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OBJECTIVE: Extremity venous aneurysms result in the risk of pulmonary embolism (PE) and chronic venous insufficiency. At present, owing to the rarity of these aneurysms, no consensus for their treatment has been established. The purpose of the present study was to review the presentation, natural history, and contemporary management of extremity venous aneurysms. METHODS: We performed a retrospective, multi-institutional review of all patients with extremity venous aneurysms treated from 2008 to 2018. A venous aneurysm was defined as saccular or fusiform with an aneurysm/vein ratio of >1.5. RESULTS: A total of 66 extremity aneurysms from 11 institutions were analyzed, 40 of which were in a popliteal location, 14 iliofemoral, and 12 in an upper extremity or a jugular location. The median follow-up was 27 months (range, 0–120 months). Of the 40 popliteal venous aneurysms, 8 (20%) had presented with deep vein thrombosis (DVT) or PE, 13 (33%) had presented with pain, and 19 had been discovered incidentally. The mean size of the popliteal venous aneurysms presenting with DVT or PE was larger than that of those presenting without thromboembolism (3.8 cm vs 2.5 cm; P = .003). Saccular aneurysm morphology in the lower extremity was associated with thromboembolism (30% vs 9%;P = .046) and fusiform aneurysm morphology with a thrombus burden >25% (45% vs 3%). Patients presenting with thromboembolism were more likely to have had a thrombus burden >25% in their lower extremity venous aneurysm compared with those who had presented without thromboembolism (70% vs 9%). Approximately half of all the patients underwent immediate intervention, and half were managed with observation or antithrombotic regimen. In the nonoperative cohort, three patients subsequently developed a DVT. Eight patients in the medically managed cohort went on to require surgical intervention. Of the 12 upper extremity venous aneurysms, none had presented with DVT or PE, and only 2 (17%) had presented with pain. Of the 66 patients in the entire cohort, 41 underwent surgical intervention. The most common indication was the absolute aneurysm size. Nine patients had undergone surgery because of a DVT or PE, and 11 for pain or extremity swelling. The most common surgery was aneurysmorrhaphy in 21 patients (53%), followed by excision and ligation in 14 patients (35%). Five patients (12%) had undergone interposition bypass grafting. A postoperative hematoma requiring reintervention was the most common complication, occurring in three popliteal vein repairs and one iliofemoral vein repair. None of the patients, treated either surgically or medically, had reported post-thrombotic complications during the follow-up period. CONCLUSIONS: Large lower extremity venous aneurysms and saccular aneurysms with thrombus >25% of the lumen are more likely to present with thromboembolic complications. Surgical intervention for lower extremity venous aneurysms is indicated to reduce the risk of venous thromboembolism (VTE) and the need for continued anticoagulation. Popliteal aneurysms >2.5 cm and all iliofemoral aneurysms should be considered for repair. Upper extremity aneurysms do not have a significant risk of VTE and warrant treatment primarily for symptoms other than VTE. (J Vasc Surg Venous Lymphat Disord 2022;10:1352–8.)

New half-lives for exotic isotopes approaching the neutron drip-line in the vicinity of N∼28 for Z=12-15 were measured at the Facility for Rare Isotope Beams (FRIB) with the FRIB decay station initiator. The first experimental results are compared to the latest quasiparticle random phase approximation and shell-model calculations. Overall, the measured half-lives are consistent with the available theoretical descriptions and suggest a well-developed region of deformation below ^{48}Ca in the N=28 isotones. The erosion of the Z=14 subshell closure in Si is experimentally confirmed at N=28, and a reduction in the ^{38}Mg half-life is observed as compared with its isotopic neighbors, which does not seem to be predicted well based on the decay energy and deformation trends. This highlights the need for both additional data in this very exotic region, and for more advanced theoretical efforts.

A detailed study of the $\ensuremath{\beta}$-delayed neutron emission properties of $^{137,138}\mathrm{I}$ and $^{144,145}\mathrm{Cs}$ has been performed by confining ions in the Beta-decay Paul Trap. The daughter ions following $\ensuremath{\beta}$ decay emerge from the trapped-ion cloud with negligible scattering allowing reconstruction of the recoil-ion energy from the time of flight. From this information, the neutron-emission branching ratios and neutron-energy spectra were deduced. The results for the $^{137}\mathrm{I}$ and $^{144,145}\mathrm{Cs}$ decays are in agreement with previous results performed using direct neutron-detection techniques. In the case of $^{138}\mathrm{I}$, a branching ratio of 6.18(50)% is obtained, yielding a value consistent with the more recent results, which are a factor of two larger than measurements made prior to 1978.

Beta-delayed-neutron ($\ensuremath{\beta}n$) spectroscopy was performed using the Beta-decay Paul Trap and an array of radiation detectors. The $\ensuremath{\beta}n$ branching ratios and energy spectra for $^{135,136}\mathrm{Sb}$ and $^{140}\mathrm{I}$ were obtained by measuring the time of flight of recoil ions emerging from the trapped ion cloud. These nuclei are located at the edge of an isotopic region identified as having $\ensuremath{\beta}n$ branching ratios that impact the $r$-process abundance pattern around the $A\ensuremath{\approx}130$ peak. For $^{135,136}\mathrm{Sb}$ and $^{140}\mathrm{I}, \ensuremath{\beta}n$ branching ratios of $14.6(13)%, 17.6(29)%$, and $7.6(28)%$ were determined, respectively. The $\ensuremath{\beta}n$ energy spectra obtained for $^{135}\mathrm{Sb}$ and $^{140}\mathrm{I}$ are compared with results from direct neutron measurements, and the $\ensuremath{\beta}n$ energy spectrum for $^{136}\mathrm{Sb}$ has been measured for the first time.

