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A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted. © 2016 Elsevier Inc.

Heart failure is a complex syndrome in which the heart is unable to deliver sufficient blood to meet the metabolic needs of organs throughout the body in the presence of normal filling pressures. Despite approval of multiple drugs for treating heart failure patients over the past 50 years, the unmet medical need remains high, particularly for patients with preserved ejection fractions and acutely decompensated patients. This article provides background information on this syndrome and discussion on current and emerging therapies for heart failure.

Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved.

In this paper an antenna is presented that satisfies the two-fold radiation pattern requirement of communication systems utilizing both geostationary satellites and terrestrial transponders for coverage of mobile terminal away from the equator. A typical requirement for such a system is a low profile antenna that maximizes left-hand circularly polarized radiation in the satellite viewing angle, from 30/spl deg/ to 70/spl deg/ from zenith, and vertically polarized radiation in the terrestrial station viewing angle, from 70/spl deg/ to 90/spl deg/ from zenith. This dual radiation pattern coverage is achieved by integrating a small four arm spiral with a top loaded monopole into a single compact volume, an antenna termed a spirapole.

This study was conducted to determine if the time taken by sheep to eat an unfamiliar feed might be reduced if it was offered in the presence of a taste or odor that was familiar to the animals, or extended if the odor was aversive to them. Each morning in a 5 min test, groups of sheep (already adapted to the testing procedures) were offered an unfamiliar feed (rice bran) in the presence or absence of a familiar grass odor or grass flavor. Another group was offered the rice bran in association with the odor of dog feces. When offered the rice bran in the presence of grass juice odor or flavor, sheep ate a small amount on Day 1, and progressively increased their intake to 35–40 g by Day 7. The control sheep did not ingest any rice bran until Day 5, then increased their intake to 35 g by Day 11. In contrast, sheep avoided the rice bran with the odor of dog feces for 13 days and the rice bran intake of sheep in this group never exceeded 10 g during the test. The more rapid acceptance of rice bran in the presence of either a familiar flavor or odor is argued to be a consequence of stimulus generalisation.

As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

SummaryThe importance of thrombin in arterial and venous thrombosis renders thrombin inhibition an important therapeutic target. Identification of novel inhibitors requires an appropriate animal model. We modified a previously reported rat arterial thrombosis model to allow simultaneous assessment of the arterial and venous antithrombotic efficacies of heparin, hirudin, hirulog, a novel thrombin inhibitor H-(N-Me-D-Phe)-Pro-L-trans-4-aminocyclohexyl-Gly-[CO-CO]-NHCH3 (L-370,518) and the factor Xa inhibitor tick anticoagulant peptide in rabbits. Thrombosis was induced through application of 70% ferric chloride to the femoral artery and jugular vein. Incidence of occlusion, thrombus weight, aPTT and plasma inhibitor concentrations were determined. Heparin was efficacious in preventing arterial and venous occlusive thrombosis but at a dose that profoundly elevated aPTT. On a molar dosing basis, the approximate order of potency of the thrombin and factor Xa inhibitors was similar in artery and vein: hirudin>tick anticoagulant peptide>hirulog≥L-370,518. Data suggested that compounds tended to be more potent in preventing venous thrombosis than arterial. This thrombin-dependent model is an economical and efficient approach to arterial and venous antithrombotic efficacy screening that eliminates variabilities encountered when multiple model/multiple animal strategies are employed.

Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacokinetic properties via a more diverse database, we devised a resin-based route for the synthesis of analogues of these structures in which the P3 residue is replaced with a range of lipophilic carboxylic amides. Assembly proceeds from the common P2-P1 template 7 linked via an acid-labile carbamate to a polystyrene support. Application of the methodology in a repetitive fashion afforded several interesting analogues out of a collection of some 200 compounds. Among the most potent of the group, N-(9-hydroxy-9-fluorenecarboxy)-prolyl trans-4-aminocyclohexylmethyl amide (L-372,460 8, Ki = 1.5 nM), in addition to being fully efficacious in a rat model of arterial thrombosis at an infusion rate of 10 micrograms/kg/min, exhibits oral bioavailability of 74% in dogs, and oral bioavailability of 39% in monkeys with a serum half-life of just under 4 h. On the basis of its favorable biological properties, inhibitor 8 has been subject to further evaluation as a possible treatment for thrombogenic disorders.

A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (Ki 0.8-12 nM), 300-1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F = 40-76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel aminopyridyl group at P1 was a key step in our search for a clinical candidate.

As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a,b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P 3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P 3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl 3 -induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.

In an effort to prepare orally bioavailable analogs of our previously reported thrombin inhibitor 1, we have synthesized a series of compounds that utilize the unique amino acid D-dicyclohexylalanine as a P3 ligand. The resulting compounds are extremely potent and selective thrombin inhibitors, and the N-terminal Boc derivative 8 exhibited excellent oral bioavailability and pharmacokinetics in both rats and dogs. The des-Boc analog 6 was not orally bioavailable in rats. The high level of oral bioavailability observed with 8 appears to be a direct function of its increased lipophilicity versus other close analogs. Although increased lipophilicity may serve to increase the oral absorption of tripeptide thrombin inhibitors, it also appears to have detrimental effects on the antithrombotic properties observed with the compounds. Compound 6 performed extremely well in our in vivo antithrombotic assay, while the much more lipophilic but essentially equipotent analog 8 performed poorly. We have found that in general with this series of thrombin inhibitors as well as with other unreported series, increased lipophilicity and the associated increases in plasma protein binding have detrimental effects on 2X APTT values and subsequent performance in in vivo antithrombotic models.

