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Biomedical subjects

D Goldstein

Publications and source records attributed to D Goldstein.

At least 199 records · Page 11Linked to original sources
PubMed1987

Pharmacokinetics of inhaled salbutamol in patients with cystic fibrosis versus healthy young adults.

We studied the disposition of inhaled salbutamol in adolescents with cystic fibrosis (CF) and compared it with the pharmacokinetics of the drug given by the intravenous and inhaled routes in healthy adults. After inhalation of salbutamol, CF patients had a significantly larger area under the concentration-time curve derived from amounts of drug in the systemic circulation. The differences in serum concentration of salbutamol were not reflected in differences in change of heart rate. We conclude that the rate and extent of pulmonary absorption of inhaled salbutamol in patients with CF differ from those in healthy adults.

Administration, Inhalation↗
PubMed1987

Supportive care of the patient with cancer.

In assessing the needs of the elderly patient with cancer, we need first to determine the extent of cancer, its complications, and the type of comorbid physical and psychologic conditions. The next step is to determine the goals of our care and specifically the extent to which supportive care is needed to deal with problems. For supportive care to be truly effective, the specific underlying condition producing a complaint must be investigated. It is also important not to underestimate the significance of a symptom such as constipation. Furthermore, nutritional support requires as much planning as, for example, the control of pain. Some problems (eg, nausea, vomiting, pain, and constipation) are best managed with preventive measures; others (eg, anemia, granulocytopenia, and coagulopathies) have very specific indications for intervention. Considerable progress has been made toward understanding the mechanisms of clinical problems such as nausea and vomiting, and a more rational approach to supportive therapy is now possible. However, it is usually not possible to recommend any one intervention for a particular problem: no one intervention is uniformly effective or safe. Aggressive supportive care in elderly cancer patients can improve their ability to tolerate anti-cancer therapies and, more importantly, provide palliation of distressing symptoms.

Aged↗
PubMed1986

Lymphokine-induced monocyte procoagulant activity is depressed in patients with advanced malignancies.

Fibrin deposition in the microenvironment of tumor cells may be critical to tumor growth and metastasis formation. Procoagulant activities of tumor cells themselves, or of infiltrating macrophages, activated by the host's immune system to the tumor, may both contribute to coagulopathies associated with metastases. Lymphokine (LK) supernatant activated procoagulant activity on normal peripheral blood monocytes but failed to induce activity on mononuclear cells from 18/22 patients with locally advanced or disseminated non-lymphoid tumors. Monocytes from the remaining patients had very low basal levels of MPCA and were less sensitive than normal cells to LK. Monocytes from 4 patients (3 with tumors with a high growth fraction) had extremely elevated levels of basal procoagulant activity, possibly due to maximal activation in vivo. Neither LK nor bacterial lipopolysaccharide (LPS) stimulated procoagulant production of these cells. By contrast, cells from 8/13 patients produced procoagulant in response to LPS. This study indicated that monocyte function of patients with disseminated cancer is suppressed with respect to LK stimulation, but that cells with normal basal levels of MPCA respond to LPS. Preactivation of mononuclear procoagulant in vivo precluded subsequent stimulation by either LPS or LK.

Adenocarcinoma↗
PubMed1986

Duchenne muscular dystrophy, glycerol kinase deficiency, and adrenal insufficiency associated with Xp21 interstitial deletion.

We report an interstitial deletion in the short arm of the X chromosome in a 6-year-old boy with Duchenne muscular dystrophy, glycerol kinase deficiency, adrenal insufficiency, intermittent hypoglycemia, spasticity, psychomotor retardation, and growth delay. His mother also has this deletion in an X chromosome. From our findings, we propose that the human glycerol kinase locus and the human X-linked adrenal hypoplasia locus are in the Xp21 band.

Adrenal Insufficiency↗
PubMed1986

Tropomyosin isoform switching in tumorigenic human fibroblasts.