Die Analyse der notfallmedizinischen Eintrage im Critical Incident Reporting System (CIRS) zeigte Defizite in der Kommunikation auf, die in 30 % der Falle zu einer Gefahrdung von Patienten fuhrten. Aus dieser Untersuchung geht allerdings nicht hervor, bei welchen Arbeitsablaufen und Ubergabeprozessen diese Zwischenfalle besonders haufig auftreten. Die Arbeitsprozessanalyse identifiziert Kumulationspunkte in der prahospitalen Notfallversorgung, die Kommunikationsrisiken bergen. Sie soll zusatzlich Storfaktoren fur eine suffiziente Kommunikation in unterschiedlichen Abschnitten der Patientenversorgung aufzeigen. (I) CIRS-Datenbankanalyse Die Arbeitsprozessanalyse basiert auf 247 ausgewerteten CIRS-Fallen. Sie zeigten insgesamt 282 Kommunikationszwischenfalle in der prahospitalen Patientenversorgung auf, die in 6 Kategorien (KAT I–VI) eingeteilt sind. (II) Arbeitsprozessanalyse Teilnehmende Beobachtungen und Interviews von Rettungsdienstmitarbeitern, erweitert durch die 6 Kategorien der CIRS-Auswertung, bilden Grundlage der Arbeitsprozessanalyse. (I) CIRS-Datenbankanalyse Von 845 eingegebenen Fallen zeigen 247 CIRS-Eintragungen mit insgesamt 282 Zwischenfallen Kommunikationsdefizite auf. (II) Arbeitsprozessanalyse Die Analyse identifiziert 3 Abschnitte der prahospitalen Patientenversorgung. Zwischenfalle treten gehauft im Abschnitt der direkten Patientenversorgung durch parallele Arbeitsprozesse auf. Dort kritisiert mehrheitlich das nichtarztliche Personal die Notarzte, Hinweise zur Patientenversorgung auszuschlagen (KAT I mit n = 73 vs. n = 9). Medikamentenverwechslungen (KAT III mit n = 63) und unverstandliche oder ausbleibende Kommunikation im Team (KAT IV mit n = 20) sind ebenso Ursache fur Patientengefahrdung wie fehlerhafte Informationen in der Patientenubergabe (KAT II mit n = 13). Eine verbesserte Schnittstellenkommunikation kann Zwischenfalle in der Patientenversorgung verhindern, da sie Rettungsmittel gezielter zuordnet und Patienten besser in weiterbehandelnde Kliniken uberfuhrt. Ressourcen zur Versorgung stehen so koordinierter zur Verfugung. Kommunikationstraining und ein Ubergabeschema sind denkbare Strategien, um kommunikationsassoziierte Zwischenfalle zu vermeiden.

Beta-delayed neutron emission is being studied by detecting the β particles and recoiling ions emerging from the Beta-decay Paul Trap. For β decays to the ground state or γ -emitting states of the daughter nucleus, the fraction of recoiling ions which reach the ion detector in coincidence with a β particle has been determined for 134, 135Sb, 137, 138, 140I, and 144, 145Cs. This value is needed for the determination of the β -delayed neutron emission branching ratio solely from the recoil-ion time-of-flight (TOF) spectrum. The β -particle energy and recoil-ion TOF spectra were used to constrain a simple decay model, which can be used to determine the detection efficiency. The method is compared to simulations to estimate the uncertainty introduced by incomplete knowledge of the decay pattern. By fitting the simulation results to several β -ion coincidence properties measured during the experiment, the fraction of ions which reach the microchannel plate detector can be determined to within ± 4 % . This result opens the possibility of using the recoil-ion TOF spectra for high precision β -delayed neutron branching-ratio measurements.

This article presents an approach to calibrate the energy response of double-sided silicon strip detectors (DSSDs) for low-energy nuclear-science experiments by utilizing cosmic-ray muons . For the 1-mm-thick detectors used with the Beta-decay Paul Trap, the minimum-ionizing peak from these muons provides a stable and time-independent in situ calibration point at around 300 keV, which supplements the calibration data obtained above 3 MeV from α sources. The muon-data calibration is achieved by comparing experimental spectra with detailed Monte Carlo simulations performed using GEANT4 and CRY codes. This additional information constrains the calibration at lower energies, resulting in improvements in quality and accuracy.

Beta-delayed one-neutron ( β n ) emission has been investigated by confining radioactive ions in an ion trap and detecting the β particles and recoiling nuclei that emerge following decay. In this approach, the β n energy spectrum and branching ratio can be deduced without needing to detect the neutrons, as the neutron emission is inferred from the observed time of flight of the recoiling ions. This paper details the dominant effects that influence the extraction of the neutron energy from the time-of-flight measurement and explores the impact they have on the energy calibration and resolution.

The recent installation of a Multi-Reflection Time-of-Flight (MR-TOF) isobar separator at the CARIBU facility has the promising potential to significantly improve the mass separation and selection of short-lived neutron-rich beams. Ions cycled in the km-long isochronous trajectories between two electrostatic mirrors can be separated to high levels of mass-resolving power within a short time (tens of ms). The installation process is described and results from the first operation are discussed. Following an optimization of the mirror voltages a mass-resolving power of 6.8 · 10 4 was achieved and a separation of isobars was demonstrated. The higher purity beams provided by the MR-TOF and delivered to the Canadian Penning Trap (CPT) will provide access to further measurements of neutron-rich nuclei along the astrophysical r-process path.

