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T R Miller

Publications and source records attributed to T R Miller.

At least 19 recordsLinked to original sources
PubMed1992

Synthesis and biological activity of CCK heptapeptide analogues. Effects of conformational constraints and standard modifications on receptor subtype selectivity, functional activity in vitro, and appetite suppression in vivo.

A series of modifications of the CCK7 analogue (des-NH2)Tyr(SO3-)-Nle-Gly-Trp-Nle-Asp-Phe-NH2 was prepared and tested for binding to guinea pig CCK-A and CCK-B receptors and in CCK-A-mediated functional assays. Selected analogues also were tested for appetite suppressant activity in rats. Several conformationally restricted residues in the C-terminal tetrapeptide region, including delta Z-Phe33, (N-Me)Phe33, (N-Me)Asp32, (N-Me)Leu31, and 3PP31 (3PP = trans-3-n-propyl-L- proline) were found to be acceptable modifications at one or both receptor subtypes. The (N-Me)Asp32 and (N-Me)Leu31 modifications afforded potent and selective CCK-A and CCK-B ligands, respectively. SAR studies in the N-terminal acyldipeptide region examined structural requirements for the side chain at position 28, where Gly and Pro replacements were found to possess high affinity at both receptor subtypes. Other conformationally restrictive modifications were less active. All of the analogues that showed high affinity (less than 10 nM) for the CCK-A receptor also were full agonists in amylase release and most were full or nearly full agonists in the phosphoinositide (PI) turnover assay, the most notable exception being the delta Z-Phe33 analogue, which showed 69% of the maximal response in the PI assay. Potent activity in suppression of food intake in rats was found for selected analogues.

Amino Acid Sequence↗
PubMed1992

Development of potent and selective CCK-A receptor agonists from Boc-CCK-4: tetrapeptides containing Lys(N epsilon)-amide residues.

A series of Boc-CCK-4 derivatives represented by the general structure Boc-Trp-Lys(N epsilon-COR)-Asp-Phe-NH2, where R is an aromatic, heterocyclic, or aliphatic group, are potent and selective CCK-A receptor agonists. These amide-bearing compounds complement the previously described urea-based tetrapeptides (Shiosaki et al. J. Med. Chem. 1991, 34, 2837-2842); structure-activity studies revealed parallel as well as divergent trends between these two series. A significant correlation was observed between pancreatic binding affinity and the resonance constant R of the phenyl substituent in one particular series of derivatives. Sulfation of phenolic amides appended onto the epsilon-amino group of the lysine did not affect affinity for the CCK-A receptor in contrast to the 500-fold increase in binding potency observed upon sulfation of CCK-8, suggesting that the lysine appendage and the sulfated tyrosine in CCK-8, both key structural elements that impart high affinity for the CCK-A receptor, are interacting differently with the receptor. The amide-bearing tetrapeptides are full agonists relative to CCK-8 in stimulating pancreatic amylase release while being partial agonists in eliciting phosphoinositide (PI) hydrolysis. Both effects were blocked by selective CCK-A receptor antagonists.

Amino Acid Sequence↗
PubMed1992

Principles of therapeutics.

Topical administration of drugs is the treatment of choice for diseases of the anterior segment. Drug levels attained by this means are usually of short duration, however, necessitating frequent therapy or continuous perfusion if prolonged drug levels are required. A drug-delivery device (collagen shield or contact lens) or subconjunctival injections can be used to augment topical therapy if frequent treatment is not possible. Subconjunctival injections are recommended for drugs that have low solubility and, hence, low corneal penetration. Retrobulbar injections are seldom indicated, except for regional anesthesia. Systemic administration is useful for anti-inflammatory therapy but it may be difficult to establish therapeutic levels of antibiotic agents in the eye because of the blood-ocular barrier. In severe cases, intraocular injection may be required.

Administration, Topical↗
PubMed1992

Both CCK-A and CCK-B/gastrin receptors mediate pepsinogen release in guinea pig gastric glands.

We evaluated the affinity of cholecystokinin octapeptide (CCK-8), gastrin, and subtype-selective CCK agonists for CCK/gastrin receptors and compared it with the ability of these peptides to stimulate phosphoinositide (PI) hydrolysis and pepsinogen release in guinea pig gastric glands. Competitive binding studies using 125I-labeled Bolton-Hunter-CCK-8 and 125I-gastrin showed the presence of CCK-B/gastrin receptors in gastric glands and dispersed chief cells. In contrast, the potency of peptides in stimulating PI hydrolysis in both gastric glands and dispersed chief cells displayed a profile similar to CCK-A receptors found in pancreatic acini, i.e., CCK-8 = A 71378 greater than A 71623 greater than A 70874 much greater than A 72962 = CCK-8 (desulfated) greater than gastrin II greater than gastrin I. In general, the rank order of potency of peptides for stimulation of PI hydrolysis correlated well with their ability to stimulate pepsinogen release. At concentrations greater than 10 microM, efficacies of gastrin I and II in stimulating pepsinogen release from gastric glands were near 90% of the maximal activity of CCK-8. The inhibitory potency of MK-329, a selective CCK-A receptor antagonist, was similar against either CCK-8 (10 nM) or gastrin I (10 microM), except that a minor portion (approximately 30-40%) of gastrin I-induced pepsinogen release was insensitive to MK-329. The MK-329-insensitive component was inhibited by CI-988, a potent and selective CCK-B/gastrin receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Both CCK-A and CCK-B/gastrin receptors are present on rabbit vagus nerve.

