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Biomedical subjects

L J Miller

Publications and source records attributed to L J Miller.

At least 127 records · Page 7Linked to original sources
PubMed1994

Treatment of cyclophosphamide-induced hemorrhagic cystitis with prostaglandins.

OBJECTIVE: To report a case of cyclophosphamide-induced hemorrhagic cystitis, discuss prevention, and review treatment options, particularly the use of intravesicular prostaglandins. DATA SOURCES: Literature obtained through a computerized search, with subsequent bibliography scanning. Information on the individual case was obtained from the patient's medical record and the Pharmacy Clinical Research Specialist. CASE SUMMARY: A 29-year-old woman who had a postallogeneic bone marrow transplantation was hospitalized because of graft-versus-host disease. During hospitalization, she developed a cyclophosphamide-induced hematuria that, despite hydration and transfusions of blood products, progressed to refractory hemorrhagic cystitis. A response was prompted ultimately by a regimen consisting of continuous bladder irrigation and intermittent intravesical instillation of carboprost. DISCUSSION: The best treatment for hemorrhagic cystitis remains prevention. Therapies for established cystitis are varied; the choice depends on the degree of hematuria present. Therapies are often temporary or ineffective, and themselves cause significant morbidity. One promising treatment option involves the intravesicular administration of prostaglandins. Reports in the literature discuss a variety of products, dosages, and treatment schedules that have been used with some success. The available data on this technique are presented. CONCLUSIONS: Prostaglandins appear to be effective in resolving established hemorrhagic cystitis; however, their place in therapy remains unclear. Before this class can be employed routinely, several basic issues remain. These include optimal dosage, dosing schedule, duration of treatment, and comparative efficacy with other agents.

Administration, Intravesical↗
PubMed1993

Control of cholecystokinin receptor dephosphorylation in pancreatic acinar cells.

Phosphorylation of cell surface receptors regulates the physiological response to many hormones and neurotransmitters. We have demonstrated that the receptor for cholecystokinin (CCK), the major secretagogue for the exocrine pancreas, is phosphorylated on serines in response to CCK (Klueppelberg, U.G., Gates, L.K., Gorelick, F.S., and Miller, L.J. (1991) J. Biol. Chem. 266, 2403-2408). Receptor phosphorylation was transient, even in the continued presence of agonist, and suggested a role for pancreatic protein phosphatases (PP) in regulating receptor phosphorylation in the intact cell. Treatment of acinar cells with okadaic acid increased the extent and duration of receptor phosphorylation induced by CCK. Receptor phosphorylated in the intact cell in response to CCK was used as substrate to analyze protein phosphatases in pancreatic acinar cell extracts. The predominant CCK receptor phosphatase activity was found in the cytosol and was potently inhibited by okadaic acid (IC50 = 0.2 nM). This phosphatase activity was unaffected by inhibitor-2, Ca2+, or Mg2+, suggesting that the major receptor phosphatase was PP-2A. Stimulation of cells with CCK resulted in a 3-fold increase in protein phosphatase activity toward the CCK receptor, at the same time that phosphorylase a phosphatase activity was unchanged. This increase in receptor phosphatase activity was reflected only in the cytosol, with the particulate activity unchanged. Consistent with this subcellular localization, the hormone-regulated receptor phosphatase activity was PP-2A, with chromatographic separation demonstrating activity in both PP-2A1 and PP-2A2 forms. These data suggest that CCK coordinates the activity of both protein kinases and phosphatases acting on the CCK receptor to control the extent and duration of receptor phosphorylation in the pancreatic acinar cell.

Animals↗
PubMed1993

Molecular cloning and functional expression of the human gallbladder cholecystokinin A receptor.

Through binding to cholecystokinin (CCK) A receptors, CCK is an important physiologic regulator of both gallbladder contraction and pancreatic enzyme secretion. In this work, we have used a combination of hybridization screening of a cDNA library and polymerase chain reaction to clone a 2.1 kb cDNA which encodes the human gallbladder CCKA receptor. Nucleotide sequence analysis revealed an open reading frame encoding a 428 amino acid protein, with seven putative transmembrane domains and a high degree of homology with the rat CCKA receptor. COS cells transfected with this cDNA clone bound CCK-8 and L-364,718 with high affinities appropriate for the CCKA receptor, and exhibited a transient increase in intracellular calcium in response to CCK. This should provide an important resource for the analysis of the role of this receptor in human physiology and pathophysiology.

Amino Acid Sequence↗
PubMed1993

A role for cholecystokinin-stimulated protein tyrosine phosphorylation in regulated secretion by the pancreatic acinar cell.