The low-energy recoiling ions from the $\ensuremath{\beta}$ decay of $^{134}\mathrm{Sb}$ were studied by using the Beta-decay Paul Trap. Using this apparatus, singly charged ions were suspended in vacuum at the center of a detector array used to detect emitted $\ensuremath{\beta}$ particles, $\ensuremath{\gamma}$ rays, and recoil ions in coincidence. The recoil ions emerge from the trap with negligible scattering, allowing $\ensuremath{\beta}$-decay properties and the charge-state distribution of the daughter ions to be determined from the $\ensuremath{\beta}$-ion coincidences. First-forbidden $\ensuremath{\beta}$-decay theory predicts a $\ensuremath{\beta}\text{\ensuremath{-}}\ensuremath{\nu}$ correlation coefficient of nearly unity for the ${0}^{\ensuremath{-}}$ to ${0}^{+}$ transition from the ground state of $^{134}\mathrm{Sb}$ to the ground state of $^{134}\mathrm{Te}$. Although this transition was expected to have a nearly 100% branching ratio, an additional 17.2(52)% of the $\ensuremath{\beta}$-decay strength must populate high-lying excited states to obtain an angular correlation consistent with unity. The extracted charge-state distribution of the recoiling ions was compared with existing $\ensuremath{\beta}$-decay results and the average charge state was found to be consistent with the results from lighter nuclei.

In an analysis of a critical incident reporting system (CIRS) in out-of-hospital emergency medicine, it was demonstrated that in 30% of cases deficient communication led to a threat to patients; however, the analysis did not show what exactly the most dangerous work processes are. Current research shows the impact of poor communication on patient safety.An out-of-hospital workflow analysis collects data about key work processes and risk areas. The analysis points out confounding factors for a sufficient communication. Almost 70% of critical incidents are based on human factors. Factors, such as communication and teamwork have an impact but fatigue, noise levels and illness also have a major influence.(I) CIRS database analysis The workflow analysis was based on 247 CIRS cases. This was completed by participant observation and interviews with emergency doctors and paramedics. The 247 CIRS cases displayed 282 communication incidents, which are categorized into 6 subcategories of miscommunication. One CIRS case can be classified into different categories if more communication incidents were validated by the reviewers and four experienced emergency physicians sorted these cases into six subcategories. (II) Workflow analysis The workflow analysis was carried out between 2015 and 2016 in Jena and Berlin, Germany. The focal point of research was to find accumulation of communication risks in different parts of prehospital patient care. During 30 h driving with emergency ambulances, the author interviewed 12 members of the emergency medical service of which 5 were emergency physicians and 7 paramedics. A total of 11 internal medicine cases and one automobile accident were monitored. After patient care the author asked in a 15-min interview if miscommunication or communication incidents occurred.(I) CIRS analysis Between 2005 and 2015, 845 reports were reported to the database. The experts identified 247 incident reports with communication failure. All communication aspects were analyzed and classified. We identified 282 communication incidents. (II) Workflow analysis The analysis showed three phases of prehospital patient care: 1. incoming emergency call and dispatch of ambulance service, 2. prehospital treatment, 3. transportation to a hospital. Overall, the number of incidences is increasing as a consequence of parallel workflows. Category 1 was particularly significant and predominantly, paramedics criticized that emergency physicians did not acknowledge their advice (n = 73 vs. n = 9). Category 3 with n = 63, category 4 with n = 20 and category 2 with n = 13 were the major reasons for incidents.A better interface communication helps to coordinate patient transfer and is an option for optimizing resources. Frequent training in communication is an option to avoid incidents.

The low-lying energy levels of proton-rich Cu56 have been extracted using in-beam γ-ray spectroscopy with the state-of-the-art γ-ray tracking array GRETINA in conjunction with the S800 spectrograph at the National Superconducting Cyclotron Laboratory at Michigan State University. Excited states in Cu56 serve as resonances in the Ni55(p,γ)Cu56 reaction, which is a part of the rp process in type-I x-ray bursts. To resolve existing ambiguities in the reaction Q value, a more localized isobaric multiplet mass equation (IMME) fit is used, resulting in Q=639±82 keV. We derive the first experimentally constrained thermonuclear reaction rate for Ni55(p,γ)Cu56. We find that, with this new rate, the rp process may bypass the Ni56 waiting point via the Ni55(p,γ) reaction for typical x-ray burst conditions with a branching of up to ∼40%. We also identify additional nuclear physics uncertainties that need to be addressed before drawing final conclusions about the rp-process reaction flow in the Ni56 region.

