Vocal and tongue exercise in early to mid-stage Parkinson disease using the Pink1-/- rat.

Vocal and swallowing deficits are common in Parkinson disease (PD). Because these impairments are resistant to dopamine replacement therapies, vocal and lingual exercise are the primary treatment, but not all individuals respond to exercise and neural mechanisms of treatment response are unclear. To explore putative mechanisms, we used the progressive Pink1-/- rat model of early to mid-stage PD and employed vocal and lingual exercises at 6- and 10-months of age in male Pink1-/- and wild type (WT) rats. We hypothesized that vocal and lingual exercise would improve vocal and tongue use dynamics and increase serotonin (5HT) immunoreactivity in related brainstem nuclei. Rats were tested at baseline and after 8 weeks of exercise or sham exercise. At early-stage PD (6 months), vocal exercise resulted in increased call complexity, but did not change intensity, while at mid-stage (10 months), vocal exercise no longer influenced vocalization complexity. Lingual exercise increased tongue force generation and reduced relative optical density of 5HT in the hypoglossal nucleus at both time points. The effects of vocal and lingual exercise at these time points are less robust than in prodromal stages observed in previous work, suggesting that early exercise interventions may yield greater benefit. Future work targeting optimization of exercise at later time points may facilitate clinical translation.

The Poultry Red Mite, Dermanyssus gallinae, travels far but not frequently, and takes up permanent residence on farms.

Management of Dermanyssus gallinae, a cosmopolitan hematophagous mite responsible for damage in layer poultry farming, is hampered by a lack of knowledge of its spatio-temporal population dynamics. Previous studies have shown that the circulation of this pest between farms is of strictly anthropogenic origin, that a mitochondrial haplogroup has been expanding on European farms since the beginning of the 21st century and that its local population growth may be particularly rapid. To refine our understanding of how D. gallinae spreads within and among farms, we characterized the genetic structure of mite populations at different spatial scales and sought to identify the main factors interrupting gene flow between poultry houses and between mitochondrial haplogroups. To this end, we selected and validated the first set of nuclear microsatellite markers for D. gallinae and sequenced a region of the CO1-encoding mitochondrial gene in a subsample of microsatellite-genotyped mites. We also tested certain conditions required for effective contamination of a poultry house through field experimentation, and conducted a survey of practices during poultry transfers. Our results confirm the role of poultry transport in the dissemination of mite populations, but the frequency of effective contamination after the introduction of contaminated material into poultry houses seems lower than expected. The high persistence of mites on farms, even during periods when poultry houses are empty and cleaned, and the very large number of nodes in the logistic network (large number of companies supplying pullets or transporting animals) undoubtedly explain the very high prevalence on farms. Substantial genetic diversity was measured in farm populations, probably as a result of the mite's known haplodiploid mode of sexual reproduction, coupled with the dense logistic network. The possibility of the occasional occurrence of asexual reproduction in this sexually reproducing mite was also revealed in our analyses, which could explain the extreme aggressiveness of its demographic dynamics under certain conditions.

Robust phase determination in complex solid solutions using diffuse multiple scattering.

A novel methodology is presented for identifying and distinguishing between structural phases in multi-phasic systems, such as piezoelectric materials like PMN-PT [Pb(Mg1/3Nb2/3)O3-PbTiO3], PIN-PMN-PT [Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3] and PZT [Pb(Zr,Ti)O3], using diffuse multiple scattering and Kossel line diffraction techniques. The method exploits the splitting of triple line intersections from special coplanar reflections combined with logical constraints to generate a splitting fingerprint for robust crystallographic phase determination and discrimination.

Measuring behaviour in hens using an ethogram to assess analgesia during further refinement of a high welfare, on-hen, poultry red mite feeding device.

