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Biomedical subjects

D D Miller

Publications and source records attributed to D D Miller.

At least 253 records · Page 14Linked to original sources
PubMed1985

Developmental expression of nuclear genes that encode mitochondrial proteins: insect cytochromes c.

To investigate tissue-specific developmental regulation of mitochondrial biogenesis, we studied the expression of the Manduca sexta (tobacco hornworm moth) thoracic muscle cytochrome c gene during adult eclosion and used this information to obtain a cDNA clone for this gene, which in turn was used to isolate the corresponding Drosophila melanogaster gene. Over the 3 days prior to adult Manduca emergence, mitochondrial inner membranes become progressively more electron dense and lamellar, and, while there is no accumulation of apocytochrome c, the amount of the holoprotein increases 40-fold per insect thorax. As determined by in vitro translation and blot hybridization analysis, the major thoracic muscle cytochrome c gene is primarily regulated at the transcriptional level, with cytochrome c mRNA increasing from less than 0.01% to 0.04% of total poly(A)+ RNA and declining to an undetectable level by day 2 after eclosion. Furthermore, the ratio of cytochrome c to the other cytochromes remains the same at all times, indicating that these components of the respiratory chain follow coordinated developmental programs. By using polysome immunoadsorption, a poly(A)+ RNA population of greater than or equal to 95% cytochrome c mRNA was isolated from thoracic muscle tissue and was used to construct a cDNA library, which was screened by hybrid selection/translation. We report the sequence of one of those clones, pMSc750, and its use to isolate the major thoracic muscle cytochrome c gene of Drosophila.

Animals↗
PubMed1985

Availability to rats of iron in ferric hydroxide polymers.

Availability to rats of Fe in isolated ferric hydroxide polymers was assessed. Polymers were prepared by hydrolyzing an 59Fe-labeled ferric nitrate solution with base (KHCO3). After isolation by gel filtration, the polymers were characterized by spectrophotometric, dialysis, and ultracentrifugation methods. In a split-plot design experiment, Fe-adequate (Hb 11.4-14.0 g/dl) or Fe-deficient (Hb 4.7-9.6 g/dl) male Sprague-Dawley rats (10/treatment) were dosed by stomach tube with one of the following 59Fe-labeled solutions: polymers, Fe(NO3)3 (low-molecular-weight control), polymers + citrate, or Fe(NO3)3 + citrate. As expected, Fe-deficient animals absorbed more Fe than adequate animals (P less than 0.01). There was no difference in absorption of Fe between polymers and low-molecular-weight control doses (P greater than 0.05). In Fe-adequate animals, citrate significantly depressed the uptake of Fe both from Fe(NO3)3 and polymers. These results indicate 1) that polymerization of Fe species prior to ingestion is not a likely means by which Fe is rendered unavailable and 2) that the effect of citrate on Fe absorption may depend on the Fe status of the animal.

Absorption↗
PubMed1985

Effect of trimetoquinol analogs for antagonism of endoperoxide/thromboxane A2-mediated responses in human platelets and rat aorta.

The pharmacological properties of a limited series of tetrahydro-isoquinoline [trimetoquinol (TMQ)] analogs for inhibition of endoperoxide (U46619)-mediated responses in human platelets and rat aorta were examined. All analogs blocked U46619-induced aggregatory and secretory responses in platelets, and contraction of rat aorta in a concentration-dependent manner. R-(+)-TMQ was a competitive-type inhibitor of U46619-induced contractions of rat aorta. The relative inhibitory potency for TMQ analogs against U46619-induced effects was TMQ greater than N-methyl TMQ greater than or equal to erythro-alpha-methyl TMQ greater than threo-alpha-methyl TMQ greater than or equal to alpha-dimethyl TMQ. R-(+)-TMQ and the azoprostanoid analog (U51605) were potent antagonists of U46619 action in rat aorta with pA2 values of 5.97 and 5.70, respectively. Other experiments indicated that U51605 was a partial agonist and R-(+)-TMQ was an inhibitor of U51605-induced contractions of rat aorta (pKB = 5.94). R-(+)-TMQ also blocked prostaglandin E2-mediated responses in rat aorta (pA2 = 5.46) but was ineffective as an antagonist of prostaglandin F2 alpha and LTD4 responses in dog iris sphincter and guinea-pig trachea or lung parenchyma, respectively. The data indicate that 1) the TMQ analogs were antagonists of endoperoxide/thromboxane A2-mediated responses in rat aorta and human platelets involving a similar mechanism of action and 2) stereochemical requirements of these TMQ analogs for activation of beta adrenoceptors and antagonism of endoperoxide/thromboxane A2-mediated responses are different. It is concluded that selectivity for these two pharmacological properties of TMQ can be achieved by appropriate stereochemical modification of the tetrahydroisoquinoline nucleus.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1985

Radiopharmaceuticals for cardiac imaging.