Cholecystokinin (CCK) is a gastrointestinal hormone that acts through a G protein-coupled receptor to stimulate pancreatic enzyme secretion. In this work, we demonstrate that CCK stimulation of dispersed pancreatic acini results in increased tyrosine phosphorylation of several cellular proteins. This is mediated via a calcium-dependent pathway, also activated by a phenethyl ester analogue of CCK and calcium ionophores, and by a protein kinase C-dependent cascade, also activated by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. All demonstrable stimulated tyrosine phosphorylation events were inhibited by genistein, with different subsets of proteins affected by staurosporine and H-7. The importance of tyrosine phosphorylation events in agonist-stimulated amylase secretion was studied using genistein and staurosporine as protein kinase inhibitors. Genistein inhibited the secretory response to CCK, its phenethyl ester analogue, and calcium ionophores, all known to stimulate secretion in a calcium-dependent fashion. In contrast, genistein had no effect on the secretory response to 12-O-tetradecanoylphorbol-13-acetate, suggesting that the protein kinase C-dependent tyrosine phosphorylation events were not involved in the secretory mechanism. Furthermore, CCK-induced secretion was not affected by relatively specific protein kinase C inhibition by H-7, but was decreased by staurosporine, an inhibitor of both protein kinase C and tyrosine kinase activities in these cells. These results provide evidence that acinar cell tyrosine phosphorylation is stimulated by agonists acting via calcium-dependent and protein kinase C-dependent pathways, with only the calcium-dependent tyrosine phosphorylation cascade involved in triggering hormone-induced amylase release.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Characterization of cAMP-dependent protein kinase activation by CCK in rat pancreas.

This study reports on the use of a new sensitive assay of cAMP-dependent protein kinase activity to examine the effect of cholecystokinin (CCK) on the cAMP second messenger cascade in rat pancreatic acini. Treatment of acini with both low (pM) and high (nM) concentrations of CCK was associated with an increase in cAMP-dependent protein kinase activity. The increases in kinase activity were detected in the absence of phosphodiesterase inhibition, a condition required to detect a measurable increase in cellular cAMP in these cells. Furthermore, the cAMP cascade was dissociated from the secretory effects of CCK, since the CCK analogue, OPE, mediates enzyme secretion but does not increase cellular cAMP levels or kinase activity.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Intrinsic photoaffinity labeling of native and recombinant rat pancreatic secretin receptors.

BACKGROUND: Structural characterization of pancreatic secretin receptors has been limited by difficulties in generating suitable radioligands and obtaining sufficient substrate. The aims of this study were to design, synthesize, and characterize high affinity radiolabeled analogues of secretin suitable for "intrinsic" photoaffinity labeling and to clone, express, and characterize the recombinant rat pancreatic secretin receptor. METHODS: The ability of synthetic analogues to stimulate amylase secretion by pancreatic acini was studied. Receptor complementary DNA (cDNA) was cloned by screening a rat pancreatic library with a probe based on the sequence of a neural cell secretin-binding protein. Competition binding and affinity labeling were performed with membranes prepared from rat pancreas and transfected cells. RESULTS: Two probes were fully efficacious secretagogues, which bound in a specific, high-affinity, rapid, and temperature-dependent manner. Only ([125I]Tyr10, pNO2-Phe22) rat secretin 27 covalently labeled a 50,000-62,000-molecular weight pancreatic membrane protein, with labeling inhibited in a concentration-dependent manner by secretin but not vasoactive intestinal polypeptide. Hybridization screening yielded a full-length cDNA identical to the neural clone. Photoaffinity labeling of this recombinant receptor identified a 57,000-62,000-molecular weight protein with specificity similar to that of native pancreas. Both native and recombinant receptors migrated at a molecular weight of 42,000 after endoglycosidase F deglycosylation. CONCLUSIONS: This study provides evidence for the molecular identity of the pancreatic secretin receptor and presents a novel probe important in structural characterization of its agonist-binding domain.

Affinity Labels↗
PubMed1993

The preparation of frozen sections for micrographic surgery. A review of current methodology.

BACKGROUND: Various methods are currently in use for preparing histological slides for micrographic surgery. OBJECTIVE: Because many variables contribute to the quality preparation of frozen sections, a review of techniques available is useful to the Mohs surgeon. TECHNICAL METHODS AND RESULTS: Our techniques as well as the published work of others regarding mounting, embedding, freezing, slides, fixation, staining, and clearing are reviewed in detail. By the use of the options selected we were able to produce, in a short turn-around time, frozen sections with excellent quality and minimal artifact. CONCLUSION: Presently all preparation techniques may introduce some degree of artifact. However, we feel the process described herein is adaptable to all Mohs surgery laboratories and will result in high quality specimens with minimal artifact.