Potency enhancing features of two series of fibrinogen receptor antagonists were combined to give analogs with improved potency and oral activity. Antagonists containing either alkyl or aryl sulfonamides and a central isoindolinone structural constraint demonstrate high affinity for both activated and unactivated platelet receptors.

Two methods were used to encourage sheep to eat unfamiliar foods quickly. The first method entailed restricting the amount of food offered. Lambs were fed either 750 g day−1 alfalfa pellets (slightly in excess of maintenance and 34% of ad libitum), or 1500 g day−1 (sufficient for 250 g day−1 growth and 68% of ad libitum) for 10 days and then offered a novel food (split peas). Food restriction did not increase the rate of acceptance of peas. The second method involved increasing familiarity with a flavor (onion) added to novel foods. Lambs drank water, water with 1% onion powder, water with 7% glucose, or water with 1% onion powder and 7% glucose. By day 2, intake did not differ among groups, so lambs were offered a novel food (rice) with 1% onion from days 3 to 7. There was no increase in speed of acceptance of rice with onion by lambs that drank onion-flavored solutions. Nor was there an increase in acceptance of rye (novel grain) with 1% onion when it was offered on days 8 to 11. However, on days 12–15, lambs ate more lentils (a novel food) with than without onion, and they ate corn (a familiar food) readily with or without onion. Conversely, intake dropped sharply when lambs were given a familiar food (rice) with a novel flavor (onion). Thus, lambs were reluctant to eat foods with unfamiliar flavors, whether they were added or occurred in novel foods. Food neophobia is likely to be one facet of the general phenomenon of fear exhibited in new situations, which ensures ruminants do not over-ingest toxic or nutrient-rich foods.

A method for analyzing beat frequency entrained (or mode locked) systems of coupled nonlinear oscillators is presented. Stable mode locked states are almost periodic oscillations that occur outside of the fundamental entrainment region of the array, and generate a periodic pulse train when the oscillator outputs are summed. The analysis relates the stability of the states to the relationship between the frequency pullings and the time average phases of the oscillators. The method is applied to three mode locked Van der Pol oscillators with arbitrary coupling time delay, and shows that the mode locking bandwidth is maximized for specific values of coupling delay and oscillator nonlinearity parameter. >

SummaryThe antithrombotic efficacies of the coagulation factor Xa inhibitor recombinant tick anticoagulant peptide (rTAP) and heparin were compared in a canine model of left circumflex (LCX) coronary artery electrolytic lesion. Intravenous infusions of saline (controls), rTAP (50 μg/kg/min continuous infusion) or heparin (200 U/kg bolus followed by 2 U/kg/min continuous infusion) were started 60 min prior to the initiation of LCX coronary artery electrolytic injury (150 μA continuous anodal current). All 6/6 saline-treated control animals developed occlusive thrombi at 49.8 ± 13.6 min after the initiation of vessel injury, and possessed a residual thrombus mass of 20.7 ± 3.3 mg. In the rTAP treatment group, 4/6 preparations developed occlusive thrombi, but with times to thrombosis delayed significantly compared to both the saline control as well as to the heparin treatment group (202.7 ± 28.9 min; p

Analysis of platelet aggregation inhibition results and rotational isomer preferences has provided an understanding of inhibitory potency for m-phthalic acid analogs 7–7. Constraint of the N-terminal amide led to compound 9, which is potent, selective, and orally active.

To better understand some of the mechanisms that control selection of novel foods differing in postingestive consequences, we offered goats current season's (CSG) and older (OG) growth twigs from the shrub blackbrush (Coleogyne ramosissima). CSG is higher than OG in nitrogen (1.04% v. 0.74%) and it is more digestible in vitro in goat rumen fluid (48% v. 38%). Nevertheless, goats acquire a preference for OG because CSG contains much higher levels of a condensed tannin that causes a learned food aversion. When CSG and OG were offered to goat naive to blackbrush, the goats did not choose either OG or CSG exclusively, but when they finally (1) ate more CSG than OG within a meal (averages of 44 g and 16 g, respectively) and (2) ate enough CSG within the meal to acquire an aversion (average of 44 g), they ingested less CSG than OG from then onward. Accordingly, the change in food selection resulting from postingestive feedback was influenced by the amount of each food ingested within a meal. This was further shown when we varied the amounts of CSG and OG that goats ingested within a meal, and then gave them by gavage the toxin lithium chloride (LiCl). They subsequently ate less of the food eaten in the greatest amount, regardless of whether it was CSG or OG. The salience of the flavor (i.e., taste and odor) of CSG and OG also played a role in the acquired aversion to CSG. Salience evidently was due to a flavor common to both OG and CSG that was more concentrated in CSG. We conclude that the relative amounts of different foods ingested within a meal, and the salience of the flavors of those foods, are both important variables that cause goats to distinguish between novel foods that differ in postingestive consequences.