A number of new radiopharmaceuticals have been developed to increase the diagnostic utility of nuclear medicine in cardiac diseases. The radiochemistry and dosimetry of and clinical experience with these new agents are summarized, and are compared with more widely used methods for assessing myocardial perfusion (thallium-201 scintigraphy) and ventricular function (technetium-99m radioangiography). Emerging techniques for the evaluation of myocardial necrosis and metabolism are also presented, with emphasis on the use of radiolabeled antimyosin antibody and fatty acid analogue imaging in ischemic heart disease.

Glucose↗
PubMed1984

Circadian variation in variant angina.

Thirteen hospitalized patients with variant angina were studied to assess circadian variation in disease activity. Over 48 hours, all angina attacks were noted, a continuous Holter electrocardiogram was recorded and 2 ergonovine tests were performed 12 hours apart, 1 at 4 AM and the other at 4 PM. Only 2 patients gave a clearcut history of more frequent nocturnal or early morning attacks. During the study period, 1.8 +/- 1.6 AM and 0.62 +/- 1.2 PM angina episodes per patient were reported (p less than 0.02), but a circadian pattern was apparent in only 4 patients. However, Holter analysis revealed 5.3 +/- 13.8 AM and 2.6 +/- 8.5 PM episodes of ST elevation per patient (p less than 0.05) and 8.1 +/- 13.9 AM and 3.2 +/- 8.5 PM episodes of ST elevation, ST depression or T-wave pseudonormalization (p less than 0.01). Ten of 11 patients with Holter abnormalities had more frequent AM than PM attacks (p less than 0.01). ST elevation developed during all 13 of the 4-AM and 12 of 13 of the 4-PM ergonovine tests. In 10 cases the ergonovine threshold at which the attack occurred was lower in the morning, in no case was it lower in the afternoon, and in 3 patients the morning and afternoon doses were identical (p less than 0.01). Thus, circadian variation in disease activity both for spontaneous and provoked attacks is present in most patients with variant angina, even though it is often not clinically apparent.

Adult↗
PubMed1984

Human platelet activation by bacterial phospholipase C is mediated by phosphatidylinositol hydrolysis but not generation of phosphatidic acid: inhibition by a selective inhibitor of phospholipase C.

We have shown earlier that phospholipase C (PLC) from Clostridium perfringens causes human platelet aggregation and secretion in a concentration dependent manner. The present study was undertaken to further characterize the specificity of the effects of PLC and to better understand the mechanism of the action of this inducer. A methylene-dioxybenzazepine (MDBA) analog of trimetoquinol was synthesized and tested for antiplatelet activity. MDBA (3-30 microM) inhibited PLC-induced aggregation in a concentration dependent manner. Whereas up to 200 microM MDBA did not inhibit aggregation induced by either thrombin, arachidonic acid, or U46619. Effects of PLC (0.05 U/ml) on hydrolysis of phosphatidylinositol, production of phosphatidic acid and thromboxane B2 (TXB2) synthesis were investigated using [32P]-phosphate and [14C]-arachidonic acid labeled platelets. PLC (0.05 U/ml) caused a time dependent decrease in platelet phosphatidylinositol. Up to 50% of labeled phosphatidylinositol was lost from platelets in five minutes. MDBA (3-30 microM) inhibited PLC-induced loss of phosphatidylinositol in a concentration dependent manner. An increase in phosphatidic acid was also observed in PLC-stimulated platelets. Up to 100 microM MDBA did not inhibit production of phosphatidic acid. PLC-treated platelets did not produce any TXB2. In other experiments possible protease contamination of PLC preparations was tested by incubating PLC (0.03-0.5 U/ml) with [14C]-casein. PLC in concentrations up to ten times higher than the concentrations used in aggregation studies did not cause hydrolysis of [14C]-casein, whereas more than 30% of [14C]-casein was hydrolyzed by trypsin. PLC-induced aggregation was not inhibited by up to 300 microM adenosine or ATP. In other experiments, platelet aggregation by ADP was inhibited by adenosine and ATP in a concentration dependent manner. The addition of calcium (0.5- 2.0 mM) increased aggregation by PLC in a concentration dependent manner. These findings suggest that PLC-induced activation of platelets is: (a) dependent on phosphatidylinositol hydrolysis but not on the production of phosphatidic acid, TXB2 or secretion of ADP; (b) not caused by protease contaminants; (c) calcium dependent; and (d) MDBA inhibits PLC-induced aggregation by blocking phosphatidylinositol hydrolysis.