Background: To refine an on-hen mite feeding device, an ethogram was employed to measure the reactions of hens during a routine experimental procedure (feather plucking) and to assess effects of analgesic cream on those reactions. Methods: Three experimental groups were used; one treated with EMLA 5% before plucking ("EMLA group"); one with aqueous cream ("placebo group") and a "no treatment" group. Behaviours were measured and compared on three days: 'dummy handling day' i.e. no plucking; 'plucking day', plucking the left thigh; and 'treatment day' i.e with right thighs plucked post-treatment. Poultry red mite feeding assays were performed to examine effect of creams on mite feeding rates, mortality and fecundity. All data were analysed using generalised linear (mixed) modelling approaches. Results: Use of the ethogram demonstrated no significant difference in hen behaviours in the EMLA group between dummy handling day and treatment day (p = 0.949) alongside a significant reduction in measured behaviours between plucking day and treatment day in the same group (p = 0.028). There was a statistically significant increase in measured behaviours from the dummy handling day to the plucking day in both placebo (p = 0.011) and no treatment group (p < 0.001). Effect sizes and directions were similar between dummy handling and treatment days in the 'placebo' and 'no treatment' groups, though not statistically significant (placebo, p = 0.064; no treatment p = 0.069). Mite feeding in the EMLA group was significantly lower than in the no treatment group in feeding assay 1 (p = 0.029) only. Mite mortality and fertility were unaffected. Conclusions: The ethogram successfully measured changes in observed behaviours between the dummy handling session and procedures. No adverse effects of EMLA cream on hens were demonstrated at 3mg/kg in hens. Use of analgesia for this routine procedure improves hens' experiences during experimental trials.

The role of experts in the development of recovery handbooks: UK and European experience.

The importance of involving experts in the development of strategies for managing areas contaminated as a result of a nuclear accident is now well recognised. Following the Chernobyl accident in 1986, the initial focus, quite understandably, was on the technical aspects of reducing doses to the affected population. Subsequently, work carried out in the UK and elsewhere in Europe looked at the broader impacts of protective actions on agriculture, the environment, and society. From 1997, a group of experts from academia, government, and non-government organisations met regularly in the UK to debate these issues. One of the outputs included the first version of the UK Recovery Handbook for Radiation Incidents in 2005. Based on the success of the UK group, a European network of experts was established, leading to the development of European handbooks in 2009. The UK handbooks are living documents that are updated regularly with substantive input from experts.

Microscope cover-slip glass for TLD applications.

As a result of the various evolving needs, thermoluminescence dosimetry is constantly under development, with applications intended in environmental and personal radiation monitoring through to the sensing of radiotherapy and radiation processing doses. In radiotherapy dosimetry challenges include small-field profile evaluation, encompassing the fine beams of radiosurgery, evaluations confronting the steep dose gradients of electronic brachytherapy and the high dose rates of FLASH radiotherapy. Current work concerns the thermoluminescent dosimetric properties of commercial low-cost borosilicate glass in the form of thin (sub-mm to a few mm) plates, use being made of microscope cover-slips irradiated using clinical external-beam radiotherapy facilities as well as through use of 60Co gamma irradiators. In using megavoltage photons and MeV electrons, characterization of the dosimetric response has been made for cover-slips of thicknesses up to 4 mm. Reproducibility to within +/5% has been obtained. In particular, for doses up to 10 Gy, the borosilicate cover-slips have been demonstrated to have considerable potential for use in high spatial resolution radiotherapy dosimetry, down to 0.13 mm in present work, with a coefficient of determination in respect of linearity of >0.99 for the thinner cover-slips. Results are also presented for 0.13- and 1.00-mm thick cover slips irradiated to 60Co gamma-ray doses, initially in the range 5- to 25 Gy, subsequently extended to 5 kGy-25 kGy, again providing linear response.

The stability of imaging biomarkers in radiomics: a framework for evaluation.

