydrodiol. Cytochrome P-450 was detected in 105,000 x g supernatants prepared from cell extracts of S. flavovirens. The results show that the oxidation of phenanthrene by S. flavovirens was both regio- and stereospecific.

Biodegradation, Environmental↗
PubMed1989

Antagonism of methoxyflurane-induced anesthesia in rats by benzodiazepine inverse agonists.

Injection of the partial benzodiazepine inverse agonist Ro15-4513 (1-32 mg/kg i.p.) or nonconvulsant i.v. doses of the full benzodiazepine inverse agonist beta-CCE immediately following cessation of exposure of rats to an anesthetic concentration of methoxyflurane significantly antagonized the duration of methoxyflurane anesthesia as measured by recovery of the righting reflex and/or pain sensitivity. This antagonism was inhibited by the benzodiazepine antagonist Ro15-1788 at doses which alone did not alter the duration of methoxyflurane anesthesia. In addition, high-dose Ro15-4513 pretreatment (32 mg/kg) antagonized the induction and duration of methoxyflurane anesthesia but was unable to prevent methoxyflurane anesthesia or affect the induction or duration of anesthesia induced by the dissociative anesthetic ketamine (100 mg/kg). These findings indicate that methoxyflurane anesthesia can be selectively antagonized by the inverse agonistic action of Ro15-4513 and beta-CCE.

Anesthesia↗
PubMed1989

Analysis, characterization, and purification: requirements for toxicological evaluation of 1,4-dithiane.

1,4-Dithiane is an organo-sulfur chemical associated with production and storage of munitions. Toxicological evaluation of this chemical was scheduled in rats because of the paucity of such information. Prerequisite for the evaluation was the development of gas chromatographic procedures using flame ionization detection to determine the purity of the test chemical and to certify the concentration and stability of the chemical in the dosage form, sesame oil. Mass and nuclear magnetic resonance spectrometry procedures are described for assessing the structural character and purity of the test chemical. A procedure for the purification of the test chemical and data concerning its solubility in various solvents are also presented.

Chromatography, Gas↗
PubMed1989

Experimental peripheral nerve repair: environmental control directed at the cellular level.

This study recognizes recent advances in the understanding of the anatomy and physiology of peripheral nerves at the cellular level. It has reproduced study conditions originally advocated by de Medinaceli and coworkers, with modifications. Eighty-four rats were divided into three groups. Group A underwent sciatic nerve transection and standard perineurial repair. Group B nerves were frozen, severed with a vibrating blade, and reconnected by tubulization with a rubber cuff while bathed in solutions designed to inhibit Ca++-calmodulin activation, maintain colloid osmotic pressure, and mimic ambient electrolytic conditions. Group C underwent a similar procedure as group B, with the rubber cuff replaced by a polyglycolic acid mesh. All animals were randomized and evaluated functionally in terms of a sciatic index. By post-operative day 225, animals of group A recovered 37% of function, group B recovered 74%, and group C recovered 67%. Compound action potential recordings revealed a velocity recovery of 41% in group A, 70% in group B, and 81% in group C. Microscopic evaluation provided evidence for corresponding structural improvement. This new method of nerve repair is uncomplicated, relatively inexpensive, and easily adaptable to other animal models.

Animals↗
PubMed1989

A technique for placing ventriculoperitoneal shunts in a neonatal model of hydrocephalus.

Induction of hydrocephalus in a neonatal animal with subsequent surgical decompression is the most analogous situation to the clinical state of infantile hydrocephalus. Described in detail is a reliable method for the placement of pressure-dependent ventriculoperitoneal shunts in neonatal kittens with hydrocephalus. Successful decompression can be quantified using ultrasound. This model allows for observation of hydrocephalic changes that may persist or be corrected after shunting, be they morphological, behavioral or biochemical. In addition, potential pitfalls in performing the procedure and in postoperative care of the kittens are addressed.

Animals↗
PubMed1989

Formation of N-nitrosamines in microwaved versus skillet-fried bacon containing nitrite.

Differences in volatile N-nitrosamines (NNAs) found in nitrite-cured bacon cooked in an electric skillet and a microwave oven were determined. Samples of bacon were fried in an electric skillet at 171 and 206 degrees C and in a standard microwave oven (rated at 700 W full power) for 45 and 75 sec/slice. The level of NNAs were determined in the cooked bacon and fried-out fat by using gas chromatography-thermal energy analysis. Both N-nitrosopyrrolidine (NPYR) and N-nitrosodimethylamine (NDMA) were detected in the fried-out bacon fat at levels up to 20.8 and 23.3 ng/g, respectively. The total NNAs (NDMA and NPYR) in the skillet-fried bacon was c. 11 ng/g for both the 171 and 206 degrees C fried samples. No NNAs were detected in the bacon or fried-out fat after cooking in a microwave oven for 45 sec/slice. However, excessive cooking of the bacon in a microwave oven (75 sec/slice) does produce levels of NPYR up to 5 ng/g. The minimum detectable level of NPYR was 2.08 ng/g and that of NDMA was 0.76 ng/g. These results indicated that the method of cooking meats containing nitrite could affect the level of NNAs in the cooked product, thereby affecting the level of human exposure to NNAs.

