bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaural time and level interaction under free-field conditions
Authors: Rakerd Brad , Macaulay Eric J. , Hartmann William M.
Published: October 2015

Listeners judged the azimuthal location of sine tones presented in free field from an array of 25 small loudspeakers uniformly spaced over 180 degrees in the forward half of the horizontal plane. Probe microphones in the listener's ear canals recorded the tones, and transaural synthesis was used to reverse the interaural time difference (ITD) or the interaural level difference (ILD) across the mid-sagittal plane. Alternatively, the synthesis maintained the natural, consistent ITD and ILD. In the frequency range of 1000 Hz and below, localization judgments reflected the ITD, even as the interaural phase difference (IPD) surpassed 180 degrees with increasing azimuth or frequency, as long as the ILD and ITD had the same sign. In the reversed condition, and with small IPD, judgments reflected a compromise between ITD and ILD, with the ILD weight increasing with increasing frequency. But when the IPD exceeded a critical angle (about 120 degrees of phase) the influence of the ITD dramatically changed: Above 500 Hz, the localization judgments were consistent with ITD from a slipped cycle. At 500 Hz, judgments became chaotic. No critical angle occurred at 250 Hz. These conclusions are relevant in assessing the roles of interaural differences in sound localization. [Work supported by the AFOSR.]
Nonlinear ultrasonic technique for closed crack detection
Authors: Jhang Kyung-Young , Seo Hogeon
Published: October 2015

The detection of cracks at the early stage of fracture is important in industrial structures in order to guarantee their structural safety. Ultrasound has been widely utilized in the field of nondestructive testing of materials. However, most of these conventional methods using ultrasonic characteristics in the linear elastic region are mostly sensitive to opened cracks but much less sensitive to such closed cracks. The nonlinear ultrasonic technique (NUT) based on the contact acoustic nonlinearity (CAN) has been considered as a promising method for the closed crack detection. However, most of the previous studies were limited to the modeling of the second-order harmonic wave generation at contacted interfaces and its verification by testing artificially contacted interfaces in the through-transmission method. In this study, we investigated experimentally the contact acoustic nonlinearity at a real crack by using the measurement system constructed in the reflection mode that permits the transducers to access the only single side of a test structure. Results showed that the magnitude of the second-order harmonic wave represented the existence of the closed area clearly and that the crack sizing performance was greatly improved by the combination of the linear and nonlinear ultrasonic techniques.
Acoustic response of a multipurpose auditorium at Grand Valley State University
Authors: Groendyke Bailey , Gipson Karen
Published: October 2015

Like many multipurpose auditoriums, the Louis Armstrong Theatre (LAT) at Grand Valley State University has been reported by a considerable number of students and faculty to have unsatisfactory acoustics for music performance. This study focused on physical measurements and simulated changes to LAT. Reverberation time (RT) was measured by filling LAT with sound and measuring the decay for select frequencies as per ASTM E2235 protocol, and the initial time delay gap (ITDG) was determined using slapsticks as an impulsive sound source. A model of LAT was also constructed from blueprints and physical measurements; simulations using this model were conducted using Odeon. Data from the physical measurements as well as the simulation confirmed that the RTs over a wide range of frequencies were smaller than desired for music, whereas ITDG measurements showed prevalent spurious reflections. Modifications to the model were made to increase reverberation time and reduce undesirable reflections in order to improve LAT for musical performance without compromising its functionality for speech.
Vibration damping and isolation using negative stiffness structures
Authors: Haberman Michael R. , Seepersad Carolyn C. , Wilson Preston S.
Published: October 2015

This work presents a novel class of engineered structures with significant promise to improve vibration damping treatments and isolation systems: negative stiffness (NS) elements. A mechanical system displaying negative stiffness is characterized by a loading state that requires a decreasing force level to increase the deformation of the system. Systems displaying NS will possess regions of negative curvature in their strain energy response as a function of deformation; hence, they are unstable when unconstrained. Analytical and experimental results will be presented demonstrating that NS systems comprised of buckled beams in parallel with positive stiffness springs can be used to construct quasi-zero stiffness vibration isolation systems, which provide high static but low dynamic stiffness for compact base isolation design. Transmissibility measurements of these same systems show that the nonlinearity of NS systems constructed from buckled beam structures enable tunable vibration isolation behavior and isolation from impact. Finally, modeling results will be presented demonstrating that sub-wavelength NS elements embedded in a viscoelastic material can be used to design vibration damping treatments with increased loss factor and minimally reduced stiffness to reduce the ringdown time for an impulsively loaded multi-layered beam. [Work supported by DARPA, ARO, and NSF.]
Robust plane-wave decomposition of spherical microphone array recordings for binaural sound reproduction
Authors: Alon David L. , Sheaffer Jonathan , Rafaely Boaz
Published: October 2015

