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Biomedical subjects

W Potts

Publications and source records attributed to W Potts.

At least 19 recordsLinked to original sources
PubMed2001

Discovery of novel, orally active dual NK1/NK2 antagonists.

Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (K(i)=0.12 and 0.62nM, respectively). In functional assays ZD6021 had, at 10(-7)M, in human pulmonary artery pK(B)=8.9 and in human bronchus pK(B)=7.3, for NK1 and NK2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED(50)=0.5mg/kg, and NK2 mediated bronchoconstriction, ED(50)=13mg/kg.

Administration, Oral↗
PubMed2000

Chicken beta-globin 5'HS4 insulators function to reduce variability in transgenic founder mice.

Transgenic mice and rats play a vital role in the study of human diseases and the advancement of drug development within the pharmaceutical industry. In this report we describe a method which improves the yield of phenotypically desirable transgenic founder mice resulting from each microinjection session and consequently reduces animal requirements for transgenic production. We have shown that by flanking a tyrosinase minigene with tandem copies of the chicken beta-globin 5'HS4 insulator there is a significant reduction in variability between transgenic lines, with resulting mice exhibiting similar levels of coat pigmentation. Furthermore, the presence of insulators leads to visually identical tissue distribution of pigmentation including skin, fur, eyes, points, and foot pads. The overall impact of insulators is to reduce the number of transgenic founders required in order to identity animals with an appropriate expression level and tissue distribution.

Animals↗
PubMed2000

Paternity in horseshoe crabs when spawning in multiple-male groups.

Unpaired or satellite male horseshoe crabs, Limulus polyphemus, are attracted to and often form a group around a pair (a female with an attached male) that is nesting in the high intertidal zone. These males are engaged in sperm competition. We observed nesting pairs and their associated satellites in the wild, collected and reared their eggs and used genetic markers to examine paternity. We found that the unpaired, satellite males are highly successful at fertilizing eggs; two satellites can leave the attached male with few fertilizations. Two satellites together are each as successful as one spawning with a pair. A satellite's location around the female greatly affects his success, and males compete for access to a position over the dorsal canal between the prosoma and opisthosoma of the female and under the front margin of the paired male where they are most likely to fertilize eggs. Although eggs and sperm retain their viability for some time after spawning, nearly all eggs are fertilized by the satellites that are around the nesting pair at the time of egg laying and by the attached male. A number of factors including beach current, female size and male behaviour affect the outcome of sperm competition in this externally fertilizing species. Copyright 2000 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed2000

Nonpeptide tachykinin receptor antagonists. II. Pharmacological and pharmacokinetic profile of SB-222200, a central nervous system penetrant, potent and selective NK-3 receptor antagonist.

The pharmacological and pharmacokinetic profile of SB-222200 [(S)-(-)-N-(alpha-ethylbenzyl)-3-methyl-2-phenylquinoline-4-car boxami de], a human NK-3 receptor (hNK-3R) antagonist, was determined. SB-222200 inhibited (125)I-[MePhe(7)]neurokinin B (NKB) binding to Chinese hamster ovary (CHO) cell membranes stably expressing the hNK-3 receptor (CHO-hNK-3R) with a K(i) = 4.4 nM and antagonized NKB-induced Ca(2+) mobilization in HEK 293 cells stably expressing the hNK-3 receptor (HEK 293-hNK-3R) with an IC(50) = 18.4 nM. SB-222200 was selective for hNK-3 receptors compared with hNK-1 (K(i) > 100,000 nM) and hNK-2 receptors (K(i) = 250 nM). In HEK 293 cells transiently expressing murine NK-3 receptors (HEK 293-mNK-3R), SB-222200 inhibited binding of (125)I-[MePhe(7)]NKB (K(i) = 174 nM) and antagonized NKB (1 nM)-induced calcium mobilization (IC(50) = 265 nM). In mice oral administration of SB-222200 produced dose-dependent inhibition of behavioral responses induced by i.p. or intracerebral ventricular administration of the NK-3 receptor-selective agonist, senktide, with ED(50) values of approximately 5 mg/kg. SB-222200 effectively crossed the blood-brain barrier in the mouse and rat. The inhibitory effect of SB-222200 against senktide-induced behavioral responses in the mouse correlated significantly with brain, but not plasma, concentrations of the compound. Pharmacokinetic evaluation of SB-222200 in rat after oral administration (8 mg/kg) indicated sustained plasma concentrations (C(max) = about 400 ng/ml) and bioavailability of 46%. The preclinical profile of SB-222200, demonstrating high affinity, selectivity, reversibility, oral activity, and central nervous system penetration, suggests that it will be a useful tool compound to define the physiological and pathophysiological roles of NK-3 receptors, in particular in the central nervous system.

