Natural killer (NK) cells are highly effective in controlling tumour growth, in mice, but have no significant effect in humans. The reason(s) of this phenomenon is(are) unclear.The effects of cancer cells on NK cells during target-effector cell conjugation was investigated utilising standard immunological methods including flow cytometry, chromium release and enzyme-linked immunosorbent assays while gene expression was evaluated by quantitative reverse transcriptase-polymerase chain reaction.We found that this phenomenon was associated with the different susceptibility of human and mouse NK cells to autologous tumour cell-induced NK cell abnormalities (NKCA). The latter includes CD16 down-regulation and NK cell depletion. Induction of NKCA by leukaemia and solid tumour cells was influenced neither by IL2 treatment nor by HLA class I antigen expression, but was abrogated by a 10 day culture. Following a 10 day of PBMCs culture, NK cells became resistant to leukaemia and solid tumor cell induced NKCA but maintained their cytotoxic activity. Actinomycin D restored the susceptibility of long term NK (LTNK) cells to NKCA suggesting that the generation of resistance to NKCA required RNA transcription. TAPI-0, a functional analogue of the tissue inhibitor of metalloproteinases (TIMP) 3 inhibited cancer cell induced NKCA underlying a role for a restricted number of metalloproteinases in the generation of this phenomenon. Finally, we found an association of TIMP3 gene and protein over-expression with the reduced susceptibility of LTNK cells to cancer cell induced NKCA.This study provides evidence that TIMP3 plays a role in the protection of LTNK cells from cancer cell induced NKCA.


Lohith et al.  recently identified increased metabotropic glutamate receptor 5 (mGluR5) expression in the frontal cortex (FC) of subjects with fragile X syndrome. These results are consistent with postmortem findings in cerebellar vermis and FC of subjects with autism , suggesting that increased mGluR5 signaling is common to multiple autism spectrum disorders. Increased mGluR5 signaling may be associated with reduced phosphorylation of fragile X mental retardation protein (FMRP), which could result in the inactivation of this protein. In the current study, we report on reduced expression of phosphorylated FMRP in cerebellar vermis of adults and children with autism and in FC of adults with autism. Moreoveet al. . Taken t [et al.  suggest  [et al. .Increased mGluR5 expression in autism and FXS is associated with reduced or absent expression of fragile X mental retardation protein (FMRP) ,3 and frr >0.3) we used analysis of covariance (ANCOVA) to co-vary their effects. In none of these cases were significant differences between controls and subjects with autism in phosphorylated FMRP changed by the presence of these covariates. Our new finding of a reduction in phosphorylated FMRP in the cerebellar vermis of children with autism may be associated with increased activity of mGluR5, which could result in dephosphorylation of FMRP, and its subsequent ubiquitination and degradation [We have recently completed a preliminary study of serine 499 phosphorylated FMRP protein levels in the cerebellar vermis in adults (n = 5 controls and 5 adults with autism) and children (n = 3 controls and 4 children with autism), and in the superior frontal cortex in adults (n = 6 controls and 10 adults with autism) and children (n = 6 controls and 8 children with autism). All values were normalized against neuronal specific enolase (NSE) and data were expressed as ratios of phosphorylated FMRP/NSE. We found significant reductions in phosphorylated FMRP/NSE in the vermis of adults and children with autism when compared with controls (Figure radation  support ANCOVA: Analysis of covariance; APP: Amyloid beta A4 precursor protein; BA9: Brodman area 9; FMRP: Fragile X mental retardation protein; FXS: fragile X syndrome; mGluR5: Metabotropic glutamate receptor 5; NSE: Neuronal specific enolase; RAC1: Ras-related C3 botulinum toxin substrate 1; STEP: Striatal-enriched protein tyrosine phosphatase.The authors declare that they have no competing interests. SH Fatemi has several patents on the use of Reelin as a diagnostic marker for neuropsychiatric disorders but has not derived any financial gains from these patents.SHF conceived of the study, participated in its design, supervised conduct of all experiments, and contributed to the drafting of the manuscript. OGR, MKY performed western blotting experiments. TDF performed western blotting experiments and contributed to the drafting of the manuscript. All authors read and approved the final manuscript.


Metabolic reprogramming is one of the strategies adopted by cancer cells to survive hypoxic conditions. Recent findings suggest that hypoxic cancer cells derive the energy that they need through glycolysis using glucose mobilized from intracellular glycogen reserve. Glycogen phosphorylase (GP) is the major rate-determining enzyme for glycogen mobilization in many normal cells under the condition of starvation or physical exercise. The lysosomal alpha-glucosidase (GAA) has also been implicated in glycogen mobilization since deficiency of this enzyme is known to result in Glycogen Storage Disease Type II (Pompe disease). Although a role for GP in the mobilization of glycogen by cancer cells depleted of oxygen had been demonstrated, whether a similar role for GP (and GAA) could be demonstrated under deprivation of both glucose and oxygen is not yet known. This issue is addressed in this study by examining the intracellular level of glycogen in the absence and presence of pharmacological inhibitors of GP and/or GAA.2) in the presence or absence of glucose for 3 hours. The effect of these hypoxic conditions on intracellular glycogen level was examined in the presence and absence of inhibitors for glycogen phosphorylase [CAS 648926-15-2] or lysosomal alpha glucosidase (castanospermine or miglitol).The Hela, HEK293 and HT29 cancer cell lines were subjected to hypoxic conditions  only when cultured cancer cell  were deprived of both glucose and oxygen for 3 hours. The hypoxia-induced lowering of intracellular glycogen was alleviated by the presence of glycogen phosphorylase inhibitor (CAS 648926-15-2) but not alpha glucosidase inhibitor (castanospermine or miglitol). The simultaneous presence of inhibitors for both enzymes did not have a synergistic effect in preventing hypoxia-induced glycogen mobilization as compared to that observed for (CAS 648926-15-2) alone. Hypoxia had no significant effect on both


TDP43 is a ubiquitously expressed prevalently nuclear protein involved in RNA splicing, RNA stability and miRNA processing. Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and inclusion body myopathy (IBM) are characterized by TDP43 being depleted from the nucleus and accumulating in cytoplasmic inclusions, which are the pathological hallmark of the disease – these diseases are also defined as “TDP43 proteinopathies”. Mutations in TDP43 have been found to be causative of a proportion of ALS cases reinforcing the primary importance of this molecule in disease pathogenesis. The pathogenic mechanism by which TDP43 acts is unclear, and both loss of nuclear function (LOF) and gain of function (GOF) mechanisms have been proposed. We here discuss how we used muscle tissue, which provides high quality RNA of patient disease tissue, to investigate the consequences of TDP43 mislocalization. Further, we characterize two novel mouse TDP43 mutant lines, carrying ENU-induced mutations in order to study the effects of TDP43 mutations expressed at physiological levels in the mammalian central nervous system. One mutation (deltaRNA) strongly reduces the RNA-binding capacity of the protein; the second mutation (C-TERM) is in the glycine-rich C-terminal domain where the majority of human pathogenic mutations are found. Our results underline the importance of studying models with physiological expression levels of TDP43 mutations and shed light on the different effects on RNA metabolism caused by the TDP43 loss and gain of function.


Heart failure (HF) is characterised by alterations in fatty acid and glucose metabolism. We aimed to determine if myocardial lipid is increased in HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction (EF), and assess whether it is related to cardiac structure and function.1H MR spectroscopy to quantify myocardial lipid/water (%).25 HFrEF due to dilated cardiomyopathy (DCM), 18 HFpEF  and 28 normal volunteers were prospectively recruited. All subjects underwent cardiovascular magnetic (MR) resonance at 3T for the determination of left ventricular (LV) volumes and function, and cardiac As expected DCM patients had significantly increased LV volumes and reduced EF, whilst HFpEF patients had significantly increased LV mass to end-diastolic volume ratio (LV mass/EDV). Importantly, cardiac lipid was increased in both HFrEF and HFpEF when compared to normal controls , with HFpEF group having the highest level of cardiac lipid (Table This is the first study to demonstrate that myocardial steatosis occurs in both HFrEF and HFpEF and is related to parameters of LV remodeling. This suggests that myocardial lipid may play a role in the pathophysiological processes of LV remodeling in both HFrEF and HFpEF. Cardiac lipid accumulation may be a potential therapeutic target in these conditions.N/A.


To compare thin section CT characteristics of the early local tumour recurrence after the resection of squamous cell carcinoma (SCC) with those of the stump deformity or granulation tissue.Twenty nine consecutive patients with local recurrence after definitive SCC operation from April 2006 to September 2012 were included. Pre- and post-operative CT from these patients were retrospectively reviewed and compared with those in age- and gender-matched 29 patients with stump deformity or granulation tissue at stump site after the definitive SCC operation, by two chest radiologists.p< 0.001). The univariate analysis showed that the size of soft tissue and the distance between soft tissue and stump site were associated with the predictive factors of local recurrence (p< 0.001). On the receiver operating characteristic analysis, the optimal cut-offs of the size of soft tissue and the distance between soft tissue and stump staples were 6mm and 5mm, respectively.Local recurrence were commonly observed as round/oval shape, peripheral eccentric lesion or central contour bulging lesion on CT, while the stump deformity or granulation tissue were commonly demonstrated as irregular or flat shape, focal wall thickening. The size of suspected soft tissue and the distance between stump staples and suspected soft tissue were significantly different between two groups (median; 19mm and 3mm; 18mm and 0mm, respectively, The proper knowledge of stump recurrence regarding the size and the distance around the stump on CT imaging will help us achieve an early and higher diagnostic rate of recurred SCC.