Fixatives↗
PubMed1993

Multiple kinases phosphorylate the pancreatic cholecystokinin receptor in an agonist-dependent manner.

The cholecystokinin (CCK) receptor on the rat pancreatic acinar cell is a guanine nucleotide-binding protein (G protein)-coupled receptor, which was recently demonstrated to be phosphorylated in response to agonist stimulation (Klueppelberg et al., J. Biol. Chem. 266: 17744-17746, 1991). In this work, we establish that this receptor is phosphorylated in response to a variety of homologous and heterologous secretagogues and that these phosphorylation events represent action by more than one protein kinase. One subgroup of kinases includes one or more isotype of protein kinase C (PKC), and is capable of playing a role in homologous and heterologous desensitization. A second subgroup of kinases that acts on the CCK receptor was defined by its resistance to 10 microM staurosporine, which was shown to inhibit all PKC in these cells. The activity of the second group of kinases was observed only in response to occupation of the CCK receptor by high concentrations of native hormone, raising the possibility of a "receptor-specific kinase." Similar to the prototypical kinase, beta-adrenergic receptor kinase (beta-ARK), this activity was inhibited in permeabilized cells by heparin. Furthermore, like this enzyme activity, beta-ARK was shown to be resistant to staurosporine. Based on its action on a G protein-coupled receptor, its activation at high concentrations of native agonist, and its pattern of inhibition, we believe that the staurosporine-insensitive CCK receptor kinase activity represents either beta-ARK or a closely related member of the receptor-specific kinase enzyme family.

Alkaloids↗
PubMed1993

Patients' attitudes toward hallucinations.

OBJECTIVE: This study examined patients' attitudes toward their hallucinations by assessing their beliefs about the purposes served by hallucinations and the adverse effects of hallucinations. It also investigated whether these attitudes were related to characteristics of the hallucinations or of the patients, whether the attitudes changed after treatment, and whether attitudes before treatment predicted the presence or absence of hallucinations after treatment. METHOD: Fifty hallucinating psychiatric inpatients were given semistructured interviews shortly after admission to the hospital and again shortly before discharge. The interviews elicited detailed descriptions of 12 phenomenologic characteristics of hallucinations and 11 attitude variables. RESULTS: The majority of subjects reported some positive effects of hallucinations. The presence of olfactory hallucinations and the ability to predict hallucinations were significantly related to valuing hallucinations. Attitudes usually did not change with treatment; when they did change they usually became more positive. Subjects who valued hallucinations more before treatment were significantly more likely to be hallucinating after treatment. CONCLUSIONS: The findings are consistent with the idea that psychological factors contribute to the expression of hallucinations. Assessing adaptive functions of hallucinations may predict whether hallucinations will respond to treatment and identify fruitful areas for psychosocial intervention.

Adolescent↗
PubMed1993

Pain management with intravenous ketorolac.

OBJECTIVE: To report a case in which intravenous ketorolac was used successfully on a chronic basis to treat cancer pain. DATA SOURCES: Clinical and compatibility studies obtained through a computer literature search. STUDY SELECTION: We identified five reports that specifically addressed intravenous dosing of ketorolac. DATA SYNTHESIS: A 41-year-old man received pain relief from intravenous injections of ketorolac for 11 months. As far as we know, there are no other reports in the literature in which intravenous ketorolac has been used on a chronic basis. CONCLUSIONS: Experience at our institution indicates that intravenous ketorolac is a useful, well-tolerated nonsteroidal antiinflammatory drug that should be investigated further for use in selected pain models.

Adenocarcinoma↗
PubMed1993

Nedocromil sodium.

OBJECTIVE: To summarize the available pharmacokinetic and pharmacologic data on nedocromil sodium and to present representative clinical trials of this new agent in both mild-to-moderate and severe chronic asthma and allergic rhinitis. Adverse effects are reviewed. DATA SOURCES: A MEDLINE search was used to identify pertinent literature, excluding reviews and foreign-language articles. All available English-language studies were reviewed. DATA EXTRACTION: Pivotal and representative studies are discussed relating to the following issues: pharmacology and pharmacokinetics, management of patients with non-steroid-dependent and steroid-dependent asthma, comparison with sodium cromoglycate (cromolyn), comparison with inhaled beclomethasone dipropionate, management of exercise-induced asthma, use in children with asthma, and use in allergic rhinitis. DATA SYNTHESIS: Nedocromil sodium is chemically grossly unrelated to cromolyn but has similar pharmacology, pharmacokinetics, and therapeutic benefits. Although ineffective in relieving acute asthma attacks, nedocromil appears to be superior to placebo in lessening the severity of chronic asthma and protecting against allergen-induced asthma when taken as chronic prophylaxis. Single doses attenuate exercise-induced asthma. It is also effective in the management of allergic rhinitis. Results have varied when nedocromil has been compared with cromolyn or inhaled beclomethasone. Studies to date indicate that, overall, nedocromil is not significantly better than cromolyn and is no better than or is inferior to inhaled beclomethasone, although individual response appears to be variable, with no identifiable predictive factors. CONCLUSIONS: Individual patients may receive marked improvement from nedocromil therapy, but there are no factors that identify which patients will respond. Nedocromil may be particularly useful in adults who frequently fail to respond to cromolyn.

