The present investigation compared parenting practices in a sample of preschoolers whose mothers reported smoking during pregnancy versus those who did not.A sample of n = 216, 3.0- to 5.11-year-old children, participants in an ongoing longitudinal study, was separated into those reportedly exposed to smoking in utero and those who were not. Parenting practices were compared between the two groups, using T-tests and exact logistic regressions. Multiple linear regressions and multivariate logistic regressions were used to examine the association between smoking status and parenting, controlling for variables also known to be associated with parenting practices.Current study findings suggest that smoking during pregnancy is associated with harsh parenting practices.Study results highlight the possible role of parenting in disruptive outcomes well-known in toddlers exposed to nicotine in utero and have implications for targeting early interventions in these populations. An association between prenatal cigarette exposure and disruptive behavior in childhood has been reported in the empirical literature from multiple independent investigations . HoweverNumerous individual and psychosocial differences have been found between mothers that smoke during pregnancy and mothers that do not. Such differences have included the findings of more antisocial character traits in smoking mothers and a higher likelihood of selecting mates with these traits . MothersThe above mentioned personal and psychosocial features of pregnancy smokers may themselves contribute to poor parenting skills. To further complicate the challenges of parenting in this population, the child of a pregnancy smoker may also be more difficult to parent than the child of a non-smoker on the basis of biological risk factors. For example, while the mechanism remains unclear, smoking while pregnant has been associated with increased negativity in toddlers measured as rebelliousness, risk taking, and impulsivity, behaviors often found in children with disruptive disorders . Brook eTo better understand the relationship between smoking in pregnancy and early child behavioral problems, further examination of parenting among pregnancy smokers compared to non-smokers is now warranted. There is a dearth of published studies that specifically inform this issue. While most prior investigations have focused on prenatal smoking and risk for disruptive behavior outcomes in the child, parenting constructs were also examined in some of these studies. These available study findings have suggested that mothers who smoked showed less parental nurturing, as well as poor behavioral management and dyadic communication skills , 23, 24.Additional studies have examined parenting among pregnancy smokers at multiple stages of development, from neonates  to adolePreschool age children (n = 306) between the ages of 3.0 and 5.11 and their caregivers were recruited from pediatricians’ offices, daycares, and preschools in the St. Louis metropolitan area using the Preschool Feelings Checklist (PFC) , a briefThe PAPA is an interviewer-based diagnostic assessment with established test-retest reliability designed for use in children ages 3 to 6 . The PAPThe CAPA is an interviewer-based, structured psychiatric interview for children with collection of data on symptom onset, frequency, intensity and duration according to DSM-IV, III-R or ICD-10 criteria. Modules such as substance use (tobacco), can be used separately, and test-retest reliability for diagnoses range from k = 0.55 (conduct disorder) to k = 1.0 (substance abuse) . MothersThe HBQ-P is a 140-item reliable and valid parent informant measure that produces dimensional ratings of 4- to 8-year-old children’s functioning in the domains of emotional and behavioral symptomotology, impairment, adaptive social functioning, and physical health using a 3-point Likert scale with a 20-minute completion time .Parenting practices based on self-report were examined in mothers who smoked versus those who did not smoke cigarettes during pregnancy in a sample of n = 306 children enrolled in an ongoing longitudinal investigation of preschoolers. T-tests and exact logistic regressions were used to compare the differences for parenting variables between mothers who smoked and those who did not. Mann-Whitney U tests were used to compare two smoking categories. Multiple linear regressions and multivariate logistic regressions were used to examine the association between smoking status and parenting variables (frequency or intensity) controlling for confounding variables.Of the n = 306 preschoolers from the longitudinal investigation, n = 216 participants had data available on both parenting and smoking exposure. Demographic characteristics of study participants included in this analysis are shown in T-tests and exact logistic regressions revealed that mothers who did not smoke during pregnancy were significantly less likely than mothers who smoked to: (1) give verbal dispraises   ; (2) ever leave bruises ; (3) verbally reject .A multiple linear regression controlling for demographic differences including total family income, baseline education of the biological mother, ethnicity, and several variables known to impact parenting including alcohol during pregnancy and HBQ-P externalizing scores were controlled and included as covariates shown below. In this analysis, as depicted in Smoking during pregnancy was also significantly associated with leaving marks or bruises (intensity)  . SmokingThe current study findings suggest specific parenting differences in those mothers that smoked during pregnancy compared to those who did not. Pregnancy smokers demonstrated harsher parenting in several specific domains than parents who did not smoke during pregnancy. These differences remained significant even after other factors known to be associated with poor parenting such as low SES, alcohol use, and child’s externalizing behavior scores were accounted for in the analysis. Parenting behaviors