Cholecystokinin (CCK) receptors on vagal afferents have been implicated in many of the actions of the brain-gut peptide CCK, including satiety. Autoradiographic studies in rats have demonstrated the presence of CCK-A-type receptors on vagus nerves. However, direct and detailed characterization of this important CCK receptor site has never been reported with membrane-binding techniques. Using 125I-Bolt-on-Hunter-CCK octapeptide (125I-BH-CCK-8) and the recently discovered selective agonists and antagonists of CCK receptors, we have delineated the properties of CCK receptors on rabbit vagus nerve. 125I-BH-CCK-8 binding sites appeared to be homogeneous by the Scatchard analysis, with a dissociation constant of 0.14 nM and a maximum binding of 72 fmol/mg protein. However, competition studies using selective CCK ligands showed that the vagal CCK receptors are heterogeneous. A71378, a selective CCK-A agonist, showed biphasic displacement curves, with the high-affinity portion (less than 10 nM) accounting for approximately 60% and the low-affinity portion for approximately 40%. Competitive binding studies using A63387, a selective CCK-B/gastrin receptor agonist, also showed biphasic displacement curves, with the high-affinity portion (less than 30 nM) at approximately 40% and the low-affinity portion at approximately 60%. Under conditions which selectively examined vagal CCK-A or CCK-B/gastrin receptors, we demonstrated that a number of CCK subtype selective agonists and antagonists possessed similar affinities for the vagal CCK-A and -B/gastrin receptors as those found on the guinea pig pancreas (CCK-A) and cerebral cortex (CCK-B), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Estimating costs of traffic crashes and crime: tools for informed decision making.

Traffic crashes and crime both impose significant economic and social burdens through injury and loss of life, as well as property damage and loss. Efforts to reduce crashes and crime often result in competing demands on limited public resources. Comparable and up-to-date cost data on crashes and crime contribute to informed decisions about allocation of these resources in important ways. As a first step, cost data provide information about the magnitude of the problems of crashes and crime by allowing us to estimate associated dollar losses to society. More importantly, cost data on crashes and crime are essential to evaluating costs and benefits of various policy alternatives that compete for resources. This paper presents the first comparable comprehensive cost estimates for crashes and crime and applies them to crash and crime incidence data for Michigan to generate dollar losses for the state. An example illustrates how cost estimates can be used to evaluate costs and benefits of crash-reduction and crime-reduction policies in making resource allocation decisions. Traffic crash and selected index crime incidence data from the calendar year 1988 were obtained from the Michigan State Police. Costs for crashes and index crimes were generated and applied to incidence data to estimate dollar losses from crashes and index crimes for the state of Michigan. In 1988, index crimes in Michigan resulted in $0.8 billion in monetary costs and $2.4 billion in total monetary and nonmonetary quality-of-life costs (using the willingness-to-pay approach). Traffic crashes in Michigan resulted in $2.3 billion in monetary costs and $7.1 billion in total monetary and nonmonetary quality-of-life costs, nearly three times the costs of index crimes. Based on dollar losses to the state, the magnitude of the problem of traffic crashes clearly exceeded that of index crimes in Michigan in 1988. From a policy perspective, summing the total dollar losses from crashes or crime is of less importance than understanding the costs and benefits of various policy alternatives. This paper therefore concludes with an example of how our cost estimates can be used to compare the costs and benefits of competing policies.

Accidents, Traffic↗
PubMed1992

Clinically important characteristics of maximum-likelihood reconstruction.

SPECT images of a Jaszczak rod phantom, a single-slice Hoffman brain phantom and a uniform water-bath were acquired. Simulated noisy bar phantoms incorporating depth-dependent attenuation and blur were produced and compared to simulations with depth-independent attenuation and blur, as is the case in PET. Following iterative maximum-likelihood reconstruction, regularization was performed with use of Gaussian filters. While correction for attenuation is achieved in approximately 10 iterations, spatial resolution in the SPECT reconstructions, quantified by contrast in the bar simulations and by visual inspection of the real data, was highly nonuniform, being poorest at the center and improving toward the periphery. Image resolution continued to improve well beyond 50 iterations when regularization was applied that maintained a constant signal-to-noise ratio. Contrast in the simulated PET data also improved with increasing iterations, but the PET data showed uniform contrast throughout the transaxial slices at all numbers of iterations.

Algorithms↗
PubMed1992

Fast maximum-likelihood reconstruction.

A significant problem in application of maximum-likelihood reconstruction to SPECT and PET studies is the very long computation time required for this iterative algorithm. An approach is presented in which the basic calculations involved in projection and backprojection are performed only once and stored in computer memory, thus significantly reducing the computation time.

Algorithms↗
PubMed1992

Anatomic and radiographic study of the lacrimal apparatus of llamas.