Rendering binaural signals from spherical microphone recordings is becoming an increasingly popular approach, with applications in telecommunications, virtual acoustics, hearing science, and entertainment. Such binaural signals can be generated from a plane-wave decomposition of a sound field measured by a spherical microphone array. This process may exhibit ill-conditioned transformations when performed at low frequencies and using high spherical-harmonics orders, thus resulting in a poor robustness to measurement inaccuracies and noise. Previous studies have addressed this issue by employing standard regularization techniques, such as diagonal loading and radial filter limiting. In this paper, we propose an optimal frequency-dependent regularization method that balances system robustness to measurement noise against accuracy of plane-wave decomposition. Unlike previously suggested approaches, the proposed method analytically relates the measured signal-to-noise ratio to the corresponding regularization parameters, hence facilitating a means for controlling the regularization process using a closed-form expression. The method is compared to previously suggested regularization techniques in terms of spatial, temporal, and spectral effects on the resulting binaural signals. Objective results, which illustrate the improved performance of the proposed method, are complemented with a subjective validation of the regularized signals.
Speaking rate variability in spontaneous productions by non-native speakers
Authors: Morrill Tuuli , Baese-Berk Melissa
Published: October 2015

Most research examining differences between native and non-native speech measures mean differences at the segmental level. Some work has examined non-segmental characteristics of speech such as speaking rate; however, this work has also typically examined only mean differences. In the present study, we ask whether within-speaker variability, in addition to mean differences, characterizes differences between non-native and native speech. Specifically, we examine speaking rate in spontaneous productions by both native and non-native speakers of English. Preliminary work suggests that rate change across utterances in read productions of non-native speech is more variable than in read productions of native speech (Baese-Berk and Morrill, 2014, Indianapolis ASA). However, it is possible that read speech contains sources of variability that are specific to processing difficulties during reading. In the present study, we examine native speakers of Korean and Mandarin producing spontaneous speech in English and compare their speech to both native speakers of English, and read productions by these same non-native speakers. We measure mean speaking rate within utterances, as well as the amount of rate change (slowing or speeding up of speaking rate) from utterance to utterance. Results will contribute to an understanding of the role of variability in non-native speech production.
Rethinking the Social Value of Sport Events Through an Asset-Based Community Development (ABCD) Perspective
Authors: Misener Laura , Schulenkorf Nico
Published: October 2015

With an increasing emphasis on the social value of sport and events, there has been a shift in focus regarding the management and development process of event projects as well as their associated outcomes. This shift is about emphasizing a more strategic approach to developing social benefits by recognizing and utilizing leverageable resources related to sport events as a means of fostering lasting social and economic change (Chalip, 2006; O’Brien & Chalip, 2007; Schulenkorf & Edwards, 2012). In this paper, we adapt and apply the asset-based community development (ABCD) approach as a means of developing a more action-oriented, community-based approach to leveraging the social assets of sporting events. In applying the ABCD approach, we aim to shift the focus of event-led projects away from attempts to “solve” social problems (i.e., deficit perspective) to enhancing the existing strengths of communities (i.e., strengths perspective). We reflect on case study findings that highlight the challenges and opportunities in realizing an ABCD approach for disadvantaged communities through an examination of a healthy lifestyle community event initiative in the Pacific Islands.
Past and future rainfall in the Horn of Africa
Authors: Tierney Jessica E. , Ummenhofer Caroline C. , deMenocal Peter B.
Published: October 2015

Paleoclimate data suggest that the Horn of Africa will become drier under global warming, in contrast to model projections.
Striga
uses a hypersensitive receptor
Authors: Hines Pamela J.
Published: October 2015

Features of the ligand-binding pocket explain how a parasitic plant receptor is exquisitely sensitive to host plant hormones.
Clearing up psoriasis
Authors: Marson Alexander
Published: October 2015

Two clinical studies confirm benefits of targeting the interleukin-17 pathway for psoriasis treatment.
DNA methylation: A link between genome variation and blood pressure
Authors: Suzuki Masako
Published: October 2015

A very large genome-wide association study suggests a role for DNA methylation in blood pressure regulation.
Premethylation of Foreign DNA Improves Integrative Transformation Efficiency in Synechocystis sp. Strain PCC 6803
Authors: Wang Bo , Yu Jianping , Zhang Weiwen , Meldrum Deirdre R.
Published: October 2015

Restriction digestion of foreign DNA is one of the key biological barriers against genetic transformation in microorganisms. To establish a high-efficiency transformation protocol in the model cyanobacterium,Synechocystissp. strain PCC 6803 (Synechocystis6803), we investigated the effects of premethylation of foreign DNA on the integrative transformation of this strain. In this study, two type II methyltransferase-encoding genes, i.e.,sll0729(geneM) andslr0214(geneC), were cloned from the chromosome ofSynechocystis6803 and expressed inEscherichia coliharboring an integration plasmid. After premethylation treatment inE. coli, the integration plasmid was extracted and used for transformation ofSynechocystis6803. The results showed that although expression of methyltransferase M had little impact on the transformation ofSynechocystis6803, expression of methyltransferase C resulted in 11- to 161-fold-higher efficiency in the subsequent integrative transformation ofSynechocystis6803. Effective expression of methyltransferase C, which could be achieved by optimizing the 5′ untranslated region, was critical to efficient premethylation of the donor DNA and thus high transformation efficiency inSynechocystis6803. Since premethylating foreign DNA prior to transformingSynechocystisavoids changing the host genetic background, the study thus provides an improved method for high-efficiency integrative transformation ofSynechocystis6803.
Virulence-Associated Enzymes of Cryptococcus neoformans
Authors: Almeida Fausto , Wolf Julie M. , Casadevall Arturo
Published: October 2015

