Scintillation characteristics of the EJ-299-02H scintillator.

A study of the dead layer thickness and quenching factor of a plastic scintillator for use in ultracold neutron (UCN) experiments is described. Alpha spectroscopy was used to determine the thickness of a thin surface dead layer to be 630 ± 110 nm. The relative light outputs from the decay of 241Am and Compton scattering of electrons were used to extract Birks' law coefficient, yielding a kB value of 0.087 ± 0.003 mm/MeV, consistent with some previous reports for other polystyrene-based scintillators. The results from these measurements are incorporated into the simulation to show that an energy threshold of (∼9 keV) can be achieved for the UCNProBe experiment. This low threshold enables high beta particle detection efficiency and the indirect measurement of UCN. The ability to make the scintillator deuterated, accompanied by its relatively thin dead layer, gives rise to unique applications in a wide range of UCN experiments, where it can be used to trap UCN and detect charged particles in situ.

Improved Neutron Lifetime Measurement with UCNτ.

We report an improved measurement of the free neutron lifetime τ_{n} using the UCNτ apparatus at the Los Alamos Neutron Science Center. We count a total of approximately 38×10^{6} surviving ultracold neutrons (UCNs) after storing in UCNτ's magnetogravitational trap over two data acquisition campaigns in 2017 and 2018. We extract τ_{n} from three blinded, independent analyses by both pairing long and short storage time runs to find a set of replicate τ_{n} measurements and by performing a global likelihood fit to all data while self-consistently incorporating the ß-decay lifetime. Both techniques achieve consistent results and find a value τ_{n}=877.75±0.28_{stat}+0.22/-0.16_{syst} s. With this sensitivity, neutron lifetime experiments now directly address the impact of recent refinements in our understanding of the standard model for neutron decay.

Ultracold neutron properties of the Eljen-299-02D deuterated scintillator.

In this paper, we report studies of the Fermi potential and loss per bounce of ultracold neutrons (UCNs) on a deuterated scintillator (Eljen-299-02D). These UCN properties of the scintillator enable its use in a wide variety of applications in fundamental neutron research.

Search for the Neutron Decay n→X+γ, Where X is a Dark Matter Particle.

Fornal and Grinstein recently proposed that the discrepancy between two different methods of neutron lifetime measurements, the beam and bottle methods, can be explained by a previously unobserved dark matter decay mode, n→X+γ. We perform a search for this decay mode over the allowed range of energies of the monoenergetic γ ray for X to be dark matter. A Compton-suppressed high-purity germanium detector is used to identify γ rays from neutron decay in a nickel-phosphorous-coated stainless-steel bottle. A combination of Monte Carlo and radioactive source calibrations is used to determine the absolute efficiency for detecting γ rays arising from the dark matter decay mode. We exclude the possibility of a sufficiently strong branch to explain the lifetime discrepancy with 97% confidence.

First Limit on the Direct Detection of Lightly Ionizing Particles for Electric Charge as Low as e/1000 with the Majorana Demonstrator.

The Majorana Demonstrator is an ultralow-background experiment searching for neutrinoless double-beta decay in ^{76}Ge. The heavily shielded array of germanium detectors, placed nearly a mile underground at the Sanford Underground Research Facility in Lead, South Dakota, also allows searches for new exotic physics. Free, relativistic, lightly ionizing particles with an electrical charge less than e are forbidden by the standard model but predicted by some of its extensions. If such particles exist, they might be detected in the Majorana Demonstrator by searching for multiple-detector events with individual-detector energy depositions down to 1 keV. This search is background-free, and no candidate events have been found in 285 days of data taking. New direct-detection limits are set for the flux of lightly ionizing particles for charges as low as e/1000.

New Limits on Bosonic Dark Matter, Solar Axions, Pauli Exclusion Principle Violation, and Electron Decay from the Majorana Demonstrator.

