bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Autocleavage in the Function of a Type III Secretion Specificity Switch Protein in Salmonella enterica Serovar Typhimurium
Authors: Monjarás Feria Julia V. , Lefebre Matthew D. , Stierhof York-Dieter , Galán Jorge E. , Wagner Samuel 
Published: October 2015

ABSTRACT

Type III secretion systems (T3SSs) are multiprotein machines employed by many Gram-negative bacteria to inject bacterial effector proteins into eukaryotic host cells to promote bacterial survival and colonization. The core unit of T3SSs is the needle complex, a supramolecular structure that mediates the passage of the secreted proteins through the bacterial envelope. A distinct feature of the T3SS is that protein export occurs in a strictly hierarchical manner in which proteins destined to form the needle complex filament and associated structures are secreted first, followed by the secretion of effectors and the proteins that will facilitate their translocation through the target host cell membrane. The secretion hierarchy is established by complex mechanisms that involve several T3SS-associated components, including the “switch protein,” a highly conserved, inner membrane protease that undergoes autocatalytic cleavage. It has been proposed that the autocleavage of the switch protein is the trigger for substrate switching. We show here that autocleavage of the
Salmonella enterica
serovar Typhimurium switch protein SpaS is an unregulated process that occurs after its folding and before its incorporation into the needle complex. Needle complexes assembled with a precleaved form of SpaS function in a manner indistinguishable from that of the wild-type form. Furthermore, an engineered mutant of SpaS that is processed by an external protease also displays wild-type function. These results demonstrate that the cleavage event
per se
does not provide a signal for substrate switching but support the hypothesis that cleavage allows the proper conformation of SpaS to render it competent for its switching function.

IMPORTANCE
Bacterial interaction with eukaryotic hosts often involves complex molecular machines for targeted delivery of bacterial effector proteins. One such machine, the type III secretion system of some Gram-negative bacteria, serves to inject a multitude of structurally diverse bacterial proteins into the host cell. Critical to the function of these systems is their ability to secrete proteins in a strict hierarchical order, but it is unclear how the mechanism of switching works. Central to the switching mechanism is a highly conserved inner membrane protease that undergoes autocatalytic cleavage. Although it has been suggested previously that the autocleavage event is the trigger for substrate switching, we show here that this is not the case. Rather, our results show that cleavage allows the proper conformation of the protein to render it competent for its switching function. These findings may help develop inhibitors of type III secretion machines that offer novel therapeutic avenues to treat various infectious diseases.
Efficacy of treatments and pain management for trapeziometacarpal (thumb base) osteoarthritis: protocol for a systematic review
Authors: Hamasaki Tokiko , Lalonde Lyne , Harris Patrick , Bureau Nathalie J , Gaudreault Nathaly , Ziegler Daniela , Choinière Manon 
Published: October 2015

IntroductionThe thumb is essential for daily activities. Unfortunately, this digit is commonly affected by trapeziometacarpal osteoarthritis (TMO), handicapping a large number of individuals. TMO constitutes an increasing human and economic burden for our society whose population is ageing. Limited access to adequate treatment is among the most important obstacles to optimal TMO management. Poor understanding of TMO characteristics, lack of knowledge about evidence-based treatments, simplistic pain management plans based solely on the patient's physical condition, absence of interprofessional communication and lack of multidisciplinary treatment guidelines contribute to inadequate TMO management. On the long term, our research project aims at improving the quality of care and services offered to patients with TMO by developing a patient-centred, evidence-based multidisciplinary management clinical pathway coordinated across the healthcare system. This proposed systematic review is a prerequisite to ensuring evidence-based practices and aims to document the efficacy of all the existing modalities for TMO management.Methods and analysisThe protocol of the systematic review is registered with PROSPERO and will be conducted using the guidelinesCochrane Handbook for Systematic Reviews of Interventions.We will identify studies in English and French concerning TMO treatments through searches in Cochrane Central, EMBASE, MEDLINE, PsychINFO, CINHAL, PubMed, OT Seekers, PEDRO and the grey literature. 2 reviewers will independently screen study eligibility, extract data and appraise studies using published assessment tools. Meta-analyses will be undertaken where feasible; otherwise, narrative syntheses will be carried out. The robustness of evidence will be assessed using the GRADE system.Ethics and disseminationEthics approval is not required for this study. A comprehensive knowledge exchange and transfer plan incorporating effective strategies will be used to disseminate the findings of this review and utilise them to optimise TMO management.Trial registration numberPROSPERO CRD42015015623.
Measuring the relationship between interruptions, multitasking and prescribing errors in an emergency department: a study protocol
Authors: Raban Magdalena Z , Walter Scott R , Douglas Heather E , Strumpman Dana , Mackenzie John , Westbrook Johanna I 
Published: October 2015

