Behavioral and genetic evidence for a novel animal model of Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Subtype

<p>Abstract</p> <p>Background</p> <p>According to DSM-IV there are three subtypes of Attention-Deficit/Hyperactivity Disorder, namely: ADHD predominantly inattentive type (ADHD-PI), ADHD predominantly Hyperactive-Impulsive Type (ADHD-HI), and ADHD combined type (ADHD-C). These subtypes may represent distinct neurobehavioral disorders of childhood onset with separate etiologies. The diagnosis of ADHD is behaviorally based; therefore, investigations into its possible etiologies should be based in behavior. Animal models of ADHD demonstrate construct validity when they accurately reproduce elements of the etiology, biochemistry, symptoms, and treatment of the disorder. Spontaneously hypertensive rats (SHR) fulfill many of the validation criteria and compare well with clinical cases of ADHD-C. The present study describes a novel rat model of the predominantly inattentive subtype (ADHD-PI).</p> <p>Methods</p> <p>ADHD-like behavior was tested with a visual discrimination task measuring overactivity, impulsiveness and inattentiveness. Several strains with varied genetic background were needed to determine what constitutes a normal comparison. Five groups of rats were used: SHR/NCrl spontaneously hypertensive and WKY/NCrl Wistar/Kyoto rats from Charles River; SD/NTac Sprague Dawley and WH/HanTac Wistar rats from Taconic Europe; and WKY/NHsd Wistar/Kyoto rats from Harlan. DNA was analyzed to determine background differences in the strains by PCR genotyping of eight highly polymorphic microsatellite markers and 2625 single nucleotide polymorphisms (SNPs).</p> <p>Results</p> <p>Compared to appropriate comparison strains (WKY/NHsd and SD/NTac rats), SHR/NCrl showed ADHD-C-like behavior: striking overactivity and poor sustained attention. Compared to WKY/NHsd rats, WKY/NCrl rats showed inattention, but no overactivity or impulsiveness. WH/HanTac rats deviated significantly from the other control groups by being more active and less attentive than the WKY/NHsd and SD/NTac rats. We also found substantial genomic differences between the WKY/NCrl and WKY/NHsd rats for eight short tandem repeat loci and 2625 SNPs. About 33.5 percent of the genome differs between the two WKY rat substrains, with large stretches of divergence on each chromosome.</p> <p>Discussion</p> <p>These data provide solid behavioral and genetic evidence that the WKY/NCrl and WKY/NHsd rats should be considered as separate substrains. Moreover, the behavioral features of the WKY/NCrl rat indicate that it should be a useful model for ADHD-PI, the primarily inattentive subtype of ADHD. The SD/NTac and the WH/HanTac rats show significant genetic and/or behavioral differences from WKY/NHsd rats and appear not to be appropriate controls in studies using the SHR/NCrl. The present results support the conclusion that SHR/NCrl is the best validated animal model of ADHD-C. The overactivity, impulsiveness and deficient sustained attention of the SHR/NCrl strain are independent behaviors. Thus, overactivity does not account for this strain's impulsiveness and deficient sustained attention. Finally, the present study shows that great care has to be exercised to select the model and comparison groups.</p

Enhanced recovery after surgery: An opportunity to improve fractured neck of femur management

ABSTRACT INTRODUCTION Approximately 67,000 hip fractures occurred in England, Wales and Northern Ireland in 2014, and annual hospital costs for fracture are around £1.1 billion. We review the potential scope for improving length of stay (LOS). METHODS Hospital Episode Statistics data on non-elective admissions to 137 hospital trusts between November 2013 and October 2014 with a primary diagnosis of fractured neck of femur were analysed. The primary outcome was superspell LOS, which is the total LOS for all related spells for a single patient during an episode of care. Secondary outcomes were discharge to home, readmission at 28 days and in-hospital mortality. RESULTS The mean observed LOS was 22.1±3.8 days (range 12.3–33.7 days). The range for case mix-adjusted expected LOS was 21.5–24.4 days. On average, 6.7±1.5% (range 3.6%–10.9%) of patients died while in hospital, at a relative risk of in-hospital mortality of 28.2–182.9. A mean of 12.3±3.2% (range 3.9% to 23.0%) of patients were readmitted at 28 days, at a relative relative risk of 34.8–203.2. CONCLUSIONS The wide range of observed LOS in our study is unlikely to be due to the case mix, as the case mix-adjusted range of LOS is less than 3 days, but rather due to local processes and pathways. There is therefore considerable scope for quality and efficiency of care improvements in our hospitals. We propose this could be best achieved if clinicians experienced in enhanced recovery focused on FNOF pathways

