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Biomedical subjects

M M Miller

Publications and source records attributed to M M Miller.

At least 127 records · Page 7Linked to original sources

Effect of vasoactive intestinal polypeptide on the canine cardiovascular system.

Our purpose was to determine the effect of vasoactive intestinal polypeptide (VIP) on the cardiovascular system with special emphasis on coronary vascular effects. In section I, VIP was infused into six healthy and six cobalt-cardiomyopathic dogs at two infusion rates (0.02 and 0.05 micrograms/kg/min). Left ventricular end diastolic pressure and mean systemic pressure fell significantly in both groups. Heart rate rose in both, and maximum systolic dP/dt increased in the myopathic group. Cardiac output and regional blood flows were determined by serial left atrial injections of radioactive 15 +/- 3 mum (mean +/- SD) microspheres. In both groups, blood flow increased significantly to the esophagus, pancreas, atria, and ventricles and to the endocardial and epicardial regions of the left ventricular free wall. Blood flow to the brain decreased. In section II, VIP was infused intravenously at 0.1 micrograms/kg/min into six anesthetized dogs with coronary sinus flow, pulmonary artery, and systemic artery catheters inserted. Cardiac index rose from baseline (3.1 +/- 0.5 to 4.8 +/- 1.3 L/min/m2, P less than 0.005), as did coronary blood flow (90 +/- 25 to 159 +/- 54 ml/min, P less than 0.005) during the VIP infusion. Myocardial oxygen consumption rose from 14.1 +/- 3.9 to 19.8 +/- 5.4 ml/min (P less than 0.001), but the aorta-to-coronary sinus O2 difference decreased from 157 +/- 19 ml/L to 132 +/- 42 ml/L (P less than 0.05), and the percent O2 extracted from coronary blood also decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Effects of gonadal steroids on the in vivo binding of [125I]alpha-bungarotoxin to the suprachiasmatic nucleus.

The radioligand [125I]alpha-bungarotoxin (alpha-BTX) has been used to test receptor binding to putative nicotinic cholinergic receptors in the hypothalamus. Using light microscopic autoradiography following third ventricular infusion of the radioligand we have previously demonstrated that in normally cycling rats and in normal males, the suprachiasmatic nucleus (SCN) consistently binds the alpha-neurotoxin. In chronically (5 weeks) oophorectomized female, binding of [125I]alpha-BTX to the SCN is markedly diminished. The present series of experiments were designed to test the effects of gonadal steroids on the binding of [125I]alpha-BTX to the SCN. We first tested whether or not estradiol administered to ovariectomized females could duplicate the presence of the ovary. In females ovariectomized and immediately provided with a constant dose of estradiol-17 beta (E2)--1.0 cm silastic capsules for 5 weeks, (n = 4), the binding of the neurotoxin to the SCN was maintained. In females ovariectomized for 3 weeks and replaced with E2 for 2 weeks (n = 4), the binding of [125I]alpha-BTX to the SCN was restored. In chronically (4 weeks) ovariectomized females receiving E2 for 6 days (n = 2), the binding of the neurotoxin was partially restored. We next tested the effect of chronic (5 weeks) castration (n = 100) and observed that binding of [125I]alpha-BTX to the SCN of castrated males was like that of intact male controls (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Analysis of the B-G antigens of the chicken MHC by two-dimensional gel electrophoresis.

The B-G antigens of the chicken major histocompatibility complex (MHC) have been analyzed by high resolution two-dimensional (2-D) gel electrophoresis. Monoclonal antibodies recognizing a widely shared B-G determinant were used for immunoprecipitating the B-G antigens from radioiodinated, detergent-solubilized erythrocyte membrane preparations. The B-G antigens produce a variety of patterns on 2-D gels. The number of polypeptides within a B-G pattern varies among haplotypes from single polypeptide arrays showing slight microheterogeneity to complex patterns which contain as many as four or five polypeptide arrays differing in relative mobility and isoelectric point. Many of the patterns, but not all, include a polypeptide of Mr = 48 kd focusing near pH 6.9. At present it is not understood whether the multiple polypeptides within some B-G patterns represent the expression of multiple B-G genes or whether they are the result of modifications of single gene products during biosynthetic processing. 2-D gel analyses were also used to confirm the assignment of the same B-G haplotype in several different inbred flocks and the fate of the B-G antigens in two B system recombinant haplotypes. The 2-D gel patterns of these highly polymorphic antigens provide evidence for a complexity of the B-G locus not previously demonstrated. This technique may serve to define more objectively the diverse chicken MHC haplotypes which are now recognized and characterized only by serological techniques using alloantisera and monoclonal antibodies with varying cross-reactivities.