IntroductionInterruptions and multitasking are frequent in clinical settings, and have been shown in the cognitive psychology literature to affect performance, increasing the risk of error. However, comparatively less is known about their impact on errors in clinical work. This study will assess the relationship between prescribing errors, interruptions and multitasking in an emergency department (ED) using direct observations and chart review.Methods and analysisThe study will be conducted in an ED of a 440-bed teaching hospital in Sydney, Australia. Doctors will be shadowed at proximity by observers for 2 h time intervals while they are working on day shift (between 0800 and 1800). Time stamped data on tasks, interruptions and multitasking will be recorded on a handheld computer using the validated Work Observation Method by Activity Timing (WOMBAT) tool. The prompts leading to interruptions and multitasking will also be recorded. When doctors prescribe medication, type of chart and chart sections written on, along with the patient's medical record number (MRN) will be recorded. A clinical pharmacist will access patient records and assess the medication orders for prescribing errors. The prescribing error rate will be calculated per prescribing task and is defined as the number of errors divided by the number of medication orders written during the prescribing task. The association between prescribing error rates, and rates of prompts, interruptions and multitasking will be assessed using statistical modelling.Ethics and disseminationEthics approval has been obtained from the hospital research ethics committee. Eligible doctors will be provided with written information sheets and written consent will be obtained if they agree to participate. Doctor details and MRNs will be kept separate from the data on prescribing errors, and will not appear in the final data set for analysis. Study results will be disseminated in publications and feedback to the ED.
UNUSUAL DECREMENTAL RESPONSE IN LAMBERT EATON MYASTHENIC SYNDROME
Authors: Sadalage Girija , Ali Sajjad , Mocroft Paul , Williams Adrian , Jacob Saiju 
Published: October 2015

Lambert Eaton Myasthenic Syndrome (LEMS) is an autoimmune disorder affecting the neuromuscular junction caused by antibodies against voltage gated calcium channel antibodies. The neurophysiological hallmark of LEMS is incremental response to repetitive nerve stimulation, especially at high frequency stimulation.A 54-year-old gentleman presented to the Neurology clinic with a 9-month history of progressive walking difficulty. He had difficulty standing up from a sitting down position and the symptoms were worse towards the end of the day. He had a transient history of dry mouth when the symptoms started, but denied any postural dizziness, sweating or bowel/bladder symptoms. He denied having any double vision, droopy eyelids, speech or swallowing symptoms. He had lost 1.5 stones in weight over the preceding 7–8 months. Examination showed proximal muscle weakness with reduced reflexes, which could not be potentiated. A clinical suspicion of LEMS was made, but the neurophysiological examination (repeated on three occasions) showed consistently decremental response at low and high frequency stimulations.The VGCC antibody was positive (293, normal 0–45), confirming the clinical suspicion of LEMS. The AChR and MuSK antibodies were negative.This is an unusual neurophysiological finding of a decremental response in a patient with clinical and immunological evidence of LEMS.
A GENOME-WIDE ASSOCIATION STUDY IN PROGRESSIVE SUPRANUCLEAR PALSY
Authors: Chen Zhongbo , Shatunov Aleksey , Bensimon Gilbert , Payan Christine , Ludolph Albert , Leigh Nigel , Group NNIPPS Study , Al-Chalabi Ammar 
Published: October 2015

