Evolution of cranial shape in a continental‐scale evolutionary radiation of Australian lizards

A defining character of adaptive radiations is the evolution of a diversity of morphological forms that are associated with the use of different habitats, following the invasion of vacant niches. Island adaptive radiations have been thoroughly investigated but continental scale radiations are more poorly understood. Here, we use 52 species of Australian agamid lizards and their Asian relatives as a model group, and employ three‐dimensional geometric morphometrics to characterize cranial morphology and investigate whether variation in cranial shape reflects patterns expected from the ecological process of adaptive radiation. Phylogenetic affinity, evolutionary allometry, and ecological life habit all play major roles in the evolution of cranial shape in the sampled lizards. We find a significant association between cranial shapes and life habit. Our results are in line with the expectations of an adaptive radiation, and this is the first time detailed geometric morphometric analyses have been used to understand the selective forces that drove an adaptive radiation at a continental scale

Pyrosequencing of Mytilus galloprovincialis cDNAs: tissue-specific expression patterns.

BACKGROUND: Mytilus species are important in marine ecology and in environmental quality assessment, yet their molecular biology is poorly understood. Molecular aspects of their reproduction, hybridisation between species, mitochondrial inheritance, skewed sex ratios of offspring and adaptation to climatic and pollution factors are priority areas. METHODOLOGY/PRINCIPAL FINDINGS: To start to address this situation, expressed genetic transcripts from M. galloprovincialis were pyrosequenced. Transcripts were isolated from the digestive gland, foot, gill and mantle of both male and female mussels. In total, 175,547 sequences were obtained and for foot and mantle, 90% of the sequences could be assembled into contiguous fragments but this reduced to 75% for the digestive gland and gill. Transcripts relating to protein metabolism and respiration dominated including ribosomal proteins, cytochrome oxidases and NADH dehydrogenase subunits. Tissue specific variation was identified in transcripts associated with mitochondrial energy metabolism, with the digestive gland and gill having the greatest transcript abundance. Using fragment recruitment it was also possible to identify sites of potential small RNAs involved in mitochondrial transcriptional regulation. Sex ratios based on Vitelline Envelop Receptor for Lysin and Vitelline Coat Lysin transcript abundances, indicated that an equal sex distribution was maintained. Taxonomic profiling of the M. galloprovincialis tissues highlighted an abundant microbial flora associated with the digestive gland. Profiling of the tissues for genes involved in intermediary metabolism demonstrated that the gill and digestive gland were more similar to each other than to the other two tissues, and specifically the foot transcriptome was most dissimilar. CONCLUSIONS: Pyrosequencing has provided extensive genomic information for M. galloprovincialis and generated novel observations on expression of different tissues, mitochondria and associated microorganisms. It will also facilitate the much needed production of an oligonucleotide microarray for the organism

Unpicking the Gordian knot: a systems approach to traumatic brain injury care in low-income and middle-income countries.

The Global Burden of Diseases, Injuries, and Risk Factors Study showed that in 2010 trauma accounted for 9% of the world's deaths - around 5 million people - while also resulting in millions of non-fatal injuries with resultant disability. Around 90% of injury-related deaths occurred in low and middle income countries (LMICs) which also saw the greatest rise in these injuries due to road traffic collisions.1 More recent Global Health Estimates from the World Health Organisation for 2015 show a similar picture.2 As a disease subtype, Traumatic Brain Injury (TBI) is one of the most devastating, with clinical, societal, and economic sequelae.3 It is also startlingly common with an estimated 50 million or more cases per year; enough for half of the world's population to suffer a TBI in their lifetime and again disproportionately affecting lower-income regions.

Development of a finite element model of decompressive craniectomy.