Enzymes play key roles in fungal pathogenesis. Manipulation of enzyme expression or activity can significantly alter the infection process, and enzyme expression profiles can be a hallmark of disease. Hence, enzymes are worthy targets for better understanding pathogenesis and identifying new options for combatting fungal infections. Advances in genomics, proteomics, transcriptomics, and mass spectrometry have enabled the identification and characterization of new fungal enzymes. This review focuses on recent developments in the virulence-associated enzymes from
Cryptococcus neoformans
. The enzymatic suite of
C. neoformans
has evolved for environmental survival, but several of these enzymes play a dual role in colonizing the mammalian host. We also discuss new therapeutic and diagnostic strategies that could be based on the underlying enzymology.
A New Quaternary Structure Epitope on Dengue Virus Serotype 2 Is the Target of Durable Type-Specific Neutralizing Antibodies
Authors: Gallichotte E. N. , Widman D. G. , Yount B. L. , Wahala W. M. , Durbin A. , Whitehead S. , Sariol C. A. , Crowe J. E. , de Silva A. M. , Baric R. S.
Published: October 2015

Dengue virus serotype 2 (DENV2) is widespread and responsible for severe epidemics. While primary DENV2 infections stimulate serotype-specific protective responses, a leading vaccine failed to induce a similar protective response. Using human monoclonal antibodies (hMAbs) isolated from dengue cases and structure-guided design of a chimeric DENV, here we describe the major site on the DENV2 envelope (E) protein targeted by neutralizing antibodies. DENV2-specific neutralizing hMAb 2D22 binds to a quaternary structure epitope. We engineered and recovered a recombinant DENV4 that displayed the 2D22 epitope. DENV2 neutralizing antibodies in people exposed to infection or a live vaccine tracked with the 2D22 epitope on the DENV4/2 chimera. The chimera remained sensitive to DENV4 antibodies, indicating that the major neutralizing epitopes on DENV2 and -4 are at different sites. The ability to transplant a complex epitope between DENV serotypes demonstrates a hitherto underappreciated structural flexibility in flaviviruses, which could be harnessed to develop new vaccines and diagnostics.

IMPORTANCE
Dengue virus causes fever and dengue hemorrhagic fever. Dengue serotype 2 (DENV2) is widespread and frequently responsible for severe epidemics. Natural DENV2 infections stimulate serotype-specific neutralizing antibodies, but a leading DENV vaccine did not induce a similar protective response. While groups have identified epitopes of single monoclonal antibodies (MAbs), the molecular basis of DENV2 neutralization by polyclonal human immune sera is unknown. Using a recombinant DENV displaying serotype 2 epitopes, here we map the main target of DENV2 polyclonal neutralizing antibodies induced by natural infection and a live DENV2 vaccine candidate. Proper display of the epitope required the assembly of viral envelope proteins into higher-order structures present on intact virions. Despite the complexity of the epitope, it was possible to transplant the epitope between DENV serotypes. Our findings have immediate implications for evaluating dengue vaccines in the pipeline as well as designing next-generation vaccines.
Activities to support the implementation of complex interventions as part of routine care: a review of the quality of reporting in cluster randomised controlled trials
Authors: McMahon Naoimh E , Holland Emma-Joy , Miller Colette , Patel Kulsum , Connell Louise A
Published: October 2015

Objective

To review a sample of cluster randomised controlled trials and explore the quality of reporting of (1) enabling or support activities provided to the staff during the trial, (2) strategies used to monitor fidelity throughout the trial and (3) the extent to which the intervention being tested was delivered as planned.

Design

A descriptive review.

Data sources and study selection

We searched MEDLINE for trial reports published between 2008 and 2014 with combinations of the search terms ‘randomised’, ‘cluster’, ‘trial’, ‘study’, ‘intervention’ and ‘implement*’. We included trials in which healthcare professionals (HCPs) implemented the intervention being tested as part of routine practice. We excluded trials (1) conducted in non-health services settings, (2) where the intervention explicitly aimed to change the behaviours of the HCPs and (3) where the trials were ongoing or for which only trial protocols were available.

Data collection

We developed a data extraction form using the Template for Intervention Description and Replication (TIDieR checklist). Review authors independently extracted data from the included trials and assessed quality of reporting for individual items.

Results

We included 70 publications (45 results publications, 25 related publications). 89% of trials reported using enabling or support activities. How these activities were provided (75.6%, n=34) and how much was provided (73.3%, n=33) were the most frequently reported items. Less than 20% (n=8) of the included trials reported that competency checking occurred prior to implementation and data collection. 64% (n=29) of trials reported collecting measures of implementation. 44% (n=20) of trials reported data from these measures.

Conclusions

Although enabling and support activities are reported in trials, important gaps exist when assessed using an established checklist. Better reporting of the supports provided in effectiveness trials will allow for informed decisions to be made about financial and resource implications for wide scale implementation of effective interventions.
Patient safety climate strength: a concept that requires more attention
Authors: Ginsburg Liane , Gilin Oore Debra
Published: October 2015

Background

When patient safety climate (PSC) surveys are used in healthcare, reporting typically focuses on PSClevel(mean or per cent positive scores). This paper explores how an additional focus on PSCstrengthcan enhance the utility of PSC survey data.

Setting and participants

442 care providers from 24 emergency departments (EDs) across Canada.