We have measured the ionization efficiency of silicon nuclear recoils with kinetic energy between 1.8 and 20 keV. We bombarded a silicon-drift diode with a neutron beam to perform an elastic-scattering experiment. A broad-energy neutron spectrum was used and the nuclear recoil energy was reconstructed using a measurement of the time of flight and scattering angle of the scattered neutron. The overall trend of the results of this work is well described by the theory of Lindhard et al. above 4 keV of recoil energy. Below this energy, the presented data shows a deviation from the model. The data indicates a faster drop than the theory prediction at low energies. Fil: Izraelevitch, Federico Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina. Fermi National Accelerator Laboratory; Estados Unidos Fil: Amidei, D.. University of Michigan; Estados Unidos Fil: Aprahamian, A.. University of Notre Dame; Estados Unidos Fil: Arcos Olalla, R.. Universidad de Guanajuato; México Fil: Cancelo, Gustavo Indalecio Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fermi National Accelerator Laboratory; Estados Unidos Fil: Casarella, C.. University of Notre Dame; Estados Unidos Fil: Chavarria, A. E.. University of Chicago; Estados Unidos Fil: Collon, P.. University of Notre Dame; Estados Unidos Fil: Estrada, Juan. Fermi National Accelerator Laboratory; Estados Unidos Fil: Fernández Moroni, Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fermi National Accelerator Laboratory; Estados Unidos Fil: Guardincerri, Yann. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fermi National Accelerator Laboratory; Estados Unidos Fil: Gutiérrez, G.. Fermi National Accelerator Laboratory; Estados Unidos Fil: Gyurjinyan, A.. University of Notre Dame; Estados Unidos Fil: Kavner, A.. University of Michigan; Estados Unidos Fil: Kilminster, B.. Universitat Zurich; Suiza Fil: Liao, J.. Universitat Zurich; Suiza Fil: Liu, Q.. University of Notre Dame; Estados Unidos Fil: López, M.. Universidad Nacional de Asunción; Paraguay Fil: Molina, J.. Universidad Nacional de Asunción; Paraguay Fil: Privitera, P.. University of Chicago; Estados Unidos Fil: Reyes, M. A.. Universidad de Guanajuato; México Fil: Scarpine, V.. Fermi National Accelerator Laboratory; Estados Unidos Fil: Siegl, K.. University of Notre Dame; Estados Unidos Fil: Smith, M.. University of Notre Dame; Estados Unidos Fil: Strauss, S.. University of Notre Dame; Estados Unidos Fil: Tan, W.. University of Notre Dame; Estados Unidos Fil: Tiffenberg, Javier Sebastian. Fermi National Accelerator Laboratory; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Villanueva, L.. Universidad de Guanajuato; México

Conversion coefficients, gamma-gamma and gamma-electron coincidences were measured in the s-process branching point nucleus 176Lu . Our goal was to determine the multipolarities of the $ \gamma$ -ray transitions that connect the high and low K states of 176Lu . This 176Lu nucleus has a long-lived ground state ( $ K=7^{-}$ of 37.6Gy, a short-lived isomeric state ( $ K=0^{-}$ at 122.8keV with half-life of 3.6h, as well as a 58μs isomer at 1588keV ( $ K=14^{+}$ . The excitation structure of this nucleus contains bands of intermediate spins of both positive and negative parities. The intermediate states can under certain stellar temperatures completely change the equilibrium between the isomer and ground state of 176Lu and change the abundance of this nucleus. We populated 37 previously known levels in this nucleus via the 176Yb (p, n reaction and measured 42 conversion coefficients for $ \gamma$ -ray transitions including 17 of them for the first time.

The dark matter interpretation of the DAMA modulation signal depends on the NaI(Tl) scintillation efficiency of nuclear recoils. Previous measurements for Na recoils have large discrepancies, especially in the DAMA/LIBRA modulation energy region. We report a quenching effect measurement of Na recoils in NaI(Tl) from 3keV$_{\text{nr}}$ to 52keV$_{\text{nr}}$, covering the whole DAMA/LIBRA energy region for light WIMP interpretations. By using a low-energy, pulsed neutron beam, a double time-of-flight technique, and pulse-shape discrimination methods, we obtained the most accurate measurement of this kind for NaI(Tl) to date. The results differ significantly from the DAMA reported values at low energies, but fall between the other previous measurements. We present the implications of the new quenching results for the dark matter interpretation of the DAMA modulation signal.

We have measured the scintillation and ionization yield of recoiling nuclei in liquid argon as a function of applied electric field by exposing a dual-phase liquid argon time projection chamber (LAr-TPC) to a low energy pulsed narrow band neutron beam produced at the Notre Dame Institute for Structure and Nuclear Astrophysics. Liquid scintillation counters were arranged to detect and identify neutrons scattered in the TPC and to select the energy of the recoiling nuclei. We report measurements of the scintillation yields for nuclear recoils with energies from 10.3 to 57.3 keV and for median applied electric fields from 0 to 970 V/cm. For the ionization yields, we report measurements from 16.9 to 57.3 keV and for electric fields from 96.4 to 486 V/cm. We also report the observation of an anticorrelation between scintillation and ionization from nuclear recoils, which is similar to the anticorrelation between scintillation and ionization from electron recoils. Assuming that the energy loss partitions into excitons and ion pairs from $^{83m}$Kr internal conversion electrons is comparable to that from $^{207}$Bi conversion electrons, we obtained the numbers of excitons ($N_{ex}$) and ion pairs ($N_i$) and their ratio ($N_{ex}/N_i$) produced by nuclear recoils from 16.9 to 57.3 keV. Motivated by arguments suggesting direction sensitivity in LAr-TPC signals due to columnar recombination, a comparison of the light and charge yield of recoils parallel and perpendicular to the applied electric field is presented for the first time., v2 to reflect published version

An approach is presented to experimentally constrain previously unreachable (p, γ) reaction rates on nuclei far from stability in the astrophysical rp process. Energies of all critical resonances in the (57)Cu(p,γ)(58)Zn reaction are deduced by populating states in (58)Zn with a (d, n) reaction in inverse kinematics at 75 MeV/u, and detecting γ-ray-recoil coincidences with the state-of-the-art γ-ray tracking array GRETINA and the S800 spectrograph at the National Superconducting Cyclotron Laboratory. The results reduce the uncertainty in the (57)Cu(p,γ) reaction rate by several orders of magnitude. The effective lifetime of (56)Ni, an important waiting point in the rp process in x-ray bursts, can now be determined entirely from experimentally constrained reaction rates.