Bicuspid aortic valve (BAV) is the most common congenital heart defect affecting 1-2% of the US population. BAV has been associated with progressive secondary pathologies, such as aortic valve calcification, stenosis, regurgitation, aortic root dilatation, and/or aortic aneurysm. However, not all patients exhibit symptoms or develop aortopathy and the exact link between BAV morphology and disease progression is not fully understood. Magnetic resonance imaging (MRI) has been previously used to characterize BAV hemodynamics. However, studies have been hampered by the need for lengthy manual data analysis thereby limiting reproducibility and/or integration into a clinically feasible workflow.This work develops and applies a novel semi-automated technique to characterize geometry and hemodynamics of the aorta and the aortic valve based on 2D bSSFP cine and 4D flow MRI data. The protocol was applied to a cohort of 30 BAV and 30 control subjects. The table summarizes the preliminary analysis  of the demographics of the subject cohort. The analysis was performed at several cross-sectional locations across the ascending aorta (see figure Geometric metrics (summarized in the table) were found to be significantly larger in the BAV subjects than in the control group (preliminary results are summarized in table A semi-automated protocol for the combined analysis of the aortic valve geometry and hemodynamics in the aorta was developed to analyze MRI data obtained with 2D cine and 4D flow MRI. Application of this protocol and a preliminary analysis performed on the subset cohort of 12 BAV and 12 control cases revealed elevated mean velocity, jet angle and forward flow displacement in BAV subjects in the proximal ascending aorta. This study provides a roadmap for comprehensive large cohort assessment of correlations between geometry and hemodynamics associated with BAV disease.NHLBI grant R01HL115828, K25HL119608 and PURA scholarship.


The prevalence of different biotic processes  and historical contingency due to priority effects are in the focus of ongoing discussions about community assembly and non-random functional trait distributions.We experimentally manipulated assembly history in a grassland biodiversity experiment (Jena Experiment) by applying two factorially crossed split-plot treatments to all communities: (i) duration of weeding (never weeded since sowing or cessation of weeding after 3 or 6 years); (ii) seed addition (control vs. seed addition 4 years after sowing). Spontaneous colonization of new species in the control treatment without seed addition increased realized species richness and functional richness (FRic), indicating continuously denser packing of niches. Seed addition resulted in forced colonization and increased realized species richness, FRic, functional evenness (FEve) and functional divergence (FDiv), i.e. higher abundances of species with extreme trait values. Furthermore, the colonization of new species led to a decline in FEve through time, suggesting that weaker competitors were reduced in abundance or excluded. Communities with higher initial species richness or with longer time since cessation of weeding were more restricted in the entry of new species and showed smaller increases in FRic after seed addition than other communities. The two assembly-history treatments caused a divergence of species compositions within communities originally established with the same species. Communities originally established with different species converged in species richness and functional trait composition over time, but remained more distinct in species composition.Contrasting biotic processes  increase functional convergence between communities initially established with different species. Historical contingency with regard to realized species compositions could not be eradicated by cessation of weeding or forced colonization and was still detectable 5 years after application of these treatments, providing evidence for the role of priority effects in community assembly. A deeper insight into the mechanisms which control community assembly is central to understand ecosystem functioning and the maintenance of biodiversity. Functional diversity, i.e. the extent of trait differences among co-occurring species In natural ecosystems, the importance of biotic processes causing trait convergence and divergence in community assembly is difficult to disentangle because abiotic processes may also cause trait convergence or counterbalance biotic trait divergence In the present study, we used experimental plots of a grassland biodiversity experiment  cessation of weeding after six years (2007), no seed addition,(S6+) cessation of weeding after six years (2007), seed addition (2005),(S3−) cessation of weeding after three years (2004), no seed addition,(S3+) cessation of weeding after three years (2004), seed addition (2005),(S0−) never weeded, no seed addition, and(S0+) never weeded, seed addition (2005).Plots were mown twice per year  and the mown plant material was removed.Species richness, species identities and visually estimated species cover using a decimal scale A trait matrix comprising species mean traits related to spatial and temporal niche dimensions and to strategies of regeneration was compiled for all observed species  based on information in the floristic literature Bray-Curtis dissimilarities n-dimensional trait space occupied by the species in a community n-dimensional trait space n-dimensional trait space Measures of functional trait diversity quantify the distribution of species in a multidimensional space whose axes are defined by functional characteristics. Three components of functional trait diversity were calculated separately: functional richness (FRic), functional evenness (FEve) and functional divergence (FDiv) http://www.r-project.org) including the packages FDnlmeLinear mixed-effects models were applied to test for effects of the experimental factors on the response variables measured in the 5-year study period in the split-split-plot colonization experiment. Block and plot identity, subplot pair  and subplot were treated as random factors in a nested sequence. Although the factors species richness and number of functional groups are nearly orthogonal in the Jena Experiment, the design of the experiment is not completely balanced because it is not possible to vary species richness and functional group number completely independently. Starting from a constant null model the fitting sequence of fixed terms followed the a-priori hypotheses of the biodiversity experiment starting with the number of initially established species (log-linear term), the number of functional groups (linear term), factors for the split-plot variables colonization period (with three factor levels) and seed addition (with two factor levels) and their interactions with the main experimental factors. Finally, a term for the different study years  and its interaction with the previously mentioned experimental factors was entered. The maximum likelihood method was used and likelihood ratio tests were applied to assess the statistical significance of model improvement. The statistical software R  after colonization of new species , Table 2Realized functional evenness (FEve) after colonization declined with an increased number of initially established species , Table 2Realized functional divergence (FDiv) after colonization decreased with an increased number of initially established species , Table 2Average between-community dissimilarity in species composition was highest for communities initially established with a large number of species. Average between-community dissimilarity in functional trait composition did not depend on the initially established plant diversity . BetweenThe average within-plot dissimilarities (between different seed addition × colonization period combinations) in species and functional trait composition were smaller than between communities . Within-In spite of sustained efforts to understand patterns of community assembly, the importance of different biotic processes is poorly disentangled so far. We used the opportunity to study biotic processes of community assembly under relatively homogeneous environmental conditions in split-plots of a large grassland biodiversity experiment opened for colonization by new species and removed dispersal limitation through a seed addition treatment Species gain and increase in functional richness (FRic) after the opening of experimental communities for colonization by new species was reduced by a higher number of initially established species and a longer colonization period (shorter duration of weeding). The negative effects of a higher initially sown plant diversity on the spontaneous colonization of new species may be attributable to the lower stability of low-diverse communities even in the absence of weeding Functional richness (FRic), which quantifies the volume of functional space filled by a community, increased in parallel to species gain in sub-plots without seed addition, but the increment of FRic was flattened in subplots with a higher number of initially sown species . The conPrevious studies have reported that experimental communities initially sown with different plant diversity and opened to colonization converged in species richness and functional or phylogenetic composition while keeping different species composition It becomes increasingly apparent that multiple processes are involved in community assembly. A number of recent studies have shown that patterns of functional trait composition depend on environmental conditions and the traits considered Figure S1Between- and within-community coefficients of variation of realized species richness, FRic, FEve and FDiv.(DOC)Click here for additional data file.Text S1Reference list for data on specific leaf area of particular plant species included in the matrix of functional traits.(DOC)Click here for additional data file.


Pectus Excavatum affects between 1:400 - 1000 live births. Little academic focus has been directed to the anatomical subgroups of this condition. No anatomical classification and subgrouping has been formulated. Current surgical strategies utilize a 'one size fits all' philosophy with variations of the Nuss or Ravitch procedureOur aim was to stratify patients with Pectus Excavatum by providing an anatomical classification that would guide treatment. The novel classification we propose provides a framework for use with current and evolving medical technologiesBetween April 2006 - March 2015, 24 patients  presented to our institute with symptomatic Pectus Excavatum. All presented with symptoms of dyspnoea /fatigue/dysphagia. All patients underwent Prospective evaluation of exercise and anatomical characteristics by: Spirometry; Cardiopulmonary exercise tolerance (CPEX) testing & Non-contrast axial/sagittal CT scan of the thorax & 3D reconstruction. We propose an Anatomical classification based on 2D and 3D CT imaging: Classification A : No depression of manubrium, posterior angulation of sternal bodyClassification B: (1) Horizontal depression of manubrium and sternal body with no angulation (2) Depression of manubrium with posterior angulation of sternal bodyClassification C: Complex asymmetrical torsion of manubrium and body of sternum associated with asymmetrical distortion and depression of rib cage9 patients (38%) had a Type A defect. We recommend this sternal body angulation to be corrected with Ravitch Procedure, Transverse osteotomy and midline screw fixation bar. 14 (58%) patients had a Type B2 defect, which we recommend should be repaired as a Type A defect but elevation of the whole sternum using a transverse screw fixation bar.Our classification provides a framework for evaluation of the pathological anatomy of Pectus Excavatum. This classification has been shown to have utilitarian value in planning surgical strategy. The model will provide opportunities for future development of surgical technique and provides a descriptor that will allow academic discussion


The ability to non-invasively establish patency of cerebral spinal fluid (CSF) flow between adjacent central nervous system (CNS) compartments is of importance in the diagnosis and treatment of patients with various areas of CSF flow obstruction. Recent advances in magnetic resonance imaging (MRI) technology allows for real-time magnetic labeling of CSF to directly visualize flow through different compartments.The presence of CSF flow was examined at the aqueduct of Sylvius (AS), the foramen of Monro (FM), the floor of the third ventricle (3rd V), and the foramen magnum (FMag) using a modification of arterial spin labeling (ASL). The studies were compared with clinical information and classified as true positive, true negative, false positive, and false negative based on expectation of patency.A total of 68 flow studies were done on 44 patients. High correlation with true positive was seen at all four sites. No flow was visualized in 25 readings of the AS; in 9 of those cases we expected flow to be present. Table Establishing qualitative patency between adjacent CSF compartments using MRI is possible with a modified ASL technique. This technique has excellent (above 80%) sensitivity, specificity, and negative likelihood ratio in three out of the four regions studied.