This paper studies the sensitivity of a range of image texture parameters used in radiomics to: (i) the number of intensity levels, (ii) the method of quantisation to select the intensity levels and (iii) the use of an intensity threshold. 43 commonly used texture features were studied for the gross target volume outlined on the CT component of PET/CT scans of 50 patients with non-small cell lung carcinoma (NSCLC). All cases were quantised for all values between 4 and 128 intensity levels using four commonly used quantisation methods. All results were analysed with and without a threshold range of -200 HU to 300 HU. Cases were ranked for each texture feature and for all quantisation methods with the Spearman's rank correlation coefficient determined to evaluate stability. Results showed large fluctuations in ranking, particularly for low numbers of levels, differences between quantisation methods and with the use of a threshold, with values Spearman's Rank Correlation for many parameters below 0.2. Our results demonstrated the sensitivity of radiomics features to the parameters used during analysis and highlight the risk of low reproducibility comparing studies with slightly different parameters. In terms of the lung cancer CT datasets, this study supports the use of 128 intensity levels, the same uniform quantiser applied to all scans and thresholding of the data. It also supports several of the features recommended in the literature for such studies such as skewness and kurtosis. A recommended framework is presented for curation of the data analysis process to ensure stability of results.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) mimics: the knot unravelled by cardiovascular MRI.

AIM: To assess the role of cardiovascular magnetic resonance imaging (CMRI) in patients referred for suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), its ability to identify ARVC mimics, and subsequent clinical impact. MATERIALS AND METHODS: The CMRI registry of the year 2014 was analysed to identify all consecutive patients referred for suspected ARVC. A comprehensive CMRI protocol that included anatomy, bi-ventricular function modules, and late gadolinium enhancement (LGE) was performed in all patients. RESULTS: Out of 2,481 CMRI performed, 124 patients (5%) were referred for suspected ARVC. A pathological substrate was identified at CMRI in 36 patients (29%): five patients (4%) had ischaemic heart disease (IHD) and 10 (8%) non-IHD; five patients (4%) met CMRI criteria for ARVC and 16 (13%) were ARVC mimics. right ventricular end-diastolic volume (RVEDV) and right ventricular stroke volume (RVSV) were significantly higher in patients with ARVC mimics (RVEDV p=0.007, RVSV p=0.012) and ARVC (RVEDV p=0.013, RVSV p=0.013), as compared to those with structurally normal hearts. CMRI was superior to echocardiography in the identification of ARVC mimics (13% versus 1%, p=0.01). CONCLUSIONS: CMRI was able to identify 16 (13%) ARVC mimics, from congenital abnormalities to acquired heart disease. CMRI was superior in identifying ARVC mimics compared to echocardiography, and overall provided a change in diagnosis in 22% of patients.

High sensitivity organic inorganic hybrid X-ray detectors with direct transduction and broadband response.

X-ray detectors are critical to healthcare diagnostics, cancer therapy and homeland security, with many potential uses limited by system cost and/or detector dimensions. Current X-ray detector sensitivities are limited by the bulk X-ray attenuation of the materials and consequently necessitate thick crystals (~1 mm-1 cm), resulting in rigid structures, high operational voltages and high cost. Here we present a disruptive, flexible, low cost, broadband, and high sensitivity direct X-ray transduction technology produced by embedding high atomic number bismuth oxide nanoparticles in an organic bulk heterojunction. These hybrid detectors demonstrate sensitivities of 1712 µC mGy-1 cm-3 for "soft" X-rays and ~30 and 58 µC mGy-1 cm-3 under 6 and 15 MV "hard" X-rays generated from a medical linear accelerator; strongly competing with the current solid state detectors, all achieved at low bias voltages (-10 V) and low power, enabling detector operation powered by coin cell batteries.

Band Filling Control of the Dzyaloshinskii-Moriya Interaction in Weakly Ferromagnetic Insulators.

We observe and explain theoretically a dramatic evolution of the Dzyaloshinskii-Moriya interaction (DMI) in the series of isostructural weak ferromagnets, MnCO_{3}, FeBO_{3}, CoCO_{3}, and NiCO_{3}. The sign of the interaction is encoded in the phase of the x-ray magnetic diffraction amplitude, observed through interference with resonant quadrupole scattering. We find very good quantitative agreement with first-principles electronic structure calculations, reproducing both sign and magnitude through the series, and propose a simplified "toy model" to explain the change in sign with 3d shell filling. The model gives insight into the evolution of the DMI in Mott and charge transfer insulators.

Diagnostic yield of cardiovascular magnetic resonance in young-middle aged patients with high-grade atrio-ventricular block.