Animals↗
PubMed1998

MHC-disassortative mating preferences reversed by cross-fostering.

House mice (Mus musculus domesticus) avoid mating with individuals that are genetically similar at the major histocompatibility complex (MHC). Mice are able recognize MHC-similar individuals through specific odour cues. However, to mate disassortatively for MHC genes, individuals must have a referent, either themselves (self-inspection) or close kin (familial imprinting), with which to compare the MHC identity of potential mates. Although studies on MHC-dependent mating preferences often assume that individuals use self-inspection, laboratory experiments with male mice indicate that they use familial imprinting, i.e. males learn the MHC identity of their family and then avoid mating with females carrying 'familial' MHC alleles. To determine if female mice use familial imprinting, we cross-fostered wild-derived female mouse pups into MHC-dissimilar families, and then tested if this procedure reversed their mating preferences compared with in-fostered controls. Our observations of the female's mating behaviour in seminatural social conditions and the genetic typing of their progeny both indicated that females avoided mating with males carrying MHC genes of their foster family, supporting the familial imprinting hypothesis. We show that MHC-dependent familial imprinting potentially provides a more effective mechanism for avoiding kin matings and reducing inbreeding than self-inspection.

Animals↗
PubMed1998

Rad23 links DNA repair to the ubiquitin/proteasome pathway.

Rad23 is an evolutionarily conserved protein that is important for nucleotide excision repair. A regulatory role has been proposed for Rad23 because rad23 mutants are sensitive to ultraviolet light but are still capable of incising damaged DNA. Here we show that Rad23 interacts with the 26S proteasome through an amino-terminal ubiquitin-like domain (UbL[R23]). The carboxy terminus of Rad23 binds to the Rad4 DNA repair protein and creates a link between the DNA repair and proteasome pathways. The ultraviolet sensitivity caused by deletion of the UbL(R23) domain may therefore arise from its inability to interact with the proteasome. The fusion proteins glutathione S-transferase (GST)-Rad23 and Rad4-haemagglutinin (HA), and the proteasome subunits Cim3 and Cim5, cofractionate through consecutive chromatography steps. The ubiquitin-like domain of human Rad23 (UbL[HRB]) also interacts with the human proteasome. These results demonstrate that ubiquitin-like domains (UbLs) represent a new class of proteasome-interacting motifs.

Adenosine Triphosphatases↗
PubMed1998

Effects of isolation and culture of turkey primary follicular oocytes on morphology and germinal vesicle integrity.

A novel approach to the production of transgenic poultry is to use primary follicular oocytes (PFOs). However, fundamental information regarding the impact of isolation and culture procedures on PFO integrity is lacking. This study describes the isolation and culture of PFOs from mature turkeys and the effects of these procedures on PFO morphology and germinal vesicle (GV) integrity. To isolate PFOs, ovarian cortex was incubated in trypsin-EDTA alone or further incubated in collagenase plus hyaluronidase (CH). About 200 to 500 PFOs, ranging in size from less than 100 microns in diameter to 1,000 microns, were recovered from each ovary. The culture of PFOs less than 100 microns in diameter for 4 h resulted in blebbing of the oolemma followed by extrusion of ooplasm. Primary follicular oocytes 100 to 250 microns in diameter survived culture for 24 h whereas larger PFOs survived for up to 7 d. Those PFOs with intact granulosa cell investments survived longer than those fully or partially denuded of granulosa cells with CH. Co-culture of PFOs (100 to 250 microns in diameter) on a monolayer of granulosa cells derived from mature, yellow-yolk follicles augmented PFO survival rates. The rate of GV breakdown was not influenced by the isolation or culture of the PFO. These data provide the basis for developing procedures for the in vitro maturation and in vitro fertilization of isolated PFOs.