Investigators from the University of Western Australia report the diagnostic yield of performing next generation sequencing  in a heterogenous cohort of patients with neuromuscular disorders (NMD) presenting at or before birth. Investigators from the University of Western Australia report the diagnostic yield of performing next generation sequencing  in a heterogenous cohort of patients with neuromuscular disorders (NMD) presenting at or before birth. Forty-five patients from 38 unrelated families with fetal akinesia (9 families), arthrogryposis (13 families) and severe congenital myopathies (16 families) underwent whole exome sequencing (23), targeted sequencing (7) and both (8). Ten of these families were consanguineous. A conclusive genetic diagnosis was achieved in 18/38 families (47%). Autosomal recessive was the most common mode of inheritance (15), however dominant (1), de novo (1) and X linked (1) were also identified. Mutations were found in eight previously known neuromuscular disease genes  and four novel neuromuscular disease genes .RYR1 are associated with the arthrogryposis and fetal akinesia phenotype while missense mutations in RYR1 are associated with central core myopathy phenotype . The study also led to the identification of novel neuromuscular disease genes  involved in sarcomere assembly and muscle dysfunction. [This study highlights the widening spectrum of phenotypes associated with mutations in known neuromuscular genes. For example, null mutations in the COMMENTARY. Fetal akinesia deformation sequence , arthrogryposis , and severe congenital myopathies comprise a very heterogeneous group, both phenotypically and genetically, that present at or before birth . Prior tThis study used a combination of whole exome sequencing and targeted exome sequencing of known neuromuscular genes. Functional studies were done in cases of novel genes when feasible . A previ


Heparin is diluted in parenteral nutrition bags and administered over a period of 24 hours with in-line filtration. However, there are no data on heparin stability in parenteral nutrition bags, especially on its compatibility with 50% dextrose mainly present in bags. The aim of our n = 6 per type) were infused over a period of 24 hours with and without in-line filtration. Heparin activity was measured using a chromogenic anti-Xa method in bags just being prepared (references for other measures) and after 24-hour infusion and in effluents at the end of infusion line after 24 hours.We prepared both types of bag: parenteral nutrition bags whose composition was defined in the unit, including sodium heparin (77 UI/ml); and bags containing only sodium heparin diluted in 50% dextrose (193 UI/ml). These bags (Our results show values of heparin activity measured in bags and effluents with and without in-line filtration after 24-hour infusion for both types of bag assessed Tables  and 2. RWe conclude that there is no loss of heparin activity when drug is infused over 24 hours for both types of bag prepared, with and without in-line filtration, showing heparin activity remains stable during this period and there is no interaction of drug with other nutrient components of bags, especially 50% dextrose.


ECMO is widely used through the world, but is still surrounded by important complications, most of them at the site of the surgical approach.We describe and assess the effectiveness, the feasibility and the security of exclusive percutaneous peripheral veno-arterial ECMO including the distal reperfusion of the homolateral lower limb.It is a monocentric, retrospective and observational study. Twenty nine patients  were implanted between July 2012 and March 2014. The indications for ECMO were acute phase of myocardial infarction (n = 8), post-cardiotomy cardiogenic shock (n = 12), acute myocarditis (n = 1), cardiac rhythm disorders (n = 1), bridge to cardiac transplantation or long-term circulatory support (n = 7). The insertion was performed in hybrid operating room. After puncture of the common femoral artery (CFA) the superficial femoral artery (SFA) was opacifiated. An anterograde 6F introducer was placed in the SFA under fluoroscopic control. The arterial and venous cannulae were then introduced through guide wires placed under fluoroscopic control. The distal perfusion of the homolateral lower limb was performed through a connection between the arterial cannulae and the introducer placed initially. Femoral arterial cannula was surgically removed at the end of the assistance to avoid vascular complications, the others by compression.The mean duration of circulatory support was 9,5 days (from 1 to 52 days). Thirteen deaths occurred (45%). Bleeding of the groin required a haemostasis procedure in two cases only (5%). One external iliac artery dissection  and two acute thrombosis of the oxygenator (one of which was reversible) (5%) occurred. Neither infection, nor lower limb acute ischemia occurred. A percutaneous atrioseptostomy was performed in catheterization room in eight patients who presented an acute pulmonary edema (21%), which all resumed.These results suggest that the implantation of exclusive percutaneous peripheral veno-arterial ECMO is efficient, reproducible and minimally invasive. The pre-positioning of the distal reperfusion should be systematic. Surgical ablation of the arterial femoral cannula is necessary, but complications related to an initial surgical approach could be avoided during the time of assistance.


Disturbances of cerebral venous hemodynamics define development of child headache. However directed by the diagnosis and subsequent treatment these disturbances are not considered. The absence of diagnostics algorithm and norms of cerebral venous blood flow limits the possibility of timely therapy at children.The studies of headache caused by venous hemodynamics disturbance.600 patients (3-17 years old) who complained of headache have been examined. The data of a blood flow velocity in deep cerebral veins of a brain: in straight venous sinus, vein of Galen, sinuses cavernous defined by Transcranial Color-Coded Duplex.Headache caused by cerebral venous dysfunction notes in 47% of children. The surveyed children had typical headache (100%) of holding apart character in occipital and parietal areas after a dream (69%) ,after physical activity(14%) and a long static pose have been revealed(17%).“Venous” headache at children often can be similar to dizziness. The attacks of headache which are coming to an end with vomiting are revealed at 25% of children. Children also complained of nasal bleeding as a fountain (60%) during a night or day dream (40%), noise in ears (53%), ocular pathology refraction(43%) and expressed vegetative symptoms (80%).We have found clinical signs of the connective tissue dysplasia syndromes at 67% of children.Structural cerebral abnormalities  were revealed at 9% patients of them by MRI .“Markers” of disturbances in cerebral venous hemodynamics was venous outflow in deep brain veins. The research of parameters of a cerebral hemodynamics was carried out in the conditions of functional rest and after dynamic tests. We suggest modified Valsalva, orthostasis and head-down tilting tests in children .Definition of cerebral venous hemodynamic normal indicators in children of different age groups is very important for identification and treatment of headache with cerebral venous disturbances.No conflict of interest.


The differential diagnosis of patients in the emergency department who show symptoms of sepsis and suspected pneumonia may be difficult because of the low sensitivity and specificity of supine chest X rays (SCXR) and physical examination.A retrospective assessment of the usefulness of lung ultrasound (LU) in the diagnosis of pneumonia in patients with signs and symptoms of sepsis and respiratory disease.2 groups of patients were considered:Group A: 22 patients with a positive first SCXR (SCXR1) for pneumoniaGroup B: 18 patients with a negative SCXR1 for pneumonia, but who were subsequently diagnosed with pneumonia during their hospital stay following a second SCXR (SCXR2) or CT.Lung ultrasound examination was performed within 24 hours of admission, searching for direct and indirect echographical signs of pneumonia: focal B lines (FBL), pleural effusion (PE) and images of lung consolidation (LC).See table In our observational study, LU showed high sensitivity in the diagnosis of pneumonia:95% in patients already diagnosed using SCXR, and 100 % of early diagnosis of pneumonia in patients whose diagnosis was subsequently confirmed during hospitalization.


However, full analyses of T cell receptor (TCR) sequences have been difficult because of the inefficiency of T cell cloning, heterogeneity of T cells or the heterodimeric structures of TCRs. Here, we revealed complete landscapes of cancer antigen-specific TCRs using a novel TCR cloning system; hTEC10 -derived peptide vaccine for advanced hepatocellular carcinoma (HCC). The peptide-specific cytotoxic lymphocytes (CTLs) were detected and sorted as single cells from the patients' peripheral mononuclear cells (PBMCs) after in vitro stimulation. cDNAs of paired TCR chains were amplified from the single cells, cloned into retroviral vectors, and transduced in the T cell strain or PBMCs. The avidities of the obtained TCRs were evaluated by comparing antigen-specific cytotoxicities. This system was also applied to the healthy controls and the participants of the Phase I clinical trial of human telomerase reverse transcriptase (hTERT)-derived peptide vaccine for prevention of HCC recurrence after radiofrequency ablation (RFA) therapy.AFP-specific CTLs were induced in 4 patients whose clinical responses were CR , long SD , SD (91 days) and PD (46 days), respectively (long SD is defined as SD over 6 months). Totally, 347 specific TCR clones that consisted of 10 kinds of TCR gene rearrangements  were amplified. The TCRs obtained from the CR patient and the long SD patient possessed higher avidities than that from the SD patient, the PD patient and the healthy controls without HCC. Similarly, we could obtain highly reactive 122 TCR clones consist of 10 different gene arrangements from 3 patients who were treated with hTERT vaccine and prevented from the recurrence until 24 weeks after RFA. These results indicated that the inductions of TCRs with high avidities reflected the good clinical responses, and high-avidity TCR might be retrieved from vaccinated patients with good clinical responses, not from patients with poor responses or healthy individuals.


