Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials.

BackgroundInhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF.MethodsTwo pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations.ResultsNo infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.ConclusionsThese two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment.Trial registrationCLINICALTRIALS.GOV: Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013

Immunology of naturally transmissible tumours.

Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonize a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, canine transmissible venereal tumour (CTVT), which spreads among dogs, and devil facial tumour disease (DFTD), among Tasmanian devils. CTVT are generally not fatal as a tumour-specific host immune response controls or clears the tumours after transmission and a period of growth. In contrast, the growth of DFTD tumours is not controlled by the Tasmanian devil's immune system and the disease causes close to 100% mortality, severely impacting the devil population. To avoid the immune response of the host both DFTD and CTVT use a variety of immune escape strategies that have similarities to many single organism tumours, including MHC loss and the expression of immunosuppressive cytokines. However, both tumours appear to have a complex interaction with the immune system of their respective host, which has evolved over the relatively long life of these tumours. The Tasmanian devil is struggling to survive with the burden of this disease and it is only with an understanding of how DFTD passes between individuals that a vaccine might be developed. Further, an understanding of how these tumours achieve natural transmissibility should provide insights into general mechanisms of immune escape that emerge during tumour evolution.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/imm.1237

HIFI spectroscopy of low-level water transitions in M82

We present observations of the rotational ortho-water ground transition, the two lowest para-water transitions, and the ground transition of ionised ortho-water in the archetypal starburst galaxy M82, performed with the HIFI instrument on the Herschel Space Observatory. These observations are the first detections of the para-H2O(111-000) (1113\,GHz) and ortho-H2O+(111-000) (1115\,GHz) lines in an extragalactic source. All three water lines show different spectral line profiles, underlining the need for high spectral resolution in interpreting line formation processes. Using the line shape of the para-H2O(111-000) and ortho-H2O+(111-000) absorption profile in conjunction with high spatial resolution CO observations, we show that the (ionised) water absorption arises from a ~2000 pc^2 region within the HIFI beam located about ~50 pc east of the dynamical centre of the galaxy. This region does not coincide with any of the known line emission peaks that have been identified in other molecular tracers, with the exception of HCO. Our data suggest that water and ionised water within this region have high (up to 75%) area-covering factors of the underlying continuum. This indicates that water is not associated with small, dense cores within the ISM of M82 but arises from a more widespread diffuse gas component.Comment: 5 pages, 4 figures. Accepted for publication in A&

HIFI observations of warm gas in DR21: Shock versus radiative heating

The molecular gas in the DR21 massive star formation region is known to be affected by the strong UV field from the central star cluster and by a fast outflow creating a bright shock. The relative contribution of both heating mechanisms is the matter of a long debate. By better sampling the excitation ladder of various tracers we provide a quantitative distinction between the different heating mechanisms. HIFI observations of mid-J transitions of CO and HCO+ isotopes allow us to bridge the gap in excitation energies between observations from the ground, characterizing the cooler gas, and existing ISO LWS spectra, constraining the properties of the hot gas. Comparing the detailed line profiles allows to identify the physical structure of the different components. In spite of the known shock-excitation of H2 and the clearly visible strong outflow, we find that the emission of all lines up to > 2 THz can be explained by purely radiative heating of the material. However, the new Herschel/HIFI observations reveal two types of excitation conditions. We find hot and dense clumps close to the central cluster, probably dynamically affected by the outflow, and a more widespread distribution of cooler, but nevertheless dense, molecular clumps.Comment: Accepted for publication by A&

Born-Oppenheimer Approximation near Level Crossing

We consider the Born-Oppenheimer problem near conical intersection in two dimensions. For energies close to the crossing energy we describe the wave function near an isotropic crossing and show that it is related to generalized hypergeometric functions 0F3. This function is to a conical intersection what the Airy function is to a classical turning point. As an application we calculate the anomalous Zeeman shift of vibrational levels near a crossing.Comment: 8 pages, 1 figure, Lette

The Born Oppenheimer wave function near level crossing

The standard Born Oppenheimer theory does not give an accurate description of the wave function near points of level crossing. We give such a description near an isotropic conic crossing, for energies close to the crossing energy. This leads to the study of two coupled second order ordinary differential equations whose solution is described in terms of the generalized hypergeometric functions of the kind 0F3(;a,b,c;z). We find that, at low angular momenta, the mixing due to crossing is surprisingly large, scaling like \mu^(1/6), where \mu is the electron to nuclear mass ratio.Comment: 21 pages, 7 figure