Methods

We use anonymised data from theCan-PSCSPSC instrument collected in 2011 as part of the Qmentum accreditation programme. We examine differences in climate strength across EDs using the Rwg(j) and intraclass correlation coefficients measures of inter-rater agreement.

Results

Across the six survey dimensions, median Rwg(j) was sufficiently high to support shared climate perceptions (0.64–0.83), but varied widely across the 24 ED units. We provide an illustrative example showing vastly different climatestrength(Rwg(j) range=0.17–0.86) for units with an equivalentlevelof PSC (eg, climate mean score=3).

Conclusions

Most PSC survey results focus solely on climate level. To facilitate improvement in PSC, we advocate a simple, holisticsafety climate profileincluding three metrics: climatelevel(using mean or per cent positive climate scores), climatestrength(using the Rwg(j), or SD as a proxy) and theshapeof the distribution (using histograms to see the distribution of scores within units). In PSC research, we advocate paying attention to climate strength as an important variable in its own right. Focusing on PSC level and strength can further understanding of the extent to which PSC is a key variable in the domain of patient safety.
LONG-TERM SAFETY OF ALEMTUZUMAB IN RELAPSING-REMITTING MULTIPLE SCLEROSIS: PREGNANCY AND INFECTION DATA FROM A COHORT OF PATIENTS ON OPEN LABEL STUDIES IN CAMBRIDGE
Authors: McCarthy Claire , Tuohy Orla , Azzopardi Laura , Kousin-Ezewu Onajite , Jones Joanne , Compston Alastair , Coles Alasdair
Published: October 2015

Background

Alemtuzumab is recently licensed for use in active relapsing-remitting multiple sclerosis (RRMS) in Europe and the USA. This observational cohort study investigated the long term safety of alemtuzumab in RRMS.

Methods

Clinical data was collected from a cohort of 87 patients who participated in open label studies of alemtuzumab in Cambridge, UK from 1999 to 2012. Pregnancy outcomes and the occurrence of moderate to severe infections were recorded.

Results

Over a median 7-year follow-up (range 33–144 months), no serious infections occurred that required hospitalisation. There were 11 cases of varicella zoster virus reactivation and one case of primary varicella zoster virus infection. In this cohort 15 babies were born to 12 women treated with alemtuzumab. The median interval from their most recent alemtuzumab treatment to birth was 26 months (range 13–86 months). All of the babies were healthy and delivered without complications. One woman had experienced a miscarriage at 8 weeks gestation but went on to have two successful pregnancies.

Conclusions

During prolonged follow-up of this cohort of patients treated with alemtuzumab no serious infections occurred. No increased risk of miscarriage or foetal abnormality was seen in the small number of pregnancies studied.
MANAGEMENT OF FINGOLIMOD FIRST DOSE OBSERVATION (FDO) IN THE UK
Authors: Pamies P , Webber B , Pull E
Published: October 2015

Background

Fingolimod (Gilenya) is a sphingosine 1-phosphate receptor (S1PR) modulator approved for use in relapsing-remitting multiple sclerosis. Fingolimod can lead to reduced pacemaker cell excitability, slowing heart rate (HR) and, possibly, atrioventricular block. Cardiac monitoring is required for a minimum of 6 hours on commencing the first dose of fingolimod.

Regent's Park Heart Clinics (RPHC) is a cardiology services provider engaged by Novartis Pharmaceuticals UK to provide NHS clinicians with a fingolimod FDO service.

Objective

To describe the results of a UK FDO service for fingolimod.

Methods

RPHC provides a cardiac physiologist/nurse to visit sites between 0800–1700 hrs with electrocardiography (ECG) equipment. 12-lead ECG is performed at baseline and six hours after initiation with continuous cardiac monitoring throughout. Blood pressure and HR measurement is performed hourly. Where patients have evidence of clinically important cardiac effects, monitoring is extended up to eight hours or overnight as required.

Results

From 4/July/2012 to 26/January/2015, RPHC provided FDO for 1013 patients. 975 (96%) were discharged at six hours; 29 (3%) were discharged at eight hours. 9 (1%) required an overnight stay. 1 patient discontinued treatment.

Conclusion

96% of 1013 fingolimod patients were discharged at 6-hours post-first dose. No patients required pharmacological intervention.
A NEW CLINICAL TOOL (BRIT) TO MONITOR IVIG EFFICACY IN PATIENTS WITH STIFF PERSON SYNDROME
Authors: Weerasinghe Savinda , Sadalage Girija , Jacob Saiju
Published: October 2015

Stiff person syndrome (SPS) is a chronic, progressive neurological disorder characterized by painful muscle spasms and rigidity with high titres of circulating anti-GAD antibodies.

Intravenous immunoglobulin (IVIg) has been proven to be very effective in reducing the symptoms associated with SPS, most notably stiffness. Patients report being able to walk for the first time in months or even years and partake in activities of daily living including showering and household chores. A reduction in falls is also noted in patients receiving IVIg. Most patients report a drastically improved quality of life after receiving IVIg with significant improvement in pain, general mental health, social functioning, vitality and energy.

At present, there is no standardised method of monitoring the effectiveness of IVIg treatment in patients with stiff person syndrome. We devised a standardised questionnaire with a combination of modified Rankin scale and Flanagan's QOLS and prospectively studied 12 SPS patients receiving IVIg therapy. We named this the Birmingham Response to IVIg Treatment (BRIT) scale.

