Functional brain networks are known to be affected by focal brain lesions. However, the clinical relevance of these changes remains unclear. This study assesses resting-state functional connectivity (FC) with electroencephalography (EEG) and relates observed topography of FC to cognitive and motor deficits in patients three months after ischemic stroke. Twenty patients  and nineteen age-matched healthy participants  underwent a ten-minute EEG-resting state examination. The neural oscillations at each grey matter voxel were reconstructed using an adaptive spatial filter and imaginary component of coherence (IC) was calculated as an index of FC. Maps representing mean connectivity value at each voxel were correlated with the clinical data. Compared to healthy controls, alpha band IC of stroke patients was locally reduced in brain regions critical to observed behavioral deficits. A voxel-wise Pearson correlation of clinical performances with FC yielded maps of the neural structures implicated in motor, language, and executive function. This correlation was again specific to alpha band coherence. Ischemic lesions decrease the synchrony of alpha band oscillations between affected brain regions and the rest of the brain. This decrease is linearly related to cognitive and motor deficits observed in the patients.


Malayopython reticulatus ssp.) are primarily harvested from the wild for their skins—which are prized in the luxury leather goods industry. Trade dynamics of this CITES Appendix II listed species are complex and management approaches on the country or regional level appear obscure. Little is known about the actual geographic point-of-harvest of snakes, how genetic diversity is partitioned across the species range, how current harvest levels may affect the genetic viability of populations, and whether genetic structure could (or should) be accounted for when managing harvest quotas. As an initial survey, we use mitochondrial sequence data to define the broad-scale geographic structure of genetic diversity across a significant portion of the reticulated python’s native range. Preliminary results reveal: (1) prominent phylogenetic structure across populations east and west of Huxley’s modification of Wallace’s line. Thirty-four haplotypes were apportioned across two geographically distinct groups, estimated to be moderately (5.2%); (2) Philippine, Bornean and Sulawesian populations appear to cluster distinctly; (3) individuals from Ambon Island suggest recent human introduction. Malayopython reticulatus is currently managed as a single taxonomic unit across Southeast Asia yet these initial results may justify special management considerations of the Philippine populations as a phylogenetically distinct unit, that warrants further examination. In Indonesia, genetic structure does not conform tightly to political boundaries and therefore we advocate the precautionary designation and use of Evolutionary Significant Units within Malayopython reticulatus, to inform and guide regional adaptive management plans.As an important economic natural resource in Southeast Asia, reticulated pythons ( Habitat loss and degradation as a result of unsustainable per capita consumption of natural resources and rising human population levels  are haviMalayopython reticulatus ssp., Python bivittatus ssp., P. curtus, P. brongersmai and P. breitensteini) being heavily exploited for this purpose. Among these the reticulated python (M. reticulatus ssp.) is the most economically important species , the Philippine governments banned the export of M. reticulatus in 1986, and Viet Nam banned wild harvest of M. reticulatus in 1998 )Malayopython reticulatus across the species contemporary range, they offer an encouraging conservation genetics baseline that justifies implementing a precautionary approach [Although the results presented here offer a very provisional insight to the genetic structure of approach  to populMalayopython reticulatus are to be continually exploited for the skin trade, management strategies should not solely be tailored to obtaining the maximum economic yield. Populations should instead be managed following an adaptive management scheme to ensure their long-term sustainability . Among ity , and maTo regulate trade dynamics, wild harvest rates and exploitation levels require regular monitoring of the status of resource population(s) to reduce uncertainties.Further fine scale genetic analysis is also warranted to delineate local genetic partitions, and the potential application of adaptive genetic markers to establish conservation units should be considered (see ).To encourage and foster scientific collaborative networks with the countries of origin to permit construction of comprehensive, reference sample databases on which to base the development of robust traceability protocols.S1 TableThe table contains information about samples included in this study along with the corresponding haplotypes inferred from sequence variation across a mitochondrial cytochrome b fragment.(PDF)Click here for additional data file.


Background: Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder which develops in approximately 10% of trauma-exposed individuals. Currently, there are few early preventive interventions available for PTSD. Intranasal oxytocin administration early posttrauma may prevent PTSD symptom development, as oxytocin administration was previously found to beneficially impact neurobiological  and socio-emotional PTSD vulnerability factors.Objective: The overall aim of this dissertation was to investigate the potential of intranasal oxytocin administration as early preventive intervention for PTSD.Methods: We performed a functional magnetic resonance imaging (fMRI) study to assess the acute effects of a single administration of oxytocin on the functional fear neurocircuitry – consisting of the amygdala and (pre)frontal brain regions – in recently trauma-exposed emergency department patients (range n = 37–41). In addition, we performed a multicentre randomized double-blind placebo-controlled clinical trial (RCT) to assess the efficacy of repeated intranasal oxytocin administration early after trauma for preventing PTSD symptom development up to six months posttrauma (n = 107).Results: In our fMRI experiments we observed acutely increased amygdala reactivity to fearful faces and attenuated amygdala-ventromedial and ventrolateral prefrontal cortex functional connectivity after a single oxytocin administration in recently trauma-exposed individuals. However, in our RCT we found that repeated intranasal oxytocin administration early posttrauma reduced subsequent PTSD symptom development in recently trauma-exposed emergency department patients with high acute PTSD symptoms.Conclusions: These findings indicate that repeated intranasal oxytocin is a promising early preventive intervention for PTSD for individuals at increased risk for PTSD due to high acute symptom severity. Administration frequency dependent effects of oxytocin or the effects of oxytocin administration on salience processing may serve as explanatory frameworks for the contrasting oxytocin effects on anxiety-related measures in our clinical and neuroimaging studies. As trauma exposure constitutes an identifiable event of potential PTSD onset, the first hours to weeks posttrauma serve as a suitable time-period for the provision of early preventive interventions for PTSD, aimed to reduce subsequent PTSD symptom development. Previously, administration of benzodiazepines  study to assess the acute effects of a single administration of oxytocin on the functional fear neurocircuitry – consisting of the amygdala and (pre)frontal brain regions – in recently trauma-exposed emergency department patients. In addition, we performed a randomized controlled clinical trial to assess the efficacy of repeated intranasal oxytocin administration early after trauma for preventing PTSD symptom development.3. 3.1. In chapter 2 . We observed that the effects of oxytocin administration on amygdala reactivity to emotional faces depended on stimulus valence and on sex. In all participants, oxytocin administration increased amygdala reactivity to fearful faces. Additionally, in women only, oxytocin administration increased amygdala reactivity to neutral faces. Our exploratory analysis showed that acute PTSD symptom severity was not associated with differential intranasal oxytocin administration effects on amygdala reactivity. Given these results we argued that a single intranasal administration of oxytocin may increase neural fear processing, possibly as a result of oxytocin-induced enhanced salience processing.We assessed the acute effects of a single administration of intranasal oxytocin on the fear neurocircuitry in a randomized double-blind placebo-controlled functional magnetic resonance imaging (fMRI) study in trauma-exposed emergency department patients within 11 days posttrauma. In chapter 4 . For each participant two resting-state fMRI scans were acquired: one after listening to a personal neutral script, and the second after listening to a personal trauma script which was based on the recent traumatic event. We observed that oxytocin-treated participants had diminished amygdala-left ventrolateral prefrontal cortex (vlPFC) functional connectivity in response to the trauma script compared to the neutral script, whereas an increase in amygdala-left vlPFC functional connectivity was observed in placebo-treated participants. In addition, irrespective of script condition, oxytocin administration enhanced amygdala-left (posterior) insula functional connectivity and decreased amygdala-ventromedial prefrontal cortex (vmPFC) functional connectivity. These neural oxytocin administration effects were accompanied by lower levels of sleepiness and higher flashback intensity after the trauma script in oxytocin-treated participants. Taken together, these observations indicate that that a single intranasal oxytocin administration may acutely impede emotion regulation in recently trauma-exposed individuals.In chapter 5 . However, the effects of oxytocin administration were moderated by acute PTSD symptom severity assessed prior to the intervention. Oxytocin administration reduced PTSD symptoms up to six months posttrauma in trauma-exposed individuals with high acute PTSD symptoms only. These findings suggest that an eight-day intranasal oxytocin treatment regimen is a promising preventive early intervention for PTSD, specifically for individuals with high acute PTSD symptoms.In chapter 7  the results of our clinical trial are presented. We demonstrated that there was no overall effect of repeated oxytocin administration on PTSD, depression and anxiety symptoms up to six months posttrauma . An administration frequency dependent effect on anxiety is a well-known phenomenon for selective serotonin reuptake inhibitors (SSRIs). A single SSRI administration acutely increased fear learning in rodents and may potentiate anxiety in humans  socio-emotional functioning; there is no direct evidence that the salience theory also holds for repeated oxytocin administration effects. An alternative suggestion for previously observed differential effects of oxytocin administration between healthy individuals and patients with a psychiatric disorder is that oxytocin administration may only have beneficial effects in individuals who have something to gain with regard to social or emotional functioning  oxytocin administration effects on reducing PTSD symptom development, (perception of) context factors should be explicitly assessed and tested as moderators of oxytocin effects in future studies.4.2. Although we were the first to study intranasal oxytocin effects in recently trauma-exposed individuals, meanwhile conducting the largest clinical RCT with intranasal oxytocin to date, some limitations of our studies need to be addressed. First, the statistical power of our clinical study was limited. We halted our study halfway, as our pre-planned interim analysis indicated low conditional power to detect a significant overall effect of oxytocin administration on PTSD symptoms at our primary outcome (1.5 month posttrauma follow-up). As results from studies with low statistical power are at increased risk for Type I error, replication of our findings is clearly warranted. In addition, the sample size of our imaging studies was also modest, therefore it was not possible to reliably test whether the effects of oxytocin administration on amygdala function were moderated by interindividual differences as we observed in our clinical study. We did explore whether acute PTSD symptom severity was differently associated with amygdala reactivity to fearful faces and found no differential effect , functional fear neurocircuitry and/or other socio-emotional processes (e.g. related to reward functioning).Furthermore, considering the potential future use of intranasal oxytocin in routine clinical practice – for PTSD prevention but for also other psychiatric indications – it is highly desirable to better understand when beneficial, null or even potentially non-beneficial effects of oxytocin administration can be expected. Particularly, oxytocin effects on fear memory consolidation and fear extinction should be studied, as there are indications that oxytocin-mediated enhanced fear and extinction memory consolidation may have either anxiolytic or anxiogenic effects, depending on administration frequency and timing in relation to fear conditioning (Janezic et al., In addition, a better understanding of the pharmacodynamics of intranasally administered oxytocin is needed. Oxytocin has a half-life of 3–20 min in blood, and the peptide is immediately degraded upon oral ingestion. There is no clear consensus on if and how intranasally administered oxytocin reaches the brain. Although intranasal oxytocin administration increased salivary (van IJzendoorn, Bhandari, van der Veen, Grewen, & Bakermans-Kranenburg, If our findings are replicated, intranasal oxytocin may be a safe and cheap preventive intervention for PTSD (MacDonald et al., Finally, there is only limited evidence linking functioning of the oxytocin system directly to PTSD risk (Lucas-Thompson & Holman, 5. We observed that repeated intranasal oxytocin administration early posttrauma reduced subsequent PTSD symptom development in recently trauma-exposed emergency department patients with high acute PTSD symptoms. Although replication is necessary, these findings indicate that intranasal oxytocin is a promising novel preventive intervention for individuals at increased risk for PTSD due to high acute symptom severity. However, we also observed acutely increased neural fear processing and impeded neural emotion regulation after a single oxytocin administration in recently trauma-exposed individuals. It remains unknown whether the positive clinical effects after repeated oxytocin administration are mediated by oxytocin effects on amygdala function, or whether the beneficial effects in our clinical study are mediated by other neurobiological and/or socio-emotional processes. Administration frequency dependent effects of oxytocin may be related to these seemingly contrasting effects on anxiety-related measures in our clinical and neuroimaging studies. In addition, the salience processing theory of oxytocin effects may serve as an explanatory framework for these seemingly contrasting results between the two study paradigms. Clinically relevant contextual and interindividual moderators of oxytocin effects should be investigated in the future, as well as underlying neurobiological and socio-emotional mechanisms that mediate oxytocin effects on anxiety-related outcomes and the development of PTSD symptoms. In all, our findings encourage further research into the clinical efficacy and feasibility of repeated oxytocin administration as early preventive intervention for PTSD, in order to try and reduce the high individual and societal burden associated with trauma exposure and PTSD.


