The most robust DTI associations were identified in white matter tracts linking cognitive and evaluative processing with emotional responses: anterior thalamic radiation, fornix (emotion identification) and uncinate fasciculus (sarcasm identification). DTI associations of impaired social cognition were more consistent than corresponding grey matter associations. These findings delineate a brain network substrate for the social impairment that characterises FTLD syndromes. The findings further suggest that DTI can generate sensitive and functionally relevant indexes of white matter damage in FTLD, with potential to transcend conventional syndrome boundaries.Impairments of social cognition are often leading features in frontotemporal lobar degeneration (FTLD) and likely to reflect large-scale brain network disintegration. However, the neuroanatomical basis of impaired social cognition in FTLD and the role of white matter connections have not been defined. Here we assessed social cognition in a cohort of patients representing two core syndromes of FTLD, behavioural variant frontotemporal dementia  and semantic variant primary progressive aphasia , relative to healthy older individuals (n = 37) using two components of the Awareness of Social Inference Test, canonical emotion identification and sarcasm identification. Diffusion tensor imaging (DTI) was used to derive white matter tract correlates of social cognition performance and compared with the distribution of grey matter atrophy on voxel-based morphometry. The bvFTD and svPPA groups showed comparably severe deficits for identification of canonical emotions and sarcasm, and these deficits were correlated with distributed and overlapping white matter tract alterations particularly affecting frontotemporal connections in the right cerebral hemisphere •Social cognition deficits define frontotemporal dementias but are poorly understood.•We studied brain network correlates of sarcasm processing in these dementias with DTI.•Sarcasm deficits were particularly linked to right frontotemporal tract changes.•DTI generates functionally relevant metrics of white matter damage in these dementias. These dThese challenges are well illustrated by the canonical FTLD syndromes of behavioural variant frontotemporal dementia (bvFTD) and the semantic variant of primary progressive aphasia . Clinically, bvFTD characteristically manifests with progressive behavioural deterioration leading to severe social dysfunction that may be misdiagnosed as a primary psychiatric disorder , while sSocial cognition is a multi-dimensional and still poorly understood aspect of human brain function ; it typiThe processing of sarcasm is an attractive model for probing component processes of social cognition that are vulnerable in FTLD syndromes . SarcasmThis work contributes to a growing body of evidence associating particular social cognition deficits with regional brain damage in FTLD . To dateHere we investigated white matter correlates of social cognition impairment in bvFTD and svPPA using DTI. We correlated DTI metrics with indices of canonical emotion identification  and sarcasm identification  in naturalistic vignettes. DTI data were analysed using a tract-based spatial statistics (TBSS) processing pipeline that makes minimal prior assumptions about key sites of disease involvement and is therefore relatively anatomically unbiased. White matter alterations were correlated with the distribution of grey matter atrophy assessed using voxel-based morphometry (VBM). We hypothesised that white matter alterations would target pathways binding the distributed fronto-temporal and limbic networks previously implicated in neuroimaging studies of social cognition in the healthy brain and in neurodegenerative disease. We further hypothesised that white matter signatures of impaired social cognition would constitute ‘trans-syndromic’ substrates for the overlapping behavioural deficits that characterise the bvFTD and svPPA syndromes clinically. DTI measures of axial (AX), radial (RD) and total  diffusivity and fractional anisotropy (FA) were assessed in parallel, given previous work suggesting that different DTI measures may constitute relatively specific indices of structural or functional integrity in white matter pathways .22.1Twenty-nine patients fulfilling consensus criteria for probable or definite bvFTD  and 15 p2.2The Awareness of Social Inference Test (TASIT)  was usedSocial cognition measures, general neuropsychological data and general demographic characteristics  were compared between participant groups using Stata12©. Repeated-measures analysis of variance regression models were used to assess group differences in performance scores, age and gender. British Picture Vocabulary Scale , augmented with parallel imaging acceleration to reduce susceptibility artefact. Nine sequences without diffusion weighting were also acquired (b = 0 s/mm2). Multiple diffusion and non-diffusion weighted scans were acquired to improve signal to noise and to provide multiple independent observations, improving the fit of the tensor model and robustness of the data. In addition a sagittal 3-D magnetisation-prepared rapid gradient echo T1-weighted volumetric MRI  and a coronal fluid-attenuated inversion recovery (FLAIR) MRI were acquired. For all participants, volumetric MRI, DTI and FLAIR sequences were assessed visually in all planes to ensure adequate coverage and to exclude artefacts, unexpected pathology or significant motion.Brain MR images were acquired on a Siemens Trio 3 T MRI scanner using a 32-channel phased array head-coil . Two 64-direction DTI sequences were acquired with a single shot, spin-echo echo planar imaging sequence  and FA and other DTI metrics at each voxel derived from the tensor eigenvalues /2), TR = (λ1 + λ2 + λ3) and FA is given by:Raw diffusion weighted images were affine-aligned to the first corresponding b0 image using a linear image registration tool (FLIRTv5.5) within the FMRIB Software Library (FSLv4.1.5), in order to correct for motion and eddy currents. The weighting vectors were adjusted to correct for any rigid body motion. DTI volumes were then combined for tensor fitting using Camino  .http://www.fil.ion.ucl.ac.uk/spm) running under Matlab 7.14®. Pre-processing steps were carried out in accordance with current guidelines  and disease group membership included as covariates. To minimise confounding effects from correlated general semantic, executive or disease severity factors, raw scores on the BPVS and a Stroop ink colour naming test (a standard executive measure) were included as additional nuisance covariates in the model design. In the DTI analyses, FA, AX, RD and TR metrics were analysed separately. In each case, relationships between the behavioural and neuroimaging metrics were assessed across the two syndromic groups, in each syndromic group separately, and contrasting the two syndromic groups. In the grey matter analysis an additional step was applied to minimise voxel drop-out due to marked local regional atrophy in particular scans. The analysis was performed within a customised brain mask based on a specified voxel threshold intensity criterion  whereby cluster’ to determine if multiple anatomical clusters of white matter alteration occurred within each contrast and to extract information on the statistical significance and spatial extent of each anatomical cluster. To determine involvement of specific white matter tracts the JHU ICBM-DTI-81 DTI white matter atlas was registered to the study specific mean FA image  randomise tool within FSL with 5000 permutations generated for each test. For all analyses, a significance threshold (p = 0.05) was applied following correction for multiple comparisons using family-wise error correction with threshold-free cluster enhancement  over theFA image . The peaMaps of disease-associated grey and white matter alteration were generated for each syndromic group relative to a historical age- and gender-matched cohort of healthy individuals  for which brain MR images were previously obtained using the same scanner and acquisition parameters. Grey and white matter disease maps were generated using the same parameters as previously specified.33.1General characteristics of participants are summarised in 3.2Social cognition data are summarised in 3.3As anticipated, compared with healthy controls both syndromic groups showed extensive profiles of grey matter atrophy and changes in cerebral white matter integrity. The bvFTD group showed distributed bi-hemispheric atrophy involving the anterior temporal lobes, mesial temporal structures, insular, prefrontal and orbitofrontal cortices; while the svPPA group showed an overlapping but distinctive profile of bi-hemispheric atrophy involving the anterior inferior temporal lobes (more marked on the left) extending into the posterior inferior temporal and orbitofrontal cortices . White matter alterations were evident bi-hemispherically but with a fronto-temporal gradient . The bvFTD group had both dorsal and ventral white matter alterations, most extensive in the bilateral uncinate fasciculus, corpus callosum and cingulum bundle, with less marked changes posteriorly including the parieto-occipital inferior longitudinal fasciculus. The svPPA group had a more ventral profile of white matter alterations most prominent in the uncinate fasciculus bilaterally and also involving the corpus callosum and bilateral cingulum bundle.3.4Maps of DTI metric alterations associated with performance on social cognition tasks are shown in Across both patient groups, TASIT emotion identification score was inversely correlated with AX, RD and TR and positively correlated with FA extensively over the dorsal, ventral and commissural white matter tracts in both cerebral hemispheres ; the larAcross both patient groups, TASIT total sarcasm  identification score was inversely correlated with AX, RD and TR in bi-hemispheric but predominantly right temporal and inferior frontal white matter tracts; the largest effects in terms of statistical significance and extent  were demAcross both syndromic groups , white m3.5Statistical parametric maps of regional grey matter volume associated with performance on social cognition tasks are shown in These grey matter correlates of social cognition performance from the VBM analysis were only partly convergent with the white matter correlates identified in the DTI analysis . Converg4Here we have used an anatomically unbiased DTI protocol to delineate white matter tract associations of cognitive processes relevant to social signal encoding  and interpretation (sarcasm identification) in two canonical FTLD syndromes with prominent social difficulties. In line with previous work , both thWhite matter correlates of emotion and sarcasm processing here were identified after adjusting for generic cognitive (semantic and executive) indexes, suggesting a relatively specific association with social cognitive operations rather than a more general association with disease severity. Attempts to define neuroanatomical correlates of behaviour in disease states are potentially biased by the brain topography of particular diseases, which tend to limit the associations that can be observed. In the present study, this was addressed by adjusting DTI regression analyses for disease group membership, allowing us to identify associations extending across syndromes in the combined patient cohort as well as syndrome-specific associations. Together this evidence suggests that bvFTD and svPPA involve common large-scale networks mediating social cognition, albeit with a regional emphasis that is modulated by syndrome; and that social cognition processes may constitute ‘trans-syndromic’ signatures of brain dysfunction in FTLD. Moreover, white matter tract correlates of social cognition impairment here were only partly convergent with (and more consistent than) the grey matter correlates identified in the corresponding VBM analyses: this underlines both the potential of DTI to reveal disease signatures that may not be fully delineated using grey matter imaging techniques, and the critical role of white matter pathway integrity in maintaining normal brain network function.The most robust white matter associations of emotion and sarcasm processing here were identified within tracts previously implicated in linking cognitive and evaluative processing with emotional responses, as part of a broad repertoire of cognitive operations supported by these tracts. Abnormal diffusivity in the anterior thalamic radiation was identified as a correlate of emotion identification in the combined group and within the svPPA group; and a correlate of sarcasm identification within the bvFTD group. The anterior thalamic radiation participates in thalamo–fronto–striatal re-entrant circuits and has widespread projections to the prefrontal cortex and basal forebrain regions. Both in the healthy brain and in a range of neuropsychiatric disorders, this tract has been implicated in various cognitive operations that mediate the social context of emotional signals, including reward and punishment potential, gating and cognitive meaning of affective signals and pervasive induced mood states that may promote evaluation of emotional experiences .Impaired emotion identification in the combined cohort and within the bvFTD group was strongly associated with altered diffusivity in the fornix, consistent with other work in FTLD syndromes . The forImpaired sarcasm detection in the combined cohort and within the bvFTD group was strongly associated with abnormal diffusivity in the uncinate fasciculus: this tract is part of the ‘extended limbic system’  and playThe grey matter (VBM) and white matter (DTI) correlates identified here together support previous evidence implicating the right temporal lobe in sarcasm detection  and furtOf note, primary correlates of social cognition here did not include fronto-insular connections within the salience network previously implicated as central both to the pathogenesis of bvFTD and to processes supporting human social cognition . The preOur findings illustrate the potential value of DTI as a functional and disease metric in FTLD. Neuroanatomical data derived from DTI and VBM should be compared with caution, given the different properties and technical bases of these modalities; with these caveats in mind, we analysed the present DTI and VBM data in a common pre-processing and statistical framework. Considering both social cognition metrics here, white matter associations were extensive and more consistent than regional grey matter associations, in line with other neuroimaging and neuropathological evidence for extensive white matter pathology in FTLD syndromes . The datWhite matter signatures based on the FA metric were substantially less extensive than for other diffusivity metrics here . InformaTaken together, these findings further define neurobiological signatures for the social impairment that characterises FTLD syndromes, grounded in the emerging neural network paradigm of neurodegenerative disease . The finThe present study has several limitations that suggest directions for future work. The findings should be corroborated in larger cohort studies comparing other neurodegenerative diseases and mimic syndromes such as autism, schizophrenia and other primary psychiatric disorders . These v