This paper considers the analysis of an oscillator array with an arbitrary coupling network, described in terms of N-port circuit parameters. A Kurokawa analysis is used to transform the frequency domain network description into a set of equations for the oscillator amplitude and phase dynamics. The results reduce to previous work with "loosely" coupled Van der Pol oscillators, provided that the coupling network satisfies a broadband condition: the Q-factor of the coupling network must be much smaller than that of the oscillator. The theory is verified using a new coupling structure and a six-element patch oscillator array operating at 4 GHz, which produced a 70/spl deg/ scanning range using a phase-shifterless technique. >

The locking region for beat frequency entrained, or mode-locked arrays of discrete microwave oscillators, is exceedingly small, which presents great difficulty in array design. This paper shows that introducing a time-delayed gain control loop can enhance the entrainment region and that this region is maximized for a coupling phase of 90 degrees. For this value of coupling phase the location, size, shape, and orientation of the stable mode locking region is derived for arrays of arbitrary size. A study of the dependence of the stable mode locking region on the number of array elements shows that the region becomes highly eccentric as the number increases, thus making array tuning difficult and causing high sensitivity to particular oscillator tuning errors. The analysis is confirmed with a low frequency realization of a three-element array. >

How quickly toxins can cause ruminants to acquire food aversions has not been studied. Thus, our objectives were to determine the relationship between the time when the toxin lithium chloride (LiCl) was given and when food aversions were acquired by sheep, and to assess when peak levels of Li in the rumen occurred following different methods of administrating LiCl (dissolved in an aqueous solution vs a dry salt in a dissovable gelatin capsule). In Experiment 1, when sheep were gavaged with LiCl (150 mg kg−1 body-weight (BW) in 100 ml water) at either 2, 1 or 0 h prior to ingesting oat chaff, only sheep that received LiCl at time 0 h acquired an aversion to oat chaff, which indicates that the aversion-inducing effects of LiCl occurred within 1 h of its administration. To further assess the relationship between food ingestion, the onset of toxicosis and the acquisition of food aversions, two additional experiments were conducted. In Experiment 2, when sheep ate two familiar foods, alfalfa-grain pellets from 08 : 00 to 08 : 20 h and oat chaff from 08 : 30 to 10 : 30 h, and LiCl was ingested with the pellets, sheep acquired an aversion to the pellets, apparently because the aversion-inducing effects of LiCl occurred shortly after the sheep ate the pellets. Li concentrations in the rumen peaked within 15 min when a solution of LiCl was put directly into the rumen. Conversely, in Experiment 3, when sheep ate alfalfa-grain pellets from 08 : 00 to 08 : 20 h, then received a slowly dissolvable gelatin capsule containing LiCl and then ate oat chaff from 08 : 30 to 10 : 30 h, they acquired an aversion to oat chaff, evidently because the aversion-inducing effects of LiCl occurred coincident with eating the oat chaff. Li concentrations in the rumen peaked after just 1 h when LiCl was given in a gelatin capsule. In summary, sheep experienced the effects of Li within 1 h after it was dispersed in the rumen, which occurred at different times depending on whether LiCl was mixed with the food or administered in capsules, and the acquisition of an aversion to one of two familiar foods depended on the contiguity between food ingestion and when LiCl had its effects.

Tick anticoagulant peptide (TAP) is a 60 amino acid protein originally isolated from the soft tick, Ornithodoros moubata, which exhibits potent anticoagulant properties due to its selective inhibition of blood coagulation factor Xa. We evaluated a recombinant version of TAP (rTAP) for its ability to accelerate recombinant tissue plasminogen activator (rt-PA) -mediated lysis of an occlusive thrombus and prevent acute reocclusion in a canine model of femoral artery thrombosis. An occlusive thrombus was formed by insertion of a thrombogenic copper coil into the femoral artery of anesthetized dogs. Blood flow velocity was monitored directly and continuously by Doppler flowmetry. 60 min after occlusion, dogs received an i.v. infusion of either saline or rTAP (0.5, 2.5 or 8.0 μg/kg/min), followed 45 min later by rt-PA (0.8 mg/kg, i.v. over 90 min; n=8/group). The saline and rTAP infusions were discontinued 1 h after stopping the rt-PA. All dogs achieved reperfusion, with a time to reperfusion in the saline-treated (vehicle) group (administered rt-PA alone) of 61 ±7 min. The time to reperfusion was slightly decreased in the 0.5ug/kg/min rTAP group (47±4min, p=NS). In the groups administered rTAP at 2.5 and 8.0 ug/kg/min, significant reductions in the time to reperfusion were observed (28±4 and 32±5mins, respectively, p

A Round Robin series of tests was run to estimate the precision of ASTM C518, when used to measure the k-factor of rigid urethane modified polyiso cyanurate foam boardstock. Data on different board thicknesses was gathered [well aged 1.0 inch (2.5 cm), 2.0 inch (5.0 cm), and 3.0 inch (7 5 cm) thick, foil/kraft faced laminate board] to represent the entire product range. Thus, information will be pre sented on the precision of ASTM C518 as a function of sample thickness, as well as the between-lab and within-lab variability