We present new limits on exotic keV-scale physics based on 478 kg d of Majorana Demonstrator commissioning data. Constraints at the 90% confidence level are derived on bosonic dark matter (DM) and solar axion couplings, Pauli exclusion principle violating (PEPV) decay, and electron decay using monoenergetic peak signal limits above our background. Our most stringent DM constraints are set for 11.8 keV mass particles, limiting g_{Ae}<4.5×10^{-13} for pseudoscalars and (α^{'}/α)<9.7×10^{-28} for vectors. We also report a 14.4 keV solar axion coupling limit of g_{AN}^{eff}×g_{Ae}<3.8×10^{-17}, a 1/2ß^{2}<8.5×10^{-48} limit on the strength of PEPV electron transitions, and a lower limit on the electron lifetime of τ_{e}>1.2×10^{24} yr for e^{-}→ invisible.

Invited article: development of high-field superconducting Ioffe magnetic traps.

We describe the design, construction, and performance of three generations of superconducting Ioffe magnetic traps. The first two are low current traps, built from four racetrack shaped quadrupole coils and two solenoid assemblies. Coils are wet wound with multifilament NbTi superconducting wires embedded in epoxy matrices. The magnet bore diameters are 51 and 105 mm with identical trap depths of 1.0 T at their operating currents and at 4.2 K. A third trap uses a high current accelerator-type quadrupole magnet and two low current solenoids. This trap has a bore diameter of 140 mm and tested trap depth of 2.8 T. Both low current traps show signs of excessive training. The high current hybrid trap, on the other hand, exhibits good training behavior and is amenable to quench protection.

Contrasting roles of neuronal Msk1 and Rsk2 in Bad phosphorylation and feedback regulation of Erk signalling.

Activated extracellular-signal-regulated kinase (Erk) phosphorylates and activates downstream kinases including ribosomal S6 kinase 2 (Rsk2/RPS6KA3) and mitogen- and stress-activated kinase 1 (Msk1, RPS6KA5). Rsk2 plays an important role in neuronal plasticity, as patients with Coffin-Lowry syndrome, where Rsk2 is dysfunctional, have impaired cognitive function. However, the relative role of neuronal Rsk2 and Msk1 in activating proteins downstream of Erk is unclear. In PC12 cells and in cortical neurones, the calcium ionophore A23187-induced phosphorylation of Erk, Msk1, Rsk2 and also the Bcl-2-associated death protein (Bad), which protects against neurotoxicity. Specific knockdown of Msk1 with small interfering RNA reduced the ability of A23187 to induce Bad phosphorylation in both PC12 cells and cortical neurones. Conversely, specific knockdown of Rsk2 potentiated Bad phosphorylation following A23187 treatment, and also elevated Erk phosphorylation in both cell types. This indicates that Msk1 rather than Rsk2 mediates neuronal Bad phosphorylation following Ca(2+) influx and implicates Rsk2 in a negative-feedback regulation of Erk activity.

The pancreatic polypeptide family and the migrating motor complex of the rat: differential effects in the duodenum and jejunum.

AIM: To investigate the effects of members of the pancreatic polypeptide family on migrating myoelectric complexes in rats in vivo. METHODS: Rats were supplied with bipolar electrodes at 5 (duodenum), 15 and 25 cm (jejunum) distal to pylorus for electromyography. The natural ligands neuropeptide Y, pancreatic polypeptide, peptide YY1-36 and peptide YY3-36 were infused IV at doses of 0.5-400 pmol kg(-1) min(-1). The mechanisms of action were studied after pre-treatment with N(omega)-nitro-L-arginine (L-NNA) 1 mg kg(-1), guanethidine 3 mg kg(-1) and in bilaterally vagotomized animals. RESULTS: PP inhibited myoelectrical activity dose-dependently in both the duodenum (ED50 5.8 pmol kg(-1) min(-1)) and jejunum (2.6 pmol kg(-1) min(-1)). PYY1-36 and PYY3-36 also had inhibitory effect in the jejunum (4.4 and 130 pmol kg(-1) min(-1), respectively). PYY1-36 had no significant effect in the duodenum, whereas PYY3-36 stimulated myoelectrical activity at the highest doses. NPY was without effect. In the jejunum neither L-NNA, guanethidine or vagotomy had any significant influence on the inhibitory effects of PP, PYY1-36 and PYY3-36. In the duodenum, the effect of PP was inhibited by guanethidine, but not L-NNA or vagotomy. The stimulatory effect of PYY3-36 in the duodenum was blocked by L-NNA and vagotomy, whereas guanethidine was without effect. CONCLUSION: Peptides of the PP family modulate small bowel motility differentially. Whereas their general effect is inhibitory in the jejunum, the mixing duodenal compartment is stimulated by PYY3-36, suggested to reflect receptor distribution distinction in the gut. This implicates distribution of distinct receptors in the gut being activated by either peptide.