The neurological hallmark of TTR-FAP is a length-dependent axonal neuropathy that initially involves the unmyelinated and small myelinated nerve fibers that mediate pain and temperature sensation, causing sensory disturbances that typically start in lower limbs. Subsequent degeneration of larger myelinated fibers results in large fiber sensory deficit and muscle weakness.The disease can be difficult to recognize due to extreme phenotypic heterogeneity and nonspecific clinical symptoms even within the same mutation.In TTR-FAP related to Val30Met mutation, different neuropathy phenotypes have been reported mainly in patients from non endemic areas as well in late onset cases.We described 3 TTR-FAP Val30Met early onset cases from endemic areas with a different neuropathy phenotype that can be easily misdiagnosed as a different entity. One case presented as a bilateral carpal tunnel syndrome without neuropathy; another with a demyelinating neuropathy with predominant upper limb involvement and other with a demyelinating neuropathy with conduction blocks mimicking a CIDP.TTR-FAP is frequently misdiagnosed, e.g. as idiopathic polyneuropathy or chronic inflammatory demyelinating polyneuropathy, and may be greatly under diagnosed. However, early accurate diagnosis of TTR-FAP is crucial for effective disease control.


Lobar torsion is a fatal but fortunately rare occurrence following lung resection. Early clinical signs and radiographic features may be nonspecific resulting in diagnostic delay. A high index of suspicion is vital for early diagnosis and intervention to avoid further parenchymal necrosis and deadly gangrene. We report a case of left lower lobe torsion in a 76-year-old female following elective upper lobectomy for underlying lung adenocarcinoma. Diagnosis was made following highly suggestive radiographic findings prompting bronchoscopy and revision thoracotomy. An emergency detorsion failed to restore lung viability and was followed by completion pneumonectomy. The patient recovered and was discharged on the seventh postoperative day. Lobar torsion is a very rare but potentially fatal postlobectomy complication. It represents a diagnostic dilemma in the early postoperative period and a high index of suspicion is crucial for lung salvage. Torsion most commonly involves the middle lobe following ipsilateral lobectomy with only few cases describing left sided involvement. We will present a case of left lower lobe torsion, followed by a review of the medical literature on this topic.Our patient is a 76-year-old lady with chronic obstructive pulmonary disease, peripheral vascular disease, and smoking as past medical history, presenting with 2 months of a nonproductive cough. The patient was found to have a left upper lobe nodule on a plain chest radiograph and further evaluation with a computed tomography (CT) of the chest delineating a 1.2 cm spiculated nodule . FollowiThe immediate postoperative course was uncomplicated and the patient was transferred to the cardiothoracic unit for observation. Follow-up chest radiography on postoperative day-1 showed a small left lower lobe opacity with the patient complaining of mild pain at the surgical site. On postoperative day-2 the patient developed atrial fibrillation with rapid ventricular rate associated with hemoptysis and worsening left sided pleuritic chest pain. Plain chest radiography showed worsening left lung opacity with bronchial cutoff . A CT ofLung torsion is the rotation of a pulmonary lobe around the hilar pedicle resulting in bronchovascular compromise. It is a rare event seen mainly in the postoperative setting following thoracic surgery , 2. FeweThe underlying pathophysiology remains controversial with reports delineating few predisposing factors , 2, 10: The clinical picture of lung torsion varies depending on whether the torsion is partial or complete. Partial torsion has an insidious course presenting with partial collapse or obstructive pneumonia . On the Recognition of early imaging features is vital for prompt diagnosis and management. Plain radiography can raise early suspicion for postoperative torsion if certain findings are delineated including inappropriate hilar displacement away from the collapsed lobe, collapsed lobe in an unusual location, ipsilateral lobe opacification following surgery, and bronchial cutoff  10]. CT. CT10]. Following suspicion of torsion, an emergent surgical intervention is vital. The optimal type of intervention remains controversial depending on the lung status visualized by thoracotomy. If the involved lobe demonstrates viability, detorsion may offer the possibility for lung salvage . HoweverProphylactic lung fixation has been proposed as a successful method to prevent lung torsion using various surgical techniques including parenchymal suturing, adhesive membranes, and pleural flaps , 13, 18.In regard to our patient, she was at higher risk for a very rare complication of left lower lobe torsion secondary to surgical inferior pulmonary ligament transection and pedicle skeletonisation, a complete left longitudinal fissure, and a longer left lobar pedicle. Initially she presented with atrial arrhythmia and hemoptysis with no significant hypoxemia or respiratory distress. Early diagnosis in the first 24 hours was made possible with highly suggestive radiographic features; however the lung did not appear viable at the time of intervention. Lung detorsion performed within 24 hours did not result in clinical deterioration; however lung viability also did not improve and the patient eventually underwent complete pneumonectomy.Lung torsion remains a fatal but fortunately rare complication after lobectomy. A low threshold should be present in at risk patients for prompt investigation and intervention that is vital for lung salvage. Patients with multiple predisposing factors should be considered for prophylactic lung fixation.


Previous studies using transcranial Doppler sonography have suggested that cerebral circulation is preserved relative to cardiac output during normotensive hypovolaemia (NTH). We have further investigated the cerebral autoregulatory responses to hypovolaemia using using MRI measurements of total cerebral blood flow combined with graded levels of lower body negative pressure (LBNP) to induce steady state central hypovolaemia.11 healthy male volunteers (21-24 years) underwent MRI scanning with their legs and torso within a LBNP chamber; phase contrast angiography based flow measurements (MRI-PCA) were acquired at 10mmHg increments from baseline, to -50 mmHg . Measurements were made through the carotid and vertebral arteries to measure total cerebral volume flow (CBVF) and through the ascending and proximal descending aorta to measure cardiac output (CO).At low levels of LBNP (≤ -20mmHg) decrease in CBVF was directly proportional to the decrease in CO Figure . Between1. This difference is likely to reflect the different methods of cerebral blood flow measurement. MRI-PCA allows direct volume flow measurements from the carotid and basilar arteries whereas TCD uses flow velocity in the middle cerebral arteries as a surrogate of volume flow. This potentially important discrepancy requires further investigation to elucidate the mechanisms controlling CBF responses to nth.These findings demonstrate a correlation between decreases in CO and CBVF during normotensive hypovolaemia (NTH), which is in disagreement with previous studies using transcranial Doppler to measure CBVF. The findings do not support previous descriptions of relative sparing of CBVF due to compensatory reductions in cerebrovascular resistance in response to NTH