Decompressive craniectomy (DC), an operation whereby part of the skull is removed, is used in the management of patients with brain swelling. While the aim of DC is to reduce intracranial pressure, there is the risk that brain deformation and mechanical strain associated with the operation could damage the brain tissue. The nature and extent of the resulting strain regime is poorly understood at present. Finite element (FE) models of DC can provide insight into this applied strain and hence assist in deciding on the best surgical procedures. However there is uncertainty about how well these models match experimental data, which are difficult to obtain clinically. Hence there is a need to validate any modelling approach outside the clinical setting. This paper develops an axisymmetric FE model of an idealised DC to assess the key features of such an FE model which are needed for an accurate simulation of DC. The FE models are compared with an experimental model using gelatin hydrogel, which has similar poro-viscoelastic material property characteristics to brain tissue. Strain on a central plane of the FE model and the front face of the experimental model, deformation and load relaxation curves are compared between experiment and FE. Results show good agreement between the FE and experimental models, providing confidence in applying the proposed FE modelling approach to DC. Such a model should use material properties appropriate for brain tissue and include a more realistic whole head geometry.TLF acknowledges funding from the Engineering and Physical Sciences Research Council (EPSRC). AGK is supported by a Royal College of Surgeons of England Research Fellowship (funded by the Freemasons and the Rosetrees Trust), an NIHR Academic Clinical Fellowship and a Raymond and Beverly Sackler Studentship. PJH is supported by a NIHR Research Professorship and the NIHR Cambridge Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final published version, also available from PLOS at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0102131

Modelling of Brain Deformation After Decompressive Craniectomy.

Hyperelastic finite element models, with either an idealized cylindrical geometry or with realistic craniectomy geometries, were used to explore clinical issues relating to decompressive craniectomy. The potential damage in the brain tissue was estimated by calculating the volume of material exceeding a critical shear strain. Results from the idealized model showed how the potentially damaged volume of brain tissue increased with an increasing volume of brain tissue herniating from the skull cavity and with a reduction in craniectomy area. For a given herniated volume, there was a critical craniectomy diameter where the volume exceeding a critical shear strain fell to zero. The effects of details at the craniectomy edge, specifically a fillet radius and a chamfer on the bone margin, were found to be relatively slight, assuming that the dura is retained to provide effective protection. The location in the brain associated with volume expansion and details of the material modeling were found to have a relatively modest effect on the predicted damage volume. The volume of highly sheared material in the realistic models of the craniectomy varied roughly in line with differences in the craniectomy area.TLF acknowledges funding from the Engineering and Physical Sciences Research Council (EPSRC). BW is supported by the Studienstiftung des deutschen Volkes, the Max Weber-Programm and the Stiftung Maximilianeum. AGK is supported by a Royal College of Surgeons of England Research Fellowship (funded by the Freemasons and the Rosetrees Trust), a National Institute of Health Research (NIHR) Academic Clinical Fellowship and a Raymond and Beverly Sackler Studentship. PJH is supported by a NIHR Research Professorship and the NIHR Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s10439-016-1666-

A systematic review of cerebral microdialysis and outcomes in TBI: relationships to patient functional outcome, neurophysiologic measures, and tissue outcome.

OBJECTIVE: To perform a systematic review on commonly measured cerebral microdialysis (CMD) analytes and their association to: (A) patient functional outcome, (B) neurophysiologic measures, and (C) tissue outcome; after moderate/severe TBI. The aim was to provide a foundation for next-generation CMD studies and build on existing pragmatic expert guidelines for CMD. METHODS: We searched MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to October 2016). Strength of evidence was adjudicated using GRADE. RESULTS: (A) Functional Outcome: 55 articles were included, assessing outcome as mortality or Glasgow Outcome Scale (GOS) at 3-6 months post-injury. Overall, there is GRADE C evidence to support an association between CMD glucose, glutamate, glycerol, lactate, and LPR to patient outcome at 3-6 months. (B) Neurophysiologic Measures: 59 articles were included. Overall, there currently exists GRADE C level of evidence supporting an association between elevated CMD measured mean LPR, glutamate and glycerol with elevated ICP and/or decreased CPP. In addition, there currently exists GRADE C evidence to support an association between elevated mean lactate:pyruvate ratio (LPR) and low PbtO2. Remaining CMD measures and physiologic outcomes displayed GRADE D or no evidence to support a relationship. (C) Tissue Outcome: four studies were included. Given the conflicting literature, the only conclusion that can be drawn is acute/subacute phase elevation of CMD measured LPR is associated with frontal lobe atrophy at 6 months. CONCLUSIONS: This systematic review replicates previously documented relationships between CMD and various outcome, which have driven clinical application of the technique. Evidence assessments do not address the application of CMD for exploring pathophysiology or titrating therapy in individual patients, and do not account for the modulatory effect of therapy on outcome, triggered at different CMD thresholds in individual centers. Our findings support clinical application of CMD and refinement of existing guidelines

