An assessment of the effects of neurokinin₁ receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development.

A ‘broad-spectrum’ anti-vomiting effect of neurokinin1 receptor antagonists (NK1RA), shown in preclinical animal studies, has been supported by a more limited range of clinical studies in different indications. However, this review suggests that compared with vomiting, the self-reported sensation of nausea is less affected or possibly unaffected (depending on the stimulus) by NK1 receptor antagonism, a common finding for ‘anti-emetics’. The stimulus-independent effects of NK1RAs against vomiting are explicable by actions within the central pattern generator (CPG; ventral brainstem) and the nucleus tractus solitarius (NTS; dorsal brainstem), with additional effects on vagal afferent activity for certain stimuli (e.g., highly emetogenic chemotherapy). The CPG and NTS neurones are multifunctional so the notable lack of obvious effects of NK1RAs on other reflexes mediated by the same neurones suggests that their anti-vomiting action is dependent on the activation state of the pathway leading to vomiting. Nausea requires activation of cerebral pathways by projection of information from the NTS. Although NK1 receptors are present in cerebral nuclei implicated in nausea, and imaging studies show very high receptor occupancy at clinically used doses, the variable or limited ability of NK1RAs to inhibit nausea emphasises (a) our inadequate understanding of the mechanisms of nausea and (b) that classification of a drug as an “anti-emetic” may give a false impression of efficacy against nausea versus vomiting. We discuss the potential mechanisms for the differential efficacy of NK1RA and the implications for future development of drugs which can effectively treat nausea, an area of unmet clinical need

High power diode laser Master Oscillator-Power Amplifier (MOPA)

High power multiple quantum well AlGaAs diode laser master oscillator - power amplifier (MOPA) systems were examined both experimentally and theoretically. For two pass operation, it was found that powers in excess of 0.3 W per 100 micrometers of facet length were achievable while maintaining diffraction-limited beam quality. Internal electrical-to-optical conversion efficiencies as high as 25 percent were observed at an internal amplifier gain of 9 dB. Theoretical modeling of multiple quantum well amplifiers was done using appropriate rate equations and a heuristic model of the carrier density dependent gain. The model gave a qualitative agreement with the experimental results. In addition, the model allowed exploration of a wider design space for the amplifiers. The model predicted that internal electrical-to-optical conversion efficiencies in excess of 50 percent should be achievable with careful system design. The model predicted that no global optimum design exists, but gain, efficiency, and optical confinement (coupling efficiency) can be mutually adjusted to meet a specific system requirement. A three quantum well, low optical confinement amplifier was fabricated using molecular beam epitaxial growth. Coherent beam combining of two high power amplifiers injected from a common master oscillator was also examined. Coherent beam combining with an efficiency of 93 percent resulted in a single beam having diffraction-limited characteristics. This beam combining efficiency is a world record result for such a system. Interferometric observations of the output of the amplifier indicated that spatial mode matching was a significant factor in the less than perfect beam combining. Finally, the system issues of arrays of amplifiers in a coherent beam combining system were investigated. Based upon experimentally observed parameters coherent beam combining could result in a megawatt-scale coherent beam with a 10 percent electrical-to-optical conversion efficiency

Modelling asset management of railway overhead line equipment

The overhead line equipment (OLE) is a critical sub-system of the 25kV AC overhead railway electrification system. There is a need to evaluate OLE asset management strategies through a whole life cost analysis that considers degradation processes and maintenance activities of the OLE components so that the investment required to deliver the level of performance desired by railway customers and regulators can be based on evidence from modelling results. A Petri Net model is proposed to simulate the degradation, failure, inspection and maintenance of the main OLE components and to calculate various statistics associated with the cost and reliability of the system over its whole life. The Petri Net considers all the main OLE components in one model and can simulate both fixed interval and risk based maintenance regimes. To allow such processes to be modelled accurately and efficiently, High Level Petri Net features are used. The model developed is the first of its kind, in such detail, for OLE and the applicability of Petri Nets for modelling many processes on a large system, containing numerous components, is shown