Adenosine↗
PubMed1984

Dopaminergic agonists: comparative actions of amine and sulfonium analogues of dopamine.

We have investigated the possibility that structural modifications of the sulfonium analogue of dopamine (4) would produce the same pattern of biological activity as structural modifications of dopamine. A series of methyl- tetralinyl -, and naphthalenylsulfonium analogues 5-7 were prepared and tested for their ability to inhibit the potassium-evoked release of [3H]acetylcholine from striatal slices. All compounds were tested under normal conditions and after depletion of dopamine stores with reserpine and alpha-methyl-p-tyrosine. The amine and sulfonium analogues 2-6 all showed direct agonist activity. The sulfonium analogue 7 produced, predominantly, indirect activity. In contrast to the amine analogues, chemical modifications of the sulfonium compounds produced little change in their dopamine agonist activity.

Acetylcholine↗
PubMed1984

Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogues of hallucinogenic phenethylamines: lack of LSD-like biological activity.

cis- and trans-2-(2,4,5-trimethoxyphenyl)cyclobutylamine and trans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine were synthesized as conformationally restricted analogues of hallucinogenic phenylisopropylamines. In rats trained to discriminate saline from LSD (0.08 mg/kg, ip) in a two-lever drug discrimination paradigm, no generalization of the LSD stimulus to the cis trimethoxy compound occurred at doses up to 20 mg/kg. For both of the trans compounds, partial generalization of the LSD cue occurred at doses of 5 mg/kg or greater. In contrast, complete generalization occurred with trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine. The ED50 for this compound and the doses of the trans cyclobutyl homologues at which significant drug-appropriate responding occurred indicate that the latter are on the order of 50-75 times less potent than the cyclopropylamine analogue. The lack of generalization to the cyclobutylamines indicates either that their discriminative stimulus properties differ from LSD or that they lack discriminative effects.

Animals↗
PubMed1984

In vitro estimation of the effects of selected proteins on iron bioavailability.

The effects of proteins and protein digestion products on iron bioavailability were studied. Iron dialyzability, under simulated gastrointestinal conditions, in the presence of selected proteins and fractionated protein digestion products, was used as a measure of iron bioavailability. Dialyzability was high for bovine serum albumin and beef, intermediate for egg albumin, and low for soy flour, gelatin, casein, soy protein isolate, and gluten. Low molecular weight digestion product fractions from bovine serum albumin and beef enhanced iron dialysis; similar fractions from casein and soy protein isolate did not affect iron dialysis. The influence of proteins on iron bioavailability appears to be related to the affinity of undigested or partially digested protein for iron and to the stability of small molecular weight soluble iron complexes formed from protein digestion products.

Animals↗
PubMed1984

Serum haloperidol concentrations and clinical response in acute psychosis.

Steady state serum haloperidol concentrations measured by gas-liquid chromatography and a neuroleptic radioreceptor assay were compared to clinical response in 21 acutely psychotic inpatients. Serum concentrations measured by the two assay methods correlated well with each other, although the neuroleptic radioreceptor assay was much less sensitive. There was also a significant linear relationship between haloperidol dose (mg/kg/day) and steady state serum concentration. The correlation between haloperidol serum concentrations and clinical response after 2 to 3 weeks was nonlinear and most pronounced in the intermediate range (15 to 40 ng/ml). Further studies will be needed to establish with certainty the existence and exact limits of a therapeutic window.

Adolescent↗
PubMed1983

Differences in the applicability of the easson-stedman hypothesis to the alpha 1- and alpha 2-adrenergic effects of phenethylamines and imidazolines.

The enantiomers of 2-(3,4, alpha-trihydroxybenzyl)imidazoline and the corresponding desoxy derivative, 2-(3,4-dihydroxybenzyl)imidazoline, were evaluated at alpha 1- and alpha 2-adrenergic receptors to test the applicability of the Easson-Stedman hypothesis to the imidazoline class of alpha-adrenergic agonists. A series of closely related phenethylamines was included for comparison. The Easson-Stedman hypothesis states that optically active adrenergic agonists possessing an asymmetric hydroxyl-substituted benzylic carbon atom will have the following relative potencies: R(-) greater than S(+) = desoxy. While the phenethylamines were found to adhere to the Easson-Stedman hypothesis at both alpha 1- and alpha 2-adrenergic receptors, the optically active imidazolines did not. These findings further support our previous observations that the phenethylamines and imidazolines may interact differently with alpha-adrenergic receptors.