Animals↗

Preclinical safety evaluation of the nadolol/bendroflumethiazide combination in mice, rats, and dogs.

Nadolol, a beta-adrenergic antagonist, and bendroflumethiazide, a thiazide diuretic, were administered orally alone and in combination to animals in acute and 6-month toxicity studies and in a rat teratology study. The two drugs in combination showed no evidence of potentiation of acute toxicity in mice. Nadolol and/or bendroflumethiazide were administered orally to rats at daily doses of 1000 or 160 mg/kg of nadolol and 125 or 20 mg/kg of bendroflumethiazide and to dogs at daily doses of 160 or 40 mg/kg of nadolol and 20 or 5 mg/kg of bendroflumethiazide for 6 months. The two drugs, alone and in combination, caused only minor changes in clinical-laboratory tests and no major gross or histopathologic changes. Many of the changes noted were expected pharmacologic effects of the individual agents. The drugs, alone or in combination, produced no evidence of embryotoxicity, fetotoxicity, or teratogenicity in rats. The results of these studies indicate that nadolol and bendroflumethiazide have a low order of toxicity individually, and when given in combination show no additional or potentiated toxicity.

Animals↗

Liposome entrapment enhances the hypocalcemic action of parenterally administered calcitonin.

The hypocalcemic effect of liposomal-entrapped calcitonin (CT) was evaluated in rats. Salmon CT and human CT were entrapped in liposomes composed of egg phosphatidylcholine with or without an equimolar amount of cholesterol. The liposomes were separated by Sepharose 4B chromatography into fractions consisting of large multilamellar vesicles and small unilamellar vesicles. The incorporation of CT was monitored by counting [125I]CT and by specific RIA. Liposomal entrapment enhanced the hypocalcemic potency of parenterally administered salmon CT and human CT. After iv administration, the large multilamellar vesicles were more potent than small unilamellar vesicles in their hypocalcemic effect; cholesterol inclusion in the MLV liposome preparation prolonged the hypocalcemia. However, with im administration, the cholesterol-free liposomes were more potent than their cholesterol-containing counterparts regardless of size. These studies demonstrate that liposomal entrapment can be used to enhance the hypocalcemic potency of CT. It appears that both the size and composition of the liposome preparation are important in this effect, as is the route of administration. It may be possible to produce liposome-CT preparations with advantageous pharmacological characteristics.

Animals↗

Ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, and arthritis of inflammatory bowel disease.

These diseases are classified together as the seronegative spondyloarthritides. They are characterized by an association with the cell surface antigen HLA-B27, sacroilitis and spondylitis, inflammatory peripheral arthritis, enthesopathy (abnormalities in ligamentous attachments), and the absence of rheumatoid factor. Extra-articular complications are common. The diseases are usually treated with nonsteroidal anti-inflammatory drugs and physical therapy.

Arthritis↗

Improvement in amino acid use in the critically ill patient with parenteral formulas enriched with branched chain amino acids.

To assess the value of BCAA enriched solutions in patients under stress, we studied five critically ill, intensive care unit patients requiring total parenteral nutrition. Two complete feeding solutions were compared: one containing 15.6 per cent of the amino acids as BCAA and the other enriched to contain 50 per cent as BCAA. These solutions were prepared to be isocaloric and isonitrogenous and were administered in consecutive 24 hour periods. The order of administration was determined randomly. In the last ten hours of each infusion day, 50 microcuries of L-[1-14C]leucine were added to the solution to estimate leucine kinetics. Increased plasma leucine appearance (from 3.92 +/- 0.48 to 6.26 +/- 0.51 millimoles per hour, p less than 0.05), oxidation (from 0.83 +/- 0.23 to + 1.41 +/- 0.33 millimoles per hour, p less than 0.05) and net leucine balance (from + 0.48 +/- 0.23 to + 1.41 +/- 0.33 millimoles per hour, p less than 0.05) were found in patients while receiving the solution enriched to contain 50 per cent of the amino acids as BCAA. Plasma leucine, isoleucine and valine concentrations were also significantly increased with administration of the BCAA enriched solution, whereas plasma levels of glycine, tyrosine and phenylalanine were significantly reduced. These changes represent a normalization of plasma amino acid levels with administration of BCAA enriched solution. In addition, the improved net leucine balance observed during administration of BCAA suggests patients have an improved protein balance while receiving BCAA enriched solutions.