The StarClose Vascular Closure System: interventional results from the CLIP study.

BACKGROUND: The StarClose Vascular Closure System is a femoral access site closure technology that uses a flexible nitinol clip to complete a circumferential, extravascular arteriotomy close. The Clip CLosure In Percutaneous Procedures study was initiated to study the safety and efficacy of the StarClose device in subjects undergoing diagnostic and interventional catheterization procedures. METHODS: A total of 17 U.S. sites enrolled 596 subjects, with 483 subjects randomized at a 2:1 ratio to receive StarClose or standard compression of the arteriotomy after the percutaneous procedure. The study included roll-in (n = 113), diagnostic (n = 208), and interventional (n = 275) arms with a primary safety endpoint of major vascular complications through 30 days and a primary efficacy endpoint of postprocedure time to hemostasis. RESULTS: The results of the diagnostic StarClose cohort have been reported separately. Results for the interventional arm revealed major vascular complications occurring in 1.1% of StarClose subjects (2/184) and 1.1% in manual compression subjects (1/91; P = 1.00). No infections were seen in either cohort. Minor complications in the StarClose interventional group occurred at a rate of 4.3% (8/184) and with compression at 9.9% (9/91; P = 0.107). Pseudoaneurysm or arteriovenous fistula was not seen with StarClose. With StarClose, procedural success was 100% (136/136) for the diagnostic group and 98.9% (181/183) in the interventional group. Device success for the treatment group was 86.8%. In the interventional cohort, 87.3% (158/181) of StarClose subjects reported a pain scale of 0-3 compared with 93.3% (84/90) in the compression group, which was not statistically different. CONCLUSIONS: The clinical results of this study demonstrate that the StarClose Vascular Closure System is noninferior to manual compression with respect to the primary safety endpoint of major vascular events in subjects who undergo percutaneous interventional procedures. StarClose significantly reduced time to hemostasis, ambulation, and dischargeability when compared with compression.

Properties of neurons in the trigeminal nucleus caudalis responding to noxious dural and facial stimulation.

Extracellular single unit recordings were made in the rat trigeminal nucleus caudalis (Vc) from cells with Adelta and C-fibre latency responding to electrical stimulation of the thinned cranium overlying the middle meningeal artery (MMA). The neurons had an ipsilateral facial receptive field (FRF) that mainly extended over areas innervated by the first and second division of the trigeminal nerve but in some cases also included areas innervated by the third division of the trigeminal nerve. No wind-up of either long latency C-fibre or short latency Adelta responses was seen during trains of electrical stimulation. Sensitisation of mechanical stimulation of the FRF could also not be observed at any time during dural stimulation. In contrast, extracellular single unit recordings in the Vc activated by electrical stimulation of the facial skin resulted in a significant wind-up response of long latency response in six of ten cells studied. The facial-elicited wind-up response was significantly enhanced, 18 min after the electrical stimulation protocol was started, indicating that the process of wind-up had generated central excitability. The findings in this study demonstrate a clear difference between the effects of electrical stimulation of cutaneous and non-cutaneous inputs. In the trigeminal system, this has implications for the study of pathways such as those involved in headache, where it is believed that an enhanced dural input to the Vc may generate central sensitisation and partly explain the hyperalgesia and allodynia reported by patients.

N-methyl-D-aspartate and brain-derived neurotrophic factor induce distinct profiles of extracellular signal-regulated kinase, mitogen- and stress-activated kinase, and ribosomal s6 kinase phosphorylation in cortical neurons.