We identified six tropomyosin (Tm) isoforms in diploid human fibroblasts. We used computerized microdensitometry of 2-dimensional protein profiles to measure the relative rates of synthesis and abundance of the individual Tm isoforms and actin, the two major structural constituents of microfilaments. In carcinogen-transformed human fibroblasts (HuT-14), the rates of synthesis of three Tm isoforms (Tm1, Tm2, and Tm6) were greatly decreased relative to normal diploid parental fibroblasts and to actin. In contrast, related nontumorigenic HuT fibroblasts which are "immortalized" and anchorage independent exhibited both slight down-regulation of Tm1 and Tm6 and 3.5-fold up-regulation of Tm3. Thus, Tm isoform switching from the predominance of the larger more avid Tm isoforms (Tm1, Tm2, Tm3, and Tm6) to the smaller, less avid Tm isoforms (Tm4 and Tm5) in microfilaments was a transformation-induced change correlated with tumorigenicity in human fibroblasts.

Cell Line↗
PubMed1986

Analysis of cardiac muscarinic receptors recognized selectively by nonquaternary but not by quaternary ligands.

Three muscarinic receptor antagonists, [3H]quinuclidinyl benzilate ([3H]QNB), N-[3H]methylscopolamine ([3H]NMS and N-[methyl-3H]QNB ([3H]NMeQNB), each bind to an apparently homogeneous population of receptors on intact chick heart cells. [3H]QNB binds to approximately 9500 sites/cells, whereas [3H]NMS and [3H]NMeQNB bind to approximately 5000 sites/cell. Atropine and scopolamine compete with all three radioligands with a single, high affinity. Their quaternary analogs N-methylatropine and NMS and the quaternary agonist carbachol also show a single affinity for [3H]NMS and [3H]NMeQNB binding sites, but have biphasic competition curves for [3H]QNB sites with low "apparent" affinity for a subpopulation of sites. When 10 nM or greater propylbenzilylcholine mustard is used to alkylate receptors virtually all [3H]NMS binding is abolished, whereas [3H]QNB still labels a significant fraction of the binding sites seen in control cells. The sites with low apparent affinity for quaternary ligands are shown to have characteristics of muscarinic receptors, but do not appear necessary for muscarinic receptor-mediated phosphoinositide hydrolysis. We suggest that a subpopulation of nonfunctional muscarinic receptors are sequestered within the membrane or otherwise inaccessible to hydrophilic or charged ligands.

Alkylation↗
PubMed1986

Differences in muscarinic receptor reserve for inhibition of adenylate cyclase and stimulation of phosphoinositide hydrolysis in chick heart cells.

Carbachol is 100 times more potent for inhibiting cyclic AMP formation than for stimulating phosphoinositide (PI) hydrolysis in chick heart cells. To determine whether this reflects differences in agonist affinity of the receptor(s) coupled to the two responses, we measured these functional responses following removal of receptor reserve with propylbenzilycholine mustard (PrBCM). Conditions of PrBCM treatment that led to progressive loss of up to 95% of the [3H]-N-methylscopolamine-binding sites decreased the potency but not the maximal capacity of carbachol to inhibit cyclic AMP formation. In contrast, there was a marked decrease in the maximal PI response to carbachol. The KA for carbachol, calculated by measuring functional responses following receptor inactivation, was similar whether the cyclic AMP or the PI response was examined. These KA values (approximately 40 microM) were similar to the KD calculated by examining carbachol competition for [3H]-N-methylscopolamine-binding sites on the intact cell. PrBCM treatment also decreased the maximal effect of oxotremorine on cyclic AMP formation under conditions in which carbachol remained a full agonist for this response. We interpret our data as indicating that: there is much greater receptor reserve in the coupling of muscarinic receptors to adenylate cyclase than to PI hydrolysis; this, rather than differences in receptor affinity underlies the disparate dose-response relationships for the two responses; and differences in the effects of weak agonist on the two responses may also reflect differences in receptor reserve. We suggest that muscarinic receptors with the same affinity for carbachol interact with different efficiency with the transducers (Gi and Gx) that regulate adenylate cyclase and phospholipase C.

Adenylyl Cyclase Inhibitors↗
PubMed1986

Does maintenance therapy with alpha interferon stabilize cancer growth? A pilot study.