among pregnancy smokers remain under-investigated. Current findings suggesting increased levels of harsh parenting in pregnancy smokers extend the extant literature associating pregnancy smoking exposure to child disruptive outcomes. These findings point to modifiable risk factors in pregnancy smokers to ameliorate child disruptive outcomes. While further studies are warranted to elaborate on the mechanisms that drive this association, study results suggest that parenting should be an important target for dyads exposed prenatally to cigarettes. Other studies have suggested treatment intervention to be less effective in children prenatally exposed to cigarettes, warranting further understanding and need for targeted treatment . RegardlStudy limitations include a relatively small sample size of pregnancy smokers that were from a longitudinal investigation on depression. Other potential limitations were no bioassay confirmation of smoking measurements and no maternal personality assessment. Additionally, current study findings show less Caucasian and more African American mothers in the group of pregnancy smokers versus non-smokers, making the findings less generalizable to the population. This is also important as multiple smoking investigations find Caucasians to be the ethnic group making up the large majority of pregnancy smokers. Further investigations of such ethnic differences are warranted.Finally, our reliance on self-reported parenting in the absence of observational parenting measures is a limitation due to the possibility of bias towards appropriate, socially acceptable responses and shared method variance with the same reporter providing information on both predictor and outcome . HoweverThe present investigation compared parenting practices in preschoolers whose mothers reported smoking during pregnancy versus those who did not. Current study findings suggest that smoking during pregnancy is associated with harsh parenting practices. While the current investigation is preliminary and limited by a small sample size, study findings inform the need for larger investigations that specifically examine parenting of younger children among pregnancy smokers, taking into account key variables such as maternal personality characteristics and other related substance use. Future investigations could inform how to improve parenting skills to minimize disruptive behaviors in young children of pregnancy smokers at greatest risk for harsh parenting. Such studies would help identify those most likely to benefit from targeted parenting interventions to optimize public health resources.


Direct implantation of isolated myoblasts, cardiomyocytes, and bone-marrow-derived cells has shown prospect for improved cardiac performance in several animal models and patients suffering from heart failure. However, direct implantation of cultured cells can lead to major cell loss by leakage and cell death, inappropriate integration and proliferation, and cardiac arrhythmia. To resolve these problems an approach using 3-dimensional tissue-engineered cell constructs has been investigated. Cell engineering technology has enabled scaffold-free sheet development including generation of communication between cell graft and host tissue, creation of organized microvascular network, and relatively long-term survival after  Cardiac repair by cell therapy offers hope to improve performance of diseased heart by reconstituting or maintaining cardiac specific tissue . First sNevertheless, the hypothesis that cardiac function in heart failure can benefit from cell therapy has gained extensive attention and preliminary clinical trials have been launched –14. MiyaOne of the crucial issues in cell therapy for heart failure has been the cell delivery route. Injection of the cells has been the most typical method in clinical feasibility studies . The celIn addition, arrhythmogenicity of intramyocardial myoblast transplantation has aroused debate. Episodes of ventricular tachycardia and fibrillation have been noted after several feasibility studies. Due to small number of patients in nonrandomized series and the arrhythmogenic nature of the heart disease itself, direct causality is difficult to conclude. In an early study of Menasché et al., 4 out of 10 patients experienced sustained ventricular tachycardia , and in Another approach for cell delivery as opposed to injection involves tissue-engineered constructs. The main advantage of this technology over standard cell implantation lies on the preservation of microcellular communication and matrix, which is lost upon trypsin treatment in the typical procedure of cell preparation. Epicardial deposition of cell sheets might be a solution to prevent significant cell loss and arrhythmia after cell transplantation . Memon eCurrent tissue engineering methods allow us to reconstruct myocardial tissue grafts for clinical applications, though human fetal and neonatal cardiomyocytes are difficult to obtain. Therefore, several classes of stem cells are being investigated as a potential cell source. Despite their attractive potential to differentiate into various cell types, several issues remain, including difficulties in obtaining and amplifying the cells and the lack of understanding of the mechanisms for differentiation and proliferation. Consequently, the clinical cell sheet transplantation has mainly focused on utilization of myoblasts.bcl2 was shown to enhance the efficacy of sheet transplantation therapy in acute myocardial infarction [bcl2 improved myoblast sheet transplantation therapy also in chronic myocardial infarction model [Memon et al.,  reportedfarction . Moreoveon model .Dilated cardiomyopathy (DCM) is characterized by global myocardial remodeling, which mainly consists of myocardial fibrosis associated with changes in the cytoskeletal and sarcolemmal proteins in cardiomyocytes, leading to a reduction in the number and function of these cells . ConsequHoashi et al.,  showed tPreclinical studies in impaired porcine