Motor and vocal tics are the core symptom of Tourette syndrome (TS). Tic generation seems to develop throughout the known motor pathways. This review focuses on functional neuroimaging in order to check this assumption. Also it elucidates the alterations and interactions of motor networks in TS depending on different contexts and circumstances like resting state, spontaneous tic movements, suppression of tics and premonitory urges, voluntary goal-oriented movements as well as electrophysiological neuronal stimulation. In general, the primary tic generating motor network uses the basic motor pathways differently, interacts with secondary sensorimotor networks and neuronal systems of cognitive behavioural control in a merely hierarchical manner, changing during neurodevelopment.


Unfavorable left ventricular (LV) remodelling is associated with adverse prognosis after tetralogy of Fallot (TOF) repair. The aim of this study was to measure the extracellular volume (ECV) as a marker of diffuse LV myocardial fibrosis in children after TOF repair, and to understand its etiology and clinical significance.In this prospective, cross-sectional study ECV as a quantitative marker of diffuse fibrosis was measured in the LV myocardium using a modified look-locker inversion recovery (MOLLI) sequence. ECV was related to bypass and cross-clamp times at the time of surgery, to ventricular and myocardial function as well as to exercise tolerance.There was no difference in ECV between 31 TOF patients  and 15 controls . ECV correlated with z-scores of LV end-diastolic volumes and of right ventricular (RV) end-diastolic and end-systolic volumes . LV ECV did not correlate with with LV or RV ejection fraction, indexed right and left ventricular enddiastolic volumes or pulmonary regurgitation fraction or regurgitant volumes. Female TOF patients had higher ECVs as compared to males . There were no gender differences in controls. Bypass-time during complete repair correlated with LV ECV . Patients who had undergone either a valve sparing repair or received a valved right ventricle to pulmonary artery conduit had a lower ECV than those after transannular patch repair .Maximum workload on exercise testing, as a percent of predicted based on reference populations, correlated inversely with ECV . There were no correlations between ECV and myocardial strain, strain rate or torsion.Although children after TOF repair did not present with higher ECV than controls in this pilot study the amount of diffuse myocardial fibrosis was associated with longer bypass-times at the time of initial repair. There is early evidence that increased fibrosis is associated with decreased exercise tolerance in young patients after TOF repair. Female patients appear to have more diffuse myocardial fibrosis than males consistent with their generally less favourable hemodynamics after TOF repair.