Animals↗
PubMed1989

Identification of the glutathione conjugate of 4-nitroquinoline 1-oxide formed in the reaction catalyzed by murine glutathione transferases.

The product of the enzyme-catalyzed conjugation of glutathione and 4-nitroquinoline 1-oxide was isolated and its structure determined by MS and NMR. The results indicate that the cysteine sulfur of glutathione replaces the nitro group of 4-nitroquinoline 1-oxide in the reaction with the formation of 4-(glutathion-S-yl)-quinoline 1-oxide. No evidence was found for the binding of glutathione to any other position of 4-nitroquinoline 1-oxide or through any group other than the cysteine sulfur.

4-Nitroquinoline-1-oxide↗
PubMed1989

Effects of hydrocephalus and surgical decompression on cortical norepinephrine levels in neonatal cats.

Norepinephrine (NE) changes during hydrocephalus, and the effects of surgical decompression on these changes, were studied using a new model of neonatal hydrocephalus. Kittens 4 to 10 days old received intracisternal injections of a sterile solution of 25% kaolin. Control kittens were injected similarly with sterile injectable saline. Ultrasonography was used to follow the progression of ventriculomegaly and the initial effects of the shunts. A subgroup of hydrocephalic animals was shunted using a cerebrospinal fluid lumbar-peritoneal catheter. Hydrocephalic animals were killed at approximately 25 days of age (16-21 days after kaolin injection). Surgical decompression was performed at 12, 16, and 17 days after kaolin injection; these animals were killed 30 days after the shunts were inserted. Control animals were killed at 29 and 53 days of age, to correlate with the ages of the hydrocephalic and shunted animals, respectively. Cortical samples equivalent to Brodmann's areas 4, 22, and 17 were measured for NE using high-performance liquid chromatography. Hydrocephalus caused NE levels to decrease significantly in all cortical areas. These alterations followed a rostrocaudal gradient in severity, with mean reductions of 65.8, 83.9, and 95.8% in areas 4, 22, and 17, respectively. Partial recovery occurred in animals that received shunts 16 and 17 days after kaolin injection, such that NE reductions of 75.7, 56.2, and 81.6% were noted in areas 4, 22, and 17, respectively. Shunting at 12 days after kaolin injection produced complete recovery in areas 4 and 22, with only a 67.7% decrease in area 17. These results suggest that the projection fibers from the locus ceruleus are damaged by the direct effects of hydrocephalus. Axotomy or neuropraxia of these fibers could result in decreases in NE throughout the cerebral cortex. In addition, there appears to be a period of time during which surgical decompression will allow neuropraxic fibers to recover with partial restoration of NE levels. Earlier insertion of a shunt appears to allow for more recovery than later decompression.

Animals↗
PubMed1988

Microbial transformation of the antihistaminic drug triprolidine hydrochloride.

The production of a known mammalian metabolite of the antihistamine triprolidine through fungal metabolic transformation has been demonstrated. The filamentous fungus Cunninghamella elegans ATCC 9245 was grown in Sabouraud dextrose broth containing triprolidine hydrochloride monohydrate. One major metabolite was extracted with methylene chloride, isolated by high-performance liquid chromatography, and identified by its proton-nuclear magnetic resonance and desorption chemical ionization mass spectral properties as hydroxymethyl triprolidine (2-[1-(4-hydroxymethylphenyl)-3-(1-pyrrolidinyl-1-propenyl)] pyridine). After 240 h of incubation, the hydroxymethyl derivative represented approximately 55.0% of the initial dose. Fungal oxidation of hydroxymethyl triprolidine to the corresponding carboxylic acid triprolidine derivative (also a known mammalian triprolidine metabolite) was not observed. No mutagenic activity was observed for triprolidine and hydroxymethyl triprolidine by reversion of Salmonella typhimurium strains TA97, TA98, TA100, and TA104 at concentrations up to 1000 and 200 micrograms/plate, respectively. These results suggest that the fungal metabolism of triprolidine to the hydroxymethyl derivative occurs predominantly through pathways which do not result in mutagenic activation. Incubation of C. elegans with triprolidine under an 18O2 atmosphere and subsequent electron impact mass spectral analysis of the hydroxymethyl triprolidine formed indicate that molecular oxygen was incorporated into the methyl group and suggest a mono-oxygenase catalyzed reaction. This study parallels previous studies on the mammalian metabolism of triprolidine and clearly indicates that the microbial transformation of triprolidine is a useful alternative for the synthesis of potential mammalian metabolites.

Animals↗
PubMed1988

Development of a hospital-based proton beam treatment center.

