Effect of expectoration on inflammation in induced sputum in α-1-antitrypsin deficiency

SummaryIt is unclear how chronic expectoration influences airway inflammation in patients with chronic lung disease. The aim of this study was to investigate factors influencing inflammation in induced sputum samples, including, in particular, chronic sputum production. Myeloperoxidase, interleukin-8, leukotriene B4 (LTB4), neutrophil elastase, secretory leukoprotease inhibitor (SLPI) and protein leakage were compared in induced sputum samples from 48 patients (36 with chronic expectoration) with COPD (with and without alpha-1-antitrypsin deficiency; AATD), 9 individuals with AATD but without lung disease and 14 healthy controls. There were no differences in inflammation in induced sputum samples from healthy control subjects and from AATD deficient patients with normal lung function but without chronic expectoration (P>0.05). Inflammation in induced sputum from AATD patients with airflow obstruction and chronic sputum expectoration was significantly greater than for similar patients who did not expectorate: Interleukin-8 (P<0.01), elastase activity (P=0.01), and protein leakage (P<0.01). The presence of spontaneous sputum expectoration in AATD patients with airflow obstruction was associated with increased neutrophilic airway inflammation in induced sputum samples. The presence of chronic expectoration in some patients will clearly complicate interpretation of studies employing sputum induction where this feature has not been identified

Analysis of linezolid and tigecycline as candidates for local prophylaxis via antibiotic-loaded bone cement

Objectives To assess the Gram-positive-specific antibiotic linezolid and the broad-spectrum antibiotic tigecycline for use in local antibiotic delivery via antibiotic-loaded bone cement. Methods Linezolid and tigecycline were added to Biomet bone cement at varying concentrations. Antibiotic elution over 1 week was quantified by HPLC-MS. The effect of wear on elution over 51 h was determined using a modified TE-66 wear tester. Eluted antibiotics were used to determine the MICs for a panel of clinically relevant bacteria. The impact strength of antibiotic-loaded samples was determined using a Charpy-type impact testing apparatus. Cytotoxicity of eluted antibiotics against MG-63 cells was evaluated using an MTT assay. Results Linezolid and tigecycline eluted from bone cement to clinically relevant levels within 1 h and retained activity over 1 week. Mechanical wear significantly reduced elution of tigecycline, but had little effect on elution of linezolid. Linezolid showed low cytotoxicity towards MG-63 cells with ≤300 mg/mL resulting in >50% cell activity. Cytotoxicity of tigecycline was higher, with an IC50 of 5–10 mg/L. Conclusions Linezolid and tigecycline retain activity after elution from bone cement. The concentration of tigecycline may need to be carefully controlled due to cytotoxicity. The effect of wear on bone cement may need to be considered if tigecycline is to be used for local delivery. Up to 10% linezolid can be added without affecting the impact strength of the bone cement. These results are promising indications for future investigation of these antibiotics for use in local antibiotic delivery strategies

Polyandrous females avoid costs of inbreeding

Why do females typically mate with more than one male? Female mating patterns have broad implications for sexual selection, speciation and conflicts of interest between the sexes, and yet they are poorly understood. Matings inevitably have costs, and for females, the benefits of taking more than one mate are rarely obvious. One possible explanation is that females gain benefits because they can avoid using sperm from genetically incompatible males, or invest less in the offspring of such males. It has been shown that mating with more than one male can increase offspring viability, but we present the first clear demonstration that this occurs because females with several mates avoid the negative effects of genetic incompatibility. We show that in crickets, the eggs of females that mate only with siblings have decreased hatching success. However, if females mate with both a sibling and a non-sibling they avoid altogether the low egg viability associated with sibling matings. If similar effects occur in other species, inbreeding avoidance may be important in understanding the prevalence of multiple mating

Reported fatigue in people after Guillain-Barré Syndrome: a retrospective national survey in the UK

Aim. Despite continuing functional recovery over time, fatigue remains a persistent feature of post-acute GuillainBarré Syndrome (GBS). The aim of this study was to determine the prevalence of fatigue in people after GBS and investigate its associations with other factors after GBS. Methods. Validated questionnaires including the SF-36 and fatigue severity scale were sent to members of the GBS support group, a UK wide patient and carer organisation. Results. A total of 884 questionnaires were returned (58% response rate). Respondents’ answers demonstrated that those with severe fatigue following GBS had spent longer in hospital than those who were not severely fatigued (P=0.003). Poorer mental health was also associated with more severe fatigue. A strong predictor of prolonged fatigue was discharge from hospital in a wheelchair (OR=2.37, 95% CI 1.52 to 3.71, P<0.001) but the severity of fatigue appeared to be independent of recovery of mobility (Kendall’s taub=0.03, P=0.2). Conclusion. This survey is the largest study of fatigue in people after GBS. Its findings demonstrate that fatigue remains a persistent problem for many people after GBS. More severe fatigue was associated with decreased health related quality of life and increased levels of depression and anxiety in people after GBS. Whilst the severity of fatigue was significantly associated with poorer mobility on discharge, there was no association between the recovery of mobility after discharge and fatigue severity. This indicates that whilst other impairments and activity limitations improved over time, fatigue did not and implies that more severe fatigue is not simply an indicator of a more severe presentation of GBS. Whilst the reasons for persistent severe fatigue remain unclear, this study indicates that further investigations of mobility, mental health and fatigue are warranted so that targeted interventions can be put in place to manage this debilitating complication. (It J Physiotherapy 2013;3:154-60