The BRIT scale can be used to monitor IVIg efficacy in a variety of chronic neurological conditions (especially ones without other monitoring tools, eg: INCAT score for CIDP) and would be a very useful addition to the neurology practice.
A SIGHT-THREATENING PAPILLOEDEMA MIMIC: POLYPOIDAL CHOROIDAL VASCULOPATHY
Authors: Hrastelj James , Bryl Benjamin , Al-Bermani Ayad , Corkill Robin
Published: October 2015

A 44-year-old woman from Guyana was referred to the neurology services with headache and blurred vision. The ophthalmology services had made the referral following discovery of apparent bilateral papilloedema and a right retinal haemorrhage. A CT venogram reported enlarged optic nerve sheaths, empty sella and asymmetrical lateral sinuses. The initial lumbar puncture revealed a normal opening pressure of 14 cm H2O and clinical headache assessment suggested migraine. Further ophthalmology advice was sourobight. Having excluded drusen by B-scan ultrasound, a second lumbar puncture was performed and revealed opening pressure 23 cm H2O. Despite extensive investigation, diagnostic uncertainty persisted until the patient presented to Eye Casualty with acute deterioration in right eye visual acuity. A large retinal haemorrhage was noted and fluorescein angiography revealed multiple choroidal vascular polyps. A diagnosis of peripapillary polypoidal choroidal vasculopathy (PCV) was made. Treatment with intraocular anti-VEGF injections and photodynamic therapy successfully avoided permanent visual loss. Caution is advised when interpreting CT findings consistent with idiopathic intracranial hypertension, as PCV is an important differential diagnosis in unexplained papilloedema, which if left untreated can lead to irreversible blindness.
GOING BLIND ON DIALYSIS: NYCTALOPIA DUE TO TRANEXAMIC ACID
Authors: Rudd Darren , Jaiser Stephan , Bradshaw Karen , Archibald Neil
Published: October 2015

Tranexamic acid (TNA) is a fibrinolytic inhibitor used to control haemorrhage. Impairment of vision, particularly of colour perception, is a rare adverse effect.

A 79 year-old man with end-stage renal failure (ESRF) was treated with tranexamic acid for bleeding from duodenal angiodysplasia. Over four days his vision deteriorated bilaterally, and he complained of poor acuity unless in a brightly sunlit environment.

On examination, visual acuity was poor within the ward but improved markedly when looking out of the window or shining a bright torchlight on objects. Visual fields, pupillary reflexes, fundoscopy and remaining neurological examination were normal.

Full-field electroretinogram (ERG) demonstrated severe photoreceptor dysfunction, especially of rods. TNA was discontinued and vision improved subjectively within days. Serial ERG showed continuing recovery of rod function over several months.

Patients with ESRF often have duodenal angiodysplasia, and TNA is commonly used to minimise bleeding. Previously reported effects of TNA on colour vision (chromatopsia) presumably arise through impaired cone function. By contrast, our patient exhibited predominant rod dysfunction, and the clinical manifestation of nyctalopia expands the known spectrum of adverse effects of TNA. Rapid discontinuation of TNA is vital to minimise visual sequelae.
ZEBRAFISH AS A MODEL OF GLUCOCEREBROSIDASE 1 (GBA1) DEFICIENCY
Authors: Keatinge Marcus , DaCosta Marc , Menke Aswin , Chen Yu-Chia , Bui Hai Hoang , O'Neill Mike , Bandmann Oliver
Published: October 2015

Objectives

To establish and characterise glucocerebrosidase 1 (GBA1) mutant zebrafish line.

Background

Homozygous GBA1 mutations (GBA1−/−) cause Gaucher disease (GD), heterozygote GBA1 mutations (GBA+/−) are the most common risk factor for Parkinson's disease (PD). The aim of this project was to develop a zebrafish model of GBA1 deficiency and study PD-relevant mechanisms.

Methods

Genome editing, RT PCR, behavioural analysis, Immunohistochemistry, H/E staining, in situ hybridisation, biochemical assays.

Results

Homozygous mutants (GBA1−/−) developed normally and did not experience dopaminergic (DA) cell loss during development but displayed loss of DA neurons at 12 weeks. Video tracking revealed a large decrease in spontaneous movements in GBA1−/− compared to WT and an intermediate motor phenotype in GBA1+/− in juvenile zebrafish. All homozygous mutants had to be culled at 3 months of age due to the severity of the phenotype. Established GD biomarkers such as hexosaminidase or chitotriosidase activity were markedly abnormal (p<0.0001). Furthermore, there was marked impairment of mitochondrial respiratory chain activity in GBA−/−.

Conclusions

GBA1−/− zebrafish share key biochemical and morphological features with GBA1 knockout mice or indeed human GD. This new vertebrate model system for GBA1 deficiency will be useful to study the interaction between GBA1 haploinsufficiency, alpha-synuclein and exogenous toxins.
GENE SET ENRICHMENT ANALYSIS IN AMYOTROPHIC LATERAL SCLEROSIS
Authors: Chen Zhongbo , Lin Kuang , Shatunov Aleksey , Jones Ashley , Al-Chalabi Ammar
Published: October 2015

Background

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. We examined the phylogenetics of ALS-susceptibility genes from our previously-published genome-wide association study (GWAS).