The level structure of neutron-deficient 58 Zn has been extracted experimen- tally. This nucleus is important for the rapid proton-capture process. 58 Zn was produced by using a (d,n)-type transfer reaction on 57 Cu in inverse kinematics at beam energies of 75 MeV/u. Several -ray transitions have been identified. The experiment utilized the state-of-the-art GRETINA -ray energy tracking array in conjunction with the large- acceptance spectrometer S800 at NSCL. The excitation energies of the identified low- lying states in 58 Zn are important for constraining the 57 Cu(p, ) 58 Zn reaction rate under X-ray burst conditions.

Modification of the 6-N-alkyl-N-acyl groups of L-159,689, 6 6-(N-benzoyl-N-pentyl)-amino-2-propyl-3-[(2′-(tetrazol-5-yl)biphen-4-yl)methyl]quinazolin-4-(3H)one led to the identification of the 6-(N-benzoyl-N-(3-pyridylmethyl)) analog (L-162,537). L-162,537 had improved aqueous solubility and oral bioavailability in the dog. The SAR of this class of AT1 and AT2 ligands is discussed.

L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[[2'-(N-(3-methyl-1-butoxy) carbonylaminosulfonyl)[1,1']-biphenyl-4-yl]methyl]-3H-imidazo[4,5- b]pyridine) is a potent, orally active, nonpeptide angiotensin II receptor antagonist. Conscious rats and dogs were dosed p.o. and i.v.; in both species the plasma bioequivalents are similar at the angiotensin AT1 and AT2 receptor sites indicating balanced activity is maintained in vivo. L-163,017 prevents the pressor response to intravenous (i.v.) angiotensin II in the conscious rat, dog, and rhesus monkey. L-163,017 also significantly reduces blood pressure in a renin-dependent model of hypertension, similar to an angiotensin converting enzyme inhibitor (Enalapril) and an angiotensin AT1 receptor-selective antagonist (L-159,282). These studies indicate that neither the angiotensin AT2 receptor nor bradykinin is important in the acute antihypertensive activity of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists.

The affinities of 13 angiotensin II antagonists for the AT1 subtype determined in vitro with tissue homogenates were shown not to correlate well with in vivo pharmacologic potency. The addition of human serum albumin to the in vitro assay to mimic in vivo plasma protein interactions reduced the measured affinity by reducing the effective free concentrations of antagonists, but the resulting affinities were not predictive of the in vivo effects. Using an in vivo radioligand competition assay, in which receptor occupancy is demonstrated via competitive blockade of the in vivo binding of [125I][Sar1,Ile8]angiotensin II to AT1 receptors in rat kidney cortex, we demonstrated that the in vivo pharmacologic potencies reflect receptor occupancy. By comparing the effects of rat plasma and bovine serum albumin on the in vitro affinity of two antagonists, we suggest that the use of plasma would alter free plasma concentrations in a manner more consistent with in vivo measures of potencies.

Juxtaglomerular (JG) cell hypertrophy and hyperplasia were investigated in rhesus monkeys given angiotensin II (AII) AT1 receptor antagonists L-158,338 and DUP 753 (MK-0954, losartan).In 2 initial studies, L-158,338 was given orally at 10, 30, and 90 mg/kg/day for 3 or 14 weeks. To investigate the observed JG hypertrophy and hyperplasia, in a third 5-week experiment L-158,338 was given alone at 90 mg/kg/day, or with physiologic saline supplementation at 25 ml/kg/day, or coadministered with the angiotensin converting enzyme inhibitor enalapril at 10 mg/kg/day. Physiologic saline was given to attempt to suppress renin release through volume expansion and/or sodium retention. Enalapril was given to lower plasma AII levels and observe whether JG cell hypertrophy and hyperplasia were increased or decreased. For comparison, DUP 753 was given at 90 and 300 mg/kg/day. Plasma renin activity and AII concentration were measured in this study.Dose- and time-dependent increases in JG cell hypertrophy and hyperplasia were seen in the 2 initial experiment. In the third experiment, plasma renin activity and AII concentration were increased 3-fold and 6-fold over pretest values by L-158,338 at 90 mg/kg/day for 5 weeks. Saline supplementation had no effect on these parameters but diminished the group mean severity grade for JG hypertrophy and hyperplasia from 1.5 to 1.0. Enalapril coadministration had no effect on plasma renin activity, whereas it blunted the plasma AII increase caused by L-158,338 and increased the group mean grade to 2.5. DUP 753 at 300 mg/kg/day produced similar increases in plasma renin activity and AII concentration but only resulted in grade 1 JG cell hypertrophy and hyperplasia.L-158,338-induced JG cell hypertrophy and hyperplasia is an exaggerated pharmacologic response that can be modulated by saline supplementation and angiotensin converting enzyme inhibition. These results suggest that decreased renal perfusion or altered sodium homeostasis and plasma AII concentration are important variables that contribute to AT1 receptor blockade to induce JG cell hypertrophy and hyperplasia.

DISCOVERY OF LOSARTAN: Losartan (DuP 753, MK 954) is the first potent and selective non-peptide angiotensin II (Ang II) antagonist. The discovery of losartan followed an observation that several simple benzylimidazoles are weak Ang II antagonists. These compounds (e.g. S8307) lack potency but are orally active and selective for Ang II receptors (AT receptors). Losartan was synthesized using S8307 and other analogs of the benzylimidazoles as chemical leads.Losartan selectively inhibits all Ang II responses that have been studied and lowers blood pressure in several animal models of renin-dependent hypertension. In animals, the antihypertensive efficacy of losartan is similar to that of angiotensin converting enzyme (ACE) inhibitors but, unlike ACE inhibitors, losartan is a more selective inhibitor of the renin-angiotensin system since it does not affect the metabolism of kinins. Compared with peptide Ang II antagonists (e.g. saralasin), losartan has significant advantages, including a long duration of action, effective oral absorption and no Ang II agonist activity.The high selectivity and potency for AT receptors, the non-peptide structure and the oral activity of losartan represent a pharmacological breakthrough. This agent is now being used to elucidate the physiology of AT receptors and is likely to be useful in the therapeutic management of diseases in which the renin-angiotensin system is known to be involved.

