Historical Mammal Extinction on Christmas Island (Indian Ocean) Correlates with Introduced Infectious Disease

It is now widely accepted that novel infectious disease can be a leading cause of serious population decline and even outright extinction in some invertebrate and vertebrate groups (e.g., amphibians). In the case of mammals, however, there are still no well-corroborated instances of such diseases having caused or significantly contributed to the complete collapse of species. A case in point is the extinction of the endemic Christmas Island rat (Rattus macleari): although it has been argued that its disappearance ca. AD 1900 may have been partly or wholly caused by a pathogenic trypanosome carried by fleas hosted on recently-introduced black rats (Rattus rattus), no decisive evidence for this scenario has ever been adduced. Using ancient DNA methods on samples from museum specimens of these rodents collected during the extinction window (AD 1888–1908), we were able to resolve unambiguously sequence evidence of murid trypanosomes in both endemic and invasive rats. Importantly, endemic rats collected prior to the introduction of black rats were devoid of trypanosome signal. Hybridization between endemic and black rats was also previously hypothesized, but we found no evidence of this in examined specimens, and conclude that hybridization cannot account for the disappearance of the endemic species. This is the first molecular evidence for a pathogen emerging in a naïve mammal species immediately prior to its final collapse

Communication and control system for a 15-channel hermetic retinal prosthesis

A small, hermetic, wirelessly-controlled retinal prosthesis has been developed for pre-clinical studies in Yucatan minipigs. The device was attached conformally to the outside of the eye in the socket and received both power and data wirelessly from external sources. Based on the received image data, the prosthesis drove a subretinal thin-film polyimide array of sputtered iridium oxide stimulating electrodes. The implanted device included a hermetic titanium case containing a 15-channel stimulator and receiver chip and discrete circuit components. Feedthroughs in the hermetic case connected the chip to secondary power- and data-receiving coils, which coupled to corresponding external power and data coils driven by power amplifiers. Power was delivered by a 125 kHz carrier, and data were delivered by amplitude shift keying of a 15.5 MHz carrier at 100 kbps. Stimulation pulse strength, duration and frequency were programmed wirelessly from an external computer system. The final assembly was tested in vitro in physiological saline and in vivo in two minipigs for up to five and a half months by measuring stimulus artifacts generated by the implant's current drivers.United States. Dept. of Veteran AffairsUnited states. Dept. of Veterans Affairs. Boston Healthcare SystemNational Institutes of Health (U.S.)United States. Dept. of DefenseMassachusetts Lions Foundatio

A randomised placebo-controlled Phase III multicentre trial: low-dose intravenous immunoglobulin treatment for long-standing complex regional pain syndrome (LIPS trial)

BACKGROUND: Complex regional pain syndrome (CRPS) is a rare, severe post-traumatic pain condition affecting distal limbs. Patients who do not spontaneously improve in 12 months are classed as having ‘long-standing CRPS’ and often cannot be effectively treated, leading to a poor prognosis. CRPS is associated with functional autoantibodies. Two small trials, including a randomised controlled trial, have suggested that low-dose intravenous immunoglobulin (IVIg) may be an effective treatment for some patients. OBJECTIVE: We hypothesised that low-dose IVIg is effective for reducing pain in long-standing CRPS. METHODS: A randomised, double blinded placebo-controlled multicentre trial in seven UK pain management centres. Patients were eligible if they had moderate or severe long-standing CRPS that they had experienced for up to 5 years. Participants were randomly allocated to receive 0.5 g/kg IVIg, the active intervention, or visually indistinguishable 0.1% albumin in saline placebo. Randomisation was initiated by study sites via an independent online randomisation system and was 1 : 1 with varying block sizes, stratified by study centre. Participants, investigators and assessors were blinded to group assignment. The study drug/placebo was infused intravenously at the study centres on day 1 and day 23 after randomisation. The primary outcome was the 24-hour average pain intensity between day 6 and day 42, on an 11-point (0–10) numeric rating scale, compared between the groups. Outcomes were analysed using a mixed-effects regression model that used 37 measurements of pain intensity (the primary outcome) per participant. All patients who received an infusion and provided any outcome were included in the intention-to-treat analysis. RESULTS: A total of 111 patients were recruited and assigned between 27 August 2013 and 28 October 2015. Three patients were excluded because they had been inappropriately randomised, five patients were withdrawn from the primary analysis because they provided no outcomes and 103 patients were analysed for the primary outcome. The average pain score in the IVIg group was 0.27 units (95% confidence interval –0.24 to 0.80 units) higher than in the placebo group. Therefore, there is no significant evidence of a treatment effect at the 5% level and there was no significant difference between groups. Six serious adverse events but no suspected unexpected serious adverse reactions were reported during the blinded and open-label phase. CONCLUSION AND FUTURE WORK: Low-dose immunoglobulin was not effective in relieving pain in patients with moderate to severe CRPS of 1–5 years’ duration. Better drug treatments for long-standing CRPS are urgently required. TRIAL REGISTRATION: Current Controlled Trials ISRCTN42179756. FUNDING: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership. Additional funding was obtained by the Pain Relief Foundation. Biotest UK Ltd provided the active study medication at no cost