Subclinical infection without encephalitis in mice following intranasal exposure to Nipah virus-Malaysia and Nipah virus-Bangladesh

BACKGROUND: Nipah virus and Hendra virus are closely related and following natural or experimental exposure induce similar clinical disease. In humans, encephalitis is the most serious outcome of infection and, hitherto, research into the pathogenesis of henipavirus encephalitis has been limited by the lack of a suitable model. Recently we reported a wild-type mouse model of Hendra virus (HeV) encephalitis that should facilitate detailed investigations of its neuropathogenesis, including mechanisms of disease recrudescence. In this study we investigated the possibility of developing a similar model of Nipah virus encephalitis. FINDINGS: Aged and young adult wild type mice did not develop clinical disease including encephalitis following intranasal exposure to either the Malaysia (NiV-MY) or Bangladesh (NiV-BD) strains of Nipah virus. However viral RNA was detected in lung tissue of mice at euthanasia (21 days following exposure) accompanied by a non-neutralizing antibody response. In a subsequent time course trial this viral RNA was shown to be reflective of an earlier self-limiting and subclinical lower respiratory tract infection through successful virus re-isolation and antigen detection in lung. There was no evidence for viremia or infection of other organs, including brain. CONCLUSIONS: Mice develop a subclinical self-limiting lower respiratory tract infection but not encephalitis following intranasal exposure to NiV-BD or NiV-MY. These results contrast with those reported for HeV under similar exposure conditions in mice, demonstrating a significant biological difference in host clinical response to exposure with these viruses. This finding provides a new platform from which to explore the viral and/or host factors that determine the neuroinvasive ability of henipaviruses

Super-Eddington accretion on to the neutron star NGC7793 P13: Broad-band X-ray spectroscopy and ultraluminous X-ray sources

We present a detailed, broad-band X-ray spectral analysis of the ultraluminous X-ray source (ULX) pulsar NGC 7793 P13, a known super-Eddington source, utilizing data from the XMM–Newton, NuSTAR and Chandra observatories. The broad-band XMM–Newton+NuSTAR spectrum of P13 is qualitatively similar to the rest of the ULX sample with broad-band coverage, suggesting that additional ULXs in the known population may host neutron star accretors. Through time-averaged, phase-resolved and multi-epoch studies, we find that two non-pulsed thermal blackbody components with temperatures ∼0.5 and 1.5 keV are required to fit the data below 10 keV, in addition to a third continuum component which extends to higher energies and is associated with the pulsed emission from the accretion column. The characteristic radii of the thermal components appear to be comparable, and are too large to be associated with the neutron star itself, so the need for two components likely indicates the accretion flow outside the magnetosphere is complex. We suggest a scenario in which the thick inner disc expected for super-Eddington accretion begins to form, but is terminated by the neutron star's magnetic field soon after its onset, implying a limit of B ≲ 6 × 1012 G for the dipolar component of the central neutron star's magnetic field. Evidence of similar termination of the disc in other sources may offer a further means of identifying additional neutron star ULXs. Finally, we examine the spectrum exhibited by P13 during one of its unusual ‘off’ states. These data require both a hard power-law component, suggesting residual accretion on to the neutron star, and emission from a thermal plasma, which we argue is likely associated with the P13 system

Animal infection studies of two recently discovered African bat paramyxoviruses, Achimota 1 and Achimota 2.

Bats are implicated as the natural reservoirs for several highly pathogenic viruses that can infect other animal species, including man. Here, we investigate the potential for two recently discovered bat rubulaviruses, Achimota virus 1 (AchPV1) and Achimota virus 2 (AchPV2), isolated from urine collected under urban bat (Eidolon helvum) roosts in Ghana, West Africa, to infect small laboratory animals. AchPV1 and AchPV2 are classified in the family Paramyxoviridae and cluster with other bat derived zoonotic rubulaviruses (i.e. Sosuga, Menangle and Tioman viruses). To assess the susceptibility of AchPV1 and AchPV2 in animals, infection studies were conducted in ferrets, guinea pigs and mice. Seroconversion, immunohistological evidence of infection, and viral shedding were identified in ferrets and guinea pigs, but not in mice. Infection was associated with respiratory disease in ferrets. Viral genome was detected in a range of tissues from ferrets and guinea pigs, however virus isolation was only achieved from ferret tissues. The results from this study indicate Achimota viruses (AchPVs) are able to cross the species barrier. Consequently, vigilance for infection with and disease caused by these viruses in people and domesticated animals is warranted in sub-Saharan Africa and the Arabian Peninsula where the reservoir hosts are present.Royal Society Wolfson research merit award. NRF-CRP grant (NRF2012NRF-CRP001-056)