Human respiratory syncytial virus (RSV) remains the most common cause of severe lower respiratory tract disease amongst infants, and continues to cause annual epidemics of respiratory disease every winter worldwide. Demonstrating placental transmission of viable RSV in human samples is a major paradigm shift in respiratory routes considered likely for RSV transmission.Droplet digital PCR (ddPCR) was used to identify RSV present in cord blood mononucleocytes (CBM). CBMs testing positive for RSV were treated with phytohemagglutinin (PHA), PHA and nitric oxide (NO) or PHA, NO and palivizumab, and co-cultured with HeLa cell monolayers. Subsequent immuno-staining for RSV was used to visualize infective viral plaques.RSV was detected in 26 of 45 samples (57.7%) by ddPCR. CBM’s collected in winter were more likely to test positive for RSV  compared to non-winter months . RSV plaques were observed in non-treated and treated co-cultured HeLa monolayers.in utero transmission of infective virus to the fetus without causing overt disease. This is likely to have an important impact on immune development as well as future virus-host interactions, thereby warranting further investigation.Demonstrating active RSV in CBMs suggests  Despite more than 50 years of research, human respiratory syncytial virus (RSV) continues to cause annual epidemics of respiratory disease every winter worldwide . RSV remRSV invades the epithelial cells of the lower respiratory tract following exposure to inhaled infective aerosolized droplets, or self-inoculation of the eyes and/or nose by contaminated fingers , 3. The RSV has also been shown to infect myeloid cells such as macrophages, dendritic cells (DCs), and cord blood monocytes –10; howein utero transmission, and activation of live virus in these cells to suggest a cellular reservoir. Findings from this study could be used to explain the prevalence of RSV bronchiolitis observed in infants every winter and inform novel targets for effective treatment of RSV induced airway disease.Based on observations from studies which have shown RSV persistence and replication reactivation in cells of monocyte lineage –9, we hyCord blood samples collected from 45 term infants  from healthy mothers 18–45 years) recruited antenatally. Samples were collected from August 2002 until September 2003. Cord blood was collected immediately after delivery by means of venipuncture of placental vessels, as previously described [–45 yearsRNA purified from a pooled preparation of nasopharyngeal aspirates collected from patients diagnosed with RSV bronchiolitis were used as positive controls for RSVA and RSVB detection in cord blood samples by digital PCR analysis.De-identified cord and maternal blood samples used for this study were collected under institutional ethics approval with informed adult written consent  Human Research Ethics Committee) to investigate developmental immunology. De-identified nasopharyngeal aspirates collected from patients testing positive for RSV were obtained with agreement from PathWest Laboratory Medicine  to validate the presence of RSV by droplet digital PCR. According to the Human Tissue Acts of Australia, ethics approval was not required for use of these human samples as they were collected for therapeutic and/or diagnostic purposes and subsequently de-identified for pathology purposes, including assay validation . All resRSV gene expression was measured using a commercially available fluorescent probe real-time PCR kit designed to detect all species of RSV  on a droplet digital PCR platform . Droplet digital PCR (ddPCR) is a next generation digital PCR with greater analytical sensitivity compared to conventional real-time PCR due to an enhanced ability to read nucleic acid at a single molecule level . Viral RImmuno-probing using an anti-RSV antibody was used to detect RSV plaques in order to demonstrate infective RSV detected by ddPCR in monocyte precursor cells contained in cord blood samples. Briefly, cryopreserved cord blood mononucleocytes (CBM) were thawed and allowed to rest for 3hrs at 37°C/5% CO2 in specialised dendritic cell media, X-VIVO . Following this, cultures were treated with one of the following: phytohaemagglutinin ; PHA with a soluble nitric oxide donor ; or PHA with NO and palivizumab . All cultures were incubated for 24hrs and then added to HeLa monolayers (American Tissue Culture Collection) grown to 70% confluence in Dulbecco’s minimum essential medium (DMEM) supplemented with fetal calf serum (10% v/v). After 48 hours culture supernatants were removed and the remaining HeLa cell monolayers washed with PBS, and fixed with methanol containing hydrogen peroxide (1% v/v). These fixed HeLa cultures were then probed for RSV expression using anti-RSV HRP conjugated monoclonal antibody  followed by incubation with Sigma-Fast Red  to detect the presence of RSV as described previously . StainedA total of 45 samples were assessed for RSV expression and a minimum of 11 samples were used to compare RSV plaque assay formation in each treatment group. All samples were run in duplicate and all experiments completed at least twice to ensure reproducibility. Odd’s ratios and relative risk for RSV detected in cord samples were calculated using cross-tabulations with Fishers exact analysis. Due to an absence of data regarding the prevalence of RSV in CBMs, post-hoc power analysis was used to assess if the study interpretations were feasible based on the sample size available. The observed power was calculated at 82% based on the relative risks of RSV detection and sample size used. In order to mitigate concerns surrounding use of observed power and demonstrate the precision of these findings, confidence intervals are reported for the effect sizes calculated. Due to the small sample size and skewed distribution of the dataset, Mann Whitney-U analysis was used to compare RSV expression between birth seasons, and to assess differences in RSV plaque numbers between non-treated and treated co-cultured cells. Stata software by StataCorp  was used to complete graphs and statistical analysis for this study with significance taken as p = <0.05 for two-tailed tests. Graphs represent median values with interquartile ranges unless stated otherwise.in utero transmission of RSV to the human fetus. RSV could not be detected in a subset of 16 matched maternal bloods analysed by the same methods.Low level RSV expression was detected in human cord blood samples using droplet digital PCR , the amount of virus was not significantly different to those samples testing positive and collected in non-winter months.This is the first study to show evidence of low level RSV expression in human cord blood samples, suggesting We believe acute maternal respiratory infection acquired during annual RSV winter epidemics in late pregnancy may explain the greater number CBM samples testing positive for RSV in winter. RSV infections are common throughout adult life but generally cause mild symptoms in healthy adults, meaning presentations of RSV induced illness in healthy adults are unusual . TherefoOf the non-winter seasons RSV was most prevalent in spring. This may represent persistence following acquisition of RSV during winter months. DCs have been shown to harbor RSV  with spoin utero. RSV release was significantly enhanced when CBMs were matured with phytohaemagglutinin (PHA) and treated with nitric oxide (NO), used as an environmental trigger of RSV replication. This effect was attenuated by treatment with the therapeutic anti-RSV antibody palivizumab, confirming RSV release from these cells. Therefore, this data suggests RSV is able to transmit from and between cells of monocyte lineage without inducing inflammatory symptoms usually associated with infection.Low level spontaneous release of RSV observed in epithelial cells co-cultured with CBMs suggest the fetus is exposed to low levels of infective RSV in utero during fetal immune system development may cause RSV immune tolerance [in utero exposure and the impact of viral exposure during fetal development is warranted due to maturing antigen-presenting precursor cell populations over the course of gestation [Importantly, exposure to infective RSV olerance , 27 explolerance –30. Dimiolerance , 3, 30. olerance . In ligholerance . Howeverestation .As this study was conducted retrospectively it was not possible to explore the impact of RSV detection on infant lung structure and function. An association between viral respiratory illness in asthmatic mothers and increased lower respiratory tract symptoms amongst their infants during the first year of life has been shown previously . The autin utero infection on host immune responses will have an important role in developing effective RSV vaccines and treatment in the future.The novel data generated in this study indicates RSV can cross the placenta and infect the fetus without causing overt disease. Trans-placental transmission of RSV appeared to be most common during the winter epidemic but was not limited to this period. While the implications of these findings remain confined to understanding the dynamics of RSV transmission, it is likely the effects of


Control participants (n = 51) were recruited from the same region. Participants generated personal approach goals  and avoidance goals  and completed self-report measures of goal attainment likelihood and depressive symptoms. Participants also completed a measure of ease of disengagement from unattainable goals and re-engagement with new goals. Compared to controls, depressed participants reported fewer approach goals , rated their approach goal (rewarding) outcomes as less likely to happen and avoidance goal (threatening) outcomes as more likely to happen. Depressed participants also reported greater ease of disengagement from unattainable goals and more difficulty re-engaging with new goals than controls. Our findings extend current knowledge of the psychopathology of depression from a goal regulation perspective, suggesting that pessimism around goal pursuit accompanies fewer approach goal pursuits and a general tendency to disengage when difficulties are encountered.Despite the development of prominent theoretical models of goal motivation and its importance in daily life, research has rarely examined goal dysregulation processes in clinical depression. Here we aimed to investigate problematic aspects of goal regulation in clinically depressed adults, relative to controls. Depressed participants ( Prominent theories of motivation posit that dysfunctions in approach and avoidance systems underpin emotional susceptibility and affective disorders – 2. Gray‘to run a marathon’) whereas avoidance goals refer to representations of undesirable future outcomes  ,,greater attempts . HoweverWe found that depressed individuals also reported struggling to engage in alternative goals when they have to stop pursuing unattainable goals, mirroring the apparent difficulty depressed persons had in generating idiographic approach goals relative to controls. The relative inability to engage with new goals among depressed persons may also reflect a generalized pessimism around goal attainment. Reduced goal re-engagement is consistent with the view that individuals who have difficulty developing new plans would be at a greater risk of depression . The resIn terms of clinical implications, our results suggest that depressed persons struggle to articulate positive goals to strive for and find it more difficult to engage in alternative goals when existing goals become unattainable. These findings also suggest that depressed people have reduced expectancies for attaining goal outcomes. Although these results are cross-sectional and do not in themselves identify treatment targets, they indicate that there may be value in helping depressed people to identify approach goals to strive for and challenge pessimistic reasons why participants think that goals cannot be achieved. In this respect, the results are consistent with behavioural activation, which encourages depressed persons to engage behaviourally with goals in the world, and cognitive-behaviour therapy, which may be useful in tackling hopelessness around goal attainment. Interventions that specifically address goal pursuit have shown promise in reducing depressive symptoms in clinical and non-clinical populations. Building confidence and self-efficacy around goal pursuit may also be a useful strategy in preventing depressive onset, but further research is needed.Some methodological considerations deserve comment. Diagnosis was determined via self-report (PHQ-9), clinical assessment and a brief structured interview. In contrast to the brief interview schedule designed for this study, the use of a validated interview schedule such as the SCID would provide a more comprehensive assessment. There were two 16-year-old participants in the otherwise adult sample, but the pattern of significant results was identical when these two participants were excluded. Furthermore, the cross-sectional design means that it is unclear whether depression causes dysregulation of goal processes or whether dysregulated goal processes cause depression, or whether goal dysregulation is epiphenomenal to the depressive episode. Longitudinal studies could usefully clarify whether dysregulated goal pursuit precedes depressive episodes. Future research would benefit from supplementing self-report measures of goal flexibility with behavioural measures that capture goal-directed effort among alternative pursuits.In conclusion, our findings illustrate altered goal processes in depression, characterized by blunted approach goal motivation, pessimistic goal expectancies, and increased goal disengagement and reduced goal re-engagement in the face of goal difficulties. Notably, effect sizes for group differences were large . AlthougS1 File(SAV)Click here for additional data file.


Haemophilus influenzae (NTHi)-associated ear and respiratory diseases (including pneumonia) represent a major health burden in many parts of the world. NTHi strains retrieved from the upper airways commonly reflect those found in the lower airways. Despite growing genomic and genotyping data on NTHi, there remains a limited understanding of global and regional NTHi population structures. The aim of this study was to determine whether nasopharyngeal carriage in four Australian paediatric groups at varying risk of NTHi colonisation was dominated by the same NTHi genotypes. Genotyping data generated by PCR-ribotyping were evaluated for 3070 NTHi isolates colonising the nasopharynges of Aboriginal and non-Aboriginal children enrolled in four longitudinal studies in three separate urban and remote regions of Australia. Several NTHi PCR-ribotypes dominated in nasopharyngeal carriage, irrespective of study setting. Principal coordinates analysis confirmed a cluster of common PCR-ribotypes among all cohorts. In conclusion, we identified dominant PCR-ribotypes common to geographically disparate Australian paediatric populations. Future genomic analyses will shed further light on the precise factors underlying the dominance of certain NTHi strains in nasopharyngeal carriage.Non-typeable  Haemophilus influenzae (NTHi) represent a major health burden worldwide  and chronic [e.g. bronchiectasis]) NTHi populations by whole genome sequencing or other genotyping means is necessary to determine the relevance of carriage versus disease genotype frequency, and may shed light on the factors supporting dominance of certain NTHi genotypes. Although the Australian experience may not necessarily apply elsewhere, whole genome sequence data from Australian and international NTHi isolates have (to date) demonstrated a level of core genome similarity between global and Australian NTHi populations . Thus, w