The low level of debris disk activity at the time of the Late Heavy Bombardment: a Spitzer study of Praesepe

We present 24 micron photometry of the intermediate-age open cluster Praesepe. We assemble a catalog of 193 probable cluster members that are detected in optical databases, the Two Micron All Sky Survey (2MASS), and at 24 micron, within an area of ~ 2.47 square degrees. Mid-IR excesses indicating debris disks are found for one early-type and for three solar-type stars. Corrections for sampling statistics yield a 24 micron excess fraction (debris disk fraction) of 6.5 +- 4.1% for luminous and 1.9 +- 1.2% for solar-type stars. The incidence of excesses is in agreement with the decay trend of debris disks as a function of age observed for other cluster and field stars. The values also agree with those for older stars, indicating that debris generation in the zones that emit at 24 micron falls to the older 1-10 Gyr field star sample value by roughly 750 Myr. We discuss our results in the context of previous observations of excess fractions for early- and solar-type stars. We show that solar-type stars lose their debris disk 24 micron excesses on a shorter timescale than early-type stars. Simplistic Monte Carlo models suggest that, during the first Gyr of their evolution, up to 15-30% of solar-type stars might undergo an orbital realignment of giant planets such as the one thought to have led to the Late Heavy Bombardment, if the length of the bombardment episode is similar to the one thought to have happened in our Solar System. In the Appendix, we determine the cluster's parameters via boostrap Monte Carlo isochrone fitting, yielding an age of 757 Myr (+- 36 Myr at 1 sigma confidence) and a distance of 179 pc (+- 2 pc at 1 sigma confidence), not allowing for systematic errors.Comment: 22 pages, 14 figures, 9 tables, emulateapj format; Accepted for publication in The Astrophysical Journa

Investigating the generalisation of an atlas-based synthetic-CT algorithm to another centre and MR scanner for prostate MR-only radiotherapy

There is increasing interest in MR-only radiotherapy planning since it provides superb soft-tissue contrast without the registration uncertainties inherent in a CT–MR registration. However, MR images cannot readily provide the electron density information necessary for radiotherapy dose calculation. An algorithm which generates synthetic CTs for dose calculations from MR images of the prostate using an atlas of 3 T MR images has been previously reported by two of the authors. This paper aimed to evaluate this algorithm using MR data acquired at a different field strength and a different centre to the algorithm atlas. Twenty-one prostate patients received planning 1.5 T MR and CT scans with routine immobilisation devices on a flat-top couch set-up using external lasers. The MR receive coils were supported by a coil bridge. Synthetic CTs were generated from the planning MR images with (sCT₁v) and without (sCT) a one voxel body contour expansion included in the algorithm. This was to test whether this expansion was required for 1.5 T images. Both synthetic CTs were rigidly registered to the planning CT (pCT). A 6 MV volumetric modulated arc therapy plan was created on the pCT and recalculated on the sCT and sCT₁v. The synthetic CTs' dose distributions were compared to the dose distribution calculated on the pCT. The percentage dose difference at isocentre without the body contour expansion (sCT–pCT) was ΔDsCT = (0.9 \pm 0.8)% and with sCT₁v–pCT was ΔDsCT₁v = (-0.7 \pm 0.7)% (mean  ±  one standard deviation). The sCT₁v result was within one standard deviation of zero and agreed with the result reported previously using 3 T MR data. The sCT dose difference only agreed within two standard deviations. The mean  ±  one standard deviation gamma pass rate was ΓsCT = 96.1 \pm 2.9% for the sCT and ΓsCT₁v = 98.8 \pm 0.5% for the sCT₁v (with 2% global dose difference and 2mm distance to agreement gamma criteria). The one voxel body contour expansion improves the synthetic CT accuracy for MR images acquired at 1.5 T but requires the MR voxel size to be similar to the atlas MR voxel size. This study suggests that the atlas-based algorithm can be generalised to MR data acquired using a different field strength at a different centre