Animals↗
PubMed1998

Gross appearance of the turkey blastoderm at oviposition.

The blastoderm (fertilized ovum) and unfertilized germinal disc (UGD) of fresh laid eggs and eggs stored prior to incubation exhibit subtle but definable morphological variations. Such variations may lead to difficulty when attempting to determine true flock fertility based on the appearance of the blastoderm/UGD. The objectives of this study were to define and categorize such morphological variations and to determine whether sperm influence the frequency distribution of the different categories. Eleven categories of blastoderms were defined based on the relative density and appearance of the area alba, area pellucida, area opaca, and the periblast. The majority of the blastoderms were included in the first four categories. Unfertilized germinal discs were divided into six categories and were best differentiated from the blastoderms by the presence of vacuoles around its central dense area. They were also discernible from blastoderms based on their overall denser appearance. Differences in the frequency distribution of some of the UGD categories between virgin and inseminated hens may be due to the effect that supernumary sperm may have on the organization of the UGD (no fertilization but supernumary sperm present) or blastoderm (fertilized but failed to develop). It is recommended that before starting true fertility determinations during fresh egg breakouts, one should study the appearance of the UGD from virgin hens and then the blastoderm from inseminated hens. One then will learn to appreciate the subtle differences in shape and density of the blastoderm/UGD structural components.

Animals↗
PubMed1997

Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist.

The in vitro and in vivo pharmacological profile of SB 223412 [(S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carbo xamide], a novel human NK-3 (hNK-3) receptor antagonist, is described. SB 223412 demonstrated enantioselective affinity for inhibition of [125I][MePhe7]neurokinin B (NKB) binding to membranes of CHO cells expressing the hNK-3 receptor (CHO hNK-3). SB 223412, the (S)-isomer, (Ki = 1.0 nM), has similar affinity as the natural ligand, NKB (Ki = 0.8 nM) and another nonpeptide NK-3 receptor antagonist, SR 142801 (Ki = 1.2 nM). SB 223412 was selective for hNK-3 receptors compared with hNK-1 (>10,000-fold selective) and hNK-2 receptors (>140-fold selective), and selectivity was further demonstrated by its lack of effect, in concentrations up to 1 or 10 microM, in >60 receptor, enzyme and ion channel assays. SB 223412 enantioselectively inhibited the NKB-induced Ca++ mobilization in HEK 293 cells stably expressing the hNK-3 receptor. SB 223412 (10-1,000 nM) produced concentration-dependent rightward shifts in NKB-induced Ca++ mobilization concentration-response curves with a Kb value of 3 nM. In addition, SB 223412 antagonized senktide-induced contraction in the isolated rabbit iris sphincter muscle (Kb = 1.6 nM). In mice, oral administration of SB 223412 produced dose-dependent inhibition of behavioral responses induced by the NK-3 receptor-selective agonist, senktide (ED50 = 12.2 mg/kg). Pharmacokinetic evaluation of SB 223412 in rat and dog indicated low plasma clearance, oral bioavailability and high and sustained plasma concentrations after 4 to 8 mg/kg oral dosages. The preclinical profile of SB 223412 (high affinity, selectivity, reversibility and oral activity) suggests that it will be a useful tool compound to define the physiological and pathophysiological roles of NK-3 receptors.

Animals↗
PubMed1996

Comparison of methods of assessing vitamin A status in children.