An ALMA Constraint on the GSC 6214-210 B Circum-Substellar Accretion Disk Mass

We present Atacama Large Millimeter/submillimeter Array (ALMA) observations of GSC 6214-210 A and B, a solar-mass member of the 5-10 Myr Upper Scorpius association with a 15 $\pm$ 2 Mjup companion orbiting at $\approx$330 AU (2.2"). Previous photometry and spectroscopy spanning 0.3-5 $\mu$m revealed optical and thermal excess as well as strong H$\alpha$ and Pa~$\beta$ emission originating from a circum-substellar accretion disk around GSC 6214-210 B, making it the lowest mass companion with unambiguous evidence of a subdisk. Despite ALMA's unprecedented sensitivity and angular resolution, neither component was detected in our 880 $\mu$m (341 GHz) continuum observations down to a 3-$\sigma$ limit of 0.22 mJy/beam. The corresponding constraints on the dust mass and total mass are <0.15 Mearth and <0.05 Mjup, respectively, or <0.003% and <0.3% of the mass of GSC 6214-210 B itself assuming a 100:1 gas-to-dust ratio and characteristic dust temperature of 10-20 K. If the host star possesses a putative circum-stellar disk then at most it is a meager 0.0015% of the primary mass, implying that giant planet formation has certainly ceased in this system. Considering these limits and its current accretion rate, GSC 6214-210 B appears to be at the end stages of assembly and is not expected to gain any appreciable mass over the next few Myr.Comment: Accepted to ApJ

11-12 Gyr Old White Dwarfs 30 Pc Away

We present a detailed model atmosphere analysis of two of the oldest stars known in the solar neighbourhood, the high proper motion white dwarfs SDSS J110217.48+411315.4 (hereafter J1102) and WD 0346+246 (hereafter WD0346). We present trigonometric parallax observations of J1102, which places it at a distance of only 33.7 ± 2.0 pc. Based on the state-of-the-art model atmospheres, optical, near-infrared, mid-infrared photometry and distances, we constrain the temperatures, atmospheric compositions, masses and ages for both stars. J1102 is an 11-Gyr-old (white dwarf plus main-sequence age), 0.62 M⊙ white dwarf with a pure H atmosphere and Teff= 3830 K. WD0346 is an 11.5-Gyr-old, 0.77 M⊙ white dwarf with a mixed H/He atmosphere and Teff= 3650 K. Both stars display halo kinematics and their ages agree remarkably well with the ages of the nearest globular clusters, M4 and NGC 6397. J1102 and WD0346 are the closest examples of the oldest halo stars that we know of

Microwave Spectroscopy

Contains reports on four research projects.Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DA 36-039-AMC-03200(E

Protoplanetary Disk Masses in the Young NGC 2024 Cluster

We present the results from a Submillimeter Array survey of the 887 micron continuum emission from the protoplanetary disks around 95 young stars in the young cluster NGC 2024. Emission was detected from 22 infrared sources, with flux densities from ~5 to 330 mJy; upper limits (at 3sigma) for the other 73 sources range from 3 to 24 mJy. For standard assumptions, the corresponding disk masses range from ~0.003 to 0.2Msolar, with upper limits at 0.002--0.01Msolar. The NGC 2024 sample has a slightly more populated tail at the high end of its disk mass distribution compared to other clusters, but without more information on the nature of the sample hosts it remains unclear if this difference is statistically significant or a superficial selection effect. Unlike in the Orion Trapezium, there is no evidence for a disk mass dependence on the (projected) separation from the massive star IRS2b in the NGC 2024 cluster. We suggest that this is due to either the cluster youth or a comparatively weaker photoionizing radiation field.Comment: ApJ, in pres

ALMA Observations of the Largest Proto-Planetary Disk in the Orion Nebula, 114-426: A CO Silhouette

We present ALMA observations of the largest protoplanetary disk in the Orion Nebula, 114-426. Detectable 345 GHz (856 micron) dust continuum is produced only in the 350 AU central region of the ~1000 AU diameter silhouette seen against the bright H-alpha background in HST images. Assuming optically thin dust emission at 345 GHz, a gas-to-dust ratio of 100, and a grain temperature of 20 K, the disk gas-mass is estimated to be 3.1 +/- 0.6 Jupiter masses. If most solids and ices have have been incorporated into large grains, however, this value is a lower limit. The disk is not detected in dense-gas tracers such as HCO+ J=4-3, HCN J=4-3, or CS =7-6. These results may indicate that the 114-426 disk is evolved and depleted in some light organic compounds found in molecular clouds. The CO J=3-2 line is seen in absorption against the bright 50 to 80 K background of the Orion A molecular cloud over the full spatial extent and a little beyond the dust continuum emission. The CO absorption reaches a depth of 27 K below the background CO emission at VLSR ~6.7 km/s about 0.52 arcseconds (210 AU) northeast and 12 K below the background CO emission at VLSR ~ 9.7 km/s about 0.34 arcseconds (140 AU) southwest of the suspected location of the central star, implying that the embedded star has a mass less than 1 Solar mass .Comment: 20 pages, 4 figure