BACKGROUND: Atrio-ventricular block (AVB) is a rare finding in young or middle-aged adults, often leading to pacemaker implantation (PM) without further investigation. We sought to assess the diagnostic role of cardiovascular magnetic resonance (CMR) in young and middle-aged adults with high-grade AVB. METHODS: We consecutively enrolled young-middle aged (18-65years) patients with high grade AVB referred to CMR after standard clinical assessment (history, electrocardiogram and cardiac rhythm monitoring) prior to PM implantation. Cine and post-contrast imaging were performed in a 1.5T scanner. RESULTS: 34 patients (59% male, mean age 42±12years) with high grade AVB were referred to CMR for suspected ischemic heart disease (IHD)(n=4) and non-ischemic heart disease (NIHD)(n=20); no clear cause was found in 9 patients prior to CMR and 1 patient had suspected lung disease. A pathologic substrate was found on CMR in 15 patients (44%), while a structurally normal heart was reported in 18 (53%). Non-specific findings were reported in 1 patient (3%). There was a fair agreement between CMR and echocardiographic findings (Cohen's kappa 0.243), and CMR provided an entirely new diagnosis in 34% of patients. As compared to the standard clinical assessment, CMR had an additional role in 65% of patients and guided further testing (genetic testing, extra-cardiac imaging) in 9%. CONCLUSIONS: CMR found a pathologic substrate in 44% of patients, mainly NIHD (32%). Half of the patients (53%) had a structurally normal heart. When added to the standard clinical assessment, CMR had an incremental diagnostic role in two thirds of patients.

Out of hospital cardiac arrest survivors with inconclusive coronary angiogram: Impact of cardiovascular magnetic resonance on clinical management and decision-making.

BACKGROUND: Non-traumatic out of hospital cardiac arrest (OHCA) is the leading cause of death worldwide, mainly due to acute coronary syndromes. Urgent coronary angiography with view to revascularisation is recommended in patients with suspected acute coronary syndrome. Diagnosis and management of patients with inconclusive coronary angiogram (unobstructed coronaries or unidentified culprit lesion) is challenging. We sought to assess the role of Cardiovascular Magnetic Resonance (CMR) in the diagnosis and management of OHCA survivors with an inconclusive coronary angiogram. METHODS AND RESULTS: This is a retrospective multicentre CMR registry analysis of OHCA survivors with an inconclusive angiogram. Clinical, ECG and multi-modality imaging data were analysed. Clinical impact of CMR was defined as a change in diagnosis or management. Out of 174 OHCA survivors referred for CMR, 110 patients (63%, 84 male, median age 58) had an inconclusive angiogram. CMR identified a pathologic substrate in 76/110 patients (69%): ischemic heart disease was found in 45 (41%) and non-ischemic heart disease in 31 (28%). A structurally normal heart was found in 25 patients (23%) and non-specific findings in 9 (8%). As compared to trans-thoracic echocardiogram, CMR proved to be superior in identifying a pathologic substrate (69% vs 54%, p=0.018). The CMR study carried a clinical impact in 70% of patients, determining a change in diagnosis in 25%, in management in 29% and a change in both in 16%. CONCLUSIONS: CMR showed a promising role in the diagnostic work-up of OHCA survivors with inconclusive angiogram and its wider use should be considered.

Challenges in calculation of the gamma index in radiotherapy - Towards good practice.

The gamma index (γ) is one of the most commonly used metrics for the verification of complex modulated radiotherapy. The mathematical definition of the γ is computationally expensive and various techniques have been reported to speed up the calculation either by mathematically refining the γ or employing various computational techniques. These techniques can cause variation in output with different software implementations. The γ has traditionally been used to compare a 2D measured plane against a 2D or 3D dose distribution. Recently, software algorithm and hardware improvements have led to the possibility of using measured 2D data from commercial detector arrays to reconstruct a 3D-dose distribution and perform a volumetric comparison against the treatment planning system (TPS). A limitation in this approach is that commercial detector arrays have so far been limited by their spatial resolution which may affect the accuracy of the reconstructed 3D volume and subsequently the γ calculation. Additionally, 3D versus 3D γ comparison adds a layer of complication in the calculation of the γ given the increase in the number of calculation points and the result cannot be as easily interpreted in the same way as 2D comparison. This review summarises and highlights the computational challenges of the γ calculation and sheds light on some of these issues by means of a bespoke MATLAB software to demonstrate the impact of interpolation, γ search distance, resolution and 2D and 3D calculations. Finally, a recommendation is made on the minimum information that should be reported when publishing γ results.