Matrix Metalloproteinase Expression in Contusional Traumatic Brain Injury: A Paired Microdialysis Study.

Matrix metalloproteinases (MMPs) are extracellular enzymes that have been implicated in the pathophysiology of blood-brain barrier (BBB) breakdown, contusion expansion, and vasogenic edema after traumatic brain injury (TBI). Specifically, in focal injury models, increased MMP-9 expression has been observed in pericontusional brain, and MMP-9 inhibitors reduce brain swelling and final lesion volume. The aim of this study was to examine whether there is a similarly localized increase of MMP concentrations in patients with contusional TBI. Paired microdialysis catheters were inserted into 12 patients with contusional TBI (with or without associated mass lesion) targeting pericontusional and radiologically normal brain defined on admission computed tomography scan. Microdialysate was pooled every 8 h and analyzed for MMP-1, -2, -7, -9, and -10 using a multiplex immunoassay. Concentrations of MMP-1, -2, and -10 were similar at both monitoring sites and did not show discernible temporal trends. Overall, there was a gradual increase in MMP-7 concentrations in both normal and injured brain over the monitoring period, although this was not consistent in every patient. MMP-9 concentrations were elevated in pericontusional, compared to normal, brain, with the maximal difference at the earliest monitoring times (i.e., <24 h postinjury). Repeated-measures analysis of variance showed that MMP-9 concentrations were significantly higher in pericontusional brain (p=0.03) and within the first 72 h of injury, compared with later in the monitoring period (p=0.04). No significant differences were found for the other MMPs assayed. MMP-9 concentrations are increased in pericontusional brain early post-TBI and may represent a potential therapeutic target to reduce hemorrhagic progression and vasogenic edema.M.R.G. was supported by a National Institute for Health Research (NIHR) Academic Clinical Fellowship, a Royal College of Surgeons/Philip King Research Fellowship, and a Beverley and Raymond Sackler Fellowship. A.H. was supported by a joint Medical Research Council/ Royal College of Surgeons of England Clinical Research Training Fellowship. K.L.H.C. is supported by the NIHR Biomedical Research Center, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). J.D.P. is supported by the Traumatic Brain Injury NIHR Health Technology Cooperative. D.K.M. is supported by an NIHR Senior Investigator Award. P.J.A.H. is supported by the Cambridge NIHR BRC and an NIHR Research Professorship.This is the final published version. It was first made available by Mary Ann Liebert at http://dx.doi.org/10.1089/neu.2014.376

Glucose Dynamics of Cortical Spreading Depolarization in Acute Brain Injury: A Systematic Review.

Cortical spreading depolarization (CSD) is an emerging mode of secondary neuronal damage in acute brain injury (ABI). Subsequent repolarisation is a metabolic process requiring glucose. Instances of CSD and glucose derangement are both linked to poor neurological outcome, but their causal inter-relationship is not fully defined. This systematic review seeks to evaluate the available human evidence studying CSD and glucose to further understand their dynamic relationship. We conducted a systematic review of studies examining CSD through electrocorticography and cerebral/systemic glucose concentrations in ABI, excluding animal studies. The search yielded 478 articles, of which 13 were eligible. Across 10 manuscripts, 125 patients received simultaneous monitoring, with 1987 CSD episodes observed. Eight of 10 studies observed correlation between CSD and glucose change. Seven of eight studies observed possible cumulative effect of recurrent CSD on glucose derangement and two identified correlation between glycopenia and incidence of CSD. These findings confirm a relationship between CSD and glucose, and suggest it may be cyclical, where CSD causes local glycopenia, which may potentiate further CSD. Positive observations were not common to all studies, likely due to differing methodology or heterogeneity in CSD propensity. Further study is required to delineate the utility of the clinical modulation of serum and cerebral glucose to alter the propensity for CSD following brain injury