Radiation oncologists recognize a continuing need to improve the radiation dose distribution between a cancer and the surrounding normal tissue. A most promising method of accomplishing this goal is the use of charged particle beam irradiation, the clinical use of which has been investigated for the past 40 years. Since the first clinical studies began at the Lawrence Berkeley Laboratory in 1954, more than 5,000 patients have been treated with protons, using accelerators designed for physics laboratories. Superior results are reported for the control of selected diseases by the ten facilities which are currently investigating proton radiation therapy. The findings have resulted in expansion plans in several of these facilities, and in the formulation of plans for two new facilities. We report on the planned development of a new facility at Loma Linda University, which has contracted with Fermi National Accelerator Laboratory for the design and fabrication of a 250 MeV synchrotron and its beam transport and delivery systems. This facility will be the first in the world to employ a proton accelerator dedicated to medical service and research. As such, it will be available as an international resource to develop and improve the modality.

California↗
PubMed1988

Mechanism of formation and structural characterization of DNA adducts derived from peroxidative activation of benzidine.

Although the peroxidative metabolism of benzidine and other carcinogenic arylamines has been regarded as a significant pathway in extrahepatic tissues, the mechanism of peroxidase-mediated covalent binding to DNA has remained unclear. In this study, we have compared the metabolic activation of benzidine by prostaglandin H synthase, horseradish peroxidase, chloroperoxidase, and lactoperoxidase. All four peroxidases mediated the binding of benzidine to DNA and equimolar amounts of hydrogen peroxide (or arachidonic acid) and benzidine were required for the maximal binding in the system with either horseradish peroxidase or prostaglandin H synthase. In reactions containing both synthetic [3H]benzidine diimine and [14C]benzidine, rapid equilibration of both compounds was evident through the formation of its charge-transfer complex and the 14C-associated binding to DNA. However, the total binding (3H and 14C) correlated with the concentration of benzidine diimine rather than that of the charge-transfer complex. Two major and one minor deoxyguanosine adducts (P-I, P-III and P-IV, respectively) were isolated after the enzymatic hydrolysis of the benzidine-modified DNA. P-I was identified as N-(deoxyguanosin-8-yl)-benzidine, which was the major adduct formed by reaction of benzidine diimine with DNA. P-IV, which was also formed on reaction of benzidine diimine with DNA, was consistent with an N-(deoxyguanosin-N2-yl)-benzidine structure. P-III, which was formed only in the peroxidase incubations with DNA, was characterized as a novel N,3-(deoxyguanosin-N7,C8-yl)-benzidine derivative. Furthermore, this DNA adduct was shown to arise by the action of the peroxidase on DNA that had been previously modified by benzidine diimine. These results indicate that the two-electron oxidation product of benzidine, benzidine diimine, is the predominant reactive intermediate for the DNA binding mediated by peroxidases.

Arachidonic Acid↗
PubMed1988

Pyrene degradation by a Mycobacterium sp.: identification of ring oxidation and ring fission products.

The degradation of pyrene, a polycyclic aromatic hydrocarbon containing four aromatic rings, by pure cultures of a Mycobacterium sp. was studied. Over 60% of [14C]pyrene was mineralized to CO2 after 96 h of incubation at 24 degrees C. High-pressure liquid chromatography analyses showed the presence of one major and at least six other metabolites that accounted for 95% of the total organic-extractable 14C-labeled residues. Analyses by UV, infrared, mass, and nuclear magnetic resonance spectrometry and gas chromatography identified both pyrene cis- and trans-4,5-dihydrodiols and pyrenol as initial microbial ring-oxidation products of pyrene. The major metabolite, 4-phenanthroic acid, and 4-hydroxyperinaphthenone and cinnamic and phthalic acids were identified as ring fission products. 18O2 studies showed that the formation of cis- and trans-4,5-dihydrodiols were catalyzed by dioxygenase and monooxygenase enzymes, respectively. This is the first report of the chemical pathway for the microbial catabolism of pyrene.

Biodegradation, Environmental↗
PubMed1988

Fungal transformations of antihistamines: metabolism of methapyrilene, thenyldiamine and tripelennamine to N-oxide and N-demethylated derivatives.

1. Strains of the fungus Cunninghamella elegans ATCC 9245 and 36112 were tested for their ability to transform the antihistamines methapyrilene (I), thenyldiamine (II) and tripelennamine (III). 2. Antihistamine metabolites were isolated by h.p.l.c., and identified by their 1H-n.m.r. and mass spectral properties. 3. All three drugs were transformed by both C. elegans strains to N-oxidized and N-demethylated derivatives. Metabolism during 96 h of incubation amounted to 85% for (I), 64% for (II), and 83% for (III). Metabolites soluble in organic solvents amounted to 62% to 86% of the total metabolism; approximately 88% to 95% of the organic-soluble metabolites were N-oxide derivatives of each antihistamine.

Aminopyridines↗