Using rhythm for rehabilitation: evaluation of a novel haptic device

This project explored how new and novel approaches to stroke rehabilitation could improve physical function and the confidence of stroke survivors to remain active and engaged in the community. The innovation trialed was a ‘Haptic bracelet/cueing device’, developed at The Open University. An overview of the Haptic device, its development and role in stroke rehabilitation can be viewed at: https://www.youtube.com/watch?v=S4ZxN6H6XGk The Haptic bracelets provide a physical (embodied) beat that someone can walk to as an alternative to existing audio cuing ways of working. The haptic device provides a non-invasive, relatively cheap way of facilitating people after stroke to continue to maintain or even improve their mobility after intensive rehabilitation has finished. This research explored the impact of the haptic device to gains in mobility. The project had two key aims: 1. To develop a usable and practical prototype of a haptic device to restore gait symmetry after stroke. 2. To investigate the feasibility and acceptability of the prototype in stroke patients. Summary of findings and recommendations When introduced to the Haptic Bracelets participants hoped the product would provide them with: • More confidence and make them feel safer when walking. • Greater ability to take bigger strides rather than little steps. • A way to combat the silly mistakes participants reported making due to tiredness. • Reduced pain (knees, hips) The physiotherapists saw potential for the Haptic devices as part of post stroke rehabilitation, but expressed concern about their lack of access to mobile technologies when out in community practice settings. There were also concerns about use with some stroke survivors because of issues of cognition; and the sensation from the Haptic beat. In the Haptic gait testing • All the participants demonstrated good mobility performance prior to the study (high score on the Rivermead mobility scale) • 4/7* (57.1%) participants who were the most asymmetrical at baseline improved their gait symmetry whilst wearing the haptic device • 3/7* (42%) participant’s gait symmetry continued to improve in the post off condition. • All the participants walked quicker in post-op condition. However, gait speed varied between participants when they were wearing the haptic bracelets. • Participants were had had their strokes between 3-10 years ago, but there was still an indication that the Haptic bracelets were having some impact on mobility. • Syncing of the Haptic device and more mobile Inertial Measurement Unit (IMU) to the fixed gait laboratory (gold standard) system has improved the potential for more community based rehabilitation and commercialisation of the Haptic bracelets. • Post Haptic interviews identified that there were mixed participant feelings about the bracelets. However, some did express positive experiences from testing the Haptic bracelets, including a carry over effect after the devices were removed. Recommendations As this was a pilot study more work is now required to explore the: • use of the Haptic bracelets in community rehabilitation settings • feasibility of the using Haptic bracelets in community settings, particularly looking at staff access to new technologies • potential for the Haptic bracelets to be used in the home as part of ongoing rehabilitation • benefits of Haptic bracelets in the context of longer term stroke rehabilitation • future design needs to improve the look, size and ease of application • cost benefits of using Haptic bracelets as part of an overall program of stroke rehabilitation

Communal breeding affects offspring behaviours associated with a competitive social environment

Abstract Communal breeding is characterised by shared care of offspring produced by more than one female, and can affect the behavioural development of young. The decision to care communally can vary according to local conditions, and has been hypothesised to occur more frequently when social competition is intense. However, it is unknown whether communal rearing of young influences adult behaviours likely to be adaptive under competitive conditions. Here, using a controlled experimental approach, we investigate effects of communal rearing on competitive and exploratory behaviours of adult male house mice. In tests of competitive scent marking, only communally-reared subjects discriminated between related and unrelated rivals, depositing more scent marks in close proximity to unrelated males. Communally-reared subjects also displayed higher exploratory tendencies, with an increased probability of crossing a water barrier, while not exhibiting higher activity levels in an open field test. Since exploration tendencies and discrimination between kin and non-kin are likely to be advantageous when dispersing from the natal territory or in a high density population, our findings suggest that communal rearing prepares male house mice for a competitive social environment. Our results add to growing evidence that the early social environment influences development of important behavioural competences to cope with social challenges later in life

Inter-laboratory proficiency testing scheme for tumour next-generation sequencing in Ontario: A pilot study