Four different groups of Merino sheep were established and social interactions were examined in paddocks which were barren or with trees and other topographic features. Two groups had been established for 2 years. One group consisted of ewes of the same age and the other contained mothers and their unweaned offspring aged 2 and 1 year. Two other groups were established recently: one consisted of sheep of different sexes whose ages ranged from 1 to 5 years and the other group contained ewes of two different age groups. Age effects on cohesive and aggressive behaviours were apparent, with older animals being involved in more fights (usually between themselves), initiating more movements and showing more attention behaviours. In dominance tests the number of fights was significantly higher in the single sex, single age group. In the field, the family group was markedly less responsive in terms of fighting, movement and attention behaviours when compared with the other social groupings. This effect was most obvious in the barren environment. If a behaviour was observed frequently in one member of a family group it normally occurred in the other members of that family. It was twice as likely if the mother of the family initiated a movement that it would be followed by one of her descendants and particularly the younger one. The level of fighting was no different between members of the same family as between members of different families. The evidence for the family group being a socially more complex unit than the other three groups is discussed. The possibility is raised that a socially complex group may be less affected by environmental heterogeneity than groups that were not as well integrated socially.

The association between 10 Merino ewes and their offspring, born in 2 consecutive years, was examined over a 2.5-year period. Recognition tests were conducted and indicated a rapid decline in ewe-motivated association commencing 3–6 weeks after parturition. Field observations examined the spatial relationships between ewes and their offspring and between the two descendants of the mother. Evidence is presented to suggest the maintenance of long-term (> 2.5 years) associations between lambs and their mothers. This association appears to be caused entirely by the offspring's attraction to its mother.

An array of coupled phase locked loops is configured to produce a comb spectrum, and therefore pulsed microwave power, using a frequency locking technique analogous to the mode locked optical laser. The basic principles of operation are derived and measurements of an 11-GHz system, built from commercially available microwave components, demonstrate the frequency and time domain characteristics. >

OBJECTIVE To compare in vivo the potency and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs) (–)-cromakalim, WAY-133537 and ZD6169 and a muscarinic antagonist, tolterodine in rats. MATERIALS AND METHODS Bladder and arterial pressures were monitored simultaneously, before and after increasing intravenous doses of compounds, in each of two urethane-anaesthetized rat bladder hyperactivity models: spontaneous non-voiding myogenic contractions secondary to partial outlet obstruction and volume-induced neurogenic contractions. RESULTS (–)-Cromakalim, WAY-133537 and ZD6169 caused a dose-dependent suppression of spontaneous contractions in the obstructed model, with a 50% inhibition of the contraction area under the curve at doses of 0.06, 0.14 and 2.4 µmol/kg (intravenous), respectively. Corresponding decreases in mean arterial pressure at these effective doses were 24%, 15% and 15%, respectively. The KCO potency rank order was the same and their relative potency highly comparable in the neurogenic model. There was complete inhibition of spontaneous contractions in obstructed rats at doses corresponding to ≈ 50% inhibition of the neurogenic contractions. While tolterodine caused a dose-dependent inhibition of contractions in the neurogenic model, it was ineffective at inhibiting non-voiding contractions in obstructed rats. CONCLUSIONS All KCOs tested caused significant decreases in arterial pressure at doses effective on the bladder in the model of obstructive instability, suggesting a lack of bladder-vascular selectivity. Similar KCO potency in both assays suggests no appreciable changes in KATP channel function as a result of partial outlet obstruction.

A millimeter wave pulse generation system using mode locked arrays of coupled automatic level control oscillators is analyzed. Previous analyses have shown that 90 degrees of coupling phase maximizes the entrainment region size, however, this paper shows that pulse power can be significantly enhanced by choosing 0 degrees of coupling phase. A comparison of the entrainment size and phase sensitivity shows that for large arrays peak power enhancement can be utilized without a significant reduction in overall system robustness. >

The requirements for increased functionality within a confined volume will place greater burdens on electromagnetic platforms for air, space, and sea over the next few decades. An important piece of the any solution to these new requirements are transmitting and receiving apertures that can handle multi-octave bandwidths with beam steering capability. The ability of an aperture to be reconfigured for a particular mission will become essential. New types of devices are being developed which will enable the realization of these reconfigurable apertures. This paper presents a discussion of how one of these new devices, the RF MEMS switch, can be utilized to change the phase and frequency characteristics of conventional antenna elements to perform beam steering over a wide range of microwave frequencies.

1 (L-374,087) is a potent, selective, efficacious, and orally bioavailable thrombin inhibitor that contains a core 3-amino-2-pyridinone moiety. Replacement of the C6 pyridinone methyl group of 1 by a propyl group gave 5 (L-375,052), which retained all the excellent properties of 1, and also yielded higher plasma levels after oral dosing in dogs and rats.