Mycobacterium abscessus subsp. abscessus (MAB) is a highly drug resistant mycobacterium and the most common respiratory pathogen among the rapidly growing non-tuberculous mycobacteria. MAB is also one of the most deadly of the emerging cystic fibrosis (CF) pathogens requiring prolonged treatment with multiple antibiotics. In addition to its “mycobacterial” virulence genes, the genome of MAB harbours a large accessory genome, presumably acquired via lateral gene transfer including homologs shared with the CF pathogens Pseudomonas aeruginosa and Burkholderia cepacia. While multiple genome sequences are available there is little functional genomics data available for this important pathogen.We report here the first multi-omics approach to characterize the primary transcriptome, coding potential and potential regulatory regions of the MAB genome utilizing differential RNA sequencing (dRNA-seq), RNA-seq, Ribosome profiling and LC-MS proteomics. In addition we attempt to address the genomes contribution to the molecular systems that underlie MAB’s adaptation and persistence in the human host through an examination of MABs transcriptional response to a number of clinically relevant conditions. These include hypoxia, exposure to sub-inhibitory concentrations of antibiotics and growth in an artificial sputum designed to mimic the conditions within the cystic fibrosis lung.P. aeruginosa and mirrors the transcriptional responses that lead to persistence in mycobacteria. These strategies include an increased reliance on amino acid metabolism, and fatty acid catabolism and highlights the relevance of the glyoxylate shunt to growth in the CF lung. Our data suggests that, similar to what is seen in chronically persisting P. aeruginosa, progression towards a biofilm mode of growth would play a more prominent role in a longer-term MAB infection. Finally, MAB’s transcriptional response to antibiotics highlights the role of antibiotic modifications enzymes, active transport and the evolutionarily conserved WhiB7 driven antibiotic resistance regulon.Our integrated map provides the first comprehensive view of the primary transcriptome of MAB and evidence for the translation of over one hundred new short open reading frames (sORFs). Our map will act as a resource for ongoing functional genomics characterization of MAB and our transcriptome data from clinically relevant stresses informs our understanding of MAB’s adaptation to life in the CF lung. MAB’s adaptation to growth in artificial CF sputum highlights shared metabolic strategies with other CF pathogens including The online version of this article (doi:10.1186/s12864-016-2868-y) contains supplementary material, which is available to authorized users. Mycobacterium abscessus (MAB) is increasing and it is emerging as an important cystic fibrosis (CF) pathogen with a high innate antibiotic resistance rendering it refractory to most antimicrobial therapies .Fig.Fig35].FM. tuberculosis is thought to confer an adaptive advantage for growth in microaerophilic or anaerobic environments [devR & devS from the DosR regulon are up-regulated indicating short exposure to SCFM2 does not induce the hypoxic response and that devR & devS may be induced for reasons other than hypoxia. This is in keeping with our findings that points towards a metabolic adaptation to a restriction in the diversity of carbon sources upon SCFM2 exposure but missing a clear signature of anaerobic growth. Both antibiotic exposures included induction of the transcriptional regulator whiB7 (MAB_3508c) alongside the alleviation of a number of TetR transcriptional repressors (MAB_4647/MAB_4687/MAB_2957c). In MTB WhiB7 is induced by both antibiotics and acts in conjunction with the primary sigma factor SigA to activate a discreet regulon of 12 genes controlling intrinsic antibiotic resistance [erm41 (MAB_2297), a homolog of the multidrug efflux pump tap (MAB_1409c) and a putative macrolide transporter (MAB_1846). In addition to whib7 up-regulation, erythromycin exposure induced a large majority (7/8) of the MAB homologs of the WhiB7 regulon indicative of an evolutionarily conserved WhiB7 driven response to macrolides. whiB7 in MAB is also induced in response to sub-inhibitory concentrations of the aminoglycoside amikacin [whib7 and the putative macrolide transporter MAB_1846 were induced. This uncoupling of WhiB7 induction from upregulation of its predicted regulon was also evident in response to SCFM2 where, despite the large number of differentially expressed genes and a strong induction of whiB7, MAB homologs of its regulon were largely unaffected. One of the strongest induced operons in response to both antibiotics MAB_0357c & MAB_0356c encodes a delta-aminolevulinic acid dehydratase (ALAD) and a S-isoprenylcysteine methyltransferase (mddA), respectively. MddA has been shown to catalyze production of the volatile compound dimethyl sulphide (DMS) which has been used as a volatile biomarker for differentiating between the growth of different mycobacterial species [Our comparisons reveal some significant overlaps and number of interesting sub-networks that span differing conditions. We find 43 % (22 of 51) of the hypoxic response including the entire DosR regulon is up-regulated in MAB strains with a Rough morphotype, a link that is pronounced in clinical strains with the potential for persistence . Constitronments . In contsistance . MAB hasamikacin  and is t species .whiB7, which is up-regulated in response to all conditions tested except hypoxia.We looked at expression patterns for the novel sORFs identified by ribosomal profiling across the different conditions . Therefore we profiled MAB response to a number of biologically relevant exposures that have either been experimentally characterized or for which some comparable data is available from other species [M. abscessus hypoxic response and the role of the evolutionarily conserved DosR regulon therein. Our data lends greater weight to DosR regulon’s constitutive up-regulation in strains of the Rough morphotype as it may confer an adaptive advantage for survival in the hypoxic CF lung environment. We identify for the first time numerous antibiotic resistance genes up-regulated in response to erythromycin and kanamycin exposure including antibiotic modification enzymes, efflux pumps and the redox sensitive WhiB7 transcriptional regulator. Unexpectedly we find that although whiB7 and its predicted regulon in MAB are both induced in response to erythromycin this link appears clearly uncoupled in response to other antibiotics and stresses. Given the diversity of WhiB7 activators and its important role in inducible antibiotic resistance this deserves further study. Comparison with transcriptional data from other CF pathogens clearly indicates a convergence in metabolic strategies towards adaption to the CF lung [Central to understanding the functional networks that contribute to adaptation and persistence in MAB is a well-characterized genome coupled with rich genome-wide functional genomics datasets. It’s clear from our data that the complexity of the MAB genome is only modestly represented by current automated annotations of its coding regions. We demonstrate the presence of many novel sORFs with coding and regulatory potential and identify internal TSS as a potential source of protein isoforms. Our Ribo-seq data illustrates that many non-coding RNAs, including regulatory and antisense RNAs, are ribosomally protected. As they lack clear evidence of translation their presence means that these antisense RNAs are competing kinetically with the ribosome for access to the same region of the nascent target RNA. Functional regulatory RNAs are difficult to detect in mycobacteria due to the pervasiveness of transcription initiation  and iden species , 16, 22. CF lung , 23, 32.Detailed experimental procedures are provided in Additional file As the work was carried out on bacterial cultures the authors state that no ethical approval was required for any aspect of this study.M. abscessus ATCC19977 cultures were grown in Middlebrook 7H9 medium . When indicated, diethylenetriamine/nitric oxide (DETA/NO) adduct , kanamycin or erythromycin  were added to the culture media. For growth in an enhanced artificial sputum medium (SCFM2) bacterial cultures were washed with phosphate buffered saline solution (PBS) and then transferred to SCFM2 medium.RNA was isolated as described earlier using Qiagen miRNeasy kit with double DNase treatment . Sample Mycobacterium abscessus ATCC 19977 genome sequence  using Bowtie 1.1.1. Ribosome profiling and RNA-seq datasets were deposited into NCBI’s Gene Expression Omnibus (GEO) (accession numbers: GSE78787 and GSE72996).Following removal of sequencing adapters and quality control, all ribosome profiling and RNA-seq reads were mapped to the Recovered bacterial pellets were washed with ice-cold PBS, suspended in protein lysis buffer  and physically disrupted. Clarified total cell lysate was reduced with dithiothreitol (DTT), alkylated with iodoacetamide and subjected to overnight trypsin digestion (Pierce Biotechnology Inc.). Resulting tryptic peptides were desalted by solid phase extraction with C18 ZipTips (Millipore Corporation) and analysed on a Thermo Scientic Q Exactive mass spectrometer connected to a Dionex Ultimate 3000 (RSLCnano) chromatography system.Mycobacterium abscessus ATCC 19977 genome sequence  using a database search approach implemented in PEAKS 6.0 proteomics software. A parent mass error tolerance of 6.0 ppm was used in conjunction with a maximum of 2 missed cleavages along with one non-specific cleavage.Tryptic peptides were aligned to the Mycobacterium abscessus; SCFM, synthetic cystic fibrosis sputum; TSS, transcriptional start siteDE, differentially expressed; MAB,


ICOS (inducible co-stimulator molecule) is a T cell encoded member of the extended B7/CD28 superfamily that is up-regulated upon early T cell activation. Previous studies have shown that higher ICOS expression on circulating T cells, post treatment with ipilimumab, is associated with better clinical outcome. In complementary pre-clinical studies, efficacy observed with a whole cell vaccine consisting of ICOS-L expressing B16 melanoma (IVAX) suggests that agonism of this pathway could provide therapeutic benefit in the cancer setting.We have generated a panel of anti-ICOS monoclonal antibodies with in vitro agonist properties. These lead agonist mAbs have been shown to be efficacious both as monotherapies in multiple syngeneic tumor models and in combination with an anti-PD1 antibody. Mechanistic studies that demonstrate tumor regression is associated with enhanced ratios of cytotoxic CD8/regulatory T (Tregs) cells as well as preferential reduction in ICOS high Tregs in the tumor microenvironment have informed the selection of optimal Fc regions for clinical development.Jounce is now developing a high affinity humanized agonist monoclonal antibody to be tested as both a monotherapy as well as in combination with other T cell checkpoints in solid tumor indications.


In selected patients, our Unit has recently moved from handheld ultrasound-guided vacuum-assisted core biopsy (VACB) piecemeal acquisition of tissue to the handheld Intact Breast Lesion Excision System (Intact). Intact removes a single piece of tissue, potentially allowing radiologists to excise the entire lesion as well as allowing pathologists to visualise lesion architecture more easily and to calculate margins. We evaluated our early experience of excising benign or likely benign breast lesions using the 20 mm Intact.Prospective data collection was performed on all patients undergoing handheld ultrasound-guided Intact excision under local anaesthetic in 2014 and 2015, which comprised 19 lesions in 18 female patients aged 29−73.The device was technically straightforward to operate and well-tolerated by patients with no significant complications. Handheld needle orientation was difficult within dense glandular tissue (only one acquisition is possible per needle), but improved with increased operator experience. Achieving adequate analgesia required higher quantities of local anaesthetic than for the equivalent VACB. Pathologists found specimens easier to interpret than VACB samples. In all cases adequate excision was completed sonographically at one outpatient appointment, but in six cases a second Intact biopsy and/or a VACB was required to complete that excision, with extra cost implications. In two patients with M3 microcalcification the Intact pathology demonstrated ductal carcinoma in situ, leading to surgical wide local excision.Our early experience shows Intact as a reliable and effective tool for handheld diagnostic and/or therapeutic excision of selected breast lesions.