Stimulation of N-methyl-D-aspartate (NMDA) receptors is believed to underlie long-term memory formation, and excessive NMDA receptor activation has been linked to several neuropathological conditions. Phosphorylation and activation of p42/44 mitogen-activated protein kinase (ERK) is believed to mediate many of these effects, but the downstream targets of ERK in response to NMDA activation have not been determined. In primary cultures of rat cortical neurons, we found that NMDA was able to elevate phosphorylation of mitogen- and stress-activated kinase 1 (MSK1) as well as ERK. Likewise, brain-derived neurotrophic factor (BDNF) treatment increased phosphorylation of MSK1 and ERKs. The NMDA-induced MSK1 phosphorylation was sensitive to the MEK inhibitor 2'-amino-3'-methoxyflavone (PD98059) and the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580). MSK1 activation by NMDA was transient, although ERK remained phosphorylated within the neuronal cytoplasm for several hours. Although BDNF increased ribosomal S6 kinase (RSK) phosphorylation, NMDA had no discernable effect on the phosphorylation of RSKs. Thus, phosphorylation and activation of MSK1 but not RSK could be an important step in the pathway linking NMDA-induced ERK phosphorylation to the activation of transcription factors required for the formation of long-term memory.

Effect of IL-1beta microinjection into the posterior hypothalamic area on trigeminal nociception in the rat.

The hypothalamus has been implicated in the pathophysiology of the most disabling forms of primary headache, namely migraine and cluster headache. Interleukin-1beta (IL-1beta) is highly expressed in the hypothalamus. We recorded from the trigeminal nucleus caudalis of rats using extracellular electrophysiological methods from neurons responding to electrical stimulation of the peri-middle meningeal artery dura mater and having receptive fields in the ophthalmic division of the trigeminal nerve. Data were collected from fifteen clusters of wide-dynamic range neurons with stable baseline firing responses between 97 and 101% ( n=3 for each unit) to stimulation. Microinjection of IL-1beta into the posterior hypothalamus of 9 animals resulted in a modest inhibition of evoked trigeminal responses in three units, no effect in six and no overall effect for the entire cohort studied. The mean maximum response was a non-significant reduction in firing to 83+/-7% ( n=9) at 30 minutes post-injection of IL-1beta. There was some variation of effect dependent on site of injection with central posterior hypothalamus being the predominant area that resulted in inhibition. There was no inhibition in the six animals injected with vehicle (saline). If there is an important effect for IL-1beta in the posterior hypothalamus it is likely to be highly somatotopically restricted.

CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain.

The cannabinoid agonist, HU210 has been evaluated in vivo in nociceptive and inflammatory pain models in the rat. The ED50 for the anti-nociceptive (increasing mechanical withdrawal threshold) effect was 0.1 mg/kg-1 i.p., and for anti-hypersensitivity and anti-inflammatory activity was 5 g/kg-1 i.p. (in the carrageenan model). The selective CB1 antagonist, AM281 (0.5 microg/kg-1 i.p.) reversed effects of HU210 (10 and 30 microg/kg-1 i.p.) in both nociceptive and inflammatory models of hypersensitivity. The selective CB2 antagonist, SR144528 (1 mg/kg-1 i.p.) antagonised effects of HU210 (30 microg/kg-1 i.p.) in the carrageenan induced inflammatory hypersensitivity. The CB2 agonist, 1-(2,3-Dichlorobenzoyl)-5-methoxy-2-methyl-(2-(morpholin-4-yl)ethyl)-1H-indole (GW405833) inhibited the hypersensitivity and was anti-inflammatory in vivo. These effects were blocked by SR144528. These findings suggest that CB1 receptors are involved in nociceptive pain and that both CB1 and CB2 receptors are involved in inflammatory hypersensitivity. Future studies will investigate effects on identified inflammatory cells within the inflamed tissue to further elucidate the role of cannabinoid receptors.

Comparison of PRE-dilatation vs direct stenting in coronary treatment using the Medtronic AVE S670 Coronary Stent System (the PREDICT trial).

Current stent delivery systems make primary stenting (stent placement without predilatation) possible, but few controlled trials have been performed to evaluate the success, safety, cost saving, and potential benefit of this approach in reducing late restenosis. The Comparison of PRE-Dilatation Versus Direct Stenting In Coronary Treatment using the Medtronic AVE S670 Coronary Stent System trial was a 399-patient study comparing results with the Medtronic-AVE S670 stent to objective performance criteria based on prior approved stents, with subrandomization to direct stenting versus stenting after balloon predilatation. Overall, results with the S670 stent showed excellent success and safety, with delivery success of 99%, a 14-day adverse event rate of 6.8% (including 6.5% non-Q-wave myocardial infarction), and favorable angiographic (20%) and clinical (12%) restenosis rates. Direct stenting was successful in 92% of cases, with a 99.5% secondary success rate including additional pretreatment of initially unsuccessful direct-stenting attempts, and no increase in complications. There were modest ( approximately 10%) savings in fluoroscopy time, contrast use, and a decrease in angioplasty balloon use (0.6 vs 1.3 balloons/case), but no reduction in clinical or angiographic restenosis. Patients treated later in the study, with a device that had less balloon extension beyond the edges of the stent, had slightly lower angiographic restenosis rates (19% vs 23%). In conclusion, the S670 stent showed excellent overall performance. Although direct stenting was safe and highly successful, it offered only modest cost savings, and no reduction in late restenosis compared with stenting after predilatation.