The primary aim of this commentary is to describe trauma-related dissociation and altered states of consciousness in the context of a four-dimensional model that has recently been proposed . This model categorizes symptoms of trauma-related psychopathology into (1) those that occur within normal waking consciousness and (2) those that are dissociative and are associated with trauma-related altered states of consciousness (TRASC) along four dimensions: (1) time; (2) thought; (3) body; and (4) emotion. Clinical applications and future research directions relevant to each dimension are discussed. Conceptualizing TRASC across the dimensions of time, thought, body, and emotion has transdiagnostic implications for trauma-related disorders described in both the Diagnostic Statistical Manual and the International Classifications of Diseases. The four-dimensional model provides a framework, guided by existing models of dissociation, for future research examining the phenomenological, neurobiological, and physiological underpinnings of trauma-related dissociation. Putnam  notes suAccordingly, this commentary will review the relevance of each of the four dimensions of consciousness to the theoretical, neurobiological, and clinical underpinnings of trauma-related phenomenology in the context of a four-dimensional model (4-D model) outlining a dissociative and a non-dissociative dimension of each of the four dimensions of consciousness  those that occur within NWC and (2) those that exhibit a dissociative presentation associated with the experience of TRASC. Experiences of NWC and TRASC can be further classified along four dimensions of consciousness: (1) time (reliving flashbacks [TRASC] versus intrusive memories and reminder distress [NWC]); (2) thought ; (3) body ; and (4) emotion  see . It shouThe model makes four predictions: (1) the experience of TRASC will be less common than will be presentations of normal waking consciousness given that states of normal waking consciousness, by definition, are the most common phenomenological state of human beings; (2) TRASC are expected to be less intercorrelated than states of normal waking consciousness as the experience of TRASC is frequently experienced as more “compartmentalized”; (3) measures of TRASC are expected to be more strongly correlated with other measures of dissociative symptomatology; and (4) experiences of TRASC are predicted to be more specific to an etiology implicating early life adversity and repeated traumatization. Emerging evidence provides support for these predictions  in the context of a subjective past and anticipated future. Accordingly, under normal circumstances, time is experienced as continuously moving forward. However, traumatized individuals often relive their traumatic memories through flashbacks and lack the ability to live in the “now,” reflecting a key dissociative process associated with TRASC. Such reliving events are in contrast to intrusive memory recall most frequently associated with reminder distress and not involving an altered state of consciousness or a dissociative process but rather represent a state of normal waking consciousness  traumatized individuals with frequent symptoms of emotional numbing and shutdown and (2) traumatized individuals that solely exhibit general negative affect to identify specific maps of bodily sensations and to explore the relation of these maps to the experience of different emotional experience. These findings will then need to be related not only to the underlying neural deficits of emotion processing but also to treatment outcomes. Moreover, investigating how specific neural networks involved in the consciousness of emotion can be directly targeted through the use of real-time fMRI or EEG-based biofeedback in conjunction with pharmacotherapeutic and psychotherapeutic approaches will be an important avenue for future investigation.In summary, this commentary describes a 4-D model that categorizes symptoms of trauma-related psychopathology into (1) those that occur within normal waking consciousness and (2) those that are dissociative and associated with TRASC along four dimensions of consciousness: (1) time; (2) thought; (3) body; and (4) emotion. Conceptualizing TRASC across these four dimensions has transdiagnostic implications for trauma-spectrum disorders involving dissociation and is relevant to efforts to identify key factors related to the development and maintenance of trauma-related symptoms described both in the DSM and the International Classification of Disease. It will be crucial for future research to examine directly these symptoms along each dimension of consciousness and to identify further their neurobiological and physiological underpinnings, and to determine their role in treatment outcome (also see Sar, Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.


Background. The current study was designed to reveal possible associations between the polymorphisms of the vascular endothelial growth factor (VEGF) gene (rs2010963) and its receptor, kinase insert domain-containing receptor (KDR) gene polymorphism (rs2071559), and markers of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled. The carotid intima-media thickness (CIMT) and plaque characteristics (presence and structure) were assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. Genotyping of VEGF/KDR polymorphisms  was performed using KASPar assays. Results. Genotype distributions and allele frequencies of the VEGF/KDR polymorphisms  were not statistically significantly different between diabetic patients and controls. In our study, we demonstrated an association between the rs2071559 of KDR and either CIMT or the sum of plaque thickness in subjects with T2DM. We did not, however, demonstrate any association between the tested polymorphism of VEGF (rs2010963) and either CIMT, the sum of plaque thickness, the number of involved segments, hsCRP, the presence of carotid plaques, or the presence of unstable carotid plaques. Conclusions. In the present study, we demonstrated minor effect of the rs2071559 of KDR on markers of carotid atherosclerosis in subjects with T2DM. Type 2 diabetes mellitus (T2DM) is considered a major epidemic of this century. It is estimated that its prevalence will increase worldwide from 371 million people in 2013 to 552 million people in 2030 . The genotype distributions in both patients with T2DM and controls were in Hardy-Weinberg equilibrium for the KDR gene polymorphism [rs2071559: T2DM  and controls ]. No statistically significant differences in the VEGF rs2010963 and KDR rs2071559 genotype distribution frequencies were observed between T2DM patients and controls.The genotype distributions in both patients with T2DM and controls were in Hardy-Weinberg equilibrium for both VEGF gene polymorphisms [rs2010963: T2DM  between patients with T2DM and controls (32.3% versus 33%). However, the C allele frequency of the KDR rs2071559 polymorphism was significantly lower (p = 0.04) in T2DM subjects as compared to the controls (49% versus 54%).The observed minor allele frequency (MAF) distributions were mostly in agreement with the 1000 Genomes Project data in the European population. The C allele frequency of the VEGF rs2010963 showed no significant difference (Higher VEGF serum levels were demonstrated in subjects with T2DM with the CC genotype (rs2010963) compared to those with other (CG + GG) genotypes . MoreoveThe comparison of atherosclerosis parameters was performed with regard to different genotypes of the VEGF polymorphism rs2010963) upon enrolment. In our study, we did not demonstrate any association between the rs2010963 and either CIMT, the sum of plaque thickness, the number of involved segments, hsCRP or the presence of carotid plaques, or the presence of unstable carotid plaques  and CIMT. Variations in the VEGF gene were reported to be weakly associated with CIMT . None ofAdditionally, we also demonstrated an association between the rs2071559 of KDR and the sum of plaque thickness in subjects with T2DM, whereas no association between tested polymorphism of VEGF (rs2010963) and markers of carotid atherosclerosis was demonstrated. The rs2010963 polymorphism of the VEGF gene was not demonstrated to exert a significant influence on the risk of subclinical atherosclerosis manifested by the presence of endothelial dysfunction by brachial artery reactivity and increased CIMT in a series of patients with rheumatoid arthritis . ContrarIn our study, the effect of either rs2071559 of KDR or rs2010963 on VEGF serum levels was demonstrated. These findings are in accordance with our previous studies in which subjects with recent MI history (up to 9 months after MI) were enrolled , 16, 25.In contrast to the minor effect of the rs2071559 of KDR and the absence of the rs2010963 of the VEGF, an association of either rs2071559 or rs2010963 with MI has recently been reported in Caucasians with T2DM , 16, 24.To conclude, in our study we demonstrated a minor effect of the rs2071559 of KDR on markers of carotid atherosclerosis  in subjects with T2DM, whereas we failed to demonstrate an effect of tested polymorphism of the VEGF gene (rs2010963) on markers of carotid atherosclerosis.


Actinomycosis is a chronic infection due to anaerobic filamentous bacteria (Actinomyces), which occurs mostly in the cervicofacial region as a chronic granulomatous infection. We report the case of Mr KI, 17 years old, without past medical history, presented a painful ulceration on the right side of the chest wall which evolved since 2 months. The onset of symptoms was a nodule which ulcerated after 2 months with extruding yellowish pus. The examination objectified ulcerated and burgeoning lesion in right parasternal region from what came yellowish pus mixed with sulphur granule (A). A painful subcutaneous nodule was noted under the right breast. An examination of the oral mucosa was entirely normal as well as the rest of the physical examination. Histopathologic studies (hematoxylin-eosin staining) revealed the presence of inflammatory cells surrounding basophilic sulfur granules which were composed of a large number of filaments arranged in a radiating pattern (B). The chest x-ray was normal. The chest scan showed an infiltration of the anterior and right lateral wall without bone and lung injury. The results of aerobic and anaerobic culture showed mixed flora. The histopathologic findings led to the diagnosis of actinomycosis of the wall chest. Treatment was based on oral amoxicillin + clavulanic acid (1g + 125 mg 3 times daily). The size of the ulcerative lesion gradually decreased and completely healed by 4 weeks. Then antibiotherapy was continued for four months. No evidence of recurrence of this lesion was found after 24-month of follow-up.


Eosinophilic esophagitis (EoE) is a chronic/recurrent inflammatory disease of the esophagus characterized by the association between symptoms of esophageal dysfunction and a prominent eosinophilic infiltrate >15/HPF) of the esophageal epithelium 5/HPF of . The nat