Left ventricular pseudoaneurysm is a rare complication of myocardial infarction that carries a high mortality rate. Although conventional wisdom suggests prompt surgical repair in order to mitigate risk of expansion and rupture, there are some data to support non-operative management in asymptomatic individuals with likely chronic pseudoaneurysms, particularly when surgical candidacy is poor. We present a case of a medically managed left ventricular pseudoaneurysm subsequent to inferior ST-segment elevation myocardial infarction with 6-month follow-up data. Left ventricular pseudoaneurysm is a rare complication of myocardial infarction (MI) associated with serious morbidity and mortality . Unlike A 68-year-old man with history of chronic obstructive pulmonary disease and asbestos-related pneumoconiosis presented with chest pain and diaphoresis after a motor vehicle accident. Electrocardiogram revealed ST elevations in the inferior leads. The patient was promptly taken to the cardiac catheterization lab where he was found to have complete occlusion of the distal right coronary artery. The patient underwent successful percutaneous coronary intervention of the right coronary artery with placement of a drug eluding stent. One day after the coronary intervention, he remained asymptomatic when echocardiogram revealed a left ventricular pseudoaneurysm in the distal inferolateral wall . Left veA rare complication of either transmural MI or cardiac surgery, acquired pseudoaneurysm of the left ventricle, poses a difficult management dilemma, particularly among hemodynamically stable patients who are asymptomatic yet poor surgical candidates. The risk of expansion and eventual rupture must be balanced against a high surgical mortality, but the rarity of the condition has made understanding its natural history and identifying the highest risk patients challenging.Risk factors for development of left ventricular pseudoaneurysm include female sex, first occurrence of either lateral or anterior wall MI, age greater than 60 years and severe single-vessel coronary artery disease, the latter two of which were features in our patient . TransthConservative management of left ventricular pseudoaneurysms has been described in several case series (Our patient’s severe underlying pulmonary disease precluded aggressive surgical management. Although possible, it is unlikely that his pseudoaneurysm was chronic and diagnosed incidentally on a routine post-infarct echocardiogram, which was not obtained under a high pre-test suspicion for pseudoaneurysm. As such, his clinical profile - an asymptomatic, acute and moderately sized pseudoaneurysm - reflects a slightly different demographic than captured by the aforementioned series, and makes application of a robust evidence-based management decision challenging. Development of a centralized registry of cases may help to better elucidate the true natural history of this rare entity, and should be the focus of future studies especially as advances in non-invasive diagnostic modalities are made and diagnostic awareness increases.


The creation of false memories within the Deese-Roediger-McDermott (DRM) paradigm has been shown to be sensitive to many factors such as task instructions, participant mood, or even presentation modality. However, do other simple perceptual differences also impact performance on the DRM and the creation of false memories? This study explores the potential impact of changes in perceptual disfluency on DRM performance. To test for a potential influence of disfluency on false memory creation, participants viewed lists under either perceptually disfluent conditions or not. Results indicated that disfluency did significantly impact performance in the DRM paradigm; more disfluent presentations significantly increased the recall and recognition of unpresented information, although they did not impact recall or recognition of presented information. Thus, although disfluency did impact performance, disfluency did not produce a positive benefit related to overall task performance. This finding instead suggests that more disfluent presentations can increase the likelihood that false memories are created, and provide little positive performance benefit. The creation of false memories within the Deese-Roediger-McDermott  paradigincrease task performance ).


The left ventricular (LV) remodeling process associated with significant valvular heart disease (VHD) is characterized by an increase of myocardial interstitial space with deposition of collagen and loss of myofibers. These changes occur before LV systolic function deteriorates or the patient develops symptoms. Cardiovascular magnetic resonance (CMR) permits assessment of reactive fibrosis, with the use of T1 mapping techniques, and replacement fibrosis, with the use of late gadolinium contrast enhancement. In addition, functional consequences of these structural changes can be evaluated with myocardial tagging and feature tracking CMR, which assess the active deformation (strain) of the LV myocardium. Several studies have demonstrated that CMR techniques may be more sensitive than the conventional measures (LV ejection fraction or LV dimensions) to detect these structural and functional changes in patients with severe left-sided VHD and have shown that myocardial fibrosis may not be reversible after valve surgery. More important, the presence of myocardial fibrosis has been associated with lesser improvement in clinical symptoms and recovery of LV systolic function. Whether assessment of myocardial fibrosis may better select the patients with severe left-sided VHD who may benefit from surgery in terms of LV function and clinical symptoms improvement needs to be demonstrated in prospective studies. The present review article summarizes the current status of CMR techniques to assess myocardial fibrosis and appraises the current evidence on the use of these techniques for risk stratification of patients with severe aortic stenosis or regurgitation and mitral regurgitation. Valvular heart disease (VHD) is an important public-health problem with an increasing prevalence along with ageing of the population . ModeratChronic pressure and volume overload caused by severe left-sided VHD results in LV remodeling. Changes in the extracellular matrix with deposition of collagen I and loss of myofibers at a later stage result in myocardial fibrosis, the hallmark of LV remodeling , 6. CardLV remodeling in response to chronic pressure and volume overload caused by VHD is characterized by progressive increase of the interstitial space with increased collagen volume fraction (reactive fibrosis) and eventually apoptosis of myocardial cells which are replaced by firm fibrous tissue (replacement fibrosis or scar). T1 mapping and LGE CMR techniques are currently the most frequently used techniques to directly assess myocardial fibrosis . Although still not implemented in routine clinical practice, the measurement of myocardial ECV in patients with AS has important clinical implications [2) but without LGE (replacement fibrosis) showed significantly higher all-cause mortality and AS-related mortality rates (36 per 1000 patients-year for both) as compared to the patients with normal myocardium  , pressure and volume overload induce growth of cardiomyocytes with addition of new sarcomeres in series and interstitial fibrosis, characterized by increased fibronectin and non-collagen components . SeveralMitral regurgitation (MR) is a heterogeneous disease, broadly classified as organic (primary) or functional (secondary) based on the underlying mechanism. Organic MR is due to intrinsic valvular disease whereas functional MR is caused by regional and/or global LV remodeling without structural abnormalities of the mitral valve . DegenerThese structural changes of the LV myocardium may be associated with subtle functional abnormalities. In 15 patients with chronic moderate and severe MR and preserved LV ejection fraction who underwent CMR with tissue tagging, Maniar et al. demonstrated preserved global longitudinal and circumferential strain but abnormal regional strain values: the septal LV segments exhibited impaired strain whereas the lateral segments showed compensatory hyper-contractility . SimilarTissue characterization and strain imaging with CMR have provided new insights into the pathophysiology of VHD. Current guidelines recommend valve surgery in severe symptomatic VHD or when LV function decreases , 3. HoweThe early valve replacement guided by biomarkers of left ventricular decompensation in asymptomatic patients with advanced aortic stenosis (EVOLVED) is the first multicenter randomized controlled clinical trial that will investigate whether the early valve intervention in patients with asymptomatic severe AS and midwall fibrosis on CMR improves patients’ clinical outcomes compared to the standard care (NCT03094143). The results of this study may have an impact on future guidelines and recommendations on treatment of VHD.