Aged↗

Bloody tap amniocentesis: discrimination between fetal and maternal blood by means of hemoglobin electrophoresis.

Bloody amniotic fluid from amniocentesis or vaginal blood obtained in the late third trimester from 15 patients was analyzed for the presence of fetal blood by hemoglobin electrophoresis and Kleihauer-Betke tests. In addition, 15 experimentally formulated specimens were submitted for analysis. Where quantities were sufficient for parallel assay, the tests correlated 100%. Hemoglobin electrophoresis was an objective test for quantifying and accurately distinguishing the source of fetal-maternal bleeding.

Amniocentesis↗

Monoclonal autoantibody directed toward histone and capable of inducing LE cell formation.

LE cell formation is one feature of systemic lupus erythematosus exhibited by virtually all mice of the NZB/NZW strain and is the result of accumulation of antibodies directed against components of cell nuclei. A hybrid cell line which produces antibodies capable of inducing LE cell formation in vitro has been isolated in a hybridoma fusion using the splenocytes of unimmunized NZB/NZW mice. These monoclonal autoantibodies provide an intense staining of the chromatin in cells of a number of divergent species and tissues. They bind strongly to the histone rich (2 M NaCl) fraction of extracted, isolated nuclei. Further analyses using the antibodies in immune precipitations and in antibody labeling of capillary blots on nitrocellulose sheets of calf thymus histone demonstrate that the antibodies are directed against histones and are capable of reacting with H1, H2a, H2b, H3, and H4 histones individually. In contrast to human autoantibodies with histone specificity, no cross-reactivity of this monoclonal autoantibody with the lymphocyte surface could be detected by either immunofluorescence or immunoelectron microscopy.

Animals↗

Recurrent idiopathic angioedema in the presence of increased capillary fragility: an unusual case presentation.

A case of petechiae formation associated with recurrent idiopathic angioedema is presented. The mechanism for the petechial formation appears to be related to the underlying presence of increased capillary fragility in association with elevated venous pressure caused by angioedema. The persistence of the increased capillary fragility during the long, symptom-free intervals between acute episodes of angioedema suggests that the capillary fragility is unrelated to the pathologic process responsible for the angioedema.

Angioedema↗

Effects of ovariectomy on the binding of [125I]-alpha bungarotoxin (2.2 and 3.3) to the suprachiasmatic nucleus of the hypothalamus: an in vivo autoradiographic analysis.

alpha-Bungarotoxin (alpha-BTX) has been used to label receptor binding sites on neural membranes. alpha-BTX fractions 2.2 and 3.3 were purified from Bungarus multicinctus by the method of Ravdin and Berg (1979) and we iodinated. There was no difference between these two fractions in their binding affinity or specificity of binding with hypothalamic synaptosomes. [125I] alpha-BTX 2.2S, 3.3 and commercially obtained [125I] alpha-BTX were injected into the third ventricle of ovariectomized female rats (n = 22), normally cycling rats (n = 12) or normal male rats (n = 4) and autoradiographic examination performed. Saline injected hypothalami (n = 4) or hypothalamus. Examination of serial sections from animals injected with each [125I] alpha-BTX showed that the supraoptic, periventricular, arcuate, premamillary and mamillary nuclei were consistently labeled. While the suprachiasmatic nucleus (SCN) in the intact females and males both showed high densities of alpha-BTX binding, the SCN in ovariectomized females showed little or no alpha-BTX binding. Thus, the labeling of the SCN in females without ovaries and ovarian hormones was markedly different from that of the intact males and females. Labeling patterns in castrate and intact animals may contribute to our understanding of gonadal steroid regulation of hypothalamic function.

Animals↗

Inhibition of artificially induced decidual cell reaction by indomethacin in the mature oophorectomized rat.