L-158,809 (5,7-dimethyl-2-ethyl-3-[[2'-(1H-tetrazol-5yl)[1,1']-bi- phenyl-4-yl]-methyl]-3H-imidazo[4,5-b]pyridine) is a potent, competitive and specific antagonist of AT1 subtype of angiotensin II (AII) receptors in in vitro radioligand binding and functional isolated tissue assays. The present study was carried out to characterize the in vivo pharmacology of this potent AII receptor antagonist. In conscious, normotensive and anesthetized pithed rats, L-158,809 inhibits AII (0.1 microgram/kg i.v.) elevations in blood pressure without altering pressor responses to methoxamine or arginine vasopressin. In conscious rats, the relative potencies (ED50) were 29 micrograms/kg i.v. and 23 micrograms/kg p.o. Duration of action with single i.v. or p.o. doses exceeded 6 hr in rats. In similar experiments using rhesus monkeys, the potencies of L-158,809 were 10 micrograms/kg i.v. and approximately 100 micrograms/kg p.o. In these rats and monkeys, L-158,809 was 10 to 100 times more potent than DuP-753 (losartan) and approximately 3 times more potent than the metabolite, EXP3174. AII-induced elevation of plasma aldosterone in rats was also inhibited by L-158,809. Unlike angiotensin converting enzyme inhibitors, L-158,809 did not potentiate the hypotensive responses to i.v. bradykinin. L-158,809 was antihypertensive in high renin hypertensive rats (aortic coarction) and volume-depleted rhesus monkeys. The maximum hypotensive responses with acute doses of L-158,809 were equal to those with an angiotensin converting enzyme inhibitor in these renin-dependent animal models. From these in vivo data, L-158,809 is a selective AII receptor antagonist with high potency, good p.o. absorption, long duration and antihypertensive efficacy equal to angiotensin converting enzyme inhibition after single doses.

L-158,809 interacted in a competitive manner with rabbit aortic angiotensin II (AII) receptors as determined by Scatchard analysis of the specific binding of [125I]Sar1Ile8-AII. The affinity of L-158,809 (IC50 = 0.3 nM) for AII receptors in this tissue was appreciably greater than that of other reported nonpeptide AII antagonists such as DuP-753 (IC50 = 54 nM) and EXP3174 (IC50 = 6 nM) and similar to the natural ligand, AII. L-158,809 also exhibited a high potency at AII receptors in several other tissues from different animal species (IC50 = 0.2-0.8 nM). In vitro functional assays utilizing AII-induced aldosterone release in rat adrenal cortical cells demonstrated further that L-158,809 acts as a competitive, high affinity antagonist of AII (pA2 = 10.5) and lacks agonist activity. L-158,809 also potently inhibited AII-induced inositol phosphate accumulation in vascular smooth muscle cells and contractile responses to AII in isolated blood vessels. The specificity of L-158,809 for AII receptors was demonstrated by its lack of activity (IC50 greater than 1 microM) in several other receptor binding assays and its inability to affect in vitro functional responses produced by other agonists. L-158,809 demonstrated a very high selectivity for the AT1 compared to the AT2 receptor subtype (AT2 IC50 greater than or equal to 10 microM). The high affinity and selectivity makes L-158,809 a valuable new tool for investigating the physiological and pharmacological actions of AII.

Angiotensin II (AII) elicits a positive inotropic response in cardiac muscle preparations from several species including humans. The purpose of this study was to characterize the AII binding sites and inotropic responses in rabbit ventricle using the selective AII receptor antagonists/ligands, DuP 753 (AT1) and PD 121981 (AT2). Biphasic displacement of specific 125I-Sar1,Ile8-AII binding was observed with both DuP 753 and PD 121981, suggesting the presence of two AII binding sites. The high affinity site for DuP 753 (29 nM) was a low affinity site for PD 121981 (91 microM), and the high affinity site for PD 121981 (78 nM) was a low affinity site for DuP 753 (81 microM). Of the specific AII binding, 70% was DuP 753 (AT1)-sensitive sites. Positive inotropic responses to AII in isolated papillary muscles from rabbit heart were antagonized competitively by both DuP 753 and PD 121981. The potencies of DuP 753 (pA2 = 7.99) and PD 121981 (pA2 = 4.28) to antagonize AII inotropic responses were similar to their potencies to displace 125I-Sar1,Ile8-AII from AT1 sites. There was no apparent functional consequence of AII interaction with AT2 site. Inotropic responses to isoproterenol were unaffected by DuP 753 and PD 121981. Therefore, there are two binding sites for AII in rabbit ventricle; however, only one site, AT1, participates in the inotropic response to AII. The roles of these receptor subtypes in other cardiac responses to AII have yet to be determined. Also, DuP 753 and PD 121981 are useful tools to study these two AII binding sites in cardiac preparations.