heart using single monolayer skeletal muscle cell sheet demonstrated improved cardiac performance accompanied with increased myocardial perfusion and viable myocardial tissue .Further, Miyahara et al., used mesenchymal stem cells (MSCs) derived from adipose tissue in a rat myocardial infarction model . MSC sheDifficulties still exist in the outcome of cell therapy, as it is challenging to control the cell growth and localization of the grafted cells and to deliver a cell sheet patch that significantly aids the function of the damaged myocardium. To overcome these problems research has begun on fabricating three-dimensional cardiac grafts composed of multilayered cell sheets. Several methods have been studied with reconstructed tissues based on biodegradable scaffolds, such as poly(lactic-co-glycolic acid) and gelatin or extracellular matrix components , 49.In native cardiac tissue the cell density is considerably high, cells being tightly interconnected with gap junctions facilitating electrical communication. The use of scaffolds can lead to abnormal tissue development, electrical communication caused by insufficient cell-to-cell connections, inflammatory responses, and fibrous tissue formation. Alternatively, fabrication of scaffold-free cell sheets requires means of cell detachment from the culture surface that will preserve cell morphology, orientation within the scaffold, and adhesion to surrounding cells and the extracellular matrix. One way to achieve such detachment is to covalently employ a temperature-responsive polymer on cell culture surface. Poly(N-isopropylacrylamide) (PIPAAm) is a hydrophobic polymer at temperatures above 32°C which—after grafting to cell culture dishes—allows cell adhesion and proliferation . At tempμm. These sheets, however, were subject to necrosis due to limited oxygen supply. The same method was then used to create prevascularized sheets composed of cardiomyocytes, endothelial cells, and fibroblasts. These sheets effectively integrated with the coronary circulation after implantation and evaded necrosis. Furthermore, Itabashi et al., fabricated cardiomyocyte sheets using polymerized fibrin-coated culture dishes [Stevens et al., and Itabashi et al., described other methods for creating scaffold-free sheets. Stevens et al., created embryonic stem cell-derived cardiomyocyte sheets utilizing Teflon-coated low-attachment tissue culture dishes combined with rotating orbital shaker . The diae dishes . This meIn addition to cell-to-cell communication, the layers need to establish a connection with each other and with the host tissue. Using a multielectrode extracellular recording system, Haraguchi et al., demonstrated that the electrical coupling between 2 sheets starts approximately 34 minutes after initial layering and is completed by about 46 minutes. They also showed small molecule exchange through gap junctions and presence of connexin-43 within 30 minutes of layering .When Shimizu et al., implanted a 4-layered neonatal rat cardiomyocyte sheet into the subcutaneous space of nude rats, synchronous beating  and survMiyagawa and colleagues showed that neonatal cardiomyocyte sheets fabricated on temperature-responsive culture dishes attached to the infarcted myocardium and led to an improvement in cardiac performance and improved vascular density . The impAnother study demonstrated a similar electrical integration between a neonatal myocyte sheet and the host myocardium without serious arrhythmia . Furtherin vitro rely on diffusion. In order to reconstruct thicker and metabolically active tissue grafts sufficient blood supply network has to be created.Heart is a metabolically active organ that requires virtually constant oxygen supply in order to function in a normal fashion. The major limitation of the multilayered cell grafts is insufficient circulation causing hypoxia, nutrient insufficiency, and accumulation of waste products. Cells in living tissues receive oxygen supply through a capillary network, whereas the cultured cell aggregates in vitro in tissue-engineered constructs before transplantation. Levenberg et al., demonstrated the induction of endothelial vessel networks in engineered skeletal muscle tissue constructs using a 3D culture system consisting of myoblasts, embryonic fibroblasts, and endothelial cells coseeded on porous, biodegradable polymer scaffolds [in vitro bone coculture model with human MSCs, human umbilical vein endothelial cells (HUVECs) [One strategy could be to generate capillary-like networks caffolds . Similar(HUVECs) , 62, and(HUVECs) . As the Sasagawa et al., developed a novel cell sheet stacking manipulation technique to create multilayered cell sheets from human skeletal muscle myoblasts . They plμm thick [μm thick. In order to progress the human cell sheet applications the greater thickness of the construct would be of great advantage. Sekiya et al., investigated the relationship between the number of transplanted cell layers and cardiac function. They found a significant improvement of cardiac function, induction of angiogenesis, more elastic fibers, and less fibrosis with implantation of 3- and 5- layered myoblast sheets compared to single layer [A single myoblast layer is about 45 μm thick . Accordile layer .Shimizu et al., showed that the 1-, 2-, and 3-layer constructs transplanted into the dorsal subcutaneous tissue of nude rats thoroughly survived without necrosis . Howeverin vitro and increased blood perfusion in vivo by using a coculture of fibroblasts and human smooth muscle cells [One way to enhance the cell sheet graft survival is to promote angiogenesis. Enhanced angiogenesis and functional improvement were achieved by using cocultured cell sheets with fibroblasts and endothelial progenitor cells . Anotherle cells . In addile cells . Stimulation of angiogenesis has also been shown in single cell-type cell sheets. Miyagawa et al., demonstrated that human HGF gene transfection enhanced the cellular cardiomyoplasty likely by stimulating angiogenesis, restoring