Prostaglandin F2 alpha (PGF2 alpha) is capable of inducing a decidual cell reaction (DCR) in the hormonally prepared rat. In the present work indomethacin, a PG synthetase inhibitor, was used to determine whether PGF2 alpha is involved in the DCR induced by artificial stimulation of the endometrium. Thirty-seven animals were oophorectomized and subsequently given daily injections of progesterone for 6 days and one injection of estradiol 17 beta on the fourth day. Later on the fourth day, one of several experimental maneuvers was carried out on the right uterine horn of each animal; these included: 1) introduction of phosphate-buffered saline (PBS) twice into the uterus, 2) intrauterine injection of PGF2 alpha with no subsequent application or manipulation, 3) intrauterine injection of indomethacin followed by subsequent injection of PGF2 alpha, 4) intrauterine injection of indomethacin with subsequent artificial stimulation (scratch), 5) intrauterine injection of PBS with subsequent scratch, 6) scratch followed by injection of PBS, and 7) scratch followed by a second scratch. The extent of the ensuing DCR was assessed 48 h later by measurement of horn weight, by light and electron microscopy, by ranking the DCR, and by the mitotic index. Indomethacin significantly reduced the horn weight in animals treated with scratch but had a much less marked effect on animals treated with PGF2 alpha. Similarly the rank of the DCR and the mitotic index were significantly less in endometria treated by indomethacin with scratch than those treated by indomethacin with PGF2 alpha. From these findings it was concluded that the DCR induced by scratch was inhibited, but not abolished, when preceded by indomethacin. Conversely the DCR induced by PGF2 alpha was not inhibited by indomethacin, thus demonstrating that when local generation of PG is reduced or abolished, PGF2 alpha can sustain the decidual cell response.

Animals↗

Decidual cell reaction induced by prostaglandin F2 alpha in the mature oöphorectomized rat.

Sprague-Dawley rats were oöphorectomized and after a 2-3 week recovery period were given daily injections of progesterone (2.0 mg/0.1 ml) for six consecutive days. On the fourth day of progesterone treatment 0.2 microgram of estradiol 17 beta was given in addition and the right uterine cornua were subjected to one of five experimental maneuvers. On the sixth day of progesterone treatment the uterine cornua were weighed and processed for light and electron microscopy. The weights of all left cornua (84.6 +/- 3.7 mg) and the right cornua of PBS-injected (93.3 +/- 11.5 mg) and sham operated uteri (83.6 +/- 19.8 mg) were comparable. A significant increase (p less than 0.001) in weight was found in cornua that received PGF2 alpha (144 +/- 6.7 mg), PGF2 alpha with mild local trauma (scratch) (146 +/- 28.0 mg), and scratch alone (162 +/- 12.7 mg). The majority to cornua treated by scratch alone, or by PGF2 alpha with or without scratch, showed a decidual cell reaction by light microscopy and had a significantly higher mitotic index than those treated with saline, or by sham operation. When specimens were evaluated for the presence of the DCR, the highest rank was found in tissues treated by scratch alone or by PGF2 alpha with or without scratch. Morphometric evaluation by light microscopy indicated that the extent of decidualization in PGF2 alpha-treated tissue was comparable to that of scratch-treated tissue. Ultrastructural observation of PGF2 alpha-treated tissue revealed that decidual cells closely resembled those treated with scratch. However, electron microscopic morphometry revealed that cells that responded to PGF2 alpha had higher volume and surface densities of organelles associated with metabolic activity than did cells responding to scratch alone. These results demonstrate that locally administered PGF2 alpha can initiate, in the hormonally prepared mature oöphorectomized rat, a DCR comparable to that induced by local trauma.

Animals↗

Plasma amino acid concentrations during branched-chain amino acid infusions in stressed patients.

To determine the effect of infusing large quantities of BCAA on plasma amino acid concentrations, plasma amino acid profiles were measured in 18 stressed patients before and 48 to 96 hours after initiation of amino acid solutions enriched with or exclusively containing BCAA (15.6+, 50%, 100%). Plasma concentrations of BCAA were elevated in the 100% and 50% BCAA groups, but not in the 15.6% group. Methionine, glycine, and phenylalanine concentrations were increased in the 15.6% BCAA group: methionine and glycine were decreased in the 100% BCAA groups. In the 50% BCAA group, nonbranched-chain amino acids maintained baseline concentrations. The 50% solution best preserved nitrogen balance of the BCAA solutions. The plasma amino acid profiles of patients with maple syrup urine disease (BCAA levels 5 to 10 times normal) were compared to our patients receiving BCAA-enriched solutions. Although plasma BCAA levels were elevated in our patients, allo-isoleucine, alanine, and glutamine concentrations were normal; the amino acid abnormalities of maple syrup urine disease were not observed.

Abdomen↗