OBJECTIVE: A study of children (2-8 years; n = 613) in Belize, Central America, was conducted to determine what proportion of the children might be at risk of vitamin A (vit A) deficiency. The data provide an opportunity to compare results of three methods of assessing vit A status in a population which was not severely malnourished. Serum retinyl ester concentrations were also determined; their relevance to one of the tests, the relative dose response (RDR) test, is discussed. METHODS: The three methods of assessing vit A status were: RDR test, fasting serum retinol concentration, and conjunctival impression cytology (CIC). Retinol-binding protein (RBP), serum retinyl esters and serum zinc concentrations were also determined. RESULTS: Inadequate vit A status was indicated for 17% of subjects by the RDR test (14% cutoff), for 24% by fasting serum retinol concentration (< 0.87 mumol/L), and for 49% by "abnormal" CIC score. Retinyl esters constituted 24% of serum retinoids at the time (5 hours after a retinyl palmitate dose) at which the second blood sample is taken for the RDR test. Regression tree analyses (CART) indicated ethnicity was a predictor of RDR score; ethnicity, stunting and age were predictors of fasting serum retinol concentration; ethnicity and stunting were predictors of 0-hour retinyl ester concentration. CONCLUSION: The three indices of vit A status did not identify the same individuals nor indicate the same percentage of the population to be at risk for vit A deficiency. Increased concentrations of retinyl esters at 5 hours compared to those at 0 hours suggest that insufficient retinol may have been taken up by the liver at 5 hours to release all accumulated retinol-binding protein (RBP) in deficient individuals; prevalence of vit A deficiency might therefore be underestimated by the RDR test. The selection of ethnicity as a predictor of RDR score and of 0-hour retinol and retinyl ester concentrations suggests that factors other than vit A status affect vit A metabolism and may affect the RDR test.

Belize↗
PubMed1996

Serum carotenoid concentrations and their reproducibility in children in Belize.

Suggestions that carotenoid-containing foods are beneficial in maintaining health have led to several studies of circulating carotenoid concentrations of adults. Because few data are available for children, we report serum carotenoid concentrations of 493 children in Belize. Carotenoid concentrations were determined as part of a survey of vitamin A status of children, most between 65 and 89 mo of age. Reproducibility was tested by collecting a second blood sample 2 wk after the first collection from a subset of children (n = 23) who consumed their habitual diet with no treatment during the interim. Predominant serum carotenoids were lutein/zeaxanthin and beta-carotene, which accounted for 26% and 24% of median total carotenoids, respectively. The three provitamin A carotenoids, alpha- and beta-carotene and beta-cryptoxanthin, constituted 51% of median total carotenoid concentrations. Partial correlations of each carotenoid with fasting retinol concentration indicated that beta-carotene had the highest correlation. Concordance correlation coefficients (rc) for fasting carotenoid concentrations determined 2 wk apart were > or = 0.89 for lycopene, beta-cryptoxanthin, and alpha- and beta-carotene. The rc for lutein/zeaxanthin and total carotenoids was lower, 0.59 and 0.68, respectively, because of higher lutein/zeaxanthin concentrations at the second sampling than at the first. The reproducibility of the concentrations suggests both that individuals have characteristic profiles and that serum carotenoid concentrations can be measured randomly over > or = 2 wk without significant bias.

Belize↗
PubMed1996

Plasma flow and net nutrient flux across gut and liver of cattle fed twice daily.