Discovery of coherent pulsations from the Ultraluminous X-ray Source NGC 7793 P13

We report the detection of coherent pulsations from the ultraluminous X-ray source (ULX) NGC 7793 P13. The ≈0.42 s nearly sinusoidal pulsations were initially discovered in broadband X-ray observations using XMM-Newton and NuSTAR taken in 2016. We subsequently also found pulsations in archival XMM-Newton data taken in 2013 and 2014. The significant (≫5σ) detection of coherent pulsations demonstrates that the compact object in P13 is a neutron star, and given the observed peak luminosity of ≈10⁴⁰ erg s⁻¹ (assuming isotropy), it is well above the Eddington limit for a 1.4 M⨀ accretor. This makes P13 the second ULX known to be powered by an accreting neutron star. The pulse period varies between epochs, with a slow but persistent spin-up over the 2013–2016 period. This spin-up indicates a magnetic field of B ≈ 1.5 × 10¹² G, typical of many Galactic accreting pulsars. The most likely explanation for the extreme luminosity is a high degree of beaming; however, this is difficult to reconcile with the sinusoidal pulse profile.We would like the thank the referee for the helpful comments. M.J.M. acknowledges support from an STFC Ernest Rutherford fellowship and D.B. acknowledges financial support from the French Space Agency (CNES). This research has made use of data obtained with NuSTAR, a project led by Caltech, funded by NASA and managed by NASA/JPL, and has utilized the nustardas software package, jointly developed by the ASDC (Italy) and Caltech (USA). This research has also made use of data obtained with XMM-Newton, an ESA science mission with instruments and contributions directly funded by ESA Member States. This work made use of data supplied by the UK Swift Science Data Centre at the University of Leicester, and also made use of the XRT Data Analysis Software (XRTDAS) developed under the responsibility of the ASI Science Data Center (ASDC), Italy. This research has made use of a collection of ISIS functions (ISISscripts) provided by ECAP/Remeis observatory and MIT (http://www.sternwarte.uni-erlangen.de/isis/). Facilities: NuSTAR - The NuSTAR (Nuclear Spectroscopic Telescope Array) mission, XMM - , Swift -

A Neutralizing Human Monoclonal Antibody Protects against Lethal Disease in a New Ferret Model of Acute Nipah Virus Infection

Nipah virus is a broadly tropic and highly pathogenic zoonotic paramyxovirus in the genus Henipavirus whose natural reservoirs are several species of Pteropus fruit bats. Nipah virus has repeatedly caused outbreaks over the past decade associated with a severe and often fatal disease in humans and animals. Here, a new ferret model of Nipah virus pathogenesis is described where both respiratory and neurological disease are present in infected animals. Severe disease occurs with viral doses as low as 500 TCID50 within 6 to 10 days following infection. The underlying pathology seen in the ferret closely resembles that seen in Nipah virus infected humans, characterized as a widespread multisystemic vasculitis, with virus replicating in highly vascular tissues including lung, spleen and brain, with recoverable virus from a variety of tissues. Using this ferret model a cross-reactive neutralizing human monoclonal antibody, m102.4, targeting the henipavirus G glycoprotein was evaluated in vivo as a potential therapeutic agent. All ferrets that received m102.4 ten hours following a high dose oral-nasal Nipah virus challenge were protected from disease while all controls died. This study is the first successful post-exposure passive antibody therapy for Nipah virus using a human monoclonal antibody

The management of non-valvular atrial fibrillation (NVAF) in Australian general practice: bridging the evidence-practice gap. A national, representative postal survey