Synchronous bilateral ovarian torsion is an uncommon entity of which both ovaries twist at the same time or observed twisted during the surgical intervention. Herein, we present a neonate with bilateral ovarian torsion, which successfully managed by laparoscopic approach.  A neonate born at term to a 26-year-old primigravida by elective cesarean delivery was diagnosed with an intra-abdominal cystic mass at 35th week of pregnancy. A conservative management plan was undertaken with repeated ultrasonographic evaluations every two weeks. The pregnancy, medical history of the patient and birth were unremarkable. A female full-term infant of 39+5 week of gestation was delivered with a birth weight of 4160 gram. Physical examination was unremarkable. Post-delivery ultrasonography revealed an anechoic uncomplicated cystic mass measuring 5x3.5 cm located in the right pelvis and another semi-solid complicated cystic mass was located in the left pelvis with a measure of 5.4x3.8 cm, without any vascular signal. Both ovaries were not identified. Laparoscopy revealed brown round smooth cystic mass with a tiny stalk nearly amputated from the left fallopian tube in the left pelvis. A loop of intestinal segment also twisted around this calcified tiny stalk of the mass . Right ovary was also twisted with the cystic mass . The right ovary was untwisted 2 times (360 degree) and left in the pelvis after cyst aspiration without excision and ovarian fixation. Then the left ovary examined and seemed to be nearly amputated from the adnexa. It was removed after cyst aspiration. The calcified stalk was separated from the bowel. The post-operative period was uneventful and the patient was discharged on the 2nd post-operative day. Follow-up at 1 month with ultrasonographic evaluations showed an18 mm right ovary and no cyst. The differential diagnosis of a prenatal cystic abdominal mass includes omental cyst, mesenteric cyst, intestinal duplication, urachal cysts, renal cysts and ovarian cysts [1]. Preoperative diagnosis of ovarian torsion is difficult not only in newborns or infants but also in pre pubertal girls. The etiology of the ovarian cysts during pregnancy is related to the immature hypothalamus-pituitary-ovarian feedback that results gonadal hyperstimulation or placental insufficiency with incomplete maturation of the gonadostat. There are few reported patients of asynchronous bilateral adnexal torsion in children in the literature . Synchronous bilateral ovarian torsion has also been reported which was successfully managed by laparoscopic detorsion [4]. When a post-natal radiological evaluation reveals a complicated ovarian cyst, irrespective of the size, surgical management recommended either by laparoscopy or laparotomy [5]. Uncomplicated cysts, smaller than 5 cm diameter usually resolve spontaneously while the cysts exceeding 5 cm should be decompress via aspiration to prevent complications [6]. This case highlights the importance of high index of suspicion and early diagnosis of bilateral ovarian torsion in the newborn with bilateral pelvic cysts detected on the pre-natal and post-natal scans.Source of Support: NilConflict of Interest: Nil


Transmembrane efflux pumps play an increasing role in the success of ART. The occurrence of increasing mRNA levels of the efflux pump proteins P-gp and MRP subtypes has been associated with ART therapeutics like PIs and NNRTIs. Moreover, a relation has been suggested of MRP subtypes and CD4 cell counts. So there is a challenge to find selective MRP inhibitors which may reduce MRP-induced drug resistances as well as discussed effects on CD4 cells. We developed novel nonpeptidic inhibitors of important MRP subtypes related to both MRP-mediated resistances as well as reduced cell counts.The molecular structures of the various efflux pumps guided the development of both symmetric and nonsymmetric inhibitors dedicated to selectively inhibit the relevant MRP-subtypes. Inhibiting properties were evaluated in exclusively P-gp as well as MRP-overexpressing cell lines in comparison to nonexpressing parental cell lines with fluorescent substrates using flow cytometry.Our inhibitors with allover symmetric substitution patterns are excellent P-gp inhibitors, while a reduction of those symmetric elements concerning their number and exact positioning significantly lowers the P-gp inhibition whereas the MRP1 inhibition is found mainly increased. So selective inhibitors are demonstrated to influence the efflux pump type-related antiretroviral drug resistance.The success of ART may be mainly increased by selective MRP inhibitors which reduce the MRP-related effects on drug resistance as well as on discussed cell counts. Structure-guided studies of the efflux pump inhibition helped to design novel selective inhibitors with structure-reasoned effects of the nonsymmetric substitution patterns. So far only nonselective inhibitors have been used in ART with undesired effects on transporter-related pharmacokinetics. Selective inhibitors will mean a progress in ART especially with less limiting side effects.


Conventional anti retroviral treatment (ART) has been a core treatment for HIV over the past three decades. Despite the effectiveness of these drugs, most of them abide significant drawbacks such as poor bioavailability and undesirable side effects; thus reducing patient compliance and rendering treatment regime ineffective. This research work is an attempt to develop a dual pronged carrier system using gold nanoparticles (GNP) for increasing effectiveness and sustained drug release of saquinavir.Azadirachta indica was used as an efficient sink for synthesis of GNPs by microwave assistance. Saquinavir (Saq) was attached onto GNPs that were pre functionalized by capping polypeptide linkers of A.indica and characterized by FTIR. Percentage drug loading efficiency (%DLE) and release kinetics were studied by statistical model dependent method. Biocompatibility of drug nanoparticle conjugate was studied by MTT assay. Antiviral efficacy was assessed by quantifying aspartic protease of HIV by fluorescence (FRET) method.Leaf extract of Mono dispersed GNPs (30-40 nm) were synthesized and found to carry high payloads of saquinavir with %DLE of 93.6% as analyzed by Transmission electron microscopy and UV Vis spectroscopy respectively. GNP-saq conjugate demonstrated 16.7% increase in anti viral efficacy as compared to saquinavir alone. The conjugate showed sustained drug release and followed 1st order release kinetics at physiological pH (7.2).Biogenic GNPs serve as a potent candidate for ferrying high payloads of anti retroviral drugs with increased efficacy and reduced side effects. This approach can help reduce dosage frequency and improvise treatment strategy against HIV.


Traumatic brain injury can trigger chronic neuroinflammation, which may predispose to neurodegeneration. Animal models and human pathological studies demonstrate persistent inflammation in the thalamus associated with axonal injury, but this relationship has never been shown in vivo.11C]-PK11195 positron emission tomography, a marker of microglial activation, we previously demonstrated thalamic inflammation up to 17 years after traumatic brain injury. Here, we use diffusion MRI to estimate axonal injury and show that thalamic inflammation is correlated with thalamo-cortical tract damage.Using [These findings support a link between axonal damage and persistent inflammation after brain injury. Why thaThe spatial pattern of microglial activation following brain injury may relate to the white matter architecture of the CNS , 6. ExpeDiffusion tensor imaging (DTI) can map the structure of thalamo-cortical white matter tracts using probabilistic tractography , but TBIHere, we combine this approach with PK PET to test the hypothesis that chronic thalamic inflammation after TBI can be explained by thalamo-cortical white matter damage.Ten patients with a history of moderate-severe TBI (Mayo classification)  had PK PET and structural MRI scans including DTI (see [Standard MRI T1 and DTI protocols were used (see ). For DTTo test whether thalamic PK binding is more strongly correlated to proximal than distal thalamo-cortical damage, FA was sampled from a series of non-overlapping ring-shaped ROIs extending centripetally from the thalamus from 2 to 60-mm diameter and intersected with the thalamo-cortical tract mask. ROIs were created by repeatedly dilating a thalamic mask by two voxels (2 mm). Ring-shaped ROIs were produced by subtracting the previous mask from each step.ND), we used a supervised clustering procedure to identify reference clusters of voxels in grey matter having PK time activity curves mirroring those of controls [ND was sampled in the bilateral thalamus as well as the cortical grey matter regions that were used to define the thalamo-cortical tracts [PK PET acquisition and analysis are described in . To prodcontrols . PK BPNDl tracts .ND was compared between groups using independent sample t tests. Mean FA values were similarly compared. Bonferroni multiple comparisons correction was used. In TBI, we tested for a relationship between regional PK BPND and thalamo-cortical FA using linear partial correlations, controlling for age and time since injury as both factors potentially influence DTI [Regional PK BPence DTI  and PK bence DTI .ND in TBI patients versus controls , the corpus callosum  and the white matter skeleton   Fig. .ND and mean thalamo-cortical tract FA . The strength of this correlation decreased with the distance at which FA was sampled from thalamo-cortical tracts (Fig. In TBI, we found a significant negative correlation between thalamic PK BPcts Fig. . Thalamicts Fig. . There wcts Fig. . We alsoAxonal injury underlies many long-term problems after TBI . Glia beSeveral mechanisms might underlie persistent thalamic inflammation after TBI Fig. . It may Following experimental axotomy, microglial activation is seen in both anterograde and retrograde projection areas . Hence, An anterograde evolution of microglial activation is seen in other conditions. After stroke, microglial activation spreads in an anterograde fashion along damaged tracts , 9, and Whether chronic thalamic inflammation is harmful or restorative is uncertain. This question is challenging partly because the relationship between activated microglial phenotype and TSPO expression is not clear . It may An important limitation of the study is that it involved a small sample of patients and with a history of a single moderate-severe TBI. There is a need to replicate these preliminary findings in larger cohorts, which might benefit from investigating a wider range of diffusion metrics. Studies from animal models of repetitive mild TBI show persistent inflammation both at sites of axonal injury and locations remote from the site of focal lesions, suggesting a similar microglial response in cases of lower injury severity , 27.Evidence of persistent neuroinflammation suggests that the window of opportunity for therapeutic intervention following TBI may be longer than is usually considered. Inflammatory PET imaging provides a biomarker to investigate this prolonged inflammatory reaction and potentially the effects of interventions targeting glial activation. Our findings emphasise the need for large multi-modal longitudinal studies combining inflammatory PET with diffusion MRI to image axonal injury.


Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurring self-limited fever, abdominal pain and chest pain caused by serositis. FMF mainly affects Middle-East populations with a high prevalence in Sephardic Jews, Turkish, Arabs and Armenians. Carnitine is an important molecule in cellular energy metabolism. Secondary carnitine deficiency can be detected in chronic diseases by either renal loss or increased needs.Our hypothesis was that FMF patients would have lower free carnitine levels than their healthy age and gender matched controls due to increased need of carnitine because of recurrent auto-inflammation. The present study was conducted to determine the patterns of free carnitine and acyl-carnitine esters in FMF patients.This is a cross-sectional study of 205 FMF patients who were attending the outpatient Pediatric Rheumatology clinic of Cerrahpasa Medical Faculty Children's Hospital. The patients were selected by random sampling and FMF diagnosis was confirmed by a pediatric rheumatologist according to Yalcınkaya criteria. 50 healthy subsects were enrolled to the present study. A fasting died blood sample was taken for studying free carnitine and acyl-carnitine esters with tandem mass spectrometry from children in both groups.Acyl-carnitine analyses in spot dried blood samples with ESI-MS/MS were performed in all patients and control group. Screening of acyl-carnitine profile revealed free carnitine, C16-OH and C18:2 carnitine levels were higher , while C4-OH and C4DC carnitine levels were lower  in FMF patients than the control group.In the present study we were not able to define secondary carnitine deficiency in FMF patients, therefore usage of carnitine in all patients with FMF is not recommended.