The objectives of this study were 1) to quantify daily patterns of plasma flow and metabolite flux through portal-drained viscera (PDV) and liver in cattle fed twice daily and 2) to identify an interval for blood sampling that would approximate the average daily plasma flow and nutrient flux values. Data are from three experiments in which multicatheterized cattle were fed at or near ad libitum intake twice daily. Five lactating primiparous Holstein cows (506 kg, fed at 0730 and 1930) ate 17.3 kg DM/d as chopped alfalfa hay:corn grain plus supplement (urea and minerals) 50:50 (Exp 1). Five beef steers (474 kg, fed at 0900 and 2100) ate 8.3 kg DM/d as chopped switchgrass hay:corn grain plus supplement 37:63 (Exp 2). Six beef steers (306 kg fed at 0900 and 2100) ate 6.9 kg DM/d as chopped alfalfa hay (Exp 3). Plasma flow (by dilution of para-aminohippurate) was measured hourly for 24 h. Plasma flows (mean +/- SE) through PDV were 1,264 +/- 147, 538 +/- 56, and 499 +/- 26 L/h for Exp. 1, 2, and 3, respectively. Corresponding liver flows were 1,662 +/- 216, 642 +/- 41, and 591 +/- 30 L/h. The within-animal differences from their respective daily means were estimated as a function of time of day using nonparametric smoothing. Across experiments, PDV and liver flows were above the daily mean from 1200 to 1400, were not different from the daily mean from 1600 to 1700, and were below the daily mean from 1930 to 2130. Metabolites measured were ammonia, urea, alpha-amino N, and glucose. In general, metabolite flux was not different from the average daily mean values between 1200 and 1600. Blood sampling over 12 h or one 12-h feeding cycle is sufficient for daily plasma flow and metabolite flux estimation in cattle fed twice daily.

Ammonia↗
PubMed1996

Effects of dietary concentrate level on nutrient absorption, liver metabolism, and urea kinetics of beef steers fed isonitrogenous and isoenergetic diets.

Six multicatheterized beef steers (421 +/- 21 kg BW) were used to predict the effect of dietary concentrate level on blood flow and net flux of urea and other metabolites across splanchnic tissues. Diets ranged from 0% (switchgrass hay) to 90% concentrate (10% switchgrass hay, 89% cracked corn, 1% urea). Daily DMI varied from 8.01 to 5.34 kg/d. Nitrogen intake (99 g/d) and calculated ME intake (16.8 Mcal/d) were equal among diets. As dietary concentrate increased from 0 to 90%, liver blood flow decreased from 850 to 795 L/h, portal-drained visceral (PDV) blood flow decreased from 750 to 620 L/h, and mesenteric-drained visceral (MDV) blood flow decreased from 270 to 250 L/h. Liver release of urea N was 94 mmol/h when dietary concentrate was less than 20%, then increased to 146 mmol/h at 55% concentrate. Urinary excretion of urea N was 13 mmol/h or less when dietary concentrate was 20% or less, increased to 53 mmol/h at 55% concentrate, then continued to increase to 76 mmol/h at 90% concentrate. Transfer of urea N to PDV ranged from 71 to 91 mmol/h and transfer to MDV ranged from 0 to 10 mmol/h among diets. As dietary concentrate increased from 27 to 63%, VFA release by PDV decreased, net MDV and splanchnic release of glucose increased, and splanchnic tissues switched from net uptake to net release of L-lactate. Net PDV release or liver removal of ammonia or alpha-amino N and net liver release of glucose were not affected. We conclude that the liver responded to changes in the percentage of dietary concentrate by altering urea production and by altering the role of lactate in intermediary metabolism.

Ammonia↗
PubMed1995

The effects of thiocyanate on the intracellular ion concentrations of branchial epithelial cells of brown trout

Exposure of brown trout (Salmo trutta) in fresh water to 0.15 mmol l-1 external thiocyanate for 1 h resulted in a significant decrease in chlorine concentration in the branchial mitochondria-rich (MR) cells from 37 mmol l-1 to 22 mmol l-1. The intracellular sodium concentration in these cells decreased by a similar amount, whilst the intracellular phosphorus concentration increased significantly. In contrast to the MR cells, 0.15 mmol l-1 external thiocyanate had no effect on the intracellular ion concentrations in the pavement epithelial cells. Thiocyanate is known to inhibit chloride uptake in a number of freshwater animals and therefore these data suggest that it is only the MR cells that are involved in the uptake of Cl- in brown trout.

Journal Article↗
PubMed1995

Characterization of the metabolites of the peptidomimetic human immunodeficiency virus type 1 protease inhibitor SK&F 107461 in rats using liquid chromatography/mass spectrometry.