BackgroundProgressive supranuclear palsy (PSP) is a debilitating Parkinsonian movement disorder characterised by tau protein burden. We aimed to identify common genetic variants influencing PSP susceptibility through a genome-wide association analysis (GWAS) of a multi-centre European study, Neuroprotection and Natural History in Parkinson's Plus Syndromes (NNIPPS), recruiting clinically well-characterised patients. We combined this with a meta-analysis of previously-identified gene variants.MethodsWe genotyped 275,684 single nucleotide polymorphisms using Illumina microarrays in 212 PSP cases from the UK, Germany and France, and compared these with 4,707 matched controls. GWAS was performed using PLINK. Meta-analysis was performed with METAL. Genome-wide significance was defined as p<5×10^–8.ResultsWe observed multiple associations on chromosome 17 within or close to the MAPT gene, a well-established risk locus for PSP, confirming the sample and method validity. Of nine other previously reported associations, meta-analysis only confirmed that the MOBP variation (rs1768208) modified PSP risk (p=3.29×10^–13).ConclusionIn the GWAS and meta-analysis, we found the chromosome 17 inversion region to be associated with PSP susceptibility. Furthermore, we have shown that MOBP can modify the risk of PSP, possibly through influencing oligodendrocyte tau inclusions. These identified gene variants provide novel insights into the underlying genetics of sporadic PSP.
HOME COMPUTERISED COGNITIVE TESTING FOR TBI IS FEASIBLE AND POPULAR
Authors: Jenkins Peter , Fleminger Jessica , De-Simoni Sara , Jolly Amy , Gorgoraptis Nikos , Hampshire Adam , Sharp David 
Published: October 2015

Serial neuropsychological testing potentially provides a powerful tool for tracking disease progress and identifying treatment response. Formal neuropsychometric assessment by a clinical psychologist is ideal but impractical for regular testing. Remote computerised assessment resolves this difficulty by allowing frequent home assessment, but is potentially limited by patient compliance and practise effects. We study the feasibility of this approach in an on-going clinical trial investigating the effects of methylphenidate on cognition after traumatic brain injury (TBI): Dopamine's Role in Enhancing Attention and Memory (DREAM).A battery of neuropsychological tests was delivered on an iPad. 12 patients with moderate/severe TBI and on-going cognitive complaints completed 7 tasks assessing information processing speed, memory, attention and executive functions. The 25-minute-long battery was performed daily for 4 weeks, following an initial training period. Compliance was good, with over 80% of the sessions completed, and patients found it both beneficial and enjoyable. Despite optimising the battery to minimise learning effects, differing tasks showed varying degrees of practise effects.We demonstrate a proof of principle that TBI patients will enthusiastically complete regular computerised neuropsychological tests at home. This provides a potentially powerful tool to assess treatment response, but also offers the prospect of facilitating self-directed cognitive rehabilitation.
MPP+ IN A ZEBRAFISH MODEL OF GLUCOCEREBROSIDASE 1 DEFICIENCY
Authors: Payne Thomas , Keatinge Marcus , Costa Marc Da , Bandmann Oliver 
Published: October 2015

ObjectiveTo determine if glucocerebrosidase 1 deficiency is a susceptibility factor to 1-methyl-4-phenylpyridinium (MPP+) toxicity using a zebrafish model.Background and hypothesisHeterozygous mutations in the glucocerebrosidase gene (GBA1) are a strong genetic risk factor for Parkinson's disease (PD). Genetic risk factors may increase susceptibility to exogenous neurotoxins. We hypothesized GBA1 haploinsufficiency may increase susceptibility to the classical PD neurotoxin MPTP.MethodsA stable gba1+/− zebrafish line was in-crossed to generate embryos of all genotypes. At 2 days post fertilization (dpf), 100 dechorionated embryos (and 100 controls) were separated into 6 well plates, and exposed to 3 mM MPP+. At 3dpf embryos were fixed in 4% paraformaldehyde. Whole mount in-situ hybridisation was performed using a tyrosine hydroxylase (TH) probe. Embryos were genotyped for gba1 by PCR. TH positive neurons were counted in 10 embryos of each genotype under 20x microscopy.ResultsMPP+ embryos exhibited approximately 25% reduction in TH neurons compared to controls with no differences between genotypes.ConclusionMPP+ exposure results in a loss of TH positive neurons. GBA1 deficiency does not potentiate this. We provide “proof of principle” data for the usefulness of PD mutant zebrafish strains to test possible interactions between PD genetic risk factors and relevant toxins.
SEROTONIN-TO-DOPAMINE TRANSPORTER RATIOS IN THE STRIATUM OF PATIENTS WITH PARKINSON'S DISEASE: IMPACT ON LEVODOPA–INDUCED DYSKINESIAS
Authors: Roussakis Andreas-Antonios , Politis Marios , Towey David , Piccini Paola 
Published: October 2015