AA amyloidosis may develop as a consequence of chronic inflammatory conditions including autoinflammatory diseases(AID). Mevalonate-kinase(MVK) deficiency(MKD) appears to be the least frequent underlying condition among monogenic periodic syndromes. Moreover, amyloidosis rarely manifests during childhood. We report a case of a small child in whom renal biopsy performed because of the cortico-resistant nephrotic syndrome revealed amyloid A.To describe clinical manifestations, laboratory features and disease outcome in a patient referred for suspected periodic fever syndrome.Case report.A 4-years old Caucasian girl with negative family history presented with features of nephrotic syndrome in 1/2011. Over the previous 2 years she has been suffering with recurrent episodes of unexplained fever with pharyngitis and lymphadenitis lasting 3 days in 2-4 weekly intervals and received a putative diagnosis of PFAPA  syndrome. Despite the increasing frequency of febrile episodes over the last year investigations aimed at excluding monogenic fevers were not performed. In early 2011 her IgD was normal, IgA mildly elevated, serum amyoid A (SAA) fluctuated from normal to 200 mg/l. After the standard corticosteroid (CS) treatment of nephrotic syndrome had failed to induce remission after 6 wks, a renal biopsy was performed revealing amyloid A deposits in about 30% glomeruli. While genetic analysis was pending, Colchicine was added to the CS treatment followed by daily anakinra injections with good clinical response. After a laborious genetic screening to exclude mutations causing monogenic AID, following heterozygous variants in MVK gene were identified: Mutation V377I and a novel deletion in exon 5 C152WfsX6 (c.450_453delGGTG). The latter terminates the protein six amino acids after the deletion occurs, effectively making the protein shorter. Within 6 months of the treatment her proteinuria stabilised and there have been no signs of other organ involvement. Despite ongoing anakinra therapy she continues to have occasional febrile episodes with temporary increase of inflammatory parameters including SAA.MKD/HyperIgD-syndrome has been so far reported in only a few cases of AA-amyloidosis. Our patient has been the youngest one to develop this severe complication. The only other child reported so far was also a compound heterozygote carrying the genotype G326R/V377I. The long-term follow-up with careful SAA serial measurements will tell us more about the prognostic significance of the newly described MVK gene deletion. This case report also underlines the importance of careful differential diagnostic re-evaluation of children presenting with PFAPA phenotype in whom febrile episodes do not show a typical prolongation of afebrile intervals over the time.None declared.


Serious thromboembolic events connected with rFVIIa therapy in hemophilia patients are rare. Only three cases are reported in children, all of them with hemophilia A.We present unique case of patient with hemophilia B and high titer inhibitors to coagulation FIX, who developed severe renal damage due to thromboembolic event during rFVIIa therapy, associated with unsuspected renovascular anomalies.Caution is necessary if hematuria B requires administration of rFVIIa. US color doppler renal imaging before and after drug administration should be sufficient as an early warning. Recombinant factor VIIa  has been shown to induce hemostasis in hemophilia patients with inhibitors against factor VIII or factor IX independent of factor VIII/factor IX. rFVIIa initiates hemostasis by forming a complex with tissue factor (TF) exposed as a result of vessel wall injury. Pharmacologic doses of rFVIIa can enhance thrombin generation. Recombinant activated factor VII  is in regular clinical use in haemophilia B patients with high-titer inhibitors to coagulation factor IX (FIX) since 1996 -4.We present the patient with hemophilia B and high titer inhibitors to coagulation FIX who was treated with rFVIIa for severe life-threatening hematuria. Although hematuria was successfully treated, renal thromboembolic adverse event associated with unsuspected vascular anomalies resulted in severe renal damage. To our knowledge, this is the first case of tromboembolic event connected with rFVIIa therapy with this set of symptoms presented exclusively on kidney with underlying vascular anomalies. The second normal kidney was fully spared.99mTc-DTPA (Diethylene Triamine Pentacaetic Acid) renal scintigraphy  scintigraphy, the left kidney was very pale becoming increasingly better visualized later  ,6. But tOur patient had multiple renal vascular anomalies. Multiple renal arteries are not uncommon. Various reports estimate its incidence up to 32%, usually on the right side with very rare occurrence of triple arteries supplying one kidney -12. AnatSuch an extremely rare troboembolic event in patients with hemophilia B certainly do not compromise safe administration of rFVIIa. However, caution is necessary if hematuria requires administration of rFVIIa. US color doppler renal imaging before and after drug administration should be sufficient as an early warning.Written informed consent was obtained from the patient’s parents for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.


The availability of high quality critical care is increasingly recognised as a global health problem , 2. The Evaluation of a capacity building project to enable local nurses to deliver critical care training courses in a resource limited setting (Sri Lanka).A short critical care course for nurses  was co-designed & delivered by specialist overseas nurse trainers in partnership with Sri Lankan nurse tutors. The impact of the course was assessed using: a pre & post course Multiple Choice Questionnaire (MCQ); a post course Objective Clinical Skills Assessment (OSCA) station & post course feedback questionnaires. Training was delivered in 7 blocks, from June 2013 to November 2014. A graded handover of training responsibilities occurred with lectures, skills stations & workshops increasingly delivered by local rather than overseas faculty. From March 2014 onwards the course was delivered entirely by local faculty, with coaching by overseas faculty. This process was coordinated with a Train the Trainers (TTT) programme for local faculty. The impact of the TTT for building effective training capacity was assessed by analysing the NICST course participant MCQ marks over time.In total 584 ICU nurses were trained over 16 NICST courses. Figure This training is highly rated by participants & is effective in improving clinical knowledge. The roll out of NICST has also fostered a new community of practice amongst the nurse tutor workforce in Sri Lanka, focused on delivering improved critical care skills training. The TTT approach provides sustainable training capacity within the local workforce. This approach may be of use in other resource limited settings.


Takayasu arteritis (TA) is a rare chronic granulomatous vasculitis of large vessels. Initial symptoms and signs are usually non-specific, therefore a high index of suspicion is needed to make a timely and correct diagnosis.To review our experience with treatment of children with TA.We analysed patients data.In our centre we are currently treating two adolescents with TA. Patient 1 presented with arthralgia, anaemia and fatigue. Patient 2 demonstrated leg claudication. None of them had hypertension. In both of them vascular bruits and elevated inflammatory markers were present. Diagnosis was confirmed by magnetic resonance angiography (MRA). Both patients were initially treated with pulse methylprednisolone followed by a high dose oral corticosteroid in combination with methotrexate. Both patients achieved transient clinical and laboratory improvement with decreased inflammatory parameters after initial treatment. By tapering steroid therapy inflammatory parameters started to rise. Patient 2 also demonstrated less palpable leg pulses and persistent leg claudication. Follow-up MRA imaging demonstrated only partial improvement with persistent vascular changes in both patients. Because of incomplete disease control both patients were started on anti-tumor necrosis factor (TNF) alpha therapy with infliximab which resulted in good clinical and laboratory response with decreased inflammatory parameters.According to our experience anti-TNF alpha therapy appears to be a successful treatment approach in pediatric patients with refractory TA.None declared.