The metabolic fate of SK&F 107461 [Cbz-Ala-Ala-Phe psi [CHOHCH2] Gly-Val-Val-OMe], a potent and specific inhibitor of the protease encoded by human immunodeficiency virus type 1, in male Sprague-Dawley rats is described. SK&F 107461 is a hexapeptide analog containing a hydroxyethylene linkage in place of one of the peptide bonds, and in which the amino terminus is blocked with a carbobenzyloxy group and the carboxy terminus is modified to a methyl ester. The major metabolites of SK&F 107461 found in bile and urine after intravenous administration of 3H-labeled compound were characterized by LC/MS using either thermospray or continuous flow/FAB models of ionization. Approximately 80% of the administered radioactivity was recovered in the bile of bile duct-exteriorized rats following an intravenous dose. Radiochromatographic profiling indicated that SK&F 107461 was subject to extensive biotransformation. Structures were determined for three major biliary and five major urinary metabolites. Two of the major circulating plasma metabolites observed after intravenous bolus administration had similar retention times to metabolites that were observed in both bile and urine. A pathway for the biotransformation of SK&F 107461 in the rat is proposed. The parent molecule underwent two primary modes of metabolism. Hydrolysis of the carboxy-terminal ester or hydrolysis of the Ala-Ala peptide bond near the amino terminus were the primary metabolic events. All of the other metabolites characterized can be accounted for by exopeptidase activity subsequent to one or both of these primary events. There were no major metabolites observed resulting from anything other than hydrolysis of the ester or peptide bonds in the parent molecule.

Amino Acid Sequence↗
PubMed1994

INTRACELLULAR ION CONCENTRATIONS IN BRANCHIAL EPITHELIAL CELLS OF BROWN TROUT (SALMO TRUTTA L.) DETERMINED BY X-RAY MICROANALYSIS

The intracellular concentrations of sodium, chloride, phosphorus and potassium under normal conditions in pavement epithelial (PE) cells of brown trout (Salmo trutta) gill were 66, 51, 87 and 88 mmol l-1 respectively. The concentrations of these elements under identical conditions in mitochondria-rich (MR) cells were not significantly different, except for that of chlorine, which was lower in MR cells (40 mmol l-1). The concentration of sodium in the PE cells decreased slightly after exposure of the fish to low external [Na+] (25 &micro;mol l-1) for 7 days but increased greatly within 5 min of subsequent exposure to 1 mmol l-1 external Na+. These changes in external [Na+] had no significant effect on MR cells. Exposure of fish to low [Cl-] (25 &micro;mol l-1) had no effect on PE or MR cells, but on exposure to 1 mmol l-1 Cl- the concentrations of chlorine, phosphorus and potassium in both types of cells increased, whilst the intracellular sodium concentration decreased only in MR cells. The PE cells were little affected by exposure of the fish to the carbonic anhydrase inhibitor acetazolamide. In contrast, 0.5 mmol l-1 external acetazolamide caused a significant decrease in intracellular phosphorus, chlorine and potassium concentrations in MR cells. This suggests that the PE cells are the sites of sodium uptake in the gills of the brown trout and that chloride uptake occurs via the MR cells. These results are discussed with respect to the sites and possible mechanisms of ionic exchange in freshwater vertebrates.

Journal Article↗
PubMed1993

Isolated lymphoma of genitourinary tract and adrenals.

With the routine use of computed tomographic imaging, intrinsic involvement of the genitourinary tract in newly diagnosed non-Hodgkin's lymphoma is seen in as many as 10 percent of patients. Incidental discovery of an extranodal, extra-lymphatic lesion in the genitourinary tract without clinical or radiographic evidence of disease elsewhere, however, is an uncommon occurrence. The clinical presentation and imaging findings in 4 patients with initial manifestation of lymphoma isolated to the kidney, ureter, bladder, and adrenals, respectively, are presented. These patients had no evidence of lymphoma elsewhere, and imaging studies mimicked the more common neoplasms affecting these organs.

Adrenal Gland Neoplasms↗