BackgroundSerotonergic mechanisms play a key role in the development of the Levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease (PD). We hypothesised that an unfavourable serotonin-to-dopamine terminal ratio in the putamen would be most detrimental in dyskinetic patients. We investigated the role of serotonin-to-dopamine transporter binding ratios in the development of dyskinesias in Parkinson's disease patients.Methods/SubjectsTwenty-eight Parkinson's disease patients[17 with LIDs;11 stable] and 12 age and gender-matched healthy controls were studied with [11C]DASB PET and [123I]FP-CIT SPECT, Imaging. We have employed a simplified reference tissue model using cerebellar reference for the quantification of [11C]DASB, whereas a semi-quantification approach was used for [123I]FP-CIT. We estimated uptake values in the putamen.ResultsParkinson's disease patients showed decreases in [123I]FP-CIT binding (p<0.001) compared to controls, 51% in the stable and 62% in the LIDs group. PD patients showed decreases in [11C]DASB binding (p<0.01), but there were no differences between the stable (37% loss) and LIDs(31% loss) groups. PD patients with LIDs had 103% increased [11C]DASB-to-[123I]FP-CIT binding ratio, whereas in the PD stable group the ratio was increased by 76%, relative to HCs. Higher [11C]DASB-to-[123I]FP-CIT binding ratio correlated with longer disease duration for the 28 PD patients (r=0.52;p<0.01).ConclusionSERT-to-DAT ratio increases as PD progresses and patients experience LIDs.
HIPPOCAMPAL INTERNAL ARCHITECTURE AND POSTOPERATIVE OUTCOME IN TEMPORAL LOBE EPILEPSY
Authors: Elkommos Samia , Weber Bernd , Niehusmann Pitt , Volmering Elisa , Richardson Mark , Marson Anthony , Elger Christian , Keller Simon 
Published: October 2015

IntroductionIt is unknown why over one-third of patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS) continue to experience seizures despite temporal lobe surgery. We investigated the relationship between hippocampal internal architecture (HIA) on preoperative MRI, and postoperative seizure outcome in patients with refractory mTLE and HS.MethodsHIA was assessed on preoperative T2-STIR MR images using a published scoring system1 for 79 patients undergoing evaluation at University Hospital Bonn, Germany. Patients underwent amygdalohippocampectomy and received postoperative outcome assessment using the International League Against Epilepsy (ILAE) classification. Hippocampal volumes were obtained using 3D T1-weighted images. Quantitative histopathological assessment was performed on resected hippocampal specimens.ResultsNo significant differences in ipsilateral or contralateral HIA ratings, or HIA score asymmetry, were found between patients rendered seizure free (ILAE I) compared to those continuing to experience postoperative seizures (ILAE II-VI). HIA significantly correlated with neuronal density in CA3 and CA4 in the pathologic hippocampus, and hippocampal volumes bilaterally. There was no significant correlation between HIA and clinical variables.ConclusionAlthough valuable in determining seizure laterality, HIA does not predict postoperative outcome.AcknowledgementsThis work was supported by a UK MRC grant awarded to SSK (Grant Number: MR/K023152/1). References:1Ver Hoef 2013
PREDICTING VISUAL FIELD DEFECTS FOLLOWING SELECTIVE TRANSSYLVIAN AMYGDALOHIPPOCAMPECTOMY
Authors: Fuller S , Hamandi K , Jones D K , Gray W P 
Published: October 2015