Methods

We examined the association between ALS-susceptibility genes and hybridisation from the Neanderthal genome using a modified gene set enrichment analysis (GSEA). These gene sets comprise thirteen candidate regions for Neanderthal to non-African human gene flow [UCSC Genome Browser]. We ranked the ascending p-values of 442,057 GWAS SNPs and simulated the distribution 100,000 times. The resulting empirical p-value, comparing observed with expected mean rank, identified which gene sets are over-represented at the top of the rank list. Bonferroni corrections for multiple testing were applied.

Results

6,402 imputed GWAS SNPs fell into the thirteen gene sets. We found that the regions on chromosomes 6 and 9 accrued the lowest observed mean ranks (8,594 and 7,096 respectively) and were not different from expected mean ranks after simulation for those regions – empirical p-values before Bonferroni correction were 0.086 for chromosome 6 and 0.071 for chromosome 9.

Discussion

Using GSEA to evaluate European ALS GWAS data in the context of pre-defined gene sets refutes the theory that ALS-susceptibility loci may have arisen from Neanderthal to non-African modern human gene flow.
A SPASTIC ATAXIC GAIT WITH A BIT MORE BITE
Authors: Chance Leah , Gray Orla
Published: October 2015

A 39 year old female presented to a District General Hospital with fatigue, light-headedness and shortness of breath. Investigations revealed an iron deficient anaemia, initially presumed due to poor diet. Clinical examination revealed a moderate cerebellar ataxia and spastic paraparesis. Investigations included normal MRI of Whole Spine and Vitamin B12 level. MRI Brain revealed abnormal T2 and FLAIR high signal within the superior aspect of the corticospinal tracks bilaterally.

Further investigation revealed low serum copper of 0.6 mcgmol/L (12.6–26.7), low serum caeruloplasmin of 0.05 g/L (0.16–0.45) and low twenty-four hour urinary copper of 0.05 mcgmol/24 hours (0–0.6) confirming copper deficiency. Serum zinc was elevated at 16.3mcgmol/L (8–15) at neurology clinic assessment, confirming the diagnosis of zinc toxicity. The patient's astute pharmacist highlighted the potential source of excess zinc ingestion as overuse of a well known denture adhesive.

A literature search and overview of the physiology of copper, zinc and iron metabolism helped to marry all aspects of the case supporting the diagnosis of copper deficiency secondary to zinc toxicity due to overuse of a zinc containing denture adhesive.
THE RELATIONSHIP BETWEEN CLOCK DRAWING AND COGNITION IN PARKINSON'S
Authors: Cosgrove Jeremy , Jamieson Stuart , Smith Stephen , Alty Jane
Published: October 2015

Introduction

Clock drawing (CD) requires executive function, attention and visuospatial ability. Our objective was to investigate CD in Parkinson's subjects with and without cognitive impairment.

Methods

107 subjects completed the Montreal Cognitive Assessment (MoCA), classifying into normal cognition (PD-NC – MoCA ≥26) and cognitive impairment (PD-CI–MoCA <26). CD was scored using MoCA criteria; a maximum of 3 points, one each for correct contour, clock face and clock hands.

Results

PD-CI (n=57) and PD-NC were matched for all demographics except age (PD-CI were older, P 0.032). 35% of PD-CI scored full marks compared to 90% of PD-NC (sensitivity 0.64, specificity 0.9, age adjusted-odds ratio for predicting PD-CI 15.63, 95% CI 5.18 – 47.62, P<0.001). 88% of PD-CI scored points for contour and 60% scored points for clock face. In contrast, all PD-NC scored points for contour and clock face (P <0.001). 42% of PD-CI and 90% of PD-NC correctly drew clock hands (P<0.001).

Conclusions

In this cohort, inability to score maximum points for CD was associated with PD-CI. Correctly drawing clock hands was the hardest component for both groups. Incorrect contour or clock face was highly specific for PD-CI.
NEXT GENERATION SEQUENCING IN FAMILIAL CEREBRAL SMALL VESSEL DISEASE - AN ONGOING STUDY
Authors: Tan Rhea , Markus Hugh
Published: October 2015

Cerebral small vessel disease (SVD) is the most common form of stroke and vascular dementia. CADASIL (notch3 mutations) is most frequent but other monogenic causes more recently identified include CARASIL (HTRA1 gene), RVCL (TREX1 gene) and COL4A1 and 2. Diagnostic tests for these are often inaccessible and expensive and there are families with clinical monogenic SVD in whom no known variants are detected.

Next generation sequencing offers the potential to screen for these diseases, which present with similar phenotypes, more cost-effectively and rapidly in a single test. It could also identify novel genes underlying SVD. As part of the NHS GEL and NIHR BRIDGE projects, whole genome sequencing is being applied to SVD. Individuals with younger onset SVD and a family history, with negative notch3 screening, are being recruited from centres throughout England.