Adapting clinical gamma cameras for body monitoring in the event of a large-scale radiological incident.

After a release of radionuclides, accidental or otherwise, there will be an urgent need to identify members of the general public who have received a significant intake of radioactive material, sufficient to require medical treatment or further investigation. A large number of people could be contaminated in such an incident. For gamma-ray emitting radionuclides this screening could be carried out using gamma camera medical imaging systems, such as those that are present in many large UK hospital sites. By making a number of simple reversible changes such as removal of collimators, these cameras could be employed as useful additional screening instruments as well as an aid in contamination control. A study was carried out to investigate which systems were present in sufficient number to offer wide scale coverage of UK population centres. Nine gamma cameras (eight dual head and one single head) were assessed using point source and bottle mannequin (BOMAB) phantom measurements so that a mathematical model could be developed for use with the MCNPX Monte Carlo radiation transport code. The gamma camera models were assessed for practical seated and supine geometries to give calibration factors for a list of target radionuclides that could be released in a radiological incident. The minimum detectable activities (MDAs) that were achieved for a five minute measurement demonstrated that these systems are sufficiently sensitive to be used for screening of the general public and are comparable to other body monitoring facilities. While gamma cameras have on-board software that are designed for imaging and provide for a gamma-ray energy range suitable for radionuclides for diagnostic imaging (such as 99mTc), they are not as versatile as custom-built body monitoring systems.

Immunity to Haemonchus contortus and Vaccine Development.

Sheep are capable of developing protective immunity to Haemonchus contortus through repeated exposure to this parasite, although this immune protection is the result of a complex interaction among age, gender, physiological status, pregnancy, lactation, nutrition and innate and adaptive immunity in the host animal. There are multiple effectors of the protective immune response, which differ depending on the developmental stage of the parasite being targeted, and our understanding of the effector mechanisms has developed considerably in the 2000s. The rational design of vaccines based on 'natural' or 'exposed' antigens depends on an understanding of this exposure-induced immunity. However, the most effective current vaccines rely on protection via the induction of high circulating antibody levels to 'hidden' gut antigens of H. contortus. The success of this latter strategy has resulted in the launch of a vaccine, which is based on extracts of the parasite's gut, to aid in the control of Haemonchus in Australia. The development of recombinant subunit vaccines based on the components of the successful native vaccine has not yet been achieved and most of the recent successes with recombinant subunit vaccines have focussed on antigens unrelated to the gut antigens. The future integration of an understanding of the immunobiology of this parasite with advances in antigen identification, expression (or synthesis) and presentation is likely to be pivotal to the further development of these recombinant subunit vaccines. Recent progress in each of the components underpinning this integrated approach is summarized in this review.

Changes in Patterns of Intensity-modulated Radiotherapy Verification and Quality Assurance in the UK.