One of two groups of sheep was immunosuppressed with the glucocorticoid, dexamethasone, at the time of the first but not of the second of two booster vaccinations with tetanus toxoid given at an interval of 28 days. Treatment with dexamethasone decisively reduced the anti-tetanus antibody response to the first booster vaccination and affected both IgM and IgG1 antibody. However, antibody titres increased after the second booster vaccination in the treated sheep and were similar in size to those in the untreated sheep which rose in stepwise fashion after each booster vaccination. The differences in response imply that processes involved in displaying an anamnestic response and recalling previously established memory are sensitive to glucocorticoids. Accordingly, they can be separated from the glucocorticoid-resistant processes that lead to the expansion of immunological memory following multiple exposures to an antigen.

The effects of chronic treatment with growth hormone (porcine GH, 0.56 mg ⋅ kg−1 ⋅ day−1sc) were examined in dogs with heart failure induced by rapid ventricular pacing (240 beats/min) for 4 wk. Fourteen conscious dogs were studied 2–3 wk after surgical instrumentation with catheters in the descending aorta and left atrium, a pressure gauge in the left ventricle (LV), a flow probe around the ascending aorta, pacing leads on the ventricular free wall and left atrium, and ultrasonic crystals on the opposing anterior and posterior endomyocardium of the LV. GH treatment for 4 wk significantly increased both body weight and plasma insulin-like growth factor 1 (IGF-1) compared with vehicle-treated dogs ( P < 0.01, +2.0 ± 0.5 vs. +0.3 ± 1.1 kg; 1,043 ± 218 vs. 241 ± 64 ng/ml, respectively). However, the changes in resting LV systolic (i.e., both isovolumic and ejection phases) and diastolic function (i.e., isovolumic relaxation time constant τ) and the systemic vascular resistance were similar for the GH- and vehicle-treated groups during the development of heart failure. LV contractile reserve, assessed with step infusion of isoproterenol or dobutamine challenge, was markedly attenuated after heart failure, but there were no differences between the GH- and vehicle-treated groups. During the progression of heart failure, the increases in plasma atrial natriuretic peptide correlated ( P < 0.01) directly with left atrial pressure and inversely with LV circumferential fiber shortening. However, GH treatment did not substantially modify these relationships. In addition, renal function and myocardial ultrastructure at the advanced stage of heart failure also showed similar changes for the GH- and vehicle-treated groups. We conclude that in conscious dogs during the development of congestive heart failure produced by rapid ventricular pacing, GH at a dose that increases body weight and plasma IGF-1 levels does not affect LV performance or systemic vascular dynamics.

Our objective was to better understand the importance of flavor and nutrients in food preferences of lambs. Three foods differing in flavor and nutritional quality were created by grinding and mixing grape pomace, barley, alfalfa pellets, and soybean meal in different proportions. food 1 (2.21 Mcal/kg DE, 8.1% DP), food 2 (2.42 Mcal/kg DE, 11.0% DP), and food 3 (2.68 Mcal/kg DE, 13.8% DP). Intake of each food, offered singly and together, was assessed when foods 2 and 3 were flavored with 1% onion or 1% oregano. Lambs (n = 24) preferred food 321, regardless of flavor (P.05), and they continued to prefer food 321, even when they received the toxin LiCl after eating one of the three foods (P.05). When offered a choice, lambs always ate substantial amounts of all three foods, even though they might have been expected to eat food 3 exclusively. We hypothesize selection of a varied diet resulted from a decrease in preference for food just eaten as a result of sensory input (taste, odor, texture, i.e., a food's flavor) and postingestive feedback (effects of nutrients and toxins on chemo-, osmo-, and mechano-receptors) unique to each food. Thus, we submit that offering different foods of similar nutritional value, offering foods of different nutritional value, and offering the same food in different flavors are all means of enhancing food preference and intake.

This study was designed to investigate whether delaying the age of weaning, or feeding a protein-rich supplement alters the rate at which lambs develop immunity to Haemonchus contortus and whether there is any interaction between nutrition, stress of weaning, and gender and the development of this immunity. Ninety-six Merino lambs were allocated to one of four treatment groups: supplemented-unweaned; supplemented-weaned; unsupplemented-unweaned; unsupplemented-weaned. There were approximately similar numbers of male and female lambs in each group. Supplemented lambs received 80 g/head/day of a protein-rich pellet from 16 to 23 weeks of age. Over the same period the lambs were drenched with 300 H. contortus larvae twice per week. Faecal worm egg counts were determined every week, and PCV and liveweight every 2 weeks for each lamb. Neither weaning nor sex had any effect on PCV (P0.05) but from day 50 after the start of infection, the decline in PCV was more pronounced in unsupplemented than in supplemented lambs. Faecal worm egg counts were higher (P0.001) in unsupplemented-weaned than in supplemented-weaned lambs and in females when compared with castrates (P0.03). There was a weaning x supplementation x age interaction (P0.03) with unsupplemented-weaned lambs developing a higher faecal egg count than supplemented-weaned lambs. There was also a significant (P0.02) sex x weaning x age interaction with weaned-female lambs having a higher faecal egg count than weaned-castrate lambs; egg counts increased more rapidly in unweaned-female lambs than in weaned-female lambs.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitors of platelet-fibrinogen binding offer an opportunity to interrupt the final, common pathway for platelet aggregation. Small molecule inhibitors of the platelet fibrinogen receptor GPIIb/IIIa were prepared and evaluated for their ability to prevent platelet aggregation. Compound 23m (L-700,462/MK-383) inhibited in vitro platelet aggregation with an IC50 of 9 nM and demonstrated a selectivity of > 24,000-fold between platelet and human umbilical vein endothelial cell fibrinogen receptors. Dose-dependent inhibition of ex vivo platelet aggregation induced by ADP was achieved with i.v. infusions of 0.1-10 micrograms/kg/min of 23m in anesthetized dogs, with 10 micrograms/kg/min completely inhibiting platelet aggregation during the entire 6 h infusion protocol. Platelet aggregatability returned rapidly after the termination of the 23m infusions. These features suggest that 23m may be useful in the treatment of arterial occlusive disorders.