Paravalvular aortic regurgitation (PAR) following transcatheter aortic valve implantation (TAVI) is well acknowledged. Despite improvements, echocardiographic measurement of PAR largely remains qualitative. Cardiovascular magnetic resonance (CMR) directly quantifies AR with accuracy and reproducibility. We compared CMR and transthoracic echocardiography (TTE) analysis of pre-operative and post-operative aortic regurgitation in patients undergoing both TAVI and surgical aortic valve replacement (AVR).Eighty-seven patients with severe aortic stenosis undergoing TAVI (56 patients) or AVR were recruited. CMR (1.5 T) and transthoracic echocardiography (TTE) were carried out pre-operatively and a median of 6 days post-operatively. The CMR protocol included regurgitant aortic flows using through-plane phase-contrast velocity. None/trivial, mild, moderate and severe AR by CMR was defined as ≤8%, 9-20%, 21–39%, >40% regurgitant fractions respectively.Pre- and post-operative left ventricular ejection fraction (LVEF) was similar. Post-procedure aortic regurgitant fraction using CMR was higher in the TAVI group . Comparing CMR to TTE, 27 of 56 (48%) TAVI patients had PAR which was at least one grade more severe on CMR than TTE . Sensitivity analysis confirmed the difference in PAR grade between TTE and CMR in the TAVI group .When compared to CMR based quantitative analysis, TTE underestimated the degree of paravalvular aortic regurgitation. This underestimation may in part explain the findings of increased mortality associated with mild or greater AR by TTE in the PARTNER trial. Paravalvular aortic regurgitation post TAVI assessed as mild by TTE may in fact be more severe. There now exists extensive registry and clinical trial data demonstrating an increased incidence of paravalvular aortic regurgitation (PAR) following transcatheter aortic valve implantation (TAVI), and consequently, increased mortality over short term follow-up -5. This By contrast to echocardiography, cardiovascular magnetic resonance (CMR) is able to directly quantify aortic regurgitation with high accuracy and reproducibility by using the technique of phase-contrast velocity mapping. CMR is not affected by the location, number or nature of regurgitant jets or thoracic structural patient factors, and therefore offers an ideal technique for assessing the severity of TAVI associated PAR. CMR has previously been well validated in the quantitative assessment of aortic valve regurgitation -10. The To date there has been several studies utilizing CMR flow imaging to assess PAR in TAVI cohorts. The majority of these trials have compared CMR assessment to that of either qualitative or semi-quantitative echocardiography -14. The In a single-center prospective control trial, we assessed the extent of PAR in patients undergoing TAVI and high-risk AVR using this highly accurate and reproducible CMR technique. We compared the CMR PAR assessment with semi-quantitative TTE assessment, still the most used technique worldwide. We hypothesized that TTE would systematically underestimate the severity of PAR in TAVI patients compared with CMR. Furthermore this underestimation would be more pronounced in the TAVI group than in the AVR group owing to the complexity of the paravalvular regurgitation.This study was approved by the Human Research Ethics Committee of Flinders Medical Centre  and conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent.Ninety patients with severe aortic stenosis undergoing either TAVI or high risk  AVR were enrolled between June 2011 and July 2014. The decision to proceed with either procedural technique was made by the heart team at our institution based on clinical assessment. Three patients were excluded due to inadequate image quality , leaving 56 TAVI patients and 31 AVR patients .All transcatheter valves were Edwards Sapien XT prostheses  inserted via the femoral route. The AVR group all received bioprosthetic valves, access being via a median sternotomy using cardio-pulmonary bypass. Myocardial preservation and implantation techniques were similar in the surgical group. Four different tissue valve prostheses were used: Medtronic Mosaic® - Medtronic Inc, Minnesota USA; St Jude Medical Epic™ and Trifecta™, St Jude Medical Inc, Minnesota; Edwards Perimount Magna, Edwards Lifesciences, California USA.CMR  and transthoracic echocardiography  were carried out pre-operatively and post-operatively at a median of 5 and 6 days for TAVI and AVR respectively. Both CMR and echo were performed on the same day (consecutively), in random order and analysed by separate blinded operators.CMR images were analysed offline using commercially available software . The CMR protocol consisted of standard LV short and long axis views (steady state free precession images) and forward and regurgitant aortic flows using through- plane phase-contrast velocity mapping  Figure . The imaEchocardiography was performed in the left decubitus position using commercially available Vivid E9 ultrasound machines . Data were analysed offline using EchoPAC PC Version 7  by 2 experienced echocardiography trained cardiologists. Aortic valve regurgitation was graded using a combined approach of semi-quantitative and qualitative parameters. For post-operative assessment this included visual assessment of the number of jets, jet width and the circumferential extent for paravalvular regurgitation, as per existing guidelines and the more recent VARC-2 criteria ,16. Regut-test and the chi-square statistic with Fisher’s exact test as appropriate. Agreement between grade of PAR ascertained by CMR and TTE was estimated with the Wilcoxon signed-rank test and Bland-Altman analysis. These were performed separately for TAVI and AVR in sensitivity analysis. We also applied the Kappa statistics to determine the agreement on grading of AR severity consistent with Altiok et al. All statistical tests were two-tailed, an alpha value p < .05 was considered statistically significant and no adjustment was made for multiple comparisons.Data analysis was performed with SPSS® 20.0 . Descriptive comparisons between TAVI and AVR included the independent samples A total of 87 patients were recruited, 56 TAVI and 31AVR. Although TAVI patients were older, STS scores were similar between the groups . Comparing pre-procedure aortic valve regurgitation grades between imaging techniques, CMR and TTE demonstrated near identical mean values for TAVI  and AVR groups . All regurgitation was valvular in nature and less severe than the predominating stenosis. The Wilcoxon signed-rank test did not indicate a significant difference between CMR AR grade and TTE .All post-procedure regurgitation was paravalvular in nature when assessed by both TTE and intra-operative transoesophegeal echocardiography (TOE). Post-operative mean regurgitant fraction using CMR was higher in the TAVI group when compared to the AVR group (TAVI 16% ± 13 vs. AVR 4% ± 4 p < 0.001). In the AVR group only four patients had PAR, which was mild in the majority of cases Table .Table 2In the TAVI group 52% of patients (29/56) had semi-quantitative TTE findings which graded PAR at a different value to CMR. In 93% (27/29) of these cases the PAR was graded at a lesser value by TTE . Sensitivity analysis confirmed that the difference in PAR grade was evident in the TAVI group  but not the AVR group . The CMR grade (continuous) is plotted by TTE grade in Figure Our principle findings show that: (1) using CMR quantitative analysis there was significantly more PAR in the TAVI group than AVR group; (2) semi-quantitative transthoracic echocardiography underestimates the degree of paravalvular AR when compared to quantitative CMR; (3) there was no difference between CMR and TTE in pre-procedure native valvular aortic regurgitation. To the best of our knowledge this is the first time CMR assessment of TAVI associated PAR has been reported with a matched surgical AVR control group. Additionally this is the largest series describing PAR evaluation using CMR of a single transcatheter valve type (Edwards Sapien XT), which holds relevance when transcatheter programs are selecting their preferred devices.CMR has been specifically compared to echocardiography in the assessment of TAVI associated PAR in three prior studies. Ribeiro et al. compared CMR and TTE (VARC-2 criteria) in 42 patients who had Edwards Sapien XT transcatheter valves, finding TTE underestimated PAR in 62% of cases . ConversThe potential importance of CMR quantification of PAR is underscored by the finding that, after converting CMR regurgitant fraction to regurgitant grade, 74% of patients were classified as having mild or greater PAR. This compares to a range of 21 – 61% reported in prior echocardiographic based studies . FurtherThe finding of significant corroboration between CMR and TTE in the assessment of pre-procedure  aortic regurgitation offers two key insights. The first is that it validates CMR techniques for assessing aortic valve regurgitation with those of TTE. Secondly it objectively confirms that the echocardiographic techniques which are readily applicable to native valve or intravalvular regurgitation are inherently unreliable in the transcatheter PAR setting. Our findings regarding pre-procedure regurgitation are supported by earlier work, which also found consistent agreement between TTE and CMR in pre-procedure aortic valve regurgitation . Despitemild PAR with increased mortality was a particularly unexpected finding of the PARTNER trial [Paravalvular aortic regurgitation (PAR) remains a significant and underestimated issue for transcatheter valves despite the impending arrival of third generation devices. Until TAVI can match surgical PAR rates and hence reduce associated increased mortality AVR will remain first line therapy. Furthermore, there is now a large population of patients with transcatheter valves who are affected by mild or greater PAR. It is widely accepted patients with PAR face increased morbidity and mortality and there may be an opportunity to intervene either medically or procedurally should the accurate assessment offered by CMR be broadly adopted . The assER trial . We specWe propose that PAR can be easily, reproducibly and accurately assessed using CMR. The increased incidence of PAR with TAVI compared to AVR is confirmed using quantitative CMR assessment. Furthermore we offer a hypothesis that the association of mortality with mild AR in the PARTNER trial may be due to limitations of echocardiography causing underestimation of the degree of PAR.


Sinus venosus atrial septal defects (SV-ASD) have nonspecific clinical presentations and represent a diagnostic imaging challenge. Transthoracic echocardiography (TTE) remains the initial diagnostic imaging modality. However, detection rates have been as low as 12%. Transesophageal echocardiography (TEE) improves diagnostic accuracy though it may not detect commonly associated partial anomalous pulmonary venous return (PAPVR). Cardiac magnetic resonance (CMR) imaging provides a noninvasive, highly sensitive and specific imaging modality of SV-ASD. We describe a case of an adult male with exercise-induced, paroxysmal supraventricular tachycardia who presented with palpitations and dyspnea. Despite nondiagnostic imaging results on TTE, CMR proved to be instrumental in visualizing a hemodynamically significant SV-ASD with PAPVR that ultimately led to surgical correction. Sinus venosus atrial septal defects (SV-ASD) involve the insertion of the superior or inferior vena cava and account for 2–12% of all atrial communication abnormalities [A 59-year-old male with a past medical history of hypertension presented with a two-month history of exertional palpitations, lightheadedness, and dyspnea. His resting ECG was normal. On exercise stress testing, the patient developed supraventricular tachycardia (SVT) with a ventricular rate of 292 beats per minute with reproducible symptoms . TransthA right heart catheterization (RHC) revealed severe pulmonary hypertension with a mean pulmonary arterial pressure of 35 mmHg and an elevated pulmonary arterial oxygen saturation of 81%. Left heart catheterization with selective coronary angiography demonstrated no evidence of coronary artery disease. The cardiac catheterizations were performed prior to any suspicion for intracardiac shunting, immediately following the diagnosis of supraventricular tachycardia. A full oxygen saturation evaluation on RHC was not performed for unclear reasons. Transesophageal echocardiography was also not performed at the request of the patient; CMR imaging was offered as an alternative imaging option.On CMR, a large SV-ASD was observed with severe right atrial and ventricular enlargement Figures  and 3. TThe patient subsequently underwent successful surgical correction of the SV-ASD and PAPVR with an initial resolution of symptoms. At a routine six-month follow-up, TTE demonstrated normal right atrial and ventricular size and function . There wSinus venosus atrial septal defects have nonspecific clinical presentations with a variable age of onset and should always be considered in the setting of unexplained right atrial and ventricular enlargement. Advanced imaging modalities may be required to facilitate a diagnosis given the location of the defect and their associated anomalous vascular connection(s). Transthoracic echocardiography remains first line in diagnostic evaluation though detection rates have been reported as low as 12 to 44% with the highest success rate utilizing the subcostal view , 4.Transesophageal echocardiography has been shown to increase the detection of SV-ASD and the presence of PAPVR , 6. In aCardiac magnetic resonance imaging has been shown to accurately detect SV-ASD and identify anomalous pulmonary venous connections. In a small retrospective review of patients without a conclusive diagnosis despite TEE, CMR was able to successfully identify a sinus venosus defect in 7 of 11 patients . This moA comprehensive approach must be undertaken when evaluating a patient with unexplained right heart dilation. Routine initial diagnostic imaging techniques may not prove sufficient to establish a diagnosis particularly in the case of sinus venosus defects given the location and associated anomalies. The collective data obtained by CMR provides additive diagnostic value when determining future management to include surgical correction, particularly when other methods have not established a diagnosis.


Komagataeibacter europaeus CECT 8546, an acetic acid bacterium characterized by its ability to overproduce cellulose. This species is highly resistant to acetic acid and commonly found during vinegar elaboration.The present article reports the draft genome sequence of the strain  Acetobacteraceae. They are obligate aerobic microorganisms that are able to produce acetic acid from ethanol and are the main bacteria responsible for vinegar production. The species Komagataeibacter europaeus (formerly Gluconacetobacter europaeus [The acetic acid bacteria (AAB) are a group of Gram-negative bacteria that belong to the family uropaeus ) was firK. europaeus CECT 8546 was isolated from grape vinegar produced by the traditional method in the experimental cellar Mas dels Frares . Chromosomal DNA was isolated using the MasterPure complete DNA purification kit . For whole-genome sequencing, the Genome Analyzer II  and the 454 GS-FLX TitaniumXL  pyrosequencing systems were used. Preparation of shotgun libraries was performed according to the protocols of the manufacturers and resulted in 8,419,806 paired-end Illumina reads (112 bp) and 83,045 pyrosequencing reads. Initial hybrid de novo assembly using the MIRA software (The strain K. europaeus CECT 8546 consists of a chromosome with 4.11 Mb and an overall G+C content of 61.31%. Automatic gene prediction was performed using the software tool Prodigal (The genome of Prodigal . Genes cProdigal , respectProdigal  was usedProdigal . MoreoveProdigal .In addition, the strain CECT 8546 presents the ability to biosynthesize cellulose very quickly. This biopolymer is the main component of the biofilm that AAB develop in the liquid-air interface during traditional vinegar elaboration . This biLHUQ00000000. The version described in this paper is version LHUQ01000000.This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number