AIMS: Between 2012 and 2014 the number of patients treated in the UK with intensity-modulated radiotherapy (IMRT) techniques increased significantly. One reason for this was the radiotherapy innovation fund for the centres in England. Before the announcement of the fund, a survey of radiotherapy centres was carried out in 2012 which collected data on IMRT uptake, obstacles to implementation, equipment used, delivery techniques and verification methods. A repeat survey was carried out in 2014 to identify key changes to IMRT quality assurance and verification practices. MATERIALS AND METHODS: An online questionnaire was sent out to all 65 UK radiotherapy centres in the summer of 2012 and again in the summer of 2014. Questions covered background and equipment, machine tolerance and quality assurance, machine-based verification, software-based verification and future plans. RESULTS: There have been significant changes in the delivery techniques used for IMRT, with more than twice as many centres reporting the use of volumetric-modulated arc therapy techniques in 2014 compared with 2012. This has been combined with an increase in Monte Carlo-based algorithms in treatment planning systems. In 2012 all centres reported the need to carry out machine-based measurements for IMRT plan verification, dropping to 93% in 2014. Nineteen per cent of centres now report making only one measurement per month for prostate plans and 8% of breast plans never have physical measurements. Most centres use detector arrays for quality assurance measurement (86% in 2012 and 91% in 2014), but a significant number still use film and/or ionisation chambers (51% and 41%). In the analysis of these measurements there has been an increase in the use of tighter criteria. There has been a significant increase in the use of software for verification from 63% in 2012 to 95% in 2014. All centres reported that they needed further resources in order to efficiently achieve the quality assurance required for the number of patients planned to be treated in their centre. CONCLUSIONS: The increased numbers of patients being treated with IMRT has meant that there have been significant changes in the way that quality assurance is carried out. These have been mainly in the reduction of measurements and the increase in software-based verification. However, quality assurance is still a significant burden and still has an effect on the numbers of patients who can be treated with IMRT.

Decision making for late-phase recovery from nuclear or radiological incidents: new guidance from NCRP.

In 2010, the US National Council on Radiation Protection and Measurements (NCRP) established a scientific committee (SC5-1) to prepare a comprehensive report on the framework and approach for optimising decision making in late-phase recovery from nuclear or radiological incidents that lead to wide-area contamination. The NCRP report builds on recommendations from the International Commission on Radiological Protection's (ICRP) Publication 111 which specifically addresses the protection of people living in long-term contaminated areas. Based on this approach, the report addresses all relevant dimensions: health, environment, economic, psychological, cultural, ethical, and political. NCRP, like ICRP, considers optimisation to be the best approach to decision making for balancing these multiple risk factors in situations involving wide-area contamination where the conventional clean-up approach may encounter some serious constraints. The NCRP report describes optimisation as an iterative process that can be broken down into a series of steps, all of which involve deliberations with stakeholders as a necessary element for a community-focused recovery effort. The steps, elaborated on in the report, range from defining the situation to a series of actions involving assessing impacts, evaluating options, developing a strategy, and demonstrating its successful implementation. In conclusion, the NCRP report makes a series of recommendations aimed at enhancing and strengthening late-phase recovery following a major nuclear or radiological incident.

Molecular approaches to differentiate three species of Nematodirus in sheep and goats from China based on internal transcribed spacer rDNA sequences.

Internal transcribed spacer (ITS) rDNA sequences of three Nematodirus species from naturally infected goats or sheep in two endemic provinces of China were analysed to establish an effective molecular approach to differentiate Nematodirus species in small ruminants. The respective intra-specific genetic variations in ITS1 and ITS2 rDNA regions were 0.3-1.8% and 0-0.4% in N. spathiger, 0-6.5% and 0-5.4% in N. helvetianus, and 0-4.4% and 0-6.1% in N. oiratianus from China. The respective intra-specific variations of ITS1 and ITS2 were 1.8-4.4% and 1.6-6.1% between N. oiratianus isolates from China and Iran, 5.7-7.1% and 6.3-8.3% between N. helvetianus samples from China and America. For N. spathiger, compared with samples from China, sequence differences in ITS1 rDNA were 0.3-2.4% in isolates from America, 0.3-2.9% in New Zealand and 2.1-2.4% in Australia. Genetic variations in ITS2 rDNA of N. spathiger were 0-0.4% between samples from China and America, and 0-0.8% between samples from China and New Zealand. Using mutation sites, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and specific PCR techniques were developed to differentiate these three Nematodirus species. The specific PCR assay allowed the accurate identification of N. oiratianus from other common nematodes with a sensitivity of 0.69 pg and further examination of Nematodirus samples demonstrated the reliability of these two molecular methods.

Diffuse multiple scattering.

A new form of diffraction lines has been identified, similar to Rutherford, Kikuchi and Kossel lines. This paper highlights some of the properties of these lines and shows how they can be used to eliminate the need for sample/source matching in Lonsdale's triple convergent line method in lattice-parameter determination.