A pilot study was undertaken to test whether alpha interferon (alpha-IFN) maintenance could continue to stabilize cancer measurements after induction therapy. Twenty-one patients who achieved stable disease at the end of their induction treatment were randomized to receive weekly maintenance with human lymphoblastoid interferon (HLBI) (3 MU/m2, i.m.) or to be followed and not given interferon. There were 12 patients in the maintenance groups and 9 in the control observation group. There was no time difference in disease progression between the two arms. This article considers the relevance of the stable disease category in trials of interferon.

Adult↗
PubMed1985

Substitutions of proline 76 in yeast iso-1-cytochrome c. Analysis of residues compatible and incompatible with folding requirements.

Fine-structure genetic mapping previously revealed numerous nonfunctional cyc1 mutations having alterations at or near the site corresponding to amino acid position 76 of iso-1-cytochrome c from the yeast Saccharomyces cerevisiae. DNA sequencing of the alterations in four of these cyc1 mutations indicated that the normal Pro-76 was replaced by Leu-76. Revertants containing at least partially functional iso-1-cytochromes c were isolated, and the alterations were analyzed by DNA sequencing and protein analysis. Specific activities of the altered iso-1-cytochromes c were estimated in vivo by growth of the strains in lactate medium; compared to normal iso-1-cytochrome c with Pro-76, the following activities were associated with the following replacements: approximately 90% for Val-76, approximately 60% for Thr-76, approximately 30% for Ser-76, approximately 20% for Ile-76, and 0% for Leu-76. In order to develop an understanding of the factors that determine whether or not an altered iso-1-cytochrome c will function, we undertook a theoretical analysis which led to the conclusion that the activity of the proteins was dependent on both short- and long-range interactions. Short-range interactions were estimated from studies on known protein structures which gave the likelihood that various amino acids would be found in a local backbone configuration similar to the native protein; long-range interactions with the rest of the molecule were analyzed by considering the size of the side chain. We believe this approach can be used to analyze a wide variety of mutant proteins.

Amino Acid Sequence↗
PubMed1985

Acetylcholine release from rat atria can be regulated through an alpha 1-adrenergic receptor.

Isolated superfused rat atria release [3H]acetylcholine when depolarized with 57 mM potassium. The depolarization-induced overflow of [3H]acetylcholine is markedly inhibited by micromolar concentrations of epinephrine and norepinephrine. The alpha 1-selective adrenergic agonist methoxamine also inhibits tritium overflow, but the alpha 2-selective adrenergic agonist clonidine and the beta-adrenergic agonist isoproterenol do not. Prazosin, an selective alpha 1-adrenergic antagonist, blocks adrenergic inhibition of [3H]acetylcholine overflow with a Ki of approximately 0.4 nM. Yohimbine has approximately one-hundredth the potency of prazosin for blocking adrenergic inhibition of [3H]acetylcholine overflow. [3H]Norepinephrine overflow from isolated rat atria is also inhibited by norepinephrine, but this effect is antagonized by yohimbine and not by prazosin. We suggest that the release of acetylcholine from cardiac parasympathetic neurons can be regulated through an alpha 1-adrenergic receptor, and that this mechanism may underly, at least in part, the relative lack of effects of prazosin on heart rate.

Acetylcholine↗
PubMed1985

The putative M1 muscarinic receptor does not regulate phosphoinositide hydrolysis. Studies with pirenzepine and McN-A343 in chick heart and astrocytoma cells.

Muscarinic receptor activation stimulates phosphoinositide hydrolysis and inhibits cyclic AMP formation in dissociated embryonic chick heart cells. We used this preparation to examine the hypothesis that the putative M1 and M2 receptor subtypes are selectively coupled to these two responses. Atropine blocks the effects of carbachol on cyclic AMP formation and phosphoinositide breakdown with nearly identical KI values (1.9 and 0.8 nM); these values are close to the apparent KD (1.8 nM) of atropine competition for [3H]N-methylscopolamine binding. Pirenzepine blocks the effect of carbachol on cyclic AMP formation with a KI of 48 nM, a value similar to the apparent KD (23 nM) determined in radioligand-binding studies. In contrast, a higher concentration of pirenzepine is needed to inhibit carbachol-stimulated phosphoinositide hydrolysis (KI = 255 nM). Two selective agonists, McN-A343 and AHR 602, inhibit cyclic AMP formation but do not stimulate phosphoinositide hydrolysis in chick heart cells. Muscarinic receptor-mediated phosphoinositide hydrolysis in 1321N1 astrocytoma cells is also insensitive to McN-A343 or AHR 602 and is antagonized only by relatively high concentrations of pirenzepine. The M1 receptor, as previously defined, has high affinity for pirenzepine and is activated by McN-A343. We find that these ligands have greater activity at muscarinic receptors that inhibit cyclic AMP formation than at those that stimulate phosphoinositide hydrolysis. Thus, if different receptor subtypes are associated with these two responses, the M1 receptor regulates cyclic AMP rather than phosphoinositide metabolism. Our data also demonstrate that the chick heart has muscarinic receptors with high affinity for pirenzepine, and thus, in contrast to rat heart, appears to have predominantly M1 receptors.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1985