HIFI spectroscopy of low-level water transitions in M82

We present observations of the rotational ortho-water ground transition, the two lowest para-water transitions, and the ground transition of ionised ortho-water in the archetypal starburst galaxy M82, performed with the HIFI instrument on the Herschel Space Observatory. These observations are the first detections of the para-H2O(111-000) (1113\,GHz) and ortho-H2O+(111-000) (1115\,GHz) lines in an extragalactic source. All three water lines show different spectral line profiles, underlining the need for high spectral resolution in interpreting line formation processes. Using the line shape of the para-H2O(111-000) and ortho-H2O+(111-000) absorption profile in conjunction with high spatial resolution CO observations, we show that the (ionised) water absorption arises from a ~2000 pc^2 region within the HIFI beam located about ~50 pc east of the dynamical centre of the galaxy. This region does not coincide with any of the known line emission peaks that have been identified in other molecular tracers, with the exception of HCO. Our data suggest that water and ionised water within this region have high (up to 75%) area-covering factors of the underlying continuum. This indicates that water is not associated with small, dense cores within the ISM of M82 but arises from a more widespread diffuse gas component.Comment: 5 pages, 4 figures. Accepted for publication in A&

Peak effect, vortex-lattice melting-line and order - disorder transition in conventional and high-T superconductors

We investigate the order - disorder transition line from a Bragg glass to an amorphous vortex glass in the H-T phase diagram of three-dimensional type-II superconductors with account of both pinning-caused and thermal fluctuations of the vortex lattice. Our approach is based on the Lindemann criterion and on results of the collective pinning theory and generalizes previous work of other authors. It is shown that the shapes of the order - disorder transition line and the vortex lattice melting curve are determined only by the Ginzburg number, which characterizes thermal fluctuations, and by a parameter which describes the strength of the quenched disorder in the flux-line lattice. In the framework of this unified approach we obtain the H-T phase diagrams for both conventional and high-Tc superconductors. Several well-known experimental results concerning the fishtail effect and the phase diagram of high-Tc superconductors are naturally explained by assuming that a peak effect in the critical current density versus H signalizes the order - disorder transition line in superconductors with point defects.Comment: 15 pages including 11 figure

Stable isotopic composition of fossil mammal teeth and environmental change in southwestern South Africa during the Pliocene and Pleistocene

The past 5 million years mark a global change from the warmer, more stable climate of the Pliocene to the initiation of glacial-interglacial cycles during the Pleistocene. Marine core sediment records located off the coast of southwestern Africa indicate aridification and intensified upwelling in the Benguela Current over the Pliocene and Pleistocene. However, few terrestrial records document environmental change in southwestern Africa over this time interval. Here we synthesize new and published carbon and oxygen isotope data of the teeth from large mammals (>6 kg) at Langebaanweg (~5 million years ago, Ma), Elandsfontein (1.0 – 0.6 Ma), and Hoedjiespunt (0.35 – 0.20 Ma), to evaluate environmental change in southwestern Africa between the Pliocene and Pleistocene. The majority of browsing and grazing herbivores from these sites yield enamel 13 C values within the range expected for animals with a pure C3 diet, however some taxa have enamel 13C values that suggest the presence of small amounts C4 grasses at times during the Pleistocene. Considering that significant amounts of C4 grasses require a warm growing season, these results indicate that the winter rainfall zone, characteristic of the region today, could have been in place for the past 5 million years. The average 18O value of the herbivore teeth increases ~4.4‰ between Langebaanweg and Elandsfontein for all taxa except suids. This increase may solely be a function of a change in hydrology between the fluvial system at Langebaanweg and the spring-fed environments at Elandsfontein, or a combination of factors that include depositional context, regional circulation and global climate. However, an increase in regional aridity or global cooling between the early Pliocene and mid-Pleistocene cannot explain the entire increase in enamel 18O values. Spring-fed environments like those at Elandsfontein may have 75 provided critical resources for mammalian fauna in the mid-Pleistocene within an increasingly arid southwestern Africa ecosystem

Professionalism, Golf Coaching and a Master of Science Degree: A commentary

As a point of reference I congratulate Simon Jenkins on tackling the issue of professionalism in coaching. As he points out coaching is not a profession, but this does not mean that coaching would not benefit from going through a professionalization process. As things stand I find that the stimulus article unpacks some critically important issues of professionalism, broadly within the context of golf coaching. However, I am not sure enough is made of understanding what professional (golf) coaching actually is nor how the development of a professional golf coach can be facilitated by a Master of Science Degree (M.Sc.). I will focus my commentary on these two issues