Background A pilot inter-laboratory proficiency scheme for 5 Ontario clinical laboratories testing tumour samples for the Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) study was undertaken to assess proficiency in the identification and reporting of next-generation sequencing (NGS) test results in solid tumour testing from archival formalin-fixed, paraffin-embedded (FFPE) tissue. Methods One laboratory served as the reference centre and provided samples to 4 participating laboratories. An analyte-based approach was applied: each participating laboratory received 10 FFPE tissue specimens profiled at the reference centre, with tumour site and histology provided. Laboratories performed testing per their standard NGS tumour test protocols. Items returned for assessment included genes and variants that would be typically reported in routine clinical testing and variant call format (VCF) files to allow for assessment of NGS technical quality. Results Two main aspects were assessed: Technical quality and accuracy of identification of exonic variants Site-specific reporting practices Technical assessment included evaluation of exonic variant identification, quality assessment of the VCF files to evaluate base calling, variant allele frequency, and depth of coverage for all exonic variants. Concordance at 100% was observed from all sites in the technical identification of 98 exonic variants across the 10 cases. Variability between laboratories in the choice of variants considered clinically reportable was significant. Of the 38 variants reported as clinically relevant by at least 1 site, only 3 variants were concordantly reported by all participating centres as clinically relevant. Conclusions Although excellent technical concordance for NGS tumour profiling was observed across participating institutions, differences in the reporting of clinically relevant variants were observed, highlighting reporting as a gap where consensus on the part of Ontario laboratories is needed

Asymmetric Genome Organization in an RNA Virus Revealed via Graph-Theoretical Analysis of Tomographic Data

Cryo-electron microscopy permits 3-D structures of viral pathogens to be determined in remarkable detail. In particular, the protein containers encapsulating viral genomes have been determined to high resolution using symmetry averaging techniques that exploit the icosahedral architecture seen in many viruses. By contrast, structure determination of asymmetric components remains a challenge, and novel analysis methods are required to reveal such features and characterize their functional roles during infection. Motivated by the important, cooperative roles of viral genomes in the assembly of single-stranded RNA viruses, we have developed a new analysis method that reveals the asymmetric structural organization of viral genomes in proximity to the capsid in such viruses. The method uses geometric constraints on genome organization, formulated based on knowledge of icosahedrally-averaged reconstructions and the roles of the RNA-capsid protein contacts, to analyse cryo-electron tomographic data. We apply this method to the low-resolution tomographic data of a model virus and infer the unique asymmetric organization of its genome in contact with the protein shell of the capsid. This opens unprecedented opportunities to analyse viral genomes, revealing conserved structural features and mechanisms that can be targeted in antiviral drug desig

The antimicrobial activity and biocompatibility of a controlled gentamicin-releasing single-layer sol-gel coating on hydroxyapatite-coated titanium

Aims The aim of this study was to develop a single-layer hybrid organic-inorganic sol-gel coating that is capable of a controlled antibiotic release for cementless hydroxyapatite (HA)-coated titanium orthopaedic prostheses. Methods Coatings containing gentamicin at a concentration of 1.25% weight/volume (wt/vol), similar to that found in commercially available antibiotic-loaded bone cement, were prepared and tested in the laboratory for: kinetics of antibiotic release; activity against planktonic and biofilm bacterial cultures; biocompatibility with cultured mammalian cells; and physical bonding to the material (n = 3 in all tests). The sol-gel coatings and controls were then tested in vivo in a small animal healing model (four materials tested; n = 6 per material), and applied to the surface of commercially pure HA-coated titanium rods. Results The coating released gentamicin at > 10 × minimum inhibitory concentration (MIC) for sensitive staphylococcal strains within one hour thereby potentially giving effective prophylaxis for arthroplasty surgery, and showed > 99% elution of the antibiotic within the coating after 48 hours. There was total eradication of both planktonic bacteria and established bacterial biofilms of a panel of clinically relevant staphylococci. Mesenchymal stem cells adhered to the coated surfaces and differentiated towards osteoblasts, depositing calcium and expressing the bone marker protein, osteopontin. In the in vivo small animal bone healing model, the antibiotic sol-gel coated titanium (Ti)/HA rod led to osseointegration equivalent to that of the conventional HA-coated surface. Conclusion In this study we report a new sol-gel technology that can release gentamicin from a bioceramic-coated cementless arthroplasty material. In vitro, local gentamicin levels are in excess of what can be achieved by antibiotic-loaded bone cement. In vivo, bone healing in an animal model is not impaired. This, thus, represents a biomaterial modification that may have the potential to protect at-risk patients from implant-related deep infection

OCTANE (ontario-wide cancer targeted nucleic acid evaluation): A platform for intraprovincial, national, and international clinical data-sharing

Cancer is a genetic disease resulting from germline or somatic genetic aberrations. Rapid progress in the field of genomics in recent years is allowing for increased characterization and understanding of the various forms of the disease. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (octane) clinical trial, open at cancer centres across Ontario, aims to increase access to genomic sequencing of tumours and to facilitate the collection of clinical data related to enrolled patients and their clinical outcomes. The study is designed to assess the clinical utility of next-generation sequencing (ngs) in cancer patient care, including enhancement of treatment options available to patients. A core aim of the study is to encourage collaboration between cancer hospitals within Ontario while also increasing international collaboration in terms of sharing the newly generated data. The single-payer provincial health care system in Ontario provides a unique opportunity to develop a province-wide registry of ngs testing and a repository of genomically characterized, clinically annotated samples. It also provides an important opportunity to use province-wide real-world data to evaluate outcomes and the cost of ngs for patients with advanced cancer. The octane study is attempting to translate knowledge to help deliver precision oncology in a Canadian environment. In this article, we discuss the background to the study and its implementation, current status, and future directions