Evidence of the association of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) with the full range of cardiovascular diseases (CVDs) is limited. We examined their relationship with the first clinical presentation of the 12 most common CVDs in an unselected population-based cohort of men and women.We analysed CArdiovascular disease research using LInked Bespoke studies and Electronic health Records (CALIBER) data, which links primary care and hospital and mortality data in England, from 1997 to 2010. We assembled a cohort of men and women initially free from CVD at baseline and included all patients with PMR and/or GCA (PMR/GCA) diagnosis, matched by age, sex and general practice with up to 10 individuals without PMR/GCA. Random effects Poisson regression analysis was used to study the association between PMR/GCA and the initial presentation of 12 types of CVDs.The analysis included 9776 patients with PMR only, 1164 with GCA only, 627 with PMR and GCA and 105 504 without either condition. During a median of 3.14 years of follow-up 2787 (24.1%) individuals with PMR/GCA and 21 559 (20.4%) without PMR/GCA developed CVDs. Patients with PMR/GCA had lower rates of unheralded coronary death , transient ischaemic attack  and coronary and death composite . No associations were observed for other CVDs or cerebrovascular diseases, and in patients with only PMR or GCA. No evidence of interaction by age or sex was found. Estimates decreased with longer PMR/GCA duration and findings were robust to multiple sensitivity analyses.In this large contemporary population-based cohort the presence of PMR and/or GCA was not associated with an increased risk of CVDs or cerebrovascular diseases regardless of PMR/GCA duration. Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are two chronic inflammatory diseases with similar genetic and acute-phase response patterns that affect predominantly women aged ≥50 years.3The inflammatory nature of the two conditions and presence of clinical or subclinical arteritisBecause one in two patients diagnosed with GCA will also develop PMRIn this longitudinal population-based study of individuals registered in primary healthcare practices with linked information to hospital, registry and mortality data, we examine the association between PMR and GCA and the 12 most common clinical initial presentations of CVD. We also assess whether associations differ according to disease duration, sex, age or presence of other autoimmune diseases.All patients with prospectively recorded PMR and/or GCA diagnosis between January 1997 and March 2010 were identified in the CALIBER  dataset.13–16For each patient with PMR/GCA, up to 10 individuals matched on age (±5 years), sex and practice were randomly selected among those who, on their matched inclusion date, had contacted the medical practice within 1 year and had not been diagnosed with the disease (concurrent sampling). At the start of the observation period all patients were ≥18 years old, free of prior CVD and had been registered with their practice for ≥1 year.Patients with recorded diagnosis of PMR and/or GCA were identified from electronic medical records using Read and ICD-10 codes (see online supplementary table S1). Those with supporting information for PMR or GCA diagnosis  or under the care of a rheumatologist within 6 months) were included in primary analyses (see online supplementary figure S1 and table S3). Patients without supporting information for diagnosis were included in sensitivity analyses. Individuals were initially categorised as having PMR and/or GCA (PMR/GCA group) or not having either condition. Because it is uncertain whether the two conditions are different presentations of the same disease, they were then divided into subgroups of those diagnosed only with PMR, only with GCA or with GCA regardless of previous or later PMR diagnosis during follow-up . Patients were further classified into incident and prevalent cases, depending on whether the first recorded diagnosis was made before or after/on study entry.https://www.caliberresearch.org/portal/.Baseline covariates considered were: sociodemographic , cardiovascular , ≥2 prescriptions in the past year , immunosuppressant drug, oestrogen oral contraceptives and hormone replacement therapy), diagnosis with another autoimmune diseases (see online supplementary table S4) and year of study entry. As in previous CALIBER analyses,http://www.caliberresearch.org/portal/.The primary study endpoints were the initial presentation of 12 fatal and non-fatal cardiac and arterial vascular diseases of heterogeneous pathophysiology identified across the four linked data sources in CALIBER: the CPRDFor individuals with PMR/GCA the observation period began on the date on which the patient fulfilled all the study inclusion criteria, or the date of first recorded diagnosis for patients with incident PMR/GCA (see online supplementary figure S2). For individuals without PMR/GCA, it started on the entry date of the matched individual with PMR/GCA. For all patients the study ended on the date of cardiovascular endpoint diagnosis, death, practice deregistration, last practice data collection date or diagnosis of PMR/GCA (for patients who contributed follow-up to both the PMR/GCA and non-PMR/GCA groups).Incidence rates of events per 1000 person-years of follow-up with 95% CIs were calculated in patients with and without PMR/GCA, separately for individuals with prevalent or incident PMR/GCA, and for patients exclusively diagnosed with PMR or GCA. Associations between PMR/GCA and every study endpoint were assessed with random effects Poisson regression accounting for clustering between practices. Missing values of covariates were multiply imputed (see online supplementary text S1). Models were initially adjusted for age and sex, then additionally for cardiovascular factors. To explore possible pathways or mediators of any increase in risk, estimates were further adjusted for: (i) lipid and blood pressure lowering medication; (ii) diagnosis of another autoimmune disease; and (iii) anti-inflammatory and/or immunosuppressant drugs.In secondary analyses: (i) evidence of interactions with sex and age were assessed using Wald tests for interaction; (ii) the relationships with prevalent and incident PMR/GCA were studied; (iii) associations were assessed separately for patients who had only one of the two diseases and for those who had GCA regardless of PMR diagnosis. Furthermore, to examine the association between disease duration and CVD, the follow-up of patients with incident PMR/GCA was split into duration periods . Patients with prevalent disease who had a first diagnosis recorded ≥5 years before study entry were included in the ≥5 year period group. Those with prevalent disease of shorter duration (<5 years) were excluded from this analysis because of uncertainty about exact disease duration.Sensitivity analyses comprised: (i) exclusion of patients with another autoimmune disease; (ii) restriction to patients with ≥6 months of follow-up; and (iii) exclusion of 2 years of follow-up prior to PMR/GCA diagnosis for patients who contributed to the exposed and unexposed groups (to account for delays in diagnosis); (iv) inclusion of patients without supporting information for PMR/GCA diagnosis; (v) exclusion of patients of <50 years of age; (vi) inclusion of first cardiovascular events irrespective of other earlier CVD presentations; (vii) comparison of estimates in the periods before and after the introduction of the pay for performance scheme in England ; and (viii) restriction to patients with evidence of active disease (baseline c-reactive protein (CRP) >3.0 mg/mL or elevated erythrocyte sedimentation rate (ESR)).Statistical analyses were done with Stata (V.13.1).Approval was granted by the Independent Scientific Advisory Committee of the Medicines and Healthcare Products Regulatory Agency and the MINAP Academic Group. We registered the protocol at clinicaltrials.gov (NCT02062021).In total 11 567 patients with PMR/GCA and supporting diagnosis information and 105 504 non-PMR/GCA patients free of CVD were identified . Of patiDuring follow-up, 2272 (23.2%) patients with PMR only, 348 (29.9%) with GCA only, 167 (26.6%) with both conditions and 21 559 (20.4%) without either disease experienced one of the 12 CVDs. The incidence of fatal and non-fatal CVDs was slightly lower in patients with than without PMR/GCA , greater differences being observed for heart failure, PAD and stable angina. The small number of CVD events in the subgroup of patients with GCA limited the power to examine differences in rate ratios between patients with PMR and GCA for some CVDs. However, no evidence of increased risk of CVD was observed for those with a higher number of events (see online supplementary table S8) and for composites endpoints .Exclusion of individuals diagnosed with another autoimmune disease or patients aged <50 years, inclusion of patients with >6 months of follow-up and censoring of follow-up 2 years before the diagnosis of PMR/GCA in patients who contributed to both, PMR/GCA and non-PMR/GCA groups, did not alter the results (see online supplementary table S8 and figure S10). Patterns of association remained unchanged when PMR/GCA individuals were included irrespective of whether disease supporting information was recorded (see online supplementary figure S11). Analyses comparing estimates before and after the introduction of the pay-for-performance system of CPRD, those of first presentation of CVD  and those restricted to patients with evidence of active disease also showed similar patterns of associations (see online supplementary figures S12 and S13 and table S10).This is to date the largest population-based longitudinal study comparing the initial presentation of a wide range of symptomatic CVDs in patients with and without PMR and/or GCA using contemporary data (1998–2010). The large sample size, the longitudinal design and the information available allowed examination of associations in individuals with prevalent and incident PMR/GCA, pure and concomitant PMR and GCA, different duration of disease and adjustment for sociodemographic and cardiovascular factors. In contrast to a previous CALIBER study conducted in the same population in which we reported increased rates of the initial presentation of several CVDs in patients with rheumatoid disease (awaiting publication), no evidence of increased risk of any of the 12 CVD presentations investigated was found in the presence of PMR/GCA.This study has several strengths. The longitudinal population-based design provided evidence of temporality and enabled investigation of associations with duration of PMR/GCA since diagnosis. The large sample size allowed conducting separate analyses for patients with incident and prevalent PMR/GCA and pure and concomitant PMR and GCA, and investigation of sex and age interactions. The time period covered 1997–2010) provided epidemiological evidence from a population diagnosed and treated in recent years. The analysis of linked electronic health records spanning primary, hospital and disease registry data improved disease and cardiovascular endpoint ascertainment,10 providStudy limitations include the possibility of PMR/GCA misclassification . In our study, PMR/GCA was defined based on recorded physician diagnosis in primary care and hospitals. Information on American College of Rheumatology classification criteria or histology was not available in the dataset for diagnosis confirmation. However, to reduce the likelihood of PMR/GCA misclassification in patients >60 years of age with incident seronegative rheumatoid arthritis or malignancies,There are several possible explanations for the absence of increased risk of CVD observed in patients with PMR/GCA regardless of disease duration. PMR/GCA affects an old population who might die before a detrimental effect of chronic systemic inflammation on the arteries becomes symptomatic.7Discordance with previous studies that found evidence of increased risk of CVD in patients with PMR/GCA could be related to their inclusion of patients with a history of CVDs and/or primarily diagnosed and treated in tertiary health facilities, and to betterThe chronic inflammatory nature of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) and the presence of clinical or subclinical arteritis might lead to an increased risk of cardiovascular diseases (CVDs). However, findings from the few available studies investigating these associations are heterogeneous and inconsistent.In this large, contemporary longitudinal population-based study of patients treated at primary and hospital levels, we examined the associations between prevalent and incident PMR/GCA  and pure  and concomitant PMR and GCA, and the 12 most common clinical presentations of CVDs. Regardless of PMR/GCA disease duration, presence of pure or concomitant PMR and GCA was not associated with an increased risk of CVD. No evidence of interaction by sex or age was found.The study findings suggest that, under current clinical practice targeted to patients with PMR and/or GCA, including early and long-term administration of anti-inflammatory and immunosuppressant drugs to control chronic systemic inflammation associated with PMR/GCA, and management of cardiovascular factors with primary prevention, cardiovascular patient risk is similar to the risk of patients without PMR/GCA.In conclusion, regardless of disease duration, diagnosis of pure or concomitant PMR and GCA was not associated with increased risk of CVDs in a large, contemporary population-based sample suggesting that, within the framework of current clinical practice, these diseases do not represent an important risk factor for CVD.