Ruminants learn to avoid many foods that contain toxins by associating the flavor of the foods with aversive postingestive feedback. We hypothesized the emetic system is a cause of aversive feedback, and three experiments were conducted to determine whether antiemetic drugs (diphenhydramine, metoclopramide, dexamethasone) would attenuate food aversions caused by the toxicant lithium chloride (LiCl). Lambs were assigned to one of four treatments: antiemetics plus LiCl (A + L), antiemetics alone (A), LiCl alone (L), or neither antiemetics nor LiCl (C). The LiCl was administered immediately after sheep ate oats, wheat, and milo in Exp. 1, 2, and 3, respectively. The antiemetics were given 1 h before and at the time LiCl was administered to sheep. Lambs that received antiemetics (A and A + L) consistently ate more grain than lambs that did not receive the drugs (C and L) (Exp. 1, P < .08; Exp. 2, P < .05; Exp. 3, P < .08), and there was no interaction between antiemetics and LiCl. Thus, the results of all three experiments were consistent with the hypothesis that antiemetic drugs attenuate food aversions caused by the toxicant LiCl because sheep receiving antiemetic drugs (Group A + L) ate more grain than sheep not receiving the drugs (Group L). In addition, we suggest aversive postingestive feedback limited intake of grain because sheep receiving antiemetic drugs (Group A) ate somewhat more grain than sheep not receiving the drugs (Group C).

We discovered that a food aversion could be conditioned in anesthetized sheep. Sheep were allowed to eat a familiar food (alfalfa-grain pellets) for 30 min, and 90 min later they were given either an intraruminal (IR) injection of water (C), an IR injection of LiCl (L), anesthesia followed by an IR injection of water (A), or anesthesia followed by an IR injection of LiCl (A+L). Induction of anesthesia was by an intraveneous injection of pentobarbitone sodium, and maintenance of deep anesthesia was by halothane. Sheep were maintained in deep anesthesia for 2 h to ensure that the effects of LiCl on the acquisition of a food aversion, which occur within about 1 h, were completed before they awakened. When tested 5 days later, sheep that received LiCl (treatments L and A+L) consumed less alfalfa-grain pellets than sheep that did not receive LiCl (treatments C and A) (241 g vs. 306 g; p = 0.057). Intake of sheep that were anesthetized (treatments A and A+L) did not differ from that of sheep that were not anesthetized (treatments C and L) (295 g vs. 252 g; p = 0.183). Nor was there an interaction between LiCl and anesthesia ( p = 0.423). Thus, we conclude that changes in preferences for foods caused by postingestive feedback occur automatically every time food is ingested (i.e., they are noncognitive), and the kind and amount of feedback is a function of the match between the food's chemical characteristics and its ability to meet the animal's current demands for nutrients.

Objective: The aim was to examine the abilities of the direct thrombin inhibitor, recombinant hirudin (rHIR), and the coagulation factor Xa inhibitor, recombinant tick anticoagulant peptide (rTAP), given in combination with rt-PA as high dose front loading plus low dose maintenance infusions, to enhance reperfusion and maintain vessel patency in a canine model of left circumflex coronary artery stenosis and electrolytic lesion. Methods: Occlusive coronary artery thrombosis was induced in anaesthetised dogs by electrical injury (150 μA) of the intimal surface of the vessel. Thirty minutes after occlusive thrombosis, high dose front loading infusions (45 min) of rTAP (200 μg·kg−1·min−1) and rHIR (300 μg·kg−1·mm−1) were initiated concomitant with the start of a 90 min infusion of recombinant tissue-type plasminogen activator (rt-PA). Following the termination of front loading infusions, maintenance infusions of rTAP (10 or 20 μg·kg−1·min−1) or rHIR (20 μg·kg−1·min−1) were initiated and continued for the duration of the protocol (180 min after rt-PA termination). Results: Reperfusion was incomplete in the rHIR group (7/9; 78%), whereas all rTAP-treated preparations reperfused (8/8 per group, aggregate 16/16; 100%). Following thrombolysis, the rHIR group had a high incidence of reocclusion, ranging from intermittent to long periods of occlusion, with only 2/7(29%) of the preparations which initially recanalised remaining patent during the 180 min period following rt-PA termination. In contrast, 5/8 preparations in each of the two rTAP groups [aggregate 10/16; 63%] remained patent during the same period. The greater efficacy of rTAP v rHIR in maintaining vessel patency was also reflected in integrated coronary artery blood flows [91.0(SEM 5.8)% and 84.9(6.1)% of preocclusion flow in rTAP groups v 57.5(12.2)% of preocclusion flow in rHIR group], times to reocclusion [123.3(22.8) and 128.0(6.7) min in rTAP groups v 36.6(23.2) min in rHIR group; p < 0.05], and residual thrombus masses [1.8(0.3) and 2.0(0.3) mg in rTAP groups v 10.4(3.8) mg in rHIR group; p