Adult↗
PubMed1993

Sequence comparison methodology for the analysis of movement patterns in infants and toddlers with and without motor delays.

In an attempt to quantify the theoretical construct quality of movement, a set of measurable constructs were identified by subject matter experts, and a scale (the Toddler and Infant Motor Evaluation [TIME]) incorporating those constructs was developed and pilot tested. Sequence comparison data analysis methodology was examined for its applicability to examining series of movements. The study sample consisted of randomly selected children from a pilot edition of the scale. Because research indicates that specific individual positions cannot provide an accurate indication of the normalcy or dysfunction of the motor performance of infants and toddlers, this study researched the ability of series of movement positions in each of five postures (prone, supine, sit, quadruped, and stand) to discriminate between normal and atypical motor development. It was hypothesized that children with motor delays would demonstrate different sequences of movements than children without motor delays. The findings confirmed the hypothesis, because in this sample there was a significant difference in the performance of children with developmental delays in motor abilities compared with that of children who had normal movement abilities. Children with motor delays had poorer mobility, which was characterized by fewer transitions between movement patterns than children with normal motor abilities.

Child, Preschool↗
PubMed1992

Complex role of protein kinase C in mediating the supramaximal inhibition of pancreatic secretion observed with cholecystokinin.

Protein kinase C appears to play an important, yet complex role in the supramaximal inhibition of pancreatic acinar cell secretion observed in response to cholecystokinin (CCK). The addition of protein kinase C activation to the concentration-response curve of a partial agonist acting at the CCK receptor (a phenethyl ester analogue of CCK), transforms a curve without supramaximal inhibition to a full agonist curve typical of CCK. This effect can be elicited by low concentrations of phorbol ester (50pM to 1nM 12-0-tetradecanoyl-phorbol-13-acetate) or by hormonal agonists (0.1 microM carbamylcholine, 10pM bombesin, 1pM CCK-8) which activate protein kinase C, but not by agonists acting via alternate second messengers (VIP). Of interest, this effect is dependent on preincubation of the acinar cells with the protein kinase C activator at 37 degrees C, with the effect rapidly reversed by transient exposure of the cells to lower temperature. This is consistent with mediation by a phosphorylation event. However, the requirement for an extended (greater than 15 min) preincubation period when using minimal kinase activation suggests that this phenomenon is more complicated than a simple bimolecular phosphorylation event and likely includes a series of events such as translocation of substrates and/or enzymes involved.

Animals↗
PubMed1992

Expression cloning and characterization of the canine parietal cell gastrin receptor.

Gastrin is an important stimulant of acid secretion by gastric parietal cells and is structurally related to the peptide hormone cholecystokinin (CCK). The pharmacologic properties of the parietal cell gastrin receptor are very similar to the predominant CCK receptor in the brain, CCK-B. Neither the gastrin nor the CCK-B receptor have been cloned thus far, making it difficult to resolve whether these two receptors are distinct. We have isolated a clone encoding the canine gastrin receptor by screening a parietal cell cDNA expression library using a radioligand-binding strategy. Nucleotide sequence analysis revealed an open reading frame encoding a 453-amino acid protein with seven putative hydrophobic transmembrane domains and significant homology with members of the beta-adrenergic family of G protein-coupled receptors. The expressed recombinant receptor shows the same binding specificity for gastrin/CCK agonists and antagonists as the canine parietal cell receptor. Gastrin-stimulated phosphatidylinositol hydrolysis and intracellular Ca2+ mobilization in COS-7 cells expressing the cloned receptor suggest second-messenger signaling through phospholipase C. Affinity labeling of the expressed receptor in COS-7 cells revealed a protein identical in size to the native parietal cell receptor. Gastrin receptor transcripts were identified by high-stringency RNA blot analysis in both parietal cells and cerebral cortex, suggesting that the gastrin and CCK-B receptors are either highly homologous or identical.

Amino Acid Sequence↗