The mechanism by which transmyocardial revascularization (TMR) offers clinical benefit is controversial. We hypothesized that TMR ameliorates vasoconstriction in patients with ENDCADThis study was undertaken to demonstrate that transmyocardial laser revascularization in patients with advanced CAD improves results of combined operations CABG+ TMR through reduction of vasoconstrictionWe investigated vessels of coronary microvascular network of patients with ENDCAD and analyzed the histological changes in two groups: in group of patients died after sole CABG (1-st group - 8 heart specimens) and group of patients died after combined operations CABG+TMR (2-nd group - 6 heart specimens).These data are compared with hospital results  in two large groups of patients with ENDCAD: with isolated CABG (1-st group -33 operations) and CABG+TMR (2-nd group - 87 operations), operated in 2011-2012.in all hearts after sole CABG was identified coronary arteriolar vasospasm that decreases coronary and bypass flow and thus increase the probability of thrombi formation. All cases after CABG+TMR revealed vasodilatation in lased areas. Reduction in the occurrence of vasospasm in cases with CABG+TMR can prevent graft and coronary occlusion. High indices of hospital mortality (12.1%) and morbidity(33.3%) in cases with sole CABG can be explained with coronary spasm in patients with advanced CAD. On the other hand, reduced hospital mortality (1.15%) and morbidity (2.3%) in the second group(CABG+TMR) can be explained by laser-influenced vasodilatation of distal coronary bed. Elevated resistance of the coronary bed hinders the effectiveness of the graft and myocardial blood flow(MBF). We suggest, that intraoperative effectiveness of TMR based of denervation, dilatation of microvascular network of the myocardium and intraoperative improvement of perfusion.elevated resistance of myocardial microcirculation(vasoconstriction) in patients with advanced CAD inhibit the effectiveness of the CABG. In cases with TMR effectiveness is most likely due to vasodilatation of vasoconstriction of myocardial microcirculation


Therapeutic temperature modulation (TTM) is widely used in the care setting to improve outcomes of patients with traumatic brain injury (TBI). Through fever prevention, both oxygen utilization and caloric expenditure are reduced, so metabolic efficiency can be maximized . HoweverA retrospective review was conducted looking at SICU patients managed with a normothermia protocol, with particular attention paid to the anti-shivering portion of the protocol. Serum magnesium (Mg) levels were assessed prior to initiation of TTM and Bedside Shivering Assessment Scale (BSAS) scores were collected.n = 10 of 20). Serum Mg levels at the initiation of TTM were observed to negatively correlate with the level of shivering, as indicated by the BSAS scoring system (P = 0.02). See Figure Twenty patients receiving TTM for TBI were evaluated (March to October 2013). One-half of the patients maintained targeted BSAS scores <1 for the full duration of TTM (The literature suggests the positive impact of TTM on patient outcomes can be maximized with shivering prevention . Current


Ebstein's anomaly consists of varying degrees of tricuspid dysplasia and displacement into the right ventricular (RV) cavity, along with changes in ventricular function predominantly affecting the RV. Measuring alterations in contraction pattern and dyssynchrony may provide insights into ventricular performance in this disease. We sought to quantify right and left ventricular (RV and LV) deformation and dyssynchrony in a cohort of patients with Ebstein's anomaly in comparison with normal controls using cardiovascular magnetic resonance myocardial feature tracking (CMR-FT).Twenty-six patients with uncorrected Ebstein's anomaly and 10 normal controls were prospectively studied. LV and RV global longitudinal myocardial strain (GLSLV and GLSRV) and time to peak strain (TPKLV and TPKRV) were calculated from the 4-chamber cine CMR images. Intraventricular dyssynchrony (IntraVD) was calculated as the difference between the segments with the longest and shortest TPK divided by the global TPK value of the respective ventricle: (IntraVD) = TPKlongest-TPKshortest/TPK global. The ratio of global TPKRV and TPKLV was measured as interventricular dyssynchrony (InterVD).Mean patient age was 28 ± 15 . GLSRV was significantly reduced in patients (-15.7 ± 5.2) as compared to controls , while there was no significant difference in GLSLV or global TPKRV and TPKLV between patients and controls .


There are errors in S10 Figmean annual runoff are shown. Statistics describing annual variability in runoff in these scenarios is shown in Table 2 and illustrated graphically for 4FRI scenario in S8 Fig.Effects of increasing (a) pace and (b) extent of thinning treatments of ponderosa pine forests in Salt-Verde watersheds on increases in mean annual runoff (acre-feet/year). In (a) total area thinned is held constant at 301,000 ha   to show influence of increasing the area thinned per year. In (b) duration of thinning treatments is held constant at 25 years  to show influence of increasing the total area thinned across the scenario. In order to illustrate scale effects, only increases in (TIFF)Click here for additional data file.


Surgical Site Infections (SSI) are the most frequent healthcare-associated infection in developing countries with incidence rates up to 30%. Prevention of SSI is complex and faces multiple challenges, especially in resource limited settings. Since 2013, WHO in collaboration with Johns Hopkins University, has been leading the Surgical Unit Safety Program (SUSP) in 5 African hospitals, one of which is the AIC Kijabe Hospital, a private teaching facility in rural Kenya.The SUSP intervention incorporated a bundle of 6 SSI prevention measures selected as priority by the site leaders  embedded within adaptive work to improve the safety culture. Implementation was achieved with local adaptation and creation of tools for advocacy, training, leadership and front-line staff and patient engagement. SSI surveillance and process measures evaluation reflecting the intervention have been carried out throughout the study period for about 18 months, based upon a WHO protocol using standardized definitions.Preliminary data show that the crude SSI rate significantly decreased from 9.3% (38/406 patients) before to 5% (18/353) post-intervention. Patients receiving post-operative antibiotics decreased from 50% to 26%; hair removal with shaving decreased from 25% to 2% of patients; theatre discipline improved with a drop in the average number of door openings per operation from 55 to 40.Implementation of a SSI prevention bundle and creation of a safety climate was successfully achieved at AIC Kijabe Hospital with tangible reductions in SSI rates and improvement of process measures. Local production of alcohol-based products for surgical hand and surgical site preparation was an innovative approach to overcome availability and cost barriers. Engagement of senior staff coupled with structured management of patient safety programs helped inculcate these concepts into the local culture and practice and are crucial for the long term sustainability.None declared.


Quantitative MR myocardial strain analysis is typically performed using rectilinear or Cartesian grid tagging, and regional contractility is visually assessed by the deformation of the grid1. However, it is difficult to visually isolate circumferential and radial components of displacement and strain from parallel straight lines on short axis images. This study evaluates the potential of a polar coordinate tagging system2 for quantification of circumferential myocardial displacement in a variety of clinical conditions.33 subjects including 12 patients with congenital heart disease (CHD), 11 with cardiomyopathy (CM) and 10 healthy volunteers (HV) underwent cardiac SSFP cine and myocardial tagging in the mid-ventricular short axis plane with grid tags (line separation 5-7 mm), circular tags (5 mm separation) and radial tags . Visual assessment of circumferential and radial displacement was performed by two observers for each of the six mid short axis segments. Scores were assigned for: overall tag quality , strain , confidence in the findings  and ease of interpretation . Quantitative analysis of global and segmental circumferential strain was performed using a semi-automated tool previously described3.Healthy volunteers Figure  had the Polar tagging has advantages for the visual and quantitative assessment of myocardial strain. Compared to rectilinear tagging, radial tags are easier to interpret for isolation of circumferential and radial components of myocardial motion. Overall tag quality, strain, confidence in assessment and ease of interpretation of the image were highest in healthy volunteers, second highest CHD patients and lowest in CM patients.n/a.