Data (blood sample and phenotypic information) can be collected by phone and blood sent through the post, or participants seen at a research clinic in one of the seven recruitment sites. Testing is provided free of charge. Any SVD causative mutations are fed back to the patient via the referring clinician. We are interested in receiving potential recruits who can be referred to Rhea Tan yyrt2@medschl.cam.ac.uk.
STIFF PERSON SYNDROME PRESENTING AS ‘STIFF EYES’
Authors: Vinjam Maruthi Ravi , Shanmugarajan Priya , Ford Helen
Published: October 2015

A 47-year previously fit and well lady presented with 6 weeks history of generalised lethargy, weight loss and neck pain. Her examination revealed left supra-clavicular lymph nodes. Subsequent investigations revealed left grade 2 invasive ductal carcinoma of her left breast. This was treated with local excision.

She presented to hospital four weeks following her surgery with progressive double vision and unsteadiness. Her cranial nerve examination showed severly restricted pursuit and saccadic horizontal eye movements with intact vertical eye movements. She had normal strength with intact deep tendon reflexes with plantar flexor response. Her MRI head and spine with contrast and CSF examination, including cytology was normal.

Two weeks into her admission she progressively developed generalised stiffness and severe axial and peripheral rigidity which was made worse with touch or emotions. These symptoms responded to benzodiazepines and baclofen. Her anti-amphiphysin antibodies were positive confirming the diagnosis of stiff person syndrome.

Her breast cancer was treated aggressively with chemotherapy. Her stiffness and rigidity improved briefly following her chemotherapy. Eye movement's problems were described in anti-GAD related stiff person syndrome, which is due to GABA depletion. This is first ever-reported case where eye movement problem (Stiff eyes) is the initial presentation of a anti-amphiphysin antibody related stiff person syndrome.
Substrate‐Dependent Differences in the Crystal Structures and Optical Properties of ZnSe Nanowires
Authors: Seo Keumyoung , Bong Jihye , Kim Jae-Woo , Song Yoon-Ho , Shin Yong Ho , Kim Yongmin , Ju Sanghyun
Published: October 2015

The optical and structural properties of ZnSe nanowires directly grown on three different substrates, SiO2, ITO, and graphene, were investigated. ZnSe nanowires grown on graphene and SiO2 were found to have cubic structures, while ZnSe nanowires grown on ITO had a mixed cubic and hexagonal structure. The main peaks in the photoluminescence spectra of ZnSe nanowires grown on SiO2, ITO, and graphene were located at 459, 627, and 627/460 nm, respectively. In addition, a field‐emission light‐emitting device was fabricated using ZnSe nanowires as a phosphor and graphene as an electrode. The device showed a red emission peak with Commission Internationale de L’Eclairage coordinates of (0.621, 0.315).
Risk Determination, Prioritization, and Classifying in Construction Project Case Study: Gharb Tehran Commercial-Administrative Complex
Authors: Sohrabinejad Azadeh , Rahimi Mehdi
Published: October 2015

Construction projects play an important role in infrastructure projects in developing countries. According to type, size, and complexity of the project, the number and importance of each risk could be different and many projects cannot reach the project goals due to exposure to multiple risks. Many papers have been published on the subject of risk management in construction projects; unfortunately most of them have not been implemented in practical conditions. The aim of this study is to identify and prioritize risks in construction projects. The classical approach used probability and impact for risk assessment, but these criteria do not sufficiently address all aspects of projects risks and there might be a relationship between different criteria. This study proposes the hierarchical dependencies between criteria. A case study of construction project is presented to illustrate performance and usage of the proposed model. Utilizing library studies and interview with experts, managers, and specialists, decision criteria were identified through brain storming. Risks were categorized by the experts into eleven risks. Important risks were evaluated based on the fuzzy ANP, fuzzy DEMATEL, and fuzzy TOPSIS methods. The proposed model is more suitable than the traditional decision-making methods in prioritizing risk concerning cost, time, and quality.
Ensemble of Chaotic and Naive Approaches for Performance Enhancement in Video Encryption
Authors: Chandrasekaran Jeyamala , Thiruvengadam S. J.
Published: October 2015

Owing to the growth of high performance network technologies, multimedia applications over the Internet are increasing exponentially. Applications like video conferencing, video‐on‐demand, and pay‐per‐view depend upon encryption algorithms for providing confidentiality. Video communication is characterized by distinct features such as large volume, high redundancy between adjacent frames, video codec compliance, syntax compliance, and application specific requirements. Naive approaches for video encryption encrypt the entire video stream with conventional text based cryptographic algorithms. Although naive approaches are the most secure for video encryption, the computational cost associated with them is very high. This research work aims at enhancing the speed of naive approaches through chaos based S‐box design. Chaotic equations are popularly known for randomness, extreme sensitivity to initial conditions, and ergodicity. The proposed methodology employs two‐dimensional discrete Henon map for (i) generation of dynamic and key‐dependent S‐box that could be integrated with symmetric algorithms like Blowfish and Data Encryption Standard (DES) and (ii) generation of one‐time keys for simple substitution ciphers. The proposed design is tested for randomness, nonlinearity, avalanche effect, bit independence criterion, and key sensitivity. Experimental results confirm that chaos based S‐box design and key generation significantly reduce the computational cost of video encryption with no compromise in security.
ATP Synthase Deficiency due to TMEM70 Mutation Leads to Ultrastructural Mitochondrial Degeneration and Is Amenable to Treatment
Authors: Braczynski Anne K. , Vlaho Stefan , Müller Klaus , Wittig Ilka , Blank Anna-Eva , Tews Dominique S. , Drott Ulrich , Kleinle Stephanie , Abicht Angela , Horvath Rita , Plate Karl H. , Stenzel Werner , Goebel Hans H. , Schulze Andreas , Harter Patrick N. , Kieslich Matthias , Mittelbronn Michel
Published: October 2015