The antithrombotic efficacy and duration of action of a single subcutaneous administration of the selective factor Xa inhibitor recombinant antistasin (rATS) was evaluated in a rhesus monkey model of mild disseminated intravascular coagulation. rATS (1 mg/kg) was shown to be fully effective and comparable to standard heparin (1,000 U/kg) in the suppression of thromboplastin-induced fibrinopeptide A generation for at least 5 h following a single subcutaneous administration. The absorption rate of rATS, as measured by ex vivo activated partial thromboplastin times (aPTT), mirrored that of standard heparin exhibiting peak anticoagulant activity between 1 and 2 h post administration. The anticoagulant effects of a single rATS dose lasted for longer than 30 h maintaining an aPTT value at least 2-fold higher than baseline. Repeated subcutaneous administrations of rATS resulted in the generation of fully neutralizing antibodies. These results suggest that specific factor Xa inhibition may be as effective as standard heparin in the treatment of venous thrombosis. Due to its antigenicity however, rATS is probably not suitable for chronic subcutaneous anticoagulant therapy.

Tick anticoagulant peptide (TAP) is a potent, highly selective inhibitor of blood coagulation factor Xa (Waxman, L., Smith, D. E., Arcuri, K. E., and Vlasuk, G. P. (1990) Science, 248, 593-596). Further detailed studies pertaining to the in vitro and in vivo evaluation of TAP require quantities of the inhibitor which cannot be isolated from ticks. To overcome this limitation we describe here the characterization of recombinant TAP (rTAP) secreted by Saccharomyces cerevisiae. Expression of rTAP was obtained using a chimeric gene containing a fusion between sequences encoding the secretory preproleader of the yeast mating pheromone alpha-factor and a synthetic sequence encoding the 60-amino acid inhibitor under the transcriptional control of a galactose-inducible promoter. Recombinant S. cerevisiae were found to secrete biologically active rTAP into the extracellular medium at levels of 0.1-0.15 g/liter. The secreted inhibitor was purified to homogeneity and found to be indistinguishable from the native inhibitor with respect to several criteria, including primary structure, amino acid composition, and electrophoretic mobility. In addition, purified rTAP and native TAP exhibited similar stoichiometric inhibition of factor Xa in vitro. The in vivo efficacy of rTAP was demonstrated using a model of low grade disseminated intravascular coagulation where the purified inhibitor was shown to significantly inhibit thromboplastin-induced fibrinopeptide A generation following an infusion into conscious rhesus monkeys. The availability of rTAP will allow a detailed evaluation of the in vitro and in vivo properties of this highly specific and potent factor Xa inhibitor.

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Stereospecific saturable and reversible binding of d-cis-diltiazem has been demonstrated in cardiac sarcolemmal membrane vesicles. Analysis of binding by either equilibrium or kinetic techniques indicates the presence of a single class of benzothiazepine receptors which bind diltiazem with a KD of 80 nM at 25 degrees C. Benzothiazepine receptors copurify with other sarcolemmal marker activities and exist in a complex with distinct receptors for dihydropyridine and aralkylamine Ca2+ entry blockers in a 1:1:1 stoichiometry. Ligand binding to one receptor of this complex influences binding reactions at the other two sites in a manner that depends on ambient temperature. Binding of either dihydropyridine agonists or antagonists causes partial inhibition of diltiazem binding at 25 degrees C (Bmax effect), while most dihydropyridine antagonists stimulate and agonists inhibit diltiazem binding at 37 degrees C (both are KD effects). This temperature-dependent change in receptor coupling was confirmed by Scatchard analyses and study of diltiazem dissociation kinetics. Verapamil, interacting at the aralkylamine receptor, inhibits diltiazem binding equivalently at 25 and 37 degrees C (KD effects). In addition, both classes of dihydropyridines inhibit verapamil binding in a temperature-independent fashion, as does diltiazem (all are KD effects). Allosteric coupling between benzothiazepine and dihydropyridine receptors is manifested in cardiac muscle since the negative inotropic potency of diltiazem is increased by nitrendipine and decreased by 4-(O-trifluromethy(phenyl)-2,6-dimethyl-5-nitro-1,4-dihydropyridin e-3- carboxylic acid, methyl ester. These results suggest a model in which the Ca2+ entry blocker receptor complex undergoes a change between 25 and 37 degrees C so that at the latter temperature all sites are directly coupled. Allosteric coupling may have important consequences in vivo since it can be detected in functional assays of Ca2+ channel activity.

Na+/Ca2+ exchange is inhibited in both guinea pig cardiac membrane vesicles and papillary muscles in a concentration-dependent fashion by several analogs of the pyrazine diuretic amiloride. Structure/activity studies based on transport measurements in vesicles prepared from guinea pig left ventricle indicate that hydrophobic substitutions at the terminal nitrogen atom of the guanidinium moiety of amiloride improved the inhibitory potency almost 100-fold over that of the parent compound. 3',4'- Dichlorobenzamil ( DCB ) is one of the most active inhibitors (IC50 = 17 microM). In electrically stimulated papillary muscles isolated from guinea pig heart, 10-40 microM DCB decreases contractile force. At 100 microM inhibitor, diastolic tension is significantly increased. The positive inotropic responses to veratridine and ouabain are inhibited by 20 and 40 microM DCB . Since the responses to these interventions were a consequence of increased intracellular Na+ concentration, these data indicate that DCB is an inhibitor of Na+-dependent Ca2+ influx in the intact tissue. Interpretation of mechanical responses elicited by paired pulses suggests that 40 microM but not 100 microM DCB decreases release of Ca2+ from the sarcoplasmic reticulum. The mechanical data obtained with concentrations of DCB that inhibited Na+/Ca2+ exchange in vesicles suggest that a significant amount of Ca2+ can enter the cardiac cell via Na+/Ca2+ exchange under normal conditions and that this transport system may be an important source of Ca2+ supplying the sarcoplasmic reticulum in guinea pig heart. Moreover, these amiloride analogs function as potent inhibitors of the positive inotropic effect caused by increased intracellular Na+ concentration.