The anatomy of the nasolacrimal duct of llamas was examined grossly and radiographically in 2 llamas. Dacryocystorhinography was performed on cadaver heads, using a radiographic aqueous contrast agent. Anatomic casts of the nasolacrimal apparatus were obtained by cannulation of the duct and use of polyurethane cast material. Dacryocystorhinography accurately revealed the nasolacrimal apparatus and compared favorably with gross dissections and polyurethane casts.

Animals↗
PubMed1991

Cytopathologic diagnosis of benign lesions simulating choroidal melanomas.

In three cases of benign pigmented lesions (one melanocytoma and two pigment epithelial adenomas) there was evidence of tumor growth and the lesions were referred to us as uveal melanomas. The fine needle aspiration biopsy specimens were correctly interpreted in the operating room as being benign tumors. The pigment granules in these benign pigmented lesions are much larger than are observed in uveal melanomas. When they were visible through the heavy pigmentation, the cellular detail appeared benign. In two cases the tumors were successfully resected with cyclochroidectomy techniques and the visual outcome was good. The third eye was studied after it had been removed at another institution. Fine needle aspiration biopsy can often differentiate a benign-simulating pigmented lesion from uveal melanoma.

Adenoma↗
PubMed1991

Pancreatic adenocarcinoma: regression analysis to identify improved cytologic criteria.

The incidence of pancreatic adenocarcinoma is increasing and it is usually unresectable at the time of diagnosis. Consequently, fine-needle aspiration biopsy (FNAB) is being used more frequently for diagnosis. The reported sensitivity of diagnosing pancreatic adenocarcinoma by FNAB has varied between 50% and 100%. In an attempt to increase the diagnostic sensitivity, we retrospectively reviewed a series of pancreatic FNABs. Fifteen cytologic criteria were evaluated in 78 patients who had pancreatic FNABs. Of these patients, 49 had primary adenocarcinomas and 29 had benign, non-neoplastic lesions. Using a stepwise logistic regression analysis we identified three key cytologic criteria for this diagnosis. Our study identified anisonucleosis (P = 0.001), large nuclei (P = .007), and nuclear molding (P = .03) as the significant cytologic features for diagnosing pancreatic adenocarcinoma. In combination, these three criteria had a sensitivity of 98% and a specificity of 100%.

Adenocarcinoma↗
PubMed1991

Boc-CCK-4 derivatives containing side-chain ureas as potent and selective CCK-a receptor agonists.

Novel Boc-CCK-4 derivatives were communicated recently as having high potency and selectivity for the CCK-A receptor (Shiosaki et al. J. Med. Chem. 1990, 33, 2950-2952). While Boc-CCK-4 binds selectively to the CCK-B receptor, replacement of the methionine with an N epsilon-substituted lysine dramatically reversed receptor selectivity, leading to the development of this novel series of tetrapeptides. A detailed structure-activity analysis of a series of urea-substituted tetrapeptides, represented by the general structure Boc-Trp-Lys(N epsilon-CO-NHR)-Asp-Phe-NH2, revealed that a number of substituted phenyl, naphthyl, and aliphatic urea residues in the lysine side chain yielded potent and selective CCK-A ligands. These tetrapeptides elicit full agonist responses in stimulating pancreatic amylase release that are effectively blocked by a selective CCK-A receptor antagonist. Conversion of the urea to a thiourea significantly reduced CCK-A binding potency as did replacement of the lysine with the homologous ornithine or homolysine. Tetrapeptides that were partial agonists (less than 80% efficacy) in phosphoinositide (PI) hydrolysis relative to CCK-8 did not exhibit high-dose inhibition of amylase secretion in guinea pig acini.

Amino Acid Sequence↗
PubMed1991

Mucocele-like tumors of the breast. Cytologic findings in two cases.

Mucocele-like tumors of the breast originally were reported by Rosen in 1986 as benign lesions that histologically resembled colloid carcinoma of the breast. The authors document two cases of mucocele-like tumors to illustrate the difficulty in separating these lesions from colloid carcinoma on the basis of fine-needle aspiration biopsy. Cytologically, mucocele-like tumors contained abundant mucin, few clusters, and sheets of regular epithelium that lacked nuclear atypia, and they contained no intact single cells. The authors recommend open surgical biopsy when fine-needle aspiration biopsy findings in such cases are equivocal.

Adult↗
PubMed1991

Therapeutic management of ocular squamous cell carcinoma in the horse: 43 cases (1979-1989).

The records of 50 horses with ocular squamous cell carcinoma (OSCC) presented to the University of Florida Veterinary Medical Teaching Hospital over an 11 year period were reviewed to determine the influence of therapy on the outcome of the case. Follow-up information was obtained for 43 of the 50 cases. The disease was more prevalent in the light horse breeds; however, the draft breeds also were at risk. There was no sex predisposition and the average age was 11.8 years. Tumour recurrence was significant when surgery alone was performed. The eyelid and nictitating membrane were the primary sites for tumor recurrence. Cases in which adjunctive therapy was used correlated with a lower rate of recurrence.

Age Factors↗