Dextran 500 Improves Recovery of Inflammatory Markers: An In Vitro Microdialysis Study.

Cerebral microdialysis (CMD) is used in severe traumatic brain injury (TBI) in order to recover metabolites in brain extracellular fluid (ECF). To recover larger proteins and avoid fluid loss, albumin supplemented perfusion fluid (PF) has been utilized, but because of regulatory changes in the European Union, this is no longer practicable. The aim with this study was to see whether fluid, absolute (AR), and relative (RR) recovery for the novel carrier, Dextran 500, was better than conventional PF for a range of cytokines and chemokines. An in vitro setup mimicking conditions observed in the neurocritical care of TBI patients was used, utilizing 100-kDa molecular-weight cut-off CMD catheters inserted through a triple-lumen bolt cranial access device into an external solution with diluted cytokine standards in known concentrations for 48 h (divided into 6-h epochs). Samples were run on a 39-plex Luminex (Luminex Corporation, Austin, TX) assay to assess cytokine concentrations. We found that fluid recovery was inadequate in 50% of epochs with conventional PF, whereas Dextran PF overcame this limitation. The AR was higher in the Dextran PF samples for a majority of cytokines, and RR was significantly increased for macrophage colony-stimulating factor and transforming growth factor-alpha. In summary, Dextran PF improved fluid and cytokine recovery as compared to conventional PF and is a suitable alternative to albumin supplemented PF for protein microdialysis.The work was supported by funding for SGC and KLHC from the National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). PJH is funded by a National Institute for Health Research (NIHR) Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship and the National Institute for Health Research Biomedical Research Centre, Cambridge. EPT has received salary support from Swedish Society for Medical Research. AH is supported by the Royal College of Surgeons of England and the National Institute for Health Research Biomedical Research Centre, Cambridge. The study consumables were purchased through the NIHR Research Professorship (Peter Hutchinson) and the Luminex 200 analyser was purchased with Medical Research Council (MRC) funding (G0600986 ID79068)

Longitudinal assessments highlight long-term behavioural recovery in disorders of consciousness.

Accurate diagnosis and prognosis of disorders of consciousness is complicated by the variability amongst patients' trajectories. However, the majority of research and scientific knowledge in this field is based on cross-sectional studies. The translational gap in applying this knowledge to inform clinical management can only be bridged by research that systematically examines follow-up. In this study, we present findings from a novel longitudinal study of the long-term recovery trajectory of 39 patients, repeatedly assessed using the Coma Recovery Scale-Revised once every 3 months for 2 years, generating 185 assessments. Despite the expected inter-patient variability, there was a statistically significant improvement in behaviour over time. Further, improvements began approximately 22 months after injury. Individual variation in the trajectory of recovery was influenced by initial diagnosis. Patients with an initial diagnosis of unresponsive wakefulness state, who progressed to the minimally conscious state, did so at a median of 485 days following onset-later than 12-month period after which current guidelines propose permanence. Although current guidelines are based on the expectation that patients with traumatic brain injury show potential for recovery over longer periods than those with non-traumatic injury, we did not observe any differences between trajectories in these two subgroups. However, age was a significant predictor, with younger patients showing more promising recovery. Also, progressive increases in arousal contributed exponentially to improvements in behavioural awareness, especially in minimally conscious patients. These findings highlight the importance of indexing arousal when measuring awareness, and the potential for interventions to regulate arousal to aid long-term behavioural recovery in disorders of consciousness