<p>Abstract</p> <p>Background</p> <p>General practitioners (GPs) are ideally placed to bridge the widely noted evidence-practice gap between current management of NVAF and the need to increase anticoagulant use to reduce the risk of fatal and disabling stroke in NVAF. We aimed to identify gaps in current care, and asked GPs to identify potentially useful strategies to overcome barriers to best practice.</p> <p>Methods</p> <p>We obtained contact details for a random sample of 1000 GPs from a national commercial data-base. Randomly selected GPs were mailed a questionnaire after an advance letter. Standardised reminders were administered to enhance response rates. As part of a larger survey assessing GP management of NVAF, we included questions to explore GPs' risk assessment, estimates of stroke risk and GPs' perceptions of the risks and benefits of anticoagulation with warfarin. In addition, we explored GPs' perceived barriers to the wider uptake of anticoagulation, quality control of anticoagulation and their assessment of strategies to assist in managing NVAF.</p> <p>Results</p> <p>596 out of 924 eligible GPs responded (64.4% response rate). The majority of GPs recognised that the benefits of warfarin outweighed the risks for three case scenarios in which warfarin is recommended according to Australian guidelines. In response to a hypothetical case scenario describing a patient with a supratherapeutic INR level of 5, 41.4% of the 596 GPs (n = 247) and 22.0% (n = 131) would be "highly likely" or "likely", respectively, to cease warfarin therapy and resume at a lower dose when INR levels are within therapeutic range. Only 27.9% (n = 166/596) would reassess the patient's INR levels within one day of recording the supratherapeutic INR. Patient contraindications to warfarin was reported to "usually" or "always" apply to the patients of 40.6% (n = 242/596) of GPs when considering whether or not to prescribe warfarin. Patient refusal to take warfarin "usually" or "always" applied to the patients of 22.3% (n = 133/596) of GPs. When asked to indicate the usefulness of strategies to assist in managing NVAF, the majority of GPs (89.1%, n = 531/596) reported that they would find patient educational resources outlining the benefits and risks of available treatments "quite useful" or "very useful". Just under two-thirds (65.2%; n = 389/596) reported that they would find point of care INR testing "quite" or "very" useful. An outreach specialist service and training to enable GPs to practice stroke medicine as a special interest were also considered to be "quite" or "very useful" by 61.9% (n = 369/596) GPs.</p> <p>Conclusion</p> <p>This survey identified gaps, based on GP self-report, in the current care of NVAF. GPs themselves have provided guidance on the selection of implementation strategies to bridge these gaps. These results may inform future initiatives designed to reduce the risk of fatal and disabling stroke in NVAF.</p

Genome Sequence Conservation of Hendra Virus Isolates during Spillover to Horses, Australia

Bat-to-horse transmission of Hendra virus has occurred at least 14 times. Although clinical signs in horses have differed, genome sequencing has demonstrated little variation among the isolates. Our sequencing of 5 isolates from recent Hendra virus outbreaks in horses found no correlation between sequences and time or geographic location of outbreaks

Establishment, Immortalisation and Characterisation of Pteropid Bat Cell Lines

BACKGROUND: Bats are the suspected natural reservoir hosts for a number of new and emerging zoonotic viruses including Nipah virus, Hendra virus, severe acute respiratory syndrome coronavirus and Ebola virus. Since the discovery of SARS-like coronaviruses in Chinese horseshoe bats, attempts to isolate a SL-CoV from bats have failed and attempts to isolate other bat-borne viruses in various mammalian cell lines have been similarly unsuccessful. New stable bat cell lines are needed to help with these investigations and as tools to assist in the study of bat immunology and virus-host interactions. METHODOLOGY/FINDINGS: Black flying foxes (Pteropus alecto) were captured from the wild and transported live to the laboratory for primary cell culture preparation using a variety of different methods and culture media. Primary cells were successfully cultured from 20 different organs. Cell immortalisation can occur spontaneously, however we used a retroviral system to immortalise cells via the transfer and stable production of the Simian virus 40 Large T antigen and the human telomerase reverse transcriptase protein. Initial infection experiments with both cloned and uncloned cell lines using Hendra and Nipah viruses demonstrated varying degrees of infection efficiency between the different cell lines, although it was possible to infect cells in all tissue types. CONCLUSIONS/SIGNIFICANCE: The approaches developed and optimised in this study should be applicable to bats of other species. We are in the process of generating further cell lines from a number of different bat species using the methodology established in this study