The Carnegie Supernova Project: First Near-Infrared Hubble Diagram to z~0.7

The Carnegie Supernova Project (CSP) is designed to measure the luminosity distance for Type Ia supernovae (SNe Ia) as a function of redshift, and to set observational constraints on the dark energy contribution to the total energy content of the Universe. The CSP differs from other projects to date in its goal of providing an I-band {rest-frame} Hubble diagram. Here we present the first results from near-infrared (NIR) observations obtained using the Magellan Baade telescope for SNe Ia with 0.1 < z < 0.7. We combine these results with those from the low-redshift CSP at z <0.1 (Folatelli et al. 2009). We present light curves and an I-band Hubble diagram for this first sample of 35 SNe Ia and we compare these data to 21 new SNe Ia at low redshift. These data support the conclusion that the expansion of the Universe is accelerating. When combined with independent results from baryon acoustic oscillations (Eisenstein et al. 2005), these data yield Omega_m = 0.27 +/- 0.0 (statistical), and Omega_DE = 0.76 +/- 0.13 (statistical) +/- 0.09 (systematic), for the matter and dark energy densities, respectively. If we parameterize the data in terms of an equation of state, w, assume a flat geometry, and combine with baryon acoustic oscillations, we find that w = -1.05 +/- 0.13 (statistical) +/- 0.09 (systematic). The largest source of systematic uncertainty on w arises from uncertainties in the photometric calibration, signaling the importance of securing more accurate photometric calibrations for future supernova cosmology programs. Finally, we conclude that either the dust affecting the luminosities of SNe Ia has a different extinction law (R_V = 1.8) than that in the Milky Way (where R_V = 3.1), or that there is an additional intrinsic color term with luminosity for SNe Ia independent of the decline rate.Comment: 44 pages, 23 figures, 9 tables; Accepted for publication in the Astrophysical Journa

HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV

It is well established that HIV-1 infection typically involves an interaction between the viral envelope protein gp120/41 and the CD4 molecule followed by a second interaction with a chemokine receptor, usually CCR5 or CXCR4. In the early stages of an HIV-1 infection CCR5 using viruses (R5 viruses) predominate. In some viral subtypes there is a propensity to switch to CXCR4 usage (X4 viruses). The receptor switch occurs in ~ 40% of the infected individuals and is associated with faster disease progression. This holds for subtypes B and D, but occurs less frequently in subtypes A and C. There are several hypotheses to explain the preferential transmission of R5 viruses and the mechanisms that lead to switching of co-receptor usage; however, there is no definitive explanation for either. One important consideration regarding transmission is that signaling by R5 gp120 may facilitate transmission of R5 viruses by inducing a permissive environment for HIV replication. In the case of sexual transmission, infection by HIV requires the virus to breach the mucosal barrier to gain access to the immune cell targets that it infects; however, the immediate events that follow HIV exposure at genital mucosal sites are not well understood. Upon transmission, the HIV quasispecies that is replicating in an infected donor contracts through a “genetic bottleneck”, and often infection results from a single infectious event. Many details surrounding this initial infection remain unresolved. In mucosal tissues, CD4+ T cells express high levels of CCR5, and a subset of these CD4+/CCR5high cells express the integrin α4β7, the gut homing receptor. CD4+/CCR5high/ α4β7high T cells are highly susceptible to infection by HIV-1 and are ideal targets for an efficient productive infection at the point of transmission. In this context we have demonstrated that the HIV-1 envelope protein gp120 binds to α4β7 on CD4+ T cells. On CD4+/CCR5high/ α4β7high T cells, α4β7 is closely associated with CD4 and CCR5. Furthermore, α4β7 is ~3 times the size of CD4 on the cell surface, that makes it a prominent receptor for an efficient virus capture. gp120-α4β7 interactions mediate the activation of the adhesion-associated integrin LFA-1. LFA-1 facilitates the formation of virological synapses and cell-to-cell spread of HIV-1. gp120 binding to α4β7 is mediated by a tripeptide located in the V1/V2 domain of gp120. Of note, the V1/V2 domain of gp120 has been linked to variations in transmission fitness among viral isolates raising the intriguing possibility that gp120-α4β7 interactions may be linked to transmission fitness. Although many details remain unresolved, we hypothesize that gp120-α4β7 interactions play an important role in the very early events following sexual transmission of HIV and may have important implication in the design of vaccine strategies for the prevention of acquisition of HIV infectio