We consider parks in a landscape context (including surrounding 30 km) and evaluate both mean and inter-annual variation in 25 biologically relevant climate variables related to temperature, precipitation, frost and wet day frequencies, vapor pressure, cloud cover, and seasonality. We also consider sensitivity of findings to the moving time window of analysis . Results show that parks are overwhelmingly at the extreme warm end of historical temperature distributions and this is true for several variables . Precipitation and other moisture patterns are geographically more heterogeneous across parks and show greater variation among variables. Across climate variables, recent inter-annual variation is generally well within the range of variability observed since 1901. Moving window size has a measureable effect on these estimates, but parks with extreme climates also tend to exhibit low sensitivity to the time window of analysis. We highlight particular parks that illustrate different extremes and may facilitate understanding responses of park resources to ongoing climate change. We conclude with discussion of how results relate to anticipated future changes in climate, as well as how they can inform NPS and neighboring land management and planning in a new era of change.US national parks are challenged by climate and other forms of broad-scale environmental change that operate beyond administrative boundaries and in some instances are occurring at especially rapid rates. Here, we evaluate the climate change exposure of 289 natural resource parks administered by the US National Park Service (NPS), and ask which are presently (past 10 to 30 years) experiencing extreme (<5 Recent scientific reviews of the US National Park Service (NPS) suggest the agency needs to manage its parks for changing climatic and ecological baselines in a landscape context Climate change is a principal factor driving the imperative for progressive management aimed at achieving a specified ‘desired future condition’ (DFC) Recommendations to both scale up and consider changing baselines n = 289), including a 30 km buffer around each park’s boundary Our analyses were performed for all natural resource parks considered by the NPS Inventory & Monitoring Program’s landscape dynamics monitoring project, NPScape (2 at the Equator and 2000 km2 at 70°N latitude) for each month × year, 1901–2012. Although this dataset is spatially coarse, at least relative to the size of some parks , it offers for all NPS geographies the highest spatiotemporal resolution of observed climate over the 20th and 21st centuries. We selected for analysis monthly averages of daily temperature , percentage cloud cover, and vapor pressure (haP), as well as total monthly precipitation (mm) and monthly frequencies of frost days  and wet days (rain days per month). We used the monthly climate variables to calculate a series of biologically meaningful variables, including 19 standard bioclimatic variables Gridded climate data were obtained from the Climatic Research Unit (CRU) high-resolution time series version 3.21 (TS 3.21) Although correlations exist among some of these variables, we include the full suite in our analysis because the relevance of individual climate variables can vary dramatically by park resource . As such, the elimination of certain variables due to high statistical correlations would adversely restrict the value of these analyses for park interpretation. Furthermore, the data presented here are percentiles calculated from HRV (see below), not the raw climate variables. Hence, whether variables are correlated is not simply a question of correlation at one point in time; it is a complex question of how sensitive correlations are across the entire 1901–2012 period of analysis, interacting with the moving time window of summarization.For each biologically relevant variable, over the entire time series (1901–2012), we used three moving windows  to calculate a series of running means and standard deviations (SD). Hereafter we refer to these as ‘moving window means’ and ‘moving window standard deviations’. These statistical distributions are what we use to estimate HRV. For example, with the 10 year window, we calculated the mean and SD for 103 windows  to create the HRV distribution. The three windows were designed to encompass both near- and long-term management and planning considerations, as well as important climatic periods and cycles. In the NPS, many implementation plans have short horizons (<10 years), while strategic plans forecast out 10 to 20 years th percentile for the most recent 10 year moving window of annual mean temperature signifies that the value of this climate variable during this time period was greater than 90% of all annual mean temperature 10 year moving window values). Hereafter we refer to these estimates as ‘recent percentiles’.For each variable, moving window size, and summary statistic , we calculated the area-weighted mean for each park, based on the spatial intersect of park areas of analysis with the CRU lattice. Using processing logic contained in the NPScape climate grid analysis toolset We then averaged the recent percentiles of the most recent 10, 20, and 30 year moving windows and computed the maximum difference in percentile (max Δ) among windows; this resulted in – for each park, variable, and summary statistic – both an overall measure of recent climate change exposure with respect to HRV, and an estimate of how sensitive that measure was by comparing the different moving window sizes. Note that our measure of variability (moving window SD) does not reveal any information regarding extreme events, such as droughts, heat waves, and storms, which can also impact park resources An example of these steps with annual mean temperature (Bio1) is shown for Grand Canyon National Park . In thisth percentile (low) or greater than the 95th percentile (high), and all intervening percentiles as ‘average’. We tallied the total number of temperature and precipitation variables that met either of these conditions and categorized each park as extreme low or high on temperature and precipitation if at least one variable in each class was low or high. Parks were considered ‘mixed’ if they possessed low and high estimates of temperature, or low and high estimates of precipitation. Then, considering only the low and high variables, we calculated the maximum value of their max Δ’s to provide a maximum estimate of sensitivity to window size. Given the thresholds used to define ‘extreme’, the maximum possible value for max Δ is 15%.Given the number and complexity of variables considered in our analysis, we performed two multivariate analyses in an effort to produce more integrated summaries of recent percentiles. Principal component analyses were used to identify a small set of uncorrelated axes for each combination of summary statistic  and measure (mean percentile and max Δ percentile). We also conducted a threshold-based classification analysis of mean percentiles, on both the moving window mean and SD, to characterize which parks were extreme on their annual, monthly, or quarterly temperature  or precipitation  variables. In this classification analysis, as well as in other evaluations of individual climate variables, we define ‘extreme’ as either less than the 5For a subset of parks spanning the contiguous US, we conducted another sensitivity analysis using local weather station data to examine the degree to which CRU results differ from those obtained using direct climate observations. For local station data, we identified 18 United States Historical Climatology Network stations located within park boundaries that similarly span the 1901–2012 period of analysis Lastly, as part of the CRU-based classification analysis, for each climate variable  we used a Monte Carlo simulation to test whether the number of extreme parks was significantly different than random expectations. To conduct this test, we first randomly selected 100000 samples of size 289 from a uniform distribution  to develop a sampling distribution of the expected number of extreme parks under the null hypothesis . Using that sampling distribution, we then computed the probability of obtaining the observed number of extreme parks for each climate variable.th percentile in 99% of parks), while recent percentiles associated with the annual number of frost days (Frs12) are correspondingly quite low  are greater than the 95th percentile), with low sensitivity to moving window size (125 parks (43%) have a maximum difference in percentile that is less than 5%). This general pattern holds for parks from the Pacific Islands to Alaska to the East Coast of the US.Focusing on two common climate variables, annual mean temperature (Bio1) and annual precipitation (Bio12), geographic distributions of recent percentiles are illustrated for moving window means  and stanth to 75th percentiles and 233 parks (81%) are within the 5th to 95th percentiles. Hence, only 56 parks (19%) are extreme (<5th percentile or >95th percentile) with respect to annual precipitation.Corresponding results for annual precipitation  are rathth to 75th percentiles and 275 parks (95%) are within the 5th to 95th percentiles. Annual precipitation is similar: 188 parks (65%) are within the 25th to 75th percentiles and 277 parks (96%) are within the 5th to 95th percentiles. Hence, only about 10 parks are extreme with respect to either annual mean temperature or annual precipitation, and these parks differ between the two variables  triggered by any one of the temperature  or precipitation  variables, most parks are presently dominated by extreme high temperatures (235 parks (81%) are higher than the 95th percentile), and – independent of temperature – some also by either extreme high precipitation (78 parks (27%) are higher than the 95th percentile) or low precipitation (43 parks (15%) are lower than the 5th percentile)  . Excludicentile) .The number of parks that are extreme high or low on each temperature or precipitation variable considered in the classification analysis are reported in th percentile) or low (<5th percentile) on temperature or precipitation variables , Bio1 and 10 , and Bio11  Management and planning decisions will be greatly informed by an overall assessment of vulnerability that integrates the present climate change exposure analyses with others that consider both the sensitivity and adaptive capacity of park resources to climate change a priori knowledge of how major climate drivers have changed in recent time. For resources influenced by climate variables that are presently well within the bounds of HRV, parks might decide that limited funding should be redirected to study other resources that are sensitive to variables approaching the limits of HRV. Parks might also decide to monitor variables with recent extreme percentiles to assess rates of change and detect when and where they become ‘novel’ with respect to 1901–2010 HRV. Beyond applications related to monitoring and management, results offer park interpreters scientific information that may be translated and communicated to the public.Our measures of climate change exposure support broad-scale vulnerability assessments in the NPS, but they also help individual parks understand and interpret which of their major climate drivers are beginning to approach the limits of 1901–2012 HRV. Such insights facilitate discussion of how climate change may impact diverse park resources and values , which are often sensitive to different measures of exposure, but they are not intended to replace more detailed analyses required for site-level management and planning within park boundaries. Many parks are in areas of complex topography and indeed this heterogeneity has important implications for climate adaptation In approaching the 100-year anniversary of its creation in 2016, the NPS is poised to enter its next century of natural resource stewardship and science. The new century brings new challenges in terms of stewarding park resources in the face of environmental drivers that operate beyond park boundaries. Climate change further challenges us to develop new, ecologically viable desired conditions to guide the preservation of park resources in this new era of change. While such challenges remain paramount, more integrative research and education in the climate and landscape arenas will contribute to solutions.Appendix S1Mean percentile and maximum difference in percentile (in parentheses) for moving window means: annual mean temperature (Bio1), mean diurnal range (Bio2), isothermality (Bio3), temperature seasonality (Bio4), maximum temperature of the warmest month (Bio5), and minimum temperature of the coldest month (Bio6).(PDF)Click here for additional data file.Appendix S2Mean percentile and maximum difference in percentile (in parentheses) for moving window means: temperature annual range (Bio7), mean temperature of the wettest quarter (Bio8), mean temperature of the driest quarter (Bio9), mean temperature of the warmest quarter (Bio10), and mean temperature of the coldest quarter (Bio11).(PDF)Click here for additional data file.Appendix S3Mean percentile and maximum difference in percentile (in parentheses) for moving window means: annual precipitation (Bio12), precipitation of the wettest month (Bio13), precipitation of the driest month (Bio14), precipitation seasonality (Bio15), precipitation of the wettest quarter (Bio16), precipitation of the driest quarter (Bio17), precipitation of the warmest quarter (Bio18), and precipitation of the coldest quarter (Bio19).(PDF)Click here for additional data file.Appendix S4Mean percentile and maximum difference in percentile (in parentheses) for moving window means: mean annual percentage cloud cover (Cld1), cloud seasonality (Cld4), vapor pressure of the warmest quarter (Vap18), annual number of wet days (Wet12), number of wet days of the warmest quarter (Wet18), and annual number frost days (Frs12). NA’s associated with Frs12 indicate that the variable is undefined .(PDF)Click here for additional data file.Appendix S5Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: annual mean temperature (Bio1), mean diurnal range (Bio2), isothermality (Bio3), temperature seasonality (Bio4), maximum temperature of the warmest month (Bio5), and minimum temperature of the coldest month (Bio6).(PDF)Click here for additional data file.Appendix S6Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: temperature annual range (Bio7), mean temperature of the wettest quarter (Bio8), mean temperature of the driest quarter (Bio9), mean temperature of the warmest quarter (Bio10), and mean temperature of the coldest quarter (Bio11).(PDF)Click here for additional data file.Appendix S7Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: annual precipitation (Bio12), precipitation of the wettest month (Bio13), precipitation of the driest month (Bio14), precipitation seasonality (Bio15), precipitation of the wettest quarter (Bio16), precipitation of the driest quarter (Bio17), precipitation of the warmest quarter (Bio18), and precipitation of the coldest quarter (Bio19).(PDF)Click here for additional data file.Appendix S8Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: mean annual percentage cloud cover (Cld1), cloud seasonality (Cld4), vapor pressure of the warmest quarter (Vap18), annual number of wet days (Wet12), number of wet days of the warmest quarter (Wet18), and annual number frost days (Frs12). NA’s associated with Frs12 indicate that the variable is undefined .(PDF)Click here for additional data file.