Isolated tissues from rat and guinea pig hearts were employed to investigate the relationship between the positive inotropic effects of isoproterenol and glucagon and the shortening of time to peak tension (TPT). The involvement of cAMP in the inotropic responses to histamine and isoproterenol and corresponding changes in TPT was also studied. On isoproterenol challenge, a correlation was found between the percent increase in tension and reduction in TPT. Histamine produced a positive inotropic response in both guinea pig left atria and papillary muscles; however, TPT was shortened only in the cAMP-associated response of the papillary muscle. In guinea pig left atria, isoproterenol in the absence and presence of D-600, RO-20-1724, or propranolol increased tissue levels of cAMP and decreased TPT such that a significant correlation was found between these two parameters. The significance of relationships among positive inotropic responses, tissue levels of cAMP, and TPT is discussed.

Thin strips of lung parenchyma from guinea pigs were mounted in an isolated tissue bath and placed under an initial tension of 1.2 gm. Drug-induced changes in resting tension were recorded isometrically upon the addition of representative alpha- and beta-adrenergic agonists. Lung strips relaxed following challenge with isoproterenol, 10(-9) to 10(-6)M (beta-adrenergic agonist), and contracted following challenge with phenylephrine, 10(-6) to 10(-4)M (alpha-adrenergic agonist). The responses of lung strips to norepinephrine, 10(-8) to 10(-4)M (mixed alpha- or beta-agonist) were influenced by the presence of either an alpha- or beta-adrenergic antagonist: pretreatment with phentolamine, 10(-5)M (alpha-antagonist) resulted in relaxant responses to norepinephrine, whereas pretreatment with propranolol, 10(-5)M (beta-antagonist) resulted in contractile responses. Cocaine, an uptake-1 inhibitor, potentiated the contractile effect of norepinephrine but not the relaxant effect of isoproterenol or norepinephrine. These data support the existence of alpha- and beta-adrenergic receptors mediating contraction and relaxation, respectively, in guinea pig lungs.

In patients with potentially increased intracranial pressure (ICP), continuous monitoring of ICP is a commonly used diagnostic procedure in intensive care units. Conventional chart recordings or isolated computer analyses are of limited use unless they can easily be correlated with other factors which might affect the ICP signal [e. g., arterial blood pressure (SAP), central venous pressure (CVP), and ventilation parameters]. A monitoring system should provide on-line information and be able to store data from different biological parameters economically for later evaluation.

Cyproheptadine was compared with nifedipine, verapamil and diltiazem for calcium entry blocker activity in isolated cardiovascular preparations. Using rat aortic strips, all compounds (10(-7) M) inhibited both the contraction caused by the readdition of calcium (1.0 mM) into regular buffer or buffer containing potassium (130 mM) or norepinephrine (10(-5) M) and the potassium-stimulated uptake of 45Ca. The rank order of potency for these experiments was in general nifedipine greater than cyproheptadine greater than or equal to verapamil greater than diltiazem. The same order of potency also was found for the four compounds in relaxing potassium (40 mM)-contracted aortic strips (IC50 values: nifedipine, 2.6 X 10(-9) M; cyproheptadine, 6.3 X 10(-8) M; verapamil, 7.6 X 10(-8) M; and diltiazem, 2.1 X 10(-7) M), but cyproheptadine was the least potent agent in antagonizing the spontaneous contractions of the rat portal vein (IC50 values: nifedipine, 6.6 X 10(-9) M; verapamil 7.7 X 10(-8) M; diltiazem 9.6 X 10(-8) M; and cyproheptadine 3.9 X 10(-7)M). None of the compounds (10(-7) M) inhibited the contraction to norepinephrine (10(-5) M) in rabbit aortic strips bathed in calcium-free buffer (1 mM ethylene glycol bis(beta-aminoethyl ether)-N, N'-tetraacetic acid). Nifedipine, verapamil and diltiazem were more potent in inhibiting the restoration of contractility by isoproterenol in potassium-depolarized rabbit papillary muscles than decreasing force in normally polarized muscles; cyproheptadine was equipotent when tested in these two preparations. Cyproheptadine was the least potent of the four compounds in lowering perfusion pressure in the perfused canine hindlimb.(ABSTRACT TRUNCATED AT 250 WORDS)

Isolated tissues from rat and guinea pig hearts were employed to investigate the relationship between the positive inotropic effects of isoproterenol and glucagon and the shortening of time to peak tension (TPT). The involvement of cAMP in the inotropic responses to histamine and isoproterenol and corresponding changes in TPT was also studied. On isoproterenol challenge, a correlation was found between the percent increase in tension and reduction in TPT. Histamine produced a positive inotropic response in both guinea pig left atria and papillary muscles; however, TPT was shortened only in the cAMP-associated response of the papillary muscle. In guinea pig left atria, isoproterenol in the absence and presence of D-600, RO-20-1724, or propranolol increased tissue levels of cAMP and decreased TPT such that a significant correlation was found between these two parameters. The significance of relationships among positive inotropic responses, tissue levels of cAMP, and TPT is discussed.

The positive inotropic effects of the alpha-adrenergic agonists, phenylephrine and methoxamine were compared in isolated rabbit papillary muscles. Phenylephrine in the presence of 10(-7)M propranolol produced a greater response than methoxamine. Antagonism by phentolamine was competitive for phenylephrine and apparently, noncompetitive for methoxamine. Based upon observed maximum following frequencies, 10(-4)M methoxamine had a greater cardiac depressant effect than 10(-4) phenylephrine. It was suggested that phenylephrine with a beta-adrenergic antagonist possessed advantages over methoxamine as an agonist for studying cardiac alpha-adrenergic receptors in rabbit papillary muscles.