However, most species used for epigenomic studies are annual herbaceous plants, and epigenome dynamics has been poorly investigated in perennial woody plants, including grapevine. In this context, we propose grape as an essential model for epigenetic and epigenomic studies in perennial woody plants of agricultural importance.Epigenetic marks include Histone Post-Translational Modifications and DNA methylation which are known to participate in the programming of gene expression in plants and animals. These epigenetic marks may be subjected to dynamic changes in response to endogenous and/or external stimuli and can have an impact on phenotypic plasticity. Studying how plant genomes can be epigenetically shaped under stressed conditions has become an essential issue in order to better understand the molecular mechanisms underlying plant stress responses and enabling epigenetic in addition to genetic factors to be considered when breeding crop plants. In this perspective, we discuss the contribution of epigenetic mechanisms to our understanding of plant responses to biotic and abiotic stresses. This regulation of gene expression in response to environment raises important biological questions for perennial species such as grapevine which is asexually propagated and grown worldwide in contrasting  Epigenetic mechanisms regulate chromatin structure, gene expression, transposon mobility and DNA recombination . They ge5C) is found in all sequence context, including the CG and CHG  symmetrical motives and the non-symmetrical CHH motif , the remodeling of chromatin organization and specific classes of small RNAs and long non-coding RNAs . BrieflyHistone PTMs are also essential epigenetic signals that can occur at the N-terminal tail of core histones  through acetylation, methylation, phosphorylation and ubiquitination . Histone1). So far, histone PTM analysis relies on Chromatin Immunoprecipitation (ChIP) using specific antibodies followed by hybridization to tilling arrays , and analyzed with tilling arrays (MeDip-ChIP) or by Next Generation Sequencing (Medip Seq). Both approaches were used for methylome analysis for example in Arabidopsis, or poplar  and HUB2  or non-CG methylation  were markedly resistant to bacterial colonization.The profiling of the DNA methylomes of plants exposed to bacterial pathogen, avirulent bacteria, or salicylic acid revealed numerous stress-induced differentially methylated regions (DMRs) often coupled to differential gene expression . Mutant Arabidopsis since a triple mutant rdd (ros1 dml2 dml3), presents down-regulation of stress response genes and increased susceptibility to a fungal pathogen. Furthermore, these authors showed that DNA demethylases target promoter transposable elements in stress responsive genes to positively regulate them.DNA demethylation likely primes transposable elements as well as defense gene induction through the concomitant activation of their transactivators and/or the interference with other chromatin marks . Some imFigure 1; Natural epigenomic variation occurs during species evolution  and togeArabidopsis by generating Epigenetic Recombinant Inbred Line (EpiRILs) populations derived from decrease in DNA methylation 1-2 (ddm1-2) or the met1 parents .Several studies have already emerged in crops, in particular, recent analyzes carried out in tomato fruits  constituripening  as reporripening . In thisChemical treatments that affect DNA methylation patterns could also be utilized to generate epimutations  though tFigure 1). DNA methylation may generate multiple epialleles with various expression levels, thereby leading to continuous quantitative variation of a trait .In line with these ideas, the recent analysis of the transcriptomic changes associated with grape infection with the necrotrophic pathogen  defense . Genes cV. vinifera. Comparing the epigenomes of wild and cultivated Vitis species with and without biotic and non-biotic stresses will bring insights on the epigenetic basis of grapevine resistance to adverse conditions with potential impact in breeding strategies. Moreover, epigenetic marks may participate in the priming mechanisms to better withstand biotic and abiotic stresses . Crop improvement via locus-specific epigenetic manipulation has become increasingly feasible with TALE- or CRISPR-based genome editing technologies (In a near future, epigenetic marker-assisted breeding strategies will be applied to select for agronomical desirable epigenetic quantitative traits (nologies . Such teAF and PG designed the perspective and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Neurorehabilitation plays an important role for neural plasticity and functional recovery following neurological disease. Neurorehabilitation is based on rehabilitation medicine, neuroscience, and neurophysiology. This special issue focused on the efficacy and mechanism by which neurorehabilitation can induce neural plasticity and functional recovery.Articles published in this special issue covered neurorehabilitation following stroke, spinal cord injury, and other neurological disorders.T. Fujiwara et al. reviewed the neurorehabilitation using electromyography- (EMG-) controlled neuromuscular electrical stimulation for upper extremity motor function following stroke. This review showed that application of wearable EMG-controlled NMES for 8 hours in daytime improved both arm and hand function and can induce plastic change in intracortical interneuron and spinal reciprocal interneuron.J. Fu et al. reviewed the functional recovery induced by the exercise after spinal cord injury. Therapeutic exercise can induce reshaping of the skeletal muscle, physiological change of spinal motor neuron, and remodeling of the motor cortex.Neurophysiology and neuroimaging are great tools for revealing neural plasticity induced by neurorehabilitation.Neuroimaging studies in this special issue revealed novel findings of cortical reorganization following spinal cord injury, facial nerve palsy, hearing loss, and aerobic exercise in older adults.Neurophysiological studies in this special issue revealed neural activity related to reduction of gait speed in Parkinson's disease and functional recovery of hemiplegia following stroke.Advanced neurophysiological and neuroimaging techniques provided new insight into the functional recovery in neurological disorders.We hope this special issue provides further knowledge of neurorehabilitation.Toshiyuki FujiwaraNam-Jong PaikThomas Platz


In patients with schizophrenia, distributed abnormalities are observed in grey matter volume. A recent hypothesis posits that these distributed changes are indicative of a plastic reorganization process occurring in response to a functional defect in neuronal information transmission. We investigated the structural covariance across various brain regions in early-stage schizophrenia to determine if indeed the observed patterns of volumetric loss conform to a coordinated pattern of structural reorganization.Structural MRI scans were obtained from 40 healthy adults and 41 age, gender and parental socioeconomic status matched patients with schizophrenia. Volumes of grey matter tissue was estimated at regional level across 90 atlas-based parcellations. Group level structural covariance was studied using a graph theoretical framework.Patients had distributed reduction in grey matter volume, with high degree of localized covariance (clustering) compared to controls. Patients with schizophrenia had reduced centrality of anterior cingulate and insula but increased centrality of the fusiform cortex, compared to controls. Simulating targeted removal of highly central nodes resulted in significant loss of the overall covariance patterns in patients compared to controls.Regional volumetric deficits in schizophrenia are not a result of random, mutually independent processes. Our observations support the occurrence of a spatially interconnected reorganization with systematic de-escalation of conventional ‘hub’ regions. The resulting morphological architecture may be primed for compensatory functions, albeit with a high risk of inefficiency.


Prenatal diagnosis of congenital heart disease is important to ensure both informed parental counselling before birth, and effective planning of potentially life-saving interventions after birth. MRI offers a safe, radiation-free adjunct to conventional diagnostic modalities, particularly in mothers with high BMI or at later gestations where ultrasound may be limited. However, cardiovascular imaging in the fetus presents several challenges, not least due to the small size and constant motion of the fetal heart, the lack of external cardiac gating, and gross fetal and maternal motion. We present our initial experience of 20 fetal cardiac MRI cases, each referred following fetal echocardiographic assessment to resolve specific points of diagnostic uncertainty.Referrals were based on the judgements of the attending fetal cardiologists between June 2014 and May 2015. A paediatric cardiologist with expertise in cardiac MR was present at every scan. Following a three-plan localiser, diagnostic sequences were generally limited to half-Fourier acquisition single-shot turbo spin-echo (HASTE) and balanced steady state free precession (bSSFP) gradient echo sequences. A large field of view bSSFP cine  scan with low spatial resolution but higher temporal resolution (303 ms) was used following the localiser to demonstrate the degree of gross fetal movement. If needed, further shortened localiser sequences were also used, followed by bSSFP scans with higher spatial resolution for diagnostic purposes.Single-shot turbo spin-echo (HASTE) sequences produced T2 weighted images with black-blood like contrast which was particularly useful for assessing the extracardiac vascular anatomy. Balanced SSFP images gave good contrast between the blood pool and surrounding tissue and were useful for intracardiac structures; however these were more susceptible to motion artefacts. Real-time SSFP sequences allowed for dynamic imaging of the beating heart in assessing moving structures (e.g. cardiac masses and diverticulums); when used in combination with HASTE sequences, we were able to characterise rhabdomyomas in three patients.Our preliminary experience of fetal cardiac MRI suggests that it can provide safe, clinically useful complimentary imaging in the majority of selected cases within a tertiary fetal cardiac unit, particularly for extracardiac vascular anatomy and intracardiac masses. In the future, prenatal MRI may have a more prominent role in routine fetal cardiovascular assessment.


Volumetric brain differences between persons meeting criteria for a clinical high-risk state for psychosis (CHR) and healthy controls (HC) have been previously reported, yet little is known about potential abnormalities in surface-based morphological measures. Gyrification  remains relatively stable across the lifespan and is minimally influenced by ubiquitous confounding factors . Recently, a multi-site analysis conducted in 104 CHR persons found global increases in cortical gyrification compared to HC . If replicated, gyrification abnormalities in CHR could potentially serve as early neuromarkers of elevated risk, and thus could eventually be used to identify objectively and efficiently the CHR state.www.pronia.eu), a large-scale international longitudinal study currently consisting of 10 European sites. Cortical surfaces were reconstructed from structural MRI images using a volume-based, newly introduced technique called the Projection-Based-Thickness (PBT) as available in the SPM-based-toolbox CAT12. Local gyrification was quantified automatically across the whole brain as absolute mean curvature for each vertex of the brain surface mesh consisting of thousands of individual measurement points. Vertex-wise differences of curvature values were calculated applying a General Linear Model, corrected for age, gender and site effects. Results were investigated at corrected and uncorrected levels.A total of 124 CHR and 264 HC subjects were recruited as part of the PRONIA consortium (We found no significant differences in vertex-wise gyrification between CHR and HC at either corrected or uncorrected levels (p>0.05). Further investigations of potential confounding site effects also did not reveal differences.Our preliminary findings suggest that CHR subjects do not show whole-brain gyrification abnormalities when compared with healthy subjects. These negative results agree with literature suggesting that cortical convolution might be more affected by neurodevelopmental or genetic factors, and thus deviations from normal patterns might not be detectable in heterogeneous samples of at-risk subjects wherein the etiology and ultimate prognosis is unknown. In order to better investigate differences in cortical folding and address the role of gyrification as neuroanatomical biomarker for psychosis, future investigations should focus on subgroups within CHR populations  in addition to specific analyses of individuals with higher neurodevelopmental  or genetic  loadings.