TMEM70 is involved in the biogenesis of mitochondrial ATP synthase and mutations in theTMEM70gene impair oxidative phosphorylation. Herein, we report on pathology and treatment of ATP synthase deficiency in four siblings. A consanguineous family of Roma (Gipsy) ethnic origin gave birth to 6 children of which 4 were affected presenting with dysmorphic features, failure to thrive, cardiomyopathy, metabolic crises, and 3-methylglutaconic aciduria as clinical symptoms. Genetic testing revealed a homozygous mutation (c.317-2A>G) in theTMEM70gene. While light microscopy was unremarkable, ultrastructural investigation of muscle tissue revealed accumulation of swollen degenerated mitochondria with lipid crystalloid inclusions, cristae aggregation, and exocytosis of mitochondrial material. Biochemical analysis of mitochondrial complexes showed an almost complete ATP synthase deficiency. Despite harbouring the same mutation, the clinical outcome in the four siblings was different. Two children died within 60 h after birth; the other two had recurrent life-threatening metabolic crises but were successfully managed with supplementation of anaplerotic amino acids, lipids, and symptomatic treatment during metabolic crisis. In summary,TMEM70mutations can cause distinct ultrastructural mitochondrial degeneration and almost complete deficiency of ATP synthase but are still amenable to treatment.
One-Dimensional Coulomb Multiparticle Systems
Authors: Malyshev V. A. , Zamyatin A. A.
Published: October 2015

We consider the system of particles with equal charges and nearest neighbour Coulomb interaction on the interval. We study local properties of this system, in particular the distribution of distances between neighbouring charges. For zero temperature case there is sufficiently complete picture and we give a short review. For Gibbs distribution the situation is more difficult and we present two related results.
A Pooled Analysis of Reproductive Factors, Exogenous Hormone Use, and Risk of Multiple Myeloma among Women in the International Multiple Myeloma Consortium
Authors: Costas Laura , Lambert Brice H. , Birmann Brenda M. , Moysich Kirsten B. , De Roos Anneclaire J. , Hofmann Jonathan N. , Baris Dalsu , Wang Sophia S. , Camp Nicola J. , Tricot Guido , Atanackovic Djordje , Brennan Paul , Cocco Pierluigi , Nieters Alexandra , Becker Nikolaus , Maynadié Marc , Foretová Lenka , Boffetta Paolo , Staines Anthony , Brown Elisabeth E. , de Sanjosé Silvia
Published: October 2015

Background: Female sex hormones are known to have immunomodulatory effects. Therefore, reproductive factors and exogenous hormone use could influence the risk of multiple myeloma in women. However, the role of hormonal factors in multiple myeloma etiology remains unclear because previous investigations were underpowered to detect modest associations.

Methods: We conducted a pooled analysis of seven case–control studies included in the International Multiple Myeloma Consortium, with individual data on reproductive factors and exogenous hormone use from 1,072 female cases and 3,541 female controls. Study-specific odds ratios and corresponding 95% confidence intervals (CI) were estimated using logistic regression and pooled analyses were conducted using random effects meta-analyses.

Results: Multiple myeloma was not associated with reproductive factors, including ever parous [OR = 0.92; 95% confidence interval (CI), 0.68–1.25], or with hormonal contraception use (OR = 1.04; 95% CI, 0.80–1.36). Postmenopausal hormone therapy users had nonsignificantly reduced risks of multiple myeloma compared with never users, but this association differed across centers (OR = 0.65; 95% CI, 0.37–1.15, I2 = 76.0%, Pheterogeneity = 0.01).

Conclusions: These data do not support a role for reproductive factors or exogenous hormones in myelomagenesis.

Impact: Incidence rates of multiple myeloma are higher in men than in women, and sex hormones could influence this pattern. Associations with reproductive factors and exogenous hormone use were inconclusive despite our large sample size, suggesting that female sex hormones may not play a significant role in multiple myeloma etiology. Cancer Epidemiol Biomarkers Prev; 25(1); 217–21. ©2015 AACR.
New Life for Immunotoxin Cancer Therapy
Authors: Hassan Raffit , Alewine Christine , Pastan Ira
Published: October 2015

Immunotoxins are targeted anticancer therapeutics that kill cancer cells using a cytotoxic bacterial toxin payload. Their development for use in solid tumor malignancies was delayed due to issues with their immunogenicity and limited therapeutic window. However, new research has rejuvenated the field. Coadministration with a lymphocyte-depleting regimen of pentostatin and cyclophosphamide can delay antidrug antibody formation, increasing the number of treatment cycles that patients can receive and resulting in durable responses in heavily pretreated patients. In addition, a new generation of immunotoxin molecules with reduced immunogenicity and nonspecific toxicity has been developed through protein engineering techniques, and one has recently entered the clinic. In preclinical studies in mouse models, these new agents are effective against many tumor types as single agents, and also produce synergistic antitumor responses in combination with chemotherapy. These new immunotoxins have renewed excitement in the field and may prove a promising addition to the targeted therapy repertoire. Clin Cancer Res; 22(5); 1055–8. ©2015 AACR.