Expression of neoplasia-related proteins of chemically transformed HuT fibroblasts in human osteosarcoma HOS fibroblasts and modulation of actin expression upon elevation of tumorigenic potential.

Two sets of abundant cytoplasmic transformation-specific polypeptides, p788/p789 and p219/p220, have been identified by comparing in vitro-transformed human fibroblasts with diploid human fibroblasts. These polypeptides are also expressed by the human fibrosarcoma and osteosarcoma cell lines HT1080 the human fibrosarcoma and osteosarcoma cell lines HT1080 and HOS, respectively. HOS cells, however, synthesize only one of the two electrophoretic forms of each marker set, p789 and p219, at greatly reduced rates compared to the rates of synthesis found for HT1080 cells and the in vitro-transformed cell lines. Induction of expression of these neoplastic marker polypeptides is independent of the activation of a transforming gene that will induce focus formation in confluent mouse 3T3 cell monolayers. Activation of the met oncogene in MNNG-HOS cells and simultaneous elevation of tumorigenic potential did not lead to a significant change in the rate of the 600 most abundant polypeptide species with the exception of one of the two cytoplasmic actin polypeptides. While the normal ratio of beta-to gamma-actin which is approximately 2:1 was expressed in "untransformed" HOS cells, MNNG-HOS cells synthesized 50% less beta-actin resulting in a 1:1 ratio of beta-actin to gamma-actin. Our finding here, together with our previous characterization of the human beta-actin gene, leads us to predict that one of two functional beta-actin genes expressed in HOS cells has been inactivated in MNNG-HOS cells by either a regulatory or structural gene mutation.

Actins↗
PubMed1985

Abundant synthesis of the transformation-induced protein of neoplastic human fibroblasts, plastin, in normal lymphocytes.

The transformation-induced protein plastin (p219; Mr 68,000, pl 5.3) is a reliable cytosolic marker for neoplastic human fibroblasts. Fibroblasts transformed in vitro by chemical carcinogens or SV40 virus and tumor-derived cancer cells of fibroblastoid or epithelioid origin usually express plastin and p220, a minor phosphorylated form of plastin. We report here that plastin is expressed as one of the most abundant proteins of normal, untransformed lymphocytes. The phosphorylated form of plastin was detectable in adherent monocytes but not in purified T- or NK lymphocytes. We also demonstrate that an allelic variant or mutated form of plastin exhibiting altered charge is found at a reduced frequency in the human population. We discuss the possible significance of these observations in terms of evaluating the role of plastin induction in expression of the cancerous phenotype of fibroblasts.

Amino Acids↗
PubMed1984

Plasma cortisol and catecholamine responses to intracerebroventricular administration of CRF to rhesus monkeys.

Synthetic ovine corticotropin releasing factor (CRF) was administered directly into the 4th ventricle of rhesus monkeys. A dose dependent increase in plasma cortisol was observed following 10 micrograms/kg, 20 micrograms/kg, and 60 micrograms/kg of CRF. Increases in plasma epinephrine were also evident following the highest dose of CRF. Plasma norepinephrine, mean arterial pressure, and heart rate did not increase significantly following CRF administration. These data suggest that in the rhesus monkey, central administration of ovine CRF leads to activation of the pituitary-adrenocortical axis at doses that do not raise plasma catecholamines.

Animals↗