Idiopathic Pulmonary Fibrosis (IPF) is a progressive, incurable fibrotic interstitial lung disease with a prognosis worse than many cancers. Its pathogenesis is poorly understood. Activated platelets can release pro-fibrotic mediators that have the potential to contribute to lung fibrosis. We determine platelet reactivity in subjects with IPF compared to age-matched controls.Whole blood flow cytometry was used to measure platelet-monocyte aggregate formation, platelet P-selectin expression and platelet fibrinogen binding at basal levels and following stimulation with platelet agonists. A plasma swap approach was used to assess the effect of IPF plasma on control platelets.Subjects with IPF showed greater platelet reactivity than controls. Platelet P-selectin expression was significantly greater in IPF patients than controls following stimulation with 0.1 µM ADP (1.9% positive ±0.5 (mean ± SEM) versus 0.7%±0.1; p = 0.03), 1 µM ADP  and 10 µM ADP . Platelet fibrinogen binding was also increased, and platelet activation resulted in increased platelet-monocyte aggregate formation in IPF patients. Re-suspension of control platelets in plasma taken from subjects with IPF resulted in increased platelet activation compared to control plasma.IPF patients exhibit increased platelet reactivity compared with controls. This hyperactivity may result from the plasma environment since control platelets exhibit increased activation when exposed to IPF plasma. Idiopathic pulmonary fibrosis (IPF) is the most common fibrotic interstitial lung disease and has a prognosis worse than many cancers Epidemiological studies have demonstrated an association between IPF and vascular diseases including cardiovascular disease and venous thromboembolism Blood platelets play a central role in thrombosis through rapid activation and aggregation at sites of vascular injury. Transient activation of platelets also induces pro-inflammatory and pro-fibrotic effects In the present study we measured markers of platelet activation in IPF patients under basal conditions and following stimulation with platelet agonists and investigated the effect of plasma from IPF patients on platelet activation. Our data demonstrate that IPF is associated with platelet hyperactivity that may be caused by the plasma environment.Patients with a diagnosis of idiopathic pulmonary fibrosis according to ATS/ERS criteria Written informed consent was obtained from all participants and the study was approved by the Hull and East Riding Local Research Ethics Committee (LREC ref 08/H1304/54).Venous blood was collected using a 21G butterfly needle and vacutainer system . The first 4.5 mls of blood collected was discarded because artefactual platelet activation may occur during venepuncture. Citrated whole blood was added to tubes containing a saturating concentration of one or more of the following antibodies: fluorescein isothiocyanate (FITC)-conjugated monoclonal mouse anti-human CD42b ; phycoerythrin (PE)-conjugated monoclonal mouse anti-human CD14 ; PE-conjugated monoclonal mouse anti-human CD62P ; or FITC-conjugated polyclonal rabbit anti-human fibrinogen . To study the sensitivity of platelets to activation, some tubes were supplemented with adenosine diphosphate (ADP)  or the protease activated receptor - 1 (PAR1) agonist TFLLR . Single colour flow cytometry was used to assess platelet P-selectin expression and fibrinogen binding. Two-colour flow cytometry was used to identify the proportion of monocytes forming aggregates with one or more platelets  based on established methods In order to assess the effect of IPF plasma on control platelets a plasma swap approach was used. Blood from IPF patients and controls was used for the preparation of platelet-poor plasma. Washed platelets from control subjects were suspended in phosphate buffered saline (PBS) and divided into three aliquots. Plasma from the same donor was added to the first aliquot to form an autologous control. Plasma collected from a different control patient was added to the second aliquot to form an allogeneic control. Plasma from a patient with IPF was added to the third aliquot. The ratio of platelet suspension to plasma was 1∶1 (v/v). Samples were incubated with PE-conjugated anti-human CD62P antibody  under basal conditions and in the presence of ADP  for 20 minutes prior to fixation and flow cytometric analysis. Additional detail on the methods for assessing the effects of IPF plasma on control platelets is provided in data supplement Flow cytometry was performed using a FACS Calibur flow cytometer  and the data were analysed using CellQuest Pro software . Statistical comparisons of platelet-monocyte aggregate formation, platelet P-selectin expression and platelet fibrinogen binding between IPF and controls were performed using unpaired t-tests. A paired t-test was used to assess the difference in P-selectin expression between the groups in the plasma swap experiment. A p value of <0.05 was considered significant.Patients with IPF and controls were matched for age and gender. When whole blood was stimulated with ADP (1–10 µM) or TFLLR (1–10 µM), subjects with IPF demonstrated significantly greater platelet-monocyte aggregate formation compared with controls . The perHaving established that platelet-monocyte aggregates were increased in IPF, we next examined other markers of platelet activation. Consistent with increased platelet-monocyte aggregates we found that platelet P-selectin expression was elevated in whole blood from IPF patients compared with controls. Stimulation with all concentrations of ADP led to greater increases in platelet P-selectin expression in IPF patients compared with controls . Similar findings were observed following stimulation with TFLLR . No diffThe percentage of platelets binding fibrinogen was significantly higher in IPF patients compared with controls following stimulation with 0.1 µM and 1 µM ADP . There was no significant difference in fibrinogen binding under basal (unstimulated) conditions . The increase in fibrinogen binding in IPF subjects following stimulation with TFLLR did not reach statistical significance .We next examined whether the platelet hyperactivity observed in IPF was caused by a primary platelet defect or the plasma environment. Re-suspension of washed control platelets in plasma from IPF subjects led to elevated P-selectin expression when compared with platelets suspended in autologous control or allogeneic control plasma. IPF plasma increased P-selectin expression under both basal conditions (p<0.05) and following stimulation with ADP at concentrations of 0.1 and 1 µM (P≤0.01) . FurtherWe have demonstrated platelet hyperactivity in patients with IPF using two mechanistically different agonists (ADP and TFLLR) and three different markers of platelet activation, namely platelet-monocyte aggregate formation, platelet P-selectin expression, and platelet fibrinogen binding. Increased platelet-monocyte aggregate formation is a sensitive marker of platelet activation To explore whether the hyperactivity phenotype in IPF was the result of an alteration of the platelets or their environment we used the plasma swap approach, which has been used successfully in previous studies to examine the role of plasma The two patient groups in this study were well matched in terms of age and gender. At the time of undertaking the platelet assays there was no evidence-based disease modifying treatment for IPF Although not statistically significant, there was a higher prevalence of cerebrovascular disease in the IPF group. There is a recognised association between cerebrovascular disease and platelet activation It has recently been demonstrated that patients with COPD have increased levels of circulating platelet-monocyte aggregates compared to age and smoking status matched controls IIbβ3It is recognised that the choice of ex-vivo anticoagulant can impact platelet-monocyte association. Citrate results in lower levels of platelet-monocyte aggregates secondary to calcium chelation The present study does not establish a temporal relationship between platelet activation and development of IPF, and in isolation we cannot conclude whether the observed increased platelet reactivity is an important phenomenon at the onset of the disease or represents a secondary response to pulmonary fibrosis. Although epidemiological studies have reported that the increased incidence of cardiovascular events and venous thromboembolism in IPF patients predates the presentation of lung disease Therefore, in this small study of platelet activation in IPF we present clear evidence of increased platelet reactivity in IPF patients compared to controls and demonstrate that this effect can be reproduced in control platelets incubated in IPF plasma. This provides insight into the link between IPF and vascular diseases and we have described a mechanism by which platelet activation may perpetuate fibrosis. Activation of platelets represents an early stage in thrombosis and is unaffected by treatment with the vitamin K antagonist warfarin. The lack of benefit from anticoagulant therapies in IPF may be because the wrong component of the thrombotic process has been targeted We have demonstrated increased platelet reactivity in IPF patients that is reproducible with diverse agonists and different markers of platelet activation. The increased activation and reactivity of control platelets when incubated in IPF plasma suggests that the abnormal platelet response in IPF is due to the plasma environment. This is the first report of increased platelet reactivity in IPF patients providing insight into the relationship between IPF and vascular disease and highlighting the need for further investigation of the role of platelets in IPF pathogenesis.We thank Dr Laura Sadofsky and Chris Crow for helpful comments and technical support and Dr Jakob Dudziak for his ICT expertise.File S1Tables S1-S6.(DOCX)Click here for additional data file.