Development of a homogeneous MAP kinase reporter gene screen for the identification of agonists and antagonists at the CXCR1 chemokine receptor.

Agonist activity at G protein-coupled receptors (GPCRs) that regulate heterotrimeric G proteins of the Galpha(i/o) or Galpha(q) families has been shown to result in activation of the mitogen-activated protein (MAP) kinase cascade. To facilitate compound screening for these classes of GPCR, we have developed a reporter gene that detects the activation of the ternary complex transcription factor Sap1a following MAP kinase activation. In contrast to other reporter gene assays for Galpha(i/o)-coupled GPCRs, the MAP kinase reporter generates an increase in signal in the presence of agonist. The reporter gene has been transfected into Chinese hamster ovary cells to generate a "host" reporter gene-containing cell line. The Galpha(i)-coupled human CXCR1 chemokine receptor was subsequently transfected into this cell line in order to develop a 384-well format screen for both agonists and antagonists of this receptor. Agonists activated the reporter gene with the expected rank order of potency and with similar concentration dependence as seen with the regulation of other signal transduction cascades in mammalian cells: interleukin-8 (IL-8) (pEC(50) = 7.0 +/- 0.1) > GCP-2 (pEC(50) = 6.3 +/- 0.1) > NAP-2 (pEC(50) < 6). CXCR1-mediated activation of MAP kinase was inhibited by pertussis toxin and the MEK inhibitor PD98059, demonstrating that receptor activation of MAP kinase is due to pertussis toxin-sensitive Galpha(i/o)-family G proteins to cause the activation of MEK kinase. Using the 384-well format, assay performance was unaffected by solvent concentrations of 0.5% ethanol, 0.15% glycerol, or 1% DMSO. Signal crosstalk between adjacent wells was less than 1%. The assay exhibited a Z factor of 0.53 and a coefficient of variation of response to repeated application of IL-8 (100 nM) of 15.9%.

Final results of a randomized trial comparing the NIR stent to the Palmaz-Schatz stent for narrowings in native coronary arteries.

The NIR stent is a novel second generation tubular stent that was designed to overcome some of the limitations of the earlier Palmaz-Schatz (PS) stent design. The NIR Vascular Advanced North American (NIRVANA) trial randomized 849 patients with single coronary lesions to treatment with the NIR stent or the PS stent. The study was an "equivalency" trial, designed to demonstrate that the NIR stent was not inferior to (i.e., equivalent or better than) the PS stent, for the primary end point of target vessel failure (defined as death, myocardial infarction, or target vessel revascularization) by 9 months. Successful stent delivery was achieved in 100% versus 98.8%, respectively, with a slightly lower postprocedural diameter stenosis (7% vs. 9%, p = 0.04) after NIR and PS stent placement, respectively. Major adverse cardiac events (death, myocardial infarction, repeat target lesion revascularization) were not different at 30 days (4.3% vs. 4.4%). The primary end point of target vessel failure at 9 months was seen in 16.0% of NIR versus 17.2% of PS patients, with the NIR proving to be equal or superior to the PS stent (p <0.001 by test for equivalency). Angiographic restudy in 71% of a prespecified cohort showed no significant difference in restenosis (19.3% vs 22.4%). Thus, the NIR stent showed excellent deliverability with slightly better acute angiographic results and equivalent or better 9-month target vessel failure rate when compared with the PS stent.

The PARAGON stent study: a randomized trial of a new martensitic nitinol stent versus the Palmaz-Schatz stent for treatment of complex native coronary arterial lesions.