Women with signs and symptoms of ischemia--but no obstructive coronary artery disease--often have coronary microvascular dysfunction (CMD), and are at increased risk of major cardiovascular events, including heart failure. Using cardiac magnetic resonance tissue tagging, we recently found subclinical diastolic dysfunction in these women, suggesting that ischemia-related diastolic dysfunction may be mechanistically linked to the development of heart failure. Tissue tagging involves specialized image acquisition and post processing, and thus is not typically suitable for large patient studies. We hypothesized that feature tracking of conventional  cardiac cine images would provide similar information. We therefore compared feature tracking with gold-standard tissue tagging, and then, used feature tracking to assess left ventricular function in women with suspected CMD.We first conducted a validation study comparing feature tracking (applied to standard cine images) to the gold-standard tissue tagging approach (applied to tagged cine images). To this end, in n = 59 individuals, we measured circumferential strain and diastolic circumferential strain rate (CSdR) by tissue tagging  and feature tracking . Following the validation study, we performed feature tracking on cine images from n = 116 women with suspected CMD ("cases") enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) Study, and n = 28 aged-matched healthy reference controls.In the validation study, feature tracking correlated with tissue tagging Fig. , providiFeature tracking applied to cine myocardial function images provides a convenient method to analyze wall motion in conventional CMR protocols. In this study, we used this technique to both confirm and extend previous observations in a cohort of women with suspected CMD, demonstrating subclinical diastolic and systolic dysfunction. Further analysis is warranted to better characterize the advantages and limitations of this approach in studies involving patients with suspected CMD and no obstructive disease.


Superior Longitudinal Fasciculus (SLF) differences are consistently reported in psychotic disorders. The SLF is a complex large bundle of association white matter fibers that bidirectionally connect caudal, temporal cortex and inferior parietal cortex to locations in the frontal lobe. Advances in tractography methodologies detail four discrete subdivisions ). Greater specificity of the SLF subdivisions and associated cognitive networks may clarify the mechanisms of divergent tract developmental and functional aspects associated with psychotic experience symptomology in population based samples of adolescents within the extended psychosis continuumA case-control sample of 25 adolescents reporting psychotic experiences versus 25 controls (mean age 13.7 years). We employed High Angular Resolution Diffusion Imaging (HARDI) based data with constrained spherical deconvolution (CSD) based fibre tractography to delineate the discrete subdivisions of the SLF including the arcuate fasciculous. Following tract identification, standard diffusion metrics, , and Diffusivity measures MD, AD and RD), were assessed. A secondary supportive “along-tract” analysis to ascertain more subtle patterns of variation of tract integrity over the tract length was applied. White matter nodal analysis exploring the structural connectivity was applied to investigate additional functional networks recruited by and interconnected via the SFL. We investigate the ability of tractography of the SLF subdivisions and nodal analysis to identify possible differences between adolescents experiencing subclinical psychotic like experiences and those who don’t.Our results agree with recent studies of the SLF I and AF  revealing a pattern of asymmetry of these tracts with more extensive tract bundles being consistently identified in the left hemisphere compared to the right. Along-tract analysis revealed subtle patterns of change in discrete subdivisions of the SLF while nodal analysis shows promise in its ability to define precise organisational networksDelineating the SLF subdivisions may clarify potential developmental trajectories between frontal and parieto-temporal speech-related areas contributing to the pathogenesis of psychotic like experiences. These results reveal the presence of aberrant structural connectivity in young adolescents with psychotic experiences.


Fourteen patients underwent surgery for benign intra-thoracic goitre many presented with respiratory distress due to tracheal compression, and in some desperately ill patients inoperable cancer of the lung was diagnosed. The plain chest X-ray revealed the goitre and once the true diagnosis was suggested, prompt surgical intervention followed.


A 76-year-old male presented for reverse total shoulder arthroplasty (TSA) in the beach chair position. A preoperative interscalene nerve catheter was placed under direct ultrasound-guidance utilizing a posterior in-plane approach. On POD 2, the catheter was removed. Three weeks postoperatively, the patient reported worsening dyspnea with a subsequent chest X-ray demonstrating an elevated right hemidiaphragm. Pulmonary function testing revealed worsening deficit from presurgical values consistent with phrenic nerve palsy. The patient decided to continue conservative management and declined further invasive testing or treatment. He was followed for one year postoperatively with moderate improvement of his exertional dyspnea over that period of time. The close proximity of the phrenic nerve to the brachial plexus in combination with its frequent anatomical variation can lead to unintentional mechanical trauma, intraneural injection, or chemical injury during performance of ISB. The only previously identified risk factor for PPNP is cervical degenerative disc disease. Although PPNP has been reported following TSA in the beach chair position without the presence of a nerve block, it is typically presumed as a complication of the interscalene block. Previously published case reports and case series of PPNP complicating ISBs all describe nerve blocks performed with either paresthesia technique or localization with nerve stimulation. We report a case of a patient experiencing PPNP following an ultrasound-guided placement of an interscalene nerve catheter. Interscalene blocks (ISB) are frequently used as an adjuvant therapy for shoulder surgery to optimize postoperative pain, decrease the length of hospitalization, and minimize the time in the postanesthesia care unit . Up to 1Prolonged phrenic nerve paresis (PPNP) resulting from interscalene catheters is rare. One previous investigation identified cervical degenerative disc disease as a potential risk factor for developing PPNP following ISB . OtherwiVerbal and written permission was obtained from the patient for the publication of this report. Written permission was obtained for the use of the patient's medical records.A 76-year-old male of average body habitus with history of hypertension, chronic obstructive pulmonary disease (COPD), coronary artery disease, and myocardial infarction status after three percutaneous coronary interventions presented for reverse TSA in the beach chair position under general anesthesia with an interscalene nerve catheter for postoperative pain management. After obtaining surgical and anesthetic consent, the patient was placed in a semirecumbent position with his head turned slightly toward the nonoperative shoulder with care to avoid neck discomfort. Intravenous midazolam and fentanyl were administered to achieve moderate sedation for the placement of an interscalene nerve catheter under direct ultrasound-guidance utilizing a lateral-to-medial in-plane approach as described by Antonakakis et al. . A 17-gaThree weeks postoperatively, the patient presented to his PCP with a complaint of worsening dyspnea. He was diagnosed with bronchitis and prescribed a course of antibiotics and inhalers. After completing his antibiotic regimen, the patient continued to experience dyspnea and was referred to a pulmonologist for consultation. Further investigation revealed that the patient had both orthopnea and worsened dyspnea on exertion. The physical exam revealed decreased breath sounds in the right lower lobe lung field and bilateral upper airway expiratory wheezing. A chest X-ray (CXR) demonstrated an elevated right hemidiaphragm with a small right-sided pleural effusion.A repeat CXR six weeks postoperatively continued to demonstrate an elevated right hemidiaphragm and right-sided pleural effusion, unchanged from his previous CXR . A diaphThe anatomical proximity of the brachial plexus and phrenic nerve leads to a nearly universal transient blockade of the phrenic nerve with large volume ISB; however, PPNP is a rare complication with a reported incidence to be 1 out of every 2069 single shot ISB or 0.048% . The cloAlthough decreasing the volume of local anesthetic utilized for interscalene blockade has been shown to decrease the incidence transient phrenic nerve palsy , total dProposed mechanisms for PPNP complicating an ISB include compression neuropathy from needle trauma, intraneural injection, chemical toxicity, or neuronal ischemia , 11. ShoPreviously published case reports and case series of PPNP complicating ISBs all describe nerve blocks performed with either paresthesia technique or localization with nerve stimulation (NS). Of note, this patient's interscalene catheter was performed with only US guidance and did not rely on NS or paresthesia techniques. Although the use of US guidance for regional anesthesia has not demonstrated a reduction in peripheral nerve injury, routine use of US guidance allows practitioners many practical advantages . A recenWe attempt to add to the body of literature describing the phenomenon of PPNP following ISB. The only previously identified risk factor for PPNP is cervical degenerative disc disease . Our pat