Animals↗
PubMed1983

An epidemic of pulmonary hypertension after toxic rapeseed oil ingestion in Spain.

The cardiac profile of 38 patients readmitted to the hospital with the clinical and radiologic findings of pulmonary artery hypertension and right ventricular failure 2 months after ingestion of toxic rapeseed oil was determined with M-mode and two-dimensional echocardiography, pulsed Doppler flow studies and right and left heart catheterization and ventriculography. The echocardiogram and pulsed Doppler recordings revealed right ventricular enlargement in 84% of the patients, indirect evidence of pulmonary artery hypertension in 76% and tricuspid insufficiency in 13%. At cardiac catheterization (n = 11) the mean (+/- standard deviation) pulmonary artery pressure was 40 +/- 9 mm Hg, mean pulmonary systemic vascular resistance ratio was 0.45 +/- 0.12 and mean right ventricular end-diastolic pressure was 13 +/- 4 mm Hg. Pulmonary artery hypertension was sustained after the acute administration of 100% oxygen and persisted in six patients who were restudied within 6 months. Cardiac index and left heart pressures were normal in all but one patient. The contrast ventriculographic studies revealed right ventricular dilation in all patients, tricuspid regurgitation in three patients and a normal left ventricular contraction pattern in all but one patient. The data confirm that symptomatic pulmonary artery hypertension and associated right ventricular dysfunction can complicate toxic rapeseed oil ingestion and that these findings persist for at least 6 months.

Acetanilides↗
PubMed1983

Optically active catecholimidazolines: a study of steric interactions at alpha-adrenoreceptors.

The optical isomers and deoxy form of 2-(3,4, alpha-trihydroxybenzyl)imidazoline hydrochloride were examined for their alpha-adrenergic activity on rat aorta. The rank order of stimulant activity was deoxy (2) congruent to (R)-(-)-1 greater than (S)-(+)-1. This is in contrast to catecholamines in which the order of activity is (R)-(-)-epinephrine greater than (S)-(+)-epinephrine = epinine (deoxyepinephrine). The relative order of potency for the isomers of 2-(3,4, alpha-trihydroxybenzyl)imidazoline is different than that predicted by the Easson--Stedman theory for stereoisomers of catecholamines. Also, substitution of the deoxy compound 2 with substituents, methyl or benzyl, in the 4-position lowers the alpha-adrenergic agonist activity, and differences observed between optical isomers were small.

Animals↗
PubMed1983

Effects of pH and chelating agents on iron binding by dietary fiber: implications for iron availability.

Iron binding by isolated dietary fiber in the presence of iron ligands was measured. Iron-ligand solutions were mixed with isolated fiber and incubated. Bound and polymerized iron were estimated by centrifugation and ultrafiltration, respectively. Results showed that iron binding varied greatly with ligand used and with pH. Based on these studies, it was predicted that ligands would influence iron availability in the order ascorbate less than citrate = nitrolotriacetic acid less than EDTA. When added to a complex meal containing beef, bread, green beans, and milk, iron availability (measured by an in vitro method) was little affected by fiber, citrate, and ascorbate, but enhanced by nitrolotriacetic acid and EDTA. When added to a semisynthetic meal, fiber, ascorbate, citrate, nitrolotriacetic acid, and EDTA increased iron availability. It appears that the effect of dietary fiber on iron availability is greatly dependent on the ligands present in the meal.

Ascorbic Acid↗
PubMed1983

Effects of iron status and soy protein on iron absorption by rats.

The effects of iron nutrition and soy protein on iron absorption by rats was studied. Rats were fed semipurified diets containing either 0, 5, or 20 micrograms of added iron per gram of diet to obtain groups with different iron status. After 3 weeks the rats had mean hemoglobin concentrations of 7.0, 10.7 and 13.2 g/dl, respectively. As the rats became more anemic, percent iron absorption from casein and soy protein diets increased. The relative availability of iron from soy compared with casein-based diets was 70 to 90%. Iron status did not affect the relative iron availability among treatments. The rat trials did not indicate any significant differences between iron absorption from meals containing soy flour (SF), soy protein concentrate (SC) or soy protein isolate (SI) regardless of the iron status of the rat. These studies do not support the hypothesis that the subject's iron status will affect the relative availability of iron from foods. Recent human iron absorption studies suggest that relative iron availability from meals containing soy proteins is lower than expected based on rat studies. Furthermore, differences in iron availability between soy flour and soy isolate observed in human studies are not apparent in these rat studies.

Absorption↗