A new martensitic nitinol stent with improved flexibility and radiopacity was tested to evaluate whether these differences improve initial or long-term outcome. Patients who underwent percutaneous revascularization of a discrete native coronary lesion were randomly assigned to the new stent (PARAGON, n = 349) or to the first-generation Palmaz-Schatz (PS) stent (n = 339). The primary end point was target vessel failure at 6 months (a composite of cardiac or noncardiac death, any infarction in the distribution of the treated vessel, or clinically indicated target vessel revascularization). Secondary end points were, among others, device and procedural success and angiographic restenosis. Mean age was 62 years; diabetes was present in 21% of patients, prior bypass surgery in 6%, and recent infarction in 22% (p = NS for comparison between the 2 randomized arms). The PARAGON stent group had smaller reference vessels (2.97 vs 3.05 mm, p = 0.05), more prior restenosis (8.0% vs 4.5%, p = 0.07), and a longer average stent length (21.3 vs 19.4 mm, p < 0.05). Device success was significantly higher in the PARAGON arm (99.1% vs 94.3%, p < 0.05). Death and infarction at 6-month follow-up were infrequent in both groups. There was no significant difference in death (2.0% vs 1.2%, p = 0.546), but a higher rate of infarction for the PARAGON cohort (9.2% vs 4.7%, p = 0.025). Although target vessel failure (20.3% vs 12.4%, p = 0.005) and target lesion revascularization (12.0% vs 5.9%, p = 0.005) were higher in the PARAGON group, there was no significant difference in 6-month follow-up in in-stent minimal lumen diameter or in the rate of binary angiographic restenosis. Both PARAGON and PS stents are safe and associated with infrequent adverse events. The PARAGON stent can be delivered more frequently than the first-generation PS stent. Although there was no significant difference in in-stent minimal lumen diameter or the frequency of angiographic restenosis, clinical restenosis was more frequent in the PARAGON group.

Randomized comparison of GR-II stent and Palmaz-Schatz stent for elective treatment of coronary stenoses.

BACKGROUND: This prospective multicenter randomized clinical trial was designed to evaluate the long-term angiographic and clinical outcomes of elective treatment with the GR-II stent compared with the Palmaz-Schatz (PS) stent in patients with coronary stenoses. METHODS AND RESULTS: Seven hundred fifty-five patients with myocardial ischemia and de novo native coronary stenoses in 3- to 4-mm vessels were randomly assigned to the PS (375 patients) or the GR-II stent (380 patients). The primary end point was 12-month target lesion revascularization (TLR)-free survival. Angiography was performed at baseline and at follow-up in the first 300 consecutive patients to assess the frequency of angiographic restenosis. Procedure success was 98.5% for the GR-II stent and 99.4% for the PS stent (P:=0.19). At 30 days, patients assigned to the GR-II stent had a higher stent thrombosis rate (3.9% versus 0.3% for PS stent, P:<0.001) and TLR rate (3.9% versus 0.5% for PS stent, P:<0.001). The GR-II group had a higher follow-up restenosis frequency (47.3% versus 20.6% for the PS group, P:<0.001) and a lower 12-month TLR-free survival rate (71.7% versus 83.9% for the PS group, P:<0. 001). Multivariate logistic regression analysis identified a smaller final stent minimal lumen diameter (odds ratio [OR] 2.49, 95% CI 1. 56 to 3.98; P:<0.001), diabetes mellitus (OR 2.14, 95% CI 1.42 to 3. 22; P:<0.001), and use of the GR-II stent (OR 1.78, 95% CI 1.20 to 2. 64; P:<0.01) as independent determinants of 12-month TLR. CONCLUSIONS: On the basis of these long-term follow-up data, we conclude that use of the GR-II stent should be limited to the acute treatment of abrupt or threatened closure after failed conventional balloon angioplasty procedures.

Usefulness of stent length in predicting in-stent restenosis (the MULTI-LINK stent trials).

The cumulative experience of 4 clinical trials using the MULTI-LINK coronary stent design was analyzed. Multivariable logistic regression identified postprocedure in-stent minimum lumen diameter (p = 0.0001), stent length (p = 0.0038), smoking (p = 0.0105). and diabetes (p = 0.0803) as the most important predictors of in-stent restenosis at late (6- to 9-month) angiographic follow-up.