De novo synthesis of folates in plants is tightly regulated through feedback-regulation of certain pathway catalysts. Recently, we investigated the prospects of incessant production of folates in an evolutionary conjunction, through the overexpression of feedback targeted and evolutionarily conserved heterologous E.coli dihydroneopterin aldolase (EcDHNA) in tobacco.EcDHNA surface having critical amino-acid differences as Ile 64 (His_63), Val 70 (Phe_69), His 75 (Arg_78) and Arg 79 (Glu_72). These structural characteristics are indicative of evolutionary signatures of the catalytic feedback-regulation of folate manufacturing. We exploited the biotechnological potential of such allosterically diverged trans-DHNA for improved folate production in plants. Nonetheless, genetic manipulation of single enzymes modulating complex pathways such as folate biosynthesis is often inadequate to achieve desired phenotypes; therefore, multi-gene integration with explicit genic-combination for folate enrichment in plants has also been projected for future folate agri-biofortification schemes. Also, the overexpressed bacterial DHNA protein was significantly correlated with the intracellular folate production in E. coli cells, assuming its potential usage for crop biofortification. Here, we provide additional data on the evolutionary characterization and homologies based allosteric site prediction at the surface of DHNA protein of bacterial and plant origins for the designing of genome engineering strategies, and also highlight the need of gene pyramiding for future crop biofortification programs.Recently, we reported the enhanced production of folates in tobacco leaves by the constitutive overexpression of recombinant i.e. bacteria, cyanobacteria and plants, the amino acid sequences were aligned using “A la Carte” mode of Phylogeny.fr online tool. In result, an unrooted phylogram was constructed having distinct clades of plants (both monocots and dicots), bacteria and cyanobacteria. Among bacterial DHNA sequences, E. coli and Xanthomans shared maximum sequence similarity whereas nodulating bacteria Rhizobium sp. showed prominent evolutionary relatedness with cyanobacteria members. On the contrary, selective bacterial representatives exhibited relatively more proximity to plants or algal species than other bacteria  reported that ectopic overexpression of folA enzyme in folate biosynthetic pathway led to very high production of pterins in the cell, whereas little increase in the folate level was observed. Therefore, important enzymes such as DHNA and DHPS that are subjected to feedback regulation may be genetically manipulated in crop plants by the overexpression of heterologous proteins having divergent protein-regulation sites.The phylogenetic analysis of DHNA orthologs among bacterial, cyanobacterial and plants (monocot and dicot species) revealed certain degree of protein sequence conservation highlighting their functional conservation at evolutionary scale . As follEcDHNA protein in plants would lead to the independent and uninterrupted synthesis of tetrahydrofolate, in-silico predictions of allosteric regulatory sites at EcDHNA and AtDHNA surfaces were predicted using PARS, a server for the prediction of allosteric and regulatory sites on protein structures.EcDHNA and AtDHNA were extracted from the Protein Data Bank (PDB) with accession codes 2O90 and 1SQL, respectively. In silico prediction of allosteric sites in both EcDHNA and AtDHNA responsible for protein-regulation mechanism was performed. This prediction analysis has identified seven and eight surface allosteric regulatory cavities on EcDHNA and AtDHNA, respectively. One common cavity (CAV_5_Z) in both the proteins was identified as substrate binding site  gene cassette as plant selection marker.EcDHNA to the cellular folate production under crucial metabolic constraints in cellular folate biosynthesis mainly through tight feedback regulation of native aldolases. The use of bacterial DHNA gene has definitely persuaded the turnover of end product in folate biosynthetic pathway that may have incredible impact on crop nutrigenomics programs.Could the folate levels be increased by ectopic over-expression of candidate folate biosynthetic pathway genes in plants? Based on the significant correlation between heterologous overexpression of DHNA gene and folate over-production, we assumed that the bacterial folE gene enhanced pterins biosynthesis up to 1250-fold without necessarily allaying with folate production in transgenic Arabidopsis,folE enzyme with aminodeoxychorismate synthase (ADCS) in p-ABA branch resulted into inadequate variation of the folate concentration in plants.p-ABA branch enzymes may not suffice for the ultimate genic-combination of folate vitamin enhancement in plants. If so, what genic-combination(s) should be preferred for improved folate production in the cell?Low amounts of folates in crop plants may be largely attributed to the tight feedback regulation of certain folate biosynthetic enzymes. Up to now, various plant species have been genetically modified with individual folate biosynthetic pathway genes for folate enhancement,folB) responsible for the formation of 6-hydroxymethyl-dihydropterin in folate biosynthesis pathway and DHPS (folKP) responsible for the formation of dihydropteroate are subjected to feedback regulation (EcDHNA gene potentially regulates folate biofortification in tobacco.EcDHNA has evolved with divergent allosteric sites at its surface which may avoid folate feedback regulation, it's pyramiding with other candidate genes of folate biosynthetic pathway such as folE and ADCS would be a promising experimental combination of genes for future folate metabolic engineering. As performed in our study,i.e. DHNA and DHPS genes and investigate their discrete impact on the folate production. Also, pyramiding of these two transgenes in the field through cross-pollination and analyze their collaborative impact on the folate production in F1 generation would be of tremendous scientific interest providing evidences for the genetics of folate agri-biofortification.Evidently, an aldolase enzyme DHNA (gulation . Recentl


Wolbachia, Rickettsia and Spiroplasma) across 20 species of dance flies. We found evidence of widespread infection by all three symbionts and variation in sex-specific prevalence across the taxa sampled. However, there was no relationship between infection prevalence and adult sex ratio measures and no evidence that female ornaments are associated with high prevalences of sex-biased symbiont infections. We conclude that the current distribution of endosymbiont infections is unlikely to explain the diversity in mating systems among dance fly species.Maternally inherited bacterial endosymbionts are common in many arthropod species. Some endosymbionts cause female-biased sex ratio distortion in their hosts that can result in profound changes to a host’s mating behaviour and reproductive biology. Dance flies (Diptera: Empidinae) are well known for their unusual reproductive biology, including species with female-specific ornamentation and female-biased lek-like swarming behaviour. The cause of the repeated evolution of female ornaments in these flies remains unknown, but is probably associated with female-biased sex ratios in individual species. In this study we assessed whether dance flies harbour sex ratio distorting endosymbionts that might have driven these mating system evolutionary changes. We measured the incidence and prevalence of infection by three endosymbionts that are known to cause female-biased sex ratios in other insect hosts ( Vertically transmitted symbiotic bacteria that are inherited from mother to offspring are common infections of arthropods –3. TheseA strong female bias in population sex ratio can profoundly alter the dynamics of sexual selection e.g. –8). When. When8])The dance flies (Diptera: Empididae: Empidinae) exhibit incredible interspecific mating system diversity . Dance fThe ultimate evolutionary causes of these interspecific mating system differences across the dance flies remain largely unknown. One possibility is that reproductive parasites have caused female-biased population primary sex ratios in some species. Such biases could conceivably lead to competition among females for access to males, which could in turn favour the evolution of elaborate female sexual ornaments. Such symbiont-induced skewed sex ratios may have altered mating behaviour (see ), triggeWolbachia )We tested for evidence that sex ratio distorting reproductive parasites have driven female-specific ornament evolution in the Empidinae. We found no evidence that reproductive parasites with strong impacts on host population sex ratio are common in this insect group. Furthermore, there was no association between the presence of putative sex ratio distorting endosymbionts and the presence of exaggerated female ornamentation. Further study with a focus on methods that allow for the primary or secondary sex ratio of the hosts to be measured would be helpful to more comprehensively measure sex ratio distortion in dance flies. In addition, research looking into spatial patterns of both the sex ratio of the dance fly hosts and the sex-specific prevalence of symbionts would be fruitful. While we cannot definitively rule out the possibility that historical infections by symbionts caused sex ratio distortion in ancestral populations, our data strongly suggest that female-biased OSRs and female-specific ornaments are being maintained in dance flies for some other reason than sex ratio distorting symbionts. Further research into sexual and natural selection within the mating swarms and reproductive behaviours of dance flies are important for fully understanding the diversity of reproductive phenotypes observed across this system.


Tissue damage derived from tumors, traumatic events, inflammatory diseases, or just aging causes life quality impairment. Thus, tissue regeneration not only represents the main goal of regenerative therapy but also is certainly one of the greatest challenges of modern medicine.Mesenchymal stem cells (MSCs) can be isolated from different source tissues in the adult organism. MSCs can differentiate in mature cells of different lineages; thus, if opportunely targeted, they have the potential to regenerate and heal the injured tissue. The scientific contributions which are part of this special issue present and analyzed these items both in the form of research articles and reviews.The bone marrow is still the gold standard tissue for harvesting MSCs: different clonal cells were analyzed showing heterogeneity; alkaline phosphatase assay could indicate the precursor's lineage . Dental tissues also contain MSCs: in particular, the dental follicle  and dentA great challenge in regenerative therapy is the guidance of wound healing. MSCs promote wound healing, and human umbilical cord MSCs accelerate wound repair and hair follicle regeneration via Wnt overexpression . Interestingly, as shown by X. Liu et al., overexpression of semaphorin 3A in adipose-derived stem cells leads to a phenotype switch toward the osteoblastic lineage by upregulating the Wnt pathway as well. These studies on alternative sources of MSCs highlight the importance of molecular signals that might direct MSC fate and more specifically guide them to form mineralized tissue .β signaling pathway and stimulating the expression of microRNA21 . Given that natural composition and structure of the extracellular environment has a profound impact on MSC osteogenic differentiation [To increase healing at bone fracture sites, several approaches that stimulate physically the differentiation of MSC have been developed. Pulsed electromagnetic fields promote bone marrow MSCs osteogenic differentiation by activating TGF-ntiation , a varieGiorgio MoriGiorgio MoriGiacomina BrunettiGiacomina BrunettiFiliberto MastrangeloFiliberto MastrangeloElisabetta A. Cavalcanti-AdamElisabetta A. Cavalcanti-Adam