Abstract Vapor-liquid equilibrium (VLE) calculations play an important role in the simulation of enhanced oil recovery (EOR) processes. While reservoir simulators in general must treat the VLE of hydrocarbon mixtures over a wide range of pressures and compositions, the simulation of such EOR processes as vaporizing and condensing gas drives require the VLE algorithm to operate at or near the critical point. Conventional VLE calculations based on cubic equations of state such as the Peng-Robinson or Soave-Redlich-Kwong equation fail to converge or are inaccurate in the critical region. In particular, it is well known that these methods assign the same value to the critical z-factor for all pure chemical species. The modified Leung-Griffiths model is a non-cubic, corresponding states theory that conforms to modern scaling laws, which successfully correlates, evaluates, and predicts VLE boundaries for fluid mixtures. The model performs well from the critical locus down to about half of the critical pressure. It has produced excellent correlations of many sets of binary hydrocarbon VLE data. We discuss the recent extension of the model to mixtures with three or more components and its application in a general purpose compositional simulator. This paper examines how a flash computation is performed with this model, how the single-phase region is detected, and how the derivatives required in the solution of the non-linear flow equations are obtained from the flash computation. The model is coded in a form that makes it interchangeable with conventional VLE models in a wide variety of general purpose compositional simulators. Introduction The phase behavior model is one of the important elements in a reservoir simulator. Whenever there are two or more hydrocarbon-containing phases in equilibrium it is necessary to perform some type of calculation to determine the amount and composition of the equilibrium phases. Normally black oil simulators (which track only two hydrocarbon species) are used to simulate primary and secondary production from conventional oil reservoirs, while compositional simulators (which track multiple species) are used when compositional effects are especially important such as the production of volatile oil and condensate reservoirs and in the operation of certain EOR processes. Currently state-of-the-art compositional reservoir simulators use cubic equations of state such as the Peng-Robinson or versions of the Redlich-Kwong equation to represent the phase behavior. The simulation of EOR processes such as vaporizing and condensing gas drives require the VLE algorithm to operate at or near the critical point. These equations are known to be inaccurate in the critical region. For example, they yield the wrong critical density since the critical z-factor computed from these equations is the same for all pure components. In addition, algorithms based on these equations often have convergence difficulties. Condensed matter physicists, on the other hand, have developed equations based on modern scaling theory that successfully correlate, evaluate, and predict VLE boundaries for fluid mixtures in the near critical region. These equations are not directly accessible by the simulations engineer since they are expressed in an unfamiliar set of state variables, they require an unfamiliar set of pure and binary mixture parameters, and they are optimized for maximum accuracy in the near critical region without regard for their performance far from the critical point. This paper examines one version of the modern theory known as the Modified Leung-Griffiths (MLG) model. The model for binary mixtures was initially proposed by Leung and Griffiths, modified by Moldover and Gallaqher, and subsequently improved by Rainwater and coworkers. Lynch and coworkers then extended the theory to ternary and finally to n-component mixtures. In this paper we first show how the MLG model follows directly from thermodynamic theory and certain experimental facts. Then we show how parameters in the model can be correlated in terms of critical properties of the pure components. Finally we discuss how flash computations are performed in a compositional simulator. P. 249

A lamb's mother and postingestive feedback both influence learning about foods, but their relative importance is unknown. We conducted a study to compare the ingestion of elm (1) by lambs whose mothers avoided elm because ingestion of elm by mother was previously paired with the toxin lithium chloride (LiCl) (M), (2) by lambs who received a mild dose of LiCl after they ingested elm, and whose mothers also avoided elm (M + L), and (3) by lambs who received LiCl after they ingested elm, but whose mothers ate elm avidly (M vs. L); in treatment (4) neither mothers nor lambs were given LiCl (C). In all four treatments, mothers and lambs ate poplar. Each lamb was exposed with its mother for 5 min/day to poplar on days 1,2, 5, 7, 9, and 11 and to elm on days 3, 4, 6, 8, 10, and 12. Following exposures to elm on days 8, 10, and 12, lambs in treatments M + L and M vs. L were given a low dose of LiCl (100 mg/kg body weight orally in a capsule) when they ingested elm to produce an aversion to elm. During the first test after weaning, lambs could choose between elm and poplar. Lambs in C took more bites of elm than did lambs in M, M + L, and M vs. L (13, 2, 2,1;PF=0.003), and they also took a higher percentage of bites from elm (42, 11, 6, 1;PF0.001). The number of bites of poplar did not differ among treatments (M=31, M + L=26, M vs. L=42, C=27;PF =0.458). During the second test, when lambs were offered only elm, lambs in C took significantly more bites of elm than those in the other treatments, and lambs in M took more bites of elm than lambs in M + L, but not M vs. L (C=38, M=16, M + L=3, M vs. L=6;PF0.001). During the third test, when lambs again could choose between elm and poplar, lambs in C again took more bites of elm (C=14, M=3, M + L=1, M vs. L=1;PF=0.034), and they also took a higher percentage of bites from elm (C=26, M=5, M + L=2, M vs. L=2;PF0.001), than did lambs in the other three treatments. The number of bites of poplar did not differ among treatments (M=47, M + L=43, M vs. L=62, C =41;PF=0.223). We conclude that the response by lambs to the toxin LiCl was more important than was the mother as a social model because lambs that received LiCl avoided elm whether or not the mother ate it.