IntroductionSurgery for refractory temporal lobe epilepsy can cause postoperative visual field defects (VFD). This study aimed to predict personalised risk of VFDs for patients undergoing selective transsylvian amygdalohippocampectomy.MethodsPreoperative reconstruction of the optic radiations (OR) using diffusion tensor-based tractography was completed on two patients. The ‘average resection model’ uses a template from postoperative structural scans of five patient scans to predict an average resection in the patient. The OR tractography was compared with the resection margins to determine fibre involvement. The ‘multiple individual comparison model’ compared individual postoperative scans with the preoperative tractography to determine risk of VFD.ResultsIn Patient 1 the average resection overlapped the OR, so an average resection would be expected to produce a VFD. In 3/5 postoperative scans the resection intersected with the OR, indicating that 60% of prior resections would have caused a defect. In Patient 2 no overlap between resection and OR was found in either model. Perimetry confirmed VFD in patient 1 but not in patient 2.DiscussionThis pilot study demonstrates that the risk of postoperative VFDs can be predicted. The two models provide qualitatively different form of quantitative risk which could inform the discussion between patient and clinician.
VALPROIC ACID EXTENDS LIFESPAN OF THE ZEBRAFISH MODEL OF CLN2 DISEASE (LATE INFANTILE NEURONAL CEROID LIPOFUSCINOSIS)
Authors: Mahmood Fahad , Zdebik Anselm , Au Alexandra , Cooke Jennifer , Russell Claire 
Published: October 2015

CLN2 disease is a subtype of the neuronal ceroid lipofuscinoses (NCLs), a group of lysosomal storage disorders causing progressive, untreatable, neurodegeneration, intractable epilepsy and premature death in children. We have developed a permanent genetic zebrafish model of CLN2 disease due to a mutation in tpp1 encoding the lysosomal protease Tripeptidyl-peptidase-1 that replicates the neurodegenerative and storage phenotype. We hypothesize that CLN2 zebrafish display electrical and behavioural evidence of seizure activity that responds to established anti-convulsants and can further be used to develop novel therapeutic approaches.To validate the presence of seizures we performed single electrode electroencephalography showing CLN2 zebrafish had increased spiking activity vs wildtype with Fast-Fourier transform showing significantly increased amplitude about 2–4Hz. This was attenuated by Valproate (p=0.049), but not pentobarbitone. We also demonstrate that Valproate significantly reduces seizure-related movement bouts, thereby correlating movements and epileptiform activity. Lastly, we show exposure to Valproate significantly extends the lifespan of our zebrafish model with mortality between 3–6 days post-fertilization 8.33% in treated vs 33.3% in controls (p=0.01).The CLN2 zebrafish model thus displays electrical and behavioural seizure activity that can be attenuated by Valproate, with associated prolongation in survival. Moreover this model can utilize high-throughput in vivo screening assays to develop novel anti-convulsants.
PROGRESSIVE MULTIFOCAL LEUCOENCEPHALOPATHY: AN ATYPICAL CASE
Authors: Maxwell Alice , Archer Hilary , Cohen Nicki , Love Seth , Cottrell David 
Published: October 2015

Case reportA 71 year old man presented with a three month history of gradual arm and leg weakness, followed by neck stiffness, dysphagia, dysarthria and hypophonia. Past Medical History included Burkitt's lymphoma of the jaw 14 years previously, treated with chemotherapy and radiotherapy.Examination demonstrated a restriction of upgaze and dysphonia. Tone was markedly increased, and power reduced globally at a grading of 4/5. Reflexes were brisk with an upgoing left plantar.Investigations revealed, longstanding idiopathic lymphopenia for 10 years, CT chest/abdominal/pelvis was normal, serial MRI of the brain demonstrated changes in the subcortical white matter, frontal and parietal lobes. JC virus PCR was negative, however, brain biopsy was consistent with Progressive Multifocal Leucoencephalopathy (PML).DiscussionPML is caused by reactivation of the polyomavirus JC in the CNS. Reactivation typically occurs following immunosuppression e.g. HIV, haematological malignancies and drugs. Gold standard for diagnosis is brain biopsy as JC virus PCR has a sensitivity of only 80%. Treatment is through removal of the immunosuppressive agent, and immune reconstitution.PML should be considered in all patients with a suggestive clinical and radiological presentation where there is current or historical immunosuppression, should JC virus PCR be negative a tissue biopsy should be sought.