Hepatocellular Carcinoma (HCC) commonly develops in chronically damaged liver tissues. The resulting regenerative and inflammatory processes create an adverse milieu that promotes tumor-initiation and progression. A better understanding of the hepatic tumor-microenvironment interaction might infer profound therapeutic implications.Integrative whole genome and transcriptome analyses of different tumor regions, the invasive tumor border and tumor-surrounding liver (SL) were performed to identify associated molecular alterations and integrated with our existing HCC database. Expression levels and localization of established CSC markers were assessed in pre-neoplastic lesions and confirmed in two independent patient cohorts using qRT-PCR, immunohistochemistry and immunofluorescence.Our results indicate that genomic and transcriptomic profiles between SL and different tumor regions are quite distinct. Progressive increase in genetic alterations and activation of pathways related to proliferation as well as apoptosis were observed in the tumor tissue, while activation of stemness markers was present in cirrhotic SL and continuously decreased from pre-neoplastic lesions to HCC. Interestingly, the invasive tumor border was characterized by inflammatory and EMT-related gene sets as well as activation of pro-survival signaling. Consistently, integration of gene expression signatures with two independent HCC databases containing 300 HCCs revealed that border signatures are predictive of HCC patient survival.Prognostic significance of the permissive liver microenvironment might be a consequence of a pro-oncogenic field effect that is caused by chronic regenerative processes. Activation of key oncogenic features and immune-response signaling indicates that the cross-talk between tumor and microenvironment might be a promising therapeutic and/or preventive target. Hepatocellular carcinoma (HCC) ranks among the most common cancers worldwide . In the It is well recognized that acquisition of pre-neoplastic (epi-)genetic alterations in the hepatic microenvironment induces a continuum of morphologic changes from chronic inflammatory cell death over cirrhosis to dysplastic lesions which promotes malignant transformation . IntenseSeveral immune response-related and pro-oncogenic molecules induce opposing effects when activated in diverse parenchymal and non-parenchymal cell types (e.g. immune cells versus hepatocytes) and during different states of the chronic liver disease  which underlines the critical importance of the interaction of signals from the microenvironment and the tumor cells for tumor initiation and progression , 12. OthThe importance of the chronic inflammatory liver diseases for HCC initiation and progression has been repeatedly demonstrated . To charWe next assessed the somatic genetic alterations present in the different regions by profiling the corresponding tissues using Illumina OmniExpress arrays followed by GISTIC 2.0 analyses. Overall, progression from SL to T showed a continuous increase in genetic alterations Figure . As expeOur molecular analyses indicated a predominant activation of proliferative signaling in the T region that might reflect tumor cell proliferation thereby potentially supporting tumor expansion. Extension of the GSEA for the T region confirmed this finding and demonstrated an enrichment of gene sets associated with deregulation of cellular genes particularly related to tumor cell proliferation in cervical cancer  as well Since our molecular analyses indicated an activation of stemness in the SL region, we next assessed the gene expression levels of specific HCC/differentiation markers  as well as the selected (cancer-) stemness markers  and pluripotency genes (NANOG). As expected, a strong activation in expression levels of AFP and GPC3 as well as a concomitant downregulation of albumin levels were observed from SL to T Figure . NotablyTo confirm that the diseased hepatic tumor microenvironment is the critical determinant of stemness activation, we next assessed expression levels of the stemness genes in livers containing metastasis from different primaries (n = 5). Importantly, we found that these markers were not induced in the non-diseased liver tissue (i.e. in the absence of chronic liver damage) Figure . HoweverTo confirm the activation of inflammatory gene sets and dissect the corresponding immune cells reflected by the molecular changes, we limited our GSEA query to gene sets with association to immune-related properties. We observed a significant enrichment of gene sets related to alternative M2 macrophage activation that might exert pro-tumorigenic function Figure . FurtherFinally, we tested the clinical significance of our identified SL, B and T signatures and integrated all three signatures with our previously published gene expression dataset of 53 human HCC.  SubsequeThe notion that HCC patients display two diseases that are inextricably linked to each other, i.e. a chronic liver disease and a malignant tumor, is increasingly recognized, whereby the diseased hepatic microenvironment significantly promotes cancer initiation and progression while concomitantly limiting aggressive therapeutic approaches . TherefoTo address the importance of distinct peritumoral and tumoral regions for hepatocarcinogenesis we analyzed the molecular profiles of tumor-surrounding liver tissue, the invasive tumor border and core tumor tissue by genome-wide approaches and at different molecular levels. The transcriptome analyses confirmed a distinct gene expression profile for each of the different regions Figure . As expeTissue from 28 patients with confirmed HCC undergoing resection at the Department of Surgery, University of Mainz, Germany were collected following patient informed consent and local ethics committee approval. Validation cohort of 20 patients was obtained from the Institute of Pathology, University of Basel, Switzerland. Clinicopatholigical details are provided in http://www.ncbi.nlm.nih.gov/geo, accession number: GSE84598). Details of the analyses are provided in the A total of 200 ng RNA was linearly amplified as recommended by the manufacturer  and analyses were performed as described before . The micDiagnosis of HCC was established by expert pathologists. Tissue was either fixed in 4% formaldehyde and embedded in paraffin or preserved for cryosections and cut in 3-5 μm sections. Antibodies and conditions for fluorescence and immunohistochemical staining are listed in Statistical analysis was performed using Student's t-test, Friedman- test for multiple group comparisons followed by Dunns posthoc test as indicated. P-values ≤0.05 were considered statistically significant. Results are presented as means ± SD or means ± SEM as indicated. Survival analyses were performed using log rank (Mantel-Cox) tests.


The significant proportion of schizophrenia patients refractory to treatment targeting the dopamine system suggests that more than one mechanism may cause psychotic symptoms. Reinforcement learning tasks have frequently been employed in schizophrenia to assess dopaminergic functioning and reward processing, but studies have not directly compared groups of treatment-refractory and non-refractory patients.In the current functional magnetic resonance imaging study 21 patients with treatment resistant schizophrenia (TRS), 21 patients with non-treatment resistant schizophrenia (NTR), and 24 healthy controls (HC) performed a probabilistic reinforcement learning task, utilising emotionally valenced face stimuli which elicit a social bias toward happy faces. Behavior was characterized with a reinforcement learning model. Trial-wise reward prediction error (RPE) signaling and the differential impact of emotional bias on these reward signals were compared between groups.Patients showed impaired reinforcement learning relative to controls, while all groups demonstrated an emotional bias favouring selection of the happy faces. The pattern of RPE signaling was similar in HC and TRS groups, whereas NTR patients showed significant attenuation of RPE-related activation. The TRS patients differed from the NTR patients in the relationship between emotional bias and subcortical RPE signal during negative feedback.TRS can be dissociated from NTR on the basis of a different neural mechanism underlying their symptoms. The data support the hypothesis that a favourable response to antipsychotic treatment may be contingent on dopaminergic dysfunction, characterized by aberrant RPE signaling, whereas treatment resistance may be characterized by an abnormality in distinct cognitive mechanisms interacting with this response.


Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) are often comorbid and share similarities across some cognitive phenotypes, including certain aspects of attention. However, no functional magnetic resonance imaging studies have compared the underlying neural mechanisms contributing to these shared phenotypes.n = 20), boys with OCD (n = 20), and healthy control boys (n = 20) performed a parametrically modulated psychomotor vigilance functional magnetic resonance imaging task. Brain activation and performance were compared among adolescents with OCD, adolescents with ASD, and control adolescents.Age- and IQ-matched boys (11–17 years old) with ASD (Whereas boys with ASD and OCD were not impaired on task performance, there was a significant group by attention load interaction in several brain regions. With increasing attention load, left inferior frontal cortex/insula and left inferior parietal lobe/pre/post-central gyrus were progressively less activated in boys with OCD relative to the other two groups. In addition, boys with OCD showed progressively increased activation with increasing attention load in rostromedial prefrontal/anterior cingulate cortex relative to boys with ASD and control boys. Shared neurofunctional abnormalities between boys with ASD and boys with OCD included increased activation with increasing attention load in cerebellum and occipital regions, possibly reflecting increased default mode network activation.This first functional magnetic resonance imaging study to compare boys with ASD and OCD showed shared abnormalities in posterior cerebellar–occipital brain regions. However, boys with OCD showed a disorder-specific pattern of reduced activation in left inferior frontal and temporo-parietal regions but increased activation of medial frontal regions, which may potentially be related to neurobiological mechanisms underlying cognitive and clinical phenotypes of OCD. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication difficulties and stereotyped repetitive behaviors  with a pVigilance incorporates sustained attention, or the ability to maintain focus toward infrequently occurring stimuli , and focOn cognitive and symptom-based measures, ASD has been related to inattention. Thus, ASD can be characterized by short attention span, and impulsivity and inattention symptoms are common . FurtherClinical symptoms of inattention have been reported especially in pediatric patients with OCD , and patGiven diagnostic overlap and potential etiological links between ASD and OCD, it is critical to understand neurofunctional mechanisms that are shared or unique between these disorders. Work has begun to focus on delineating neural mechanisms between these disorders , but a cA total of 60 right-handed  boys This study has several limitations. While patients with psychiatric comorbidities were excluded, we cannot rule out the presence of subthreshold symptoms of other disorders such as ADHD. This is in line with the debate around comorbidity versus overlapping phenotypes and their respective contribution to behavior and clinical presentation, particularly in the context of ASD and ADHD . It woulFuture work could compare ASD individuals with and without comorbid OCD with noncomorbid OCD individuals, building on this novel comparison to elucidate the mechanisms underlying clinical overlap of ASD and OCD. Moreover, it would be interesting to compare these patient groups with attention-related disorders such as ADHD to provide further insight into shared and/or disorder-specific neurofunctional attention mechanisms.This study provides the first evidence suggesting that adolescents with OCD have disorder-specific abnormalities in sustained attention networks, including left inferior and medial PFC and temporo-parietal regions, relative to adolescents with ASD, who had no frontal abnormalities. Findings suggest lateral inferior/medial fronto-temporo-parietal abnormalities during sustained attention may be a distinct neural signature of OCD but not of ASD. Individuals with ASD and OCD, however, shared abnormally enhanced activation in cerebellum/occipital lobe relative to healthy control individuals. These results provide promising evidence for identification of biomarkers that may clarify underlying mechanisms driving sustained attention and respective symptom profiles in autism and OCD.