Recent studies have shown that when offered a choice of feeds with different concentrations of a particular nutrient (crude protein), sheep can select a diet that meets their current requirements (Kyriazakis and Oldham 1993). To further examine this diet selection behaviour a choice of foods differing in the concentration of S was offered to sheep that were either in a sulphur (S) adequate or a S depleted state. Study of S selection was considered to be the next logical step after protein because of its role in the synthesis of proteins by the rumen micro-organisms.

Recent studies have shown that when offered a choice of feeds with different concentrations of a particular nutrient (crude protein), sheep can select a diet that meets their current requirements (Kyriazakis and Oldham 1993). To further examine this diet selection behaviour a choice of foods differing in the concentration of S was offered to sheep that were either in a sulphur (S) adequate or a S depleted state. Study of S selection was considered to be the next logical step after protein because of its role in the synthesis of proteins by the rumen micro-organisms.

A study was conducted to determine whether sheep form conditioned flavour aversions (CFAs) or preferences (CFPs) for food flavours associated, respectively, with excessive or appropriate concentrations of sulphur (S) and also whether the rate of formation and strength of CFAs and CFPs are dependent on the animal's initial S status or the level of administration of S. In experiment 1, 48 mature ewes were conditioned to associate a new food containing a novel flavour with an infusion of S delivered intra-ruminally, or the same food containing another novel flavour with an infusion of distilled water. The same flavours were then used in experiment 2. At the end of each conditioning period, the relative preference for the two flavoured foods was determined by measuring the amount of each food ingested during a two-choice, 20-min preference test. Experiment 1 consisted of two phases. In phase 1 each conditioning period lasted for 5 days and was repeated four times, whereas in phase 2 the conditioning period lasted for 8 days and was repeated three times.In experiment 1 the sheep were initially in an S-adequate state. In experiment 2, the sheep were re-randomized to treatments and started in an S-depleted state. The conditioning periods also lasted for 8 days and were repeated three times. There was no evidence to support the hypothesis that sheep develop CFAs or CFPs to food flavours associated with S doses in phase 1 of experiment 1. In phase 2, however, sheep formed CFAs towards the food with the flavour they had come to associate with administration of high levels of S. Repeated exposure to the flavour associated with high levels of S led to stronger aversions and there was an interaction between the S dose level and conditioning periods, indicating that the rate of development of these CFAs was highest for the highest S dose levels. The differences between results of phase 1 and 2 were probably due to the different numbers of reinforcements and different intervals between specific flavour/dose associations.In experiment 2 there was no evidence for the development of CFPs or CFAs to food flavours associated with S doses. The apparent indifference of the sheep to S was probably due to their responding more to their previous experience of the food flavours than to their S status. Spearman rank correlations on flavour preferences indicated that conditioned flavour responses formed in experiment 1 persisted in individual sheep when they were allocated at random into their new treatments in experiment 2 and influenced or masked the formation of new associations. This demonstration of ‘carry-over’ effects highlights the importance of considering an animal’s previous experience of flavours and their associations with post-ingestive consequences when coming to conclusions concerning current development of CFAs and CFPs. These results may also have more general implications for feeding studies in animals that are randomized into treatment groups without regard to their previous feeding experiences.

Two hundred and fifty Border Leicester x Merino ewes (40% heterozygous for the Booroola Fec B gene) were used in an experiment, replicated over 2 years, to examine the effects of cottonseed meal-based supplementation on lamb survival, birth, marking and weaning weight, as well as, liveweight and fleece characteristics of ewes. From 50 to 100 days of pregnancy, half of the ewes were supplemented with 80 g/head.day. The supplemented group was then split according to litter size and, until 30 days after lambing, were offered pellets at 80, 160 and 220 g/head .day, respectively, for ewes bearing single, twin and triplet (or more) lambs. Over the 2 years, ewes averaged 2.11 lambs per parturition and supplementation significantly increased lamb survival to weaning (73 v. 58%) with no interaction with litter size. Although supplementation had a positive effect on birth weight of all but twins, the effects of supplementation on survival were independent of birth weight effects. Significant effects of year, sire breed and litter size on lamb survival and birth weight were also noted. No effects of supplementation were apparent on lamb growth while ewe age, sire breed, sex and rearing rank all significantly influenced growth rates. Ewe weights, fleece weights and staple strength were significantly influenced by year, ewe age and litter size but not by supplementation. These findings indicate the benefits to lamb survival of providing a 'bypass' protein supplement to high fecundity flocks even when ewes are grazing good quality pastures.