At the ESC Congress 2015 in London, six different Hot Line sessions were organised. The six topics were acute myocardial infarction, atrial fibrillation/pacing, diabetes/pharmacology, hypertension, heart failure, and coronary artery disease. Hot Line sessions are usually the main attraction of the ESC Congress as novel data are being presented for the first time [Cyclosporine Improve Clinical Outcome in ST-elevation Myocardial Infarction Patients?) trial failed to show that cyclosporine improved clinical outcomes or prevented adverse left ventricular remodelling in anterior ST-segment elevation myocardial infarction (STEMI). The goal of the trial was to evaluate treatment with cyclosporine compared with placebo among subjects undergoing primary percutaneous coronary intervention for anterior STEMI.The CIRCUS  trial failed to show that aldosterone antagonists were beneficial to patients with myocardial infarction without heart failure.The ALBATROSS  trial showed that peri-infarct pacing did not prevent left ventricular remodelling or improve functional, or clinical outcomes during 18 months of follow-up in patients with a large first myocardial infarction.The PRomPT  trial aimed to evaluate dual antiplatelet therapy (DAPT) for an additional 36 months among subjects who received a drug-eluting stent and were event-free at 12 months. The trial failed to reach primary outcome; however, extended duration of DAPT non-significantly reduced ischaemic events without increasing bleeding.The OPTIDUAL  trial failed to show a reduction in NT-proBNP levels for finerenone versus eplerenone; however, secondary outcomes favoured finerenone.The ARTS-HF  trial showed that sitagliptin improves glycaemic control without increasing adverse cardiovascular events. Among diabetic subjects with documented cardiovascular disease, sitagliptin was non-inferior to placebo on the outcome of adverse cardiovascular events.The TECOS  study evaluated treatment with lixisenatide versus placebo in patients with type 2 diabetes presenting with an acute coronary syndrome. Although lixisenatide showed significant changes in biomarkers, a neutral effect upon cardiovascular death, myocardial infarction and stroke was found.The ELIXA  showed that adverse cardiovascular event rates were similar between celecoxib and nonselective nonsteroidal anti-inflammatory drugs (NSAID). The goal of the trial was to evaluate treatment with celecoxib compared with a nonselective NSAID among subjects with arthritis and no known cardiovascular disease.The SCOT  trial showed that bivalirudin did not reduce major or net adverse events versus heparin; however, bleeding/death was reduced and stent thrombosis increased. Several lines of evidence even suggest an increased risk of stent thrombosis with bivalirudin.The MATRIX  study showed that benznidazole did not reduce progression of Chagas disease cardiomyopathy among patients with Chagas disease. However, it was found that a 40–80 day treatment with this antiparasitic medication significantly reduced parasitic activity in the blood.The BENEFIT  trial showed that guided pulmonary vein isolation in comparison to conventional pulmonary vein isolation did not reduce late recurrence atrial fibrillation at 1 year follow-up.The PRESERVATION I showed that a novel Bioabsorbable Cardiac Matrix (BCM) is safe but does not benefit STEMI patients with large infarcts; it does not prevent left ventricular remodelling or other adverse outcomes.OptiVol Fluid Status Monitoring and CareLink Network’ (OptiLink) study assessed the effect of intrathoracic impedance monitoring, through automatic wireless telemedicine notification on all-cause death and cardiovascular hospitalization. The primary composite endpoint did not differ between the two groups (telemedicine guided system or controls).The ‘Optimization of Heart Failure Management Using Medtronic Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b’ (CUPID2) trial, investigating the efficacy and safety of intracoronary administration of adeno-associated virus type I (AAV1)/SERCA2a in patients with advanced heart failure, showed that treatment with AAV1/SERCA2a was safe but failed to improve the rate of recurrent events as well as the time to the first terminal event.The ‘Servo-Ventilation in Patients with Chronic Heart Failure’ (SERVE-HF) showed that the composite primary endpoint  did not differ between intervention and control group. In fact, all-cause death and cardiovascular death were elevated in the treatment arm.The ‘Treatment of Sleep-Disordered Breathing with Predominant Central Apnoea with Adaptive The focus of this Comment is to briefly highlight those trials that had a negative  outcome. Over the past years, trials with a negative outcome seem to outnumber trials with a positive outcome during the annual ESC Congresses , 3. The At a first glance the ‘negative’ outcomes of these trials seem rather disappointing. One could therefore really wonder whether all Hot Line studies were truly hot. However, it should be realised that the label ‘positive’ or ‘negative’ hinges on a p-value of < 0.05 or > 0.05; this might in principle have nothing to do with the clinical implication of a study, be it positive or negative. Secondly, ‘negative’ usually only applies to the primary endpoint; in some instances the drugs studied in the above-mentioned trials showed improved safety beyond the neutral finding. Finally, the ultimate proof of the value of a large clinical study is incorporation into the guidelines –8.l’art pour l’art approach; are all the above-described studies really needed? Are the studies truly hypothesis-driven? Will the outcome of the study change the treatment policy for the individual patient? Finally, will it impact the existing guidelines [Nevertheless, there is a flipside of the coin. Sometimes one cannot escape the feeling that also in science there is a idelines , 10? The


Clinical complications of Sjoegren’s syndrome include myelitis and skin manifestations. There is scarce observational data and a lack of randomised controlled studies regarding the treatment of Sjoegren’s syndrome in the presence of such complications.Here we report the case of a 41-year-old Caucasian female patient with biopsy-proven Sjoegren’s syndrome who initially presented with generalized exanthema and subsequently developed acute extensive transverse myelitis. In view of the rapid deterioration we opted for an intensive treatment using a combination of corticosteroid pulse therapy, plasmapheresis and cyclophosphamide, which we later changed to rituximab. Under that treatment the skin manifestations resolved entirely whereas transverse myelitis showed incomplete remission.Severe neurological and dermatological complications may occur in Sjoegren’s syndrome. This suggests a close yet currently unclear pathogenetic relationship. Intensive immunosuppressant treatment resulted in significant improvement of both symptom clusters. Skin manifestations may precede other severe complications in Sjoegren’s syndrome and therefore require particular attention. Sjoegren’s syndrome (SS) is an autoimmune disease that primarily affects the exocrine glands and leads to keratoconjunctivitis and xerostomia . SystemiThe co-existence of SS and psoriasis has rarely been described before, the mutual immunological factors being unclear . The manHere we report the case of a 41-year-old female patient with biopsy-proven SS who rapidly developed severe exanthema and extensive transverse myelitis.A 41-year-old Caucasian woman was admitted to the department of dermatology with generalized maculopapular exanthema  imaging revealed extensive transverse myelitis reaching from the caudal medulla oblongata to level C7 Figure A and B aConcerning the neurological differential diagnosis, there was no history of previous radiation to the spine or clinically apparent optic neuritis, aquaporin 4 antibodies were negative and there were no brain abnormalities suggestive of MS on magnetic resonance imaging (MRI). Furthermore, we could neither find evidence for an arterial occlusion, a compressive aetiology or a viral or fungal infection nor another connective tissue disease -especially leukocytoclastic vasculitis or lupus erythematosus. Subacute cutaneous lupus erythematosus (SCLE) as an important differential diagnosis of psoriasiform dermatitis was excluded since histological characteristics for SCLE  were absent. In synopsis of all clinical and serological findings we considered the extensive transverse myelitis to be SS-associated.2 every six months). Since then, the patient is regularly seen for the administration of rituximab and has had no relapse so far. The combination of plasmapheresis, corticosteroid pulse therapy and subsequent immunosuppression significantly improved the severe symptoms, but only an incomplete remission was achieved: while moderate paraparesis with decreased sensation of both legs and urinary retention remained , generalized maculo-papulosquamous exanthema, dyspnea and oculomotor impairment resolved completely. A follow-up MRI after cyclophosphamide therapy showed significant improvement and no evidence of myelitis . With this treatment regimen tetraparesis and dyspnoea gradually improved but generalized exanthema worsened. For long-term therapy we chose cyclophosphamide (8 cycles). When reaching the maximum cumulated dose of cyclophosphamide after 6 months we switched to rituximab  involvement remains unclear. In our case, high dose corticosteroids, plasmapheresis and long-term immunosuppression with cyclophosphamide followed by rituximab was obviously effective in stopping the suspected autoimmune inflammation but could not reverse the neurological damage. Therefore, in any case of unclear myelopathy, the coincidence of skin manifestations and cranial neuropathies should serve as a red-flag for an autoimmune disorder and should result in further screening for autoimmune disorders including SS.Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


We report on Japanese patients who showed neurological deterioration induced by sitting after cervicothoracic posterior decompression with instrumented fusion, but showed immediate neurological recovery after bed rest.Patients showed incomplete paraparesis caused by the ossification of the posterior longitudinal ligament at uppermost thoracic spine. Cervicothoracic posterior decompression with instrumented fusion was performed. Postoperatively, the patients showed partial paraparesis when they were sitting. They showed rapid recovery from lower extremity paralysis upon lying down. After strict bed rest for one month, those patients showed no apparent development of paralysis during sitting.In patients with postoperative residual anterior spinal cord compression, micromotion might exacerbate neurological symptoms. Ossification of the longitudinal ligament (OPLL) is one of anterior spinal cord compressive lesions at the uppermost thoracic spine, and is often treated using a posterior approach to decompression because of the anatomical complexity of the upper mediastinum . OPLL paA 71-year-old Japanese woman complained of difficulty walking caused by OPLL at T2-3. C7–T5 PDF surgery was performed  for case 1 and 3.5 mm cervical rod for case 2. Upper thoracic spinal cord might be vulnerable for external force because of its specific blood supply ; therefoIn conclusion, we recommend surgeons be alert to the possibility of micromotion after cervicothoracic PDF surgery for OPLL. Thicker or more rigid rods for the PDF surgery may suppress this micromotion.Written informed consent was obtained from both of the patients for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


A 12-year-old boy with known Klippel-Feil Syndrome involving fusion of the C5-C6 vertebrae presented to the clinic complaining of a 4-year history of dyspnea on exertion. The patient was referred to our practice following multiple unsuccessful bronchodilator treatments for the presumptive diagnosis of asthma. The patient's medical history included multiple hospital admissions at a different institution for critical respiratory tract infections during infancy. Of note, fluoroscopic evaluation of the patient during those admissions did not reveal diaphragmatic paralysis.What is Klippel-Feil Syndrome and how is it classified?What are the extraspinal manifestations of this condition?How was the diagnosis of unilateral diaphragmatic paralysis confirmed in this patient?Describe how diaphragmatic paralysis was treated in this patient as well as the postoperative course.,3,1Klippel-Feil Syndrome (KFS) is a congenital skeletal disorder characterized by a defect in cervical spine segmentation leading to various degrees of pathologic vertebral fusion in affected patients.1Klippel-Feil Syndrome is a physically debilitating and psychologically devastating congenital skeletal abnormality whose extraspinal manifestations remain poorly understood. More recent studies on KFS suggest an emerging awareness of a diverse variety of extraspinal manifestations of this disease including genitourinary, cardiovascular, and neurological sequelae.Together, clinical history and examination findings supported an incomplete phrenic nerve lesion leading to right hemidiaphragmatic paralysis. Intraoperatively, the patient was found to have an atrophic phrenic nerve arising solely from the C5 nerve root, without the expected adjacent contributions from C3 or C4. Dense adhesions (consistent with those resulting from compression neuropathy) were observed around both the C5 nerve root and the atrophic right phrenic nerve. These adhesions were most prominent in the proximal region of the nerve. An atrophic phrenic nerve fed by only the C5 nerve root is a novel finding in a patient with KFS. Direct nerve stimulation of both the C5 nerve root and phrenic nerve revealed intact but diminished activity in the diaphragm, requiring supraphysiologic threshold amplitudes (>3 mA) to elicit a response.Phrenic nerve reconstruction, including nerve decompression and transfer, was used to treat this patient. Following identification of the spinal accessory nerve, a nerve transfer was performed without nerve sacrifice. The patient began to experience symptomatic relief in the early postoperative period (1-2 weeks) with signs of improvement on radiographic imaging. On examination 1 year after his surgery, the patient's functional improvement was confirmed by postoperative electrodiagnostic and spirometric testing, which suggested enhanced nerve conduction and ventilation, respectively.The pathophysiology of acquired phrenic nerve dysgenesis in KFS is unclear, but we hypothesize that this may have occurred as a result of the skeletal abnormalities associated with the KFS phenotype. Phrenic nerve reconstruction for restoration of functional activity in the diaphragm has been expanded by the senior author (M.K.), and a recently published cohort analysis to evaluate outcomes of phrenic nerve reconstruction for diaphragmatic paralysis includes an updated treatment algorithm.