Here we review zebrafish modeling for two broad groups of inherited conditions that each share genetic and molecular pathways and overlap phenotypically: neurodevelopmental disorders such as Autism Spectrum Disorders (ASD), Intellectual Disability (ID) and Schizophrenia (SCZ), and neurodegenerative diseases, such as Cerebellar Ataxia (CATX), Hereditary Spastic Paraplegia (HSP) and Charcot-Marie Tooth Disease (CMT). We also conduct a small meta-analysis of zebrafish orthologs of high confidence neurodevelopmental disorder and neurodegenerative disease genes by looking at duplication rates and relative protein sizes. In the past zebrafish genetic models of these neurodevelopmental disorders and neurodegenerative diseases have provided insight into cellular, circuit and behavioral level mechanisms contributing to these conditions. Moving forward, advances in genetic manipulation, live imaging of neuronal activity and automated high-throughput molecular screening promise to help delineate the mechanistic relationships between different types of neurological conditions and accelerate discovery of therapeutic strategies.Zebrafish are a unique cell to behavior model for studying the basic biology of human inherited neurological conditions. Conserved vertebrate genetics and optical transparency provide  Therefore these genes may be associated with earlier onset cases of CMT, which can occur anywhere between birth and adulthood  is a large gene and mouse Shank3 knockout models exhibit variable phenotypes depending on whether a mutation is expressed in a predominant isoform . Because brain regions mediating human cognitive symptoms may lack parallels in zebrafish, modeling has focused on embryonic development and disorder comorbidities  that still allow testing of etiological theories for these developmental disorders. These studies have paved the way for comprehensive functional assessments that link cellular- and circuit-level phenotypes to changes in behavior.CHD8 mutations  was shown to have a dose-dependent affect in producing macrocephaly (knockdown) and microcephaly (overexpression) that supports a role for KCTD13 copy number variants causing head size phenotypes  interacts with canonical and non-canonical Wnt signaling and zdisc1 morphants and mutants exhibit disorganized axon tracts at larval stages that can be rescued by activating Wnt signaling  mutants, recapitulating a mutant mouse Cntnap2 model and suggesting that in the absence of cntnap2ab larvae fail to maintain inhibitory neuronal populations. This inhibitory decrease was shown to increase seizure susceptibility in −/−cntnap2ab mutants by applying a GABA receptor antagonist  signaling in Fragile X Syndrome  knockout models in mice, a zebrafish fmr1 knockdown model showed behavioral deficits that were ameliorated when treated with an mGluR inhibitor  and shank3a exhibit hyposensitivity with concomitant neuronal cell death and morphological changes in skin innervating sensory neurons  knockdowns and sodium channel, voltage gated, type II, alpha (scn1lab) knockouts display hyper-excitable phenotypes that are characterized by extended or disorganized swimming with epileptiform-like activity in the brain , HSP, SMA or spinal muscle atrophy (SMA), ALS, as well as some forms of CATX which have phenotypic and mechanistic overlap , a molecular motor for transporting microtubule-mediated cargo, have been reported in both CMT2  encoding atlastin-1 cause an early onset form of HSP  are the primary cause of axonal degeneration in Charcot-Marie-Tooth Neuropathy (CMT2), and MFN2 has been implicated in the fusion and transport of mitochondria in neurons , and early lethality by 1 year of age  cause a spectrum disorder classified as Costeff syndrome and includes optic atrophy, ataxia, extra pyramidal dysfunction, and increased urinary excretion of 3-methylglutaconic acid  morphants show decreases in PC progenitors while cwf19-like 1 (cwf1911) morphants show disruptions in overall hindbrain morphology  mutations that cause Spinocerebellar ataxia type 13  mutations rarely covert carrier cells into cancer cells unless in a p53 mutant background (Kaufman et al., It is also common, though not necessarily well-represented in the literature, for knockout models to lack phenotypes. In a zebrafish study that generated mutant lines with 32 distinct lesions in 24 genes, most of the mutants exhibit a wild-type phenotype (Kok et al., in situ hybridization data and determine the relative enrichment of gene expression in brain regions and spinal cord (Figure Both developmental and degenerative diseases are associated with dysfunction in specific regions of the CNS Figure . None-th0 mutant models of inherited neurological disorders (Jao et al., 0 mutants (Bernier et al., 0 generation. Combined with a large repertoire of behaviors that develop within 5 days of fertilization and diverse transgenic lines for rapid screening of cellular phenotypes, F0 CRISPR zebrafish mutagenesis promises to contribute significantly to our understanding of genetic variation linked to nervous system disorders.Because of the large number of rare mutations linked to inherited nervous system diseases, an important frontier for disease modeling is strategies that leverage to make stable Fin vivo or create conditional mutant alleles, several groups have also recently pioneered the use CRISPR/Cas9 for more sophisticated genome engineering. One novel strategy effectively “enhancer traps” a gene of interest by replacing the last exon with an engineered last exon encoding the C-terminal end of the coding sequence in frame with a cleavable p2A sequence followed by a fluorescent reporter (Li et al., Shank3 autism model, rescuing the mutant Shank3 protein in the adult was sufficient to rescue social interactions and excessive grooming but not anxiety and repetitive motor behaviors (Mei et al., To model specific patient missense mutations and to better understand the basic biology of disease genes by tagging them in vivo calcium imaging with genetically encoded calcium indicators- (GECIs; Chen et al., The development of approaches that enable monitoring of behavior-relevant neural circuits in the intact larvae will be a boon for modeling inherited neurological disease (Ahrens et al., In addition to genetic screens, due to their small size and their tendency to absorb drugs added directly to the water, zebrafish larvae are uniquely amenable for high-throughput drug screens (Rihel et al., The continued expertise and innovations of zebrafish genetic and developmental tools will continue to make zebrafish an attractive neurological disease model. Going forward, combining standard assays that allow comparisons across models with newer approaches would be ideal to enable a better understanding of the molecular, cellular, and systems-level groupings of these neurological conditions. Finally, zebrafish will certainly contribute to consortia of research groups that use multiple animal models for discovering essential molecular to circuit level mechanisms underlying neurological disease.RAK conducted all meta-analyses, made all figures and wrote introductory and developmental disorder sections and conducted extensive edits to coordinate sections. AJA wrote the bulk of the neurodegenerative section with the exception of the ataxia section that was written by EB. DMJ wrote comorbidity section that centered on GI distress in developmental disorders. QY wrote the lessons learned section. JED conceived the scope of the review, wrote frontiers section and helped RAK to conduct extensive edits to coordinate sections.This work was supported by support from the National Institutes of Health Institute of Mental Health R03MH103857 to JED and from the Institute of General Medicine, an IMSD graduate fellowship from parent grant R25GM076419 to DMJ.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To examine both migraine and pulmonary hypertension (PH) we developed a hypoxic mouse model. Under hypoxic conditions (four weeks at 10% O2) mice develop typical symptoms of PH, characterized by an increased muscularization of arterial blood vessels in the lung. The vessel remodeling can be prevented by the chronic application of 5-HT2B receptor antagonists. We found that hypoxic mice also develop increased sensitivity towards the 5-HT2 receptor agonist meta-Chlorophenylpiperazine (mCPP). In contrast to the control group (normoxic mice kept at 20% O2) at low doses of 1 µg / kg body weight, mCPP triggers plasma protein extravasation (PPE) in the dura mater in hypoxic mice. Dural PPE is a quantifiable indicator of migraine-like events in animal models.The sensitization towards mCPP may coincide with structural remodeling processes in arterial blood vessels of the dura mater, possibly exhibiting similarities to vascular alterations in the lung. A prerequisite in the investigation of vascular alterations in the dura mater is a thorough understanding of the normal organization of dural vasculature in mice and of the extent of its normal biological variance.Histological examinations of the length of dural vessels were performed to quantify and statistically analyze inter- and intraindividual differences.Interindividual differences: The arteriole total lengths are 15% far from the arithmetic mean.Intraindividual differences: The difference in the length of arterioles represents 12% of the total length of the arterioles.On the basis of these results examinations of dural vessel of hypoxic mice can be investigated.No conflict of interest.


Patients with repaired tetralogy of Fallot (TOF) frequently have right bundle branch block. However, the contribution of cardiac dyssynchrony to dysfunction remains controversial. To better understand this phenomenon and ultimately study therapies, we developed a method to quantify left (LV), right (RV) and inter-ventricular cardiac dyssynchrony using standard cine CMR.30 patients with repaired TOF  and 17 healthy controls  underwent cine CMR. Patients were imaged twice to assess inter-test reproducibility. Circumferential strain vs time curves were generated with a custom feature tracking algorithm for 12 LV and 12 RV segments in 4-7 slices encompassing the ventricles. For each segment, the temporal offset (TO) of the strain curve relative to a global reference curve derived from the controls was calculated and expressed as a percent of the cardiac cycle. The intra-ventricular dyssynchrony index (DI) for each ventricle was computed as the standard deviation (SD) of the TOs (more dyssynchrony increases the SD). The inter-ventricular DI was calculated as the difference in median RV and median LV TOs. Regional dyssynchrony was quantified in 3 LV  and 3 RV  regions using median TOs.Compared to controls, patients with repaired TOF had a greater LV, RV and inter-ventricular DI Figure . The grePatients with repaired TOF suffer from left, right and inter-ventricular cardiac dyssynchrony which can all be quantified from standard cine CMR with good inter-test reproducibility. Future studies need to determine whether these patients may benefit from resynchronization therapy.This work was supported by a National Institutes of Health (NIH) Director's Early Independence Award (1DP5OD012132-01), and NIH grant number KL2 RR033171 from the National Center for Research Resources and the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH.


The correct legend is given below. The article has since been corrected and reposted in the issue.In Figure 1 of the article “Pulmonary Fibrosis in Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis: A Series of 49 Patients and Review of the Literature”,Representative high-resolution computed tomography showing typical features of the 3 major patterns of PF associated with AAV. Predominantly basal, subpleural reticular pattern with macrocystic honeycombing lesions in usual interstitial pneumonia (A). Centrilobular and paraseptal emphysema predominating in the upper lobes (B). Ground-glass opacities in a patchy distribution in nonspecific interstitial pneumonia (C), and reticular subpleural changes in the lower lobes, associated with few microcystic lesions suggesting honeycombing (D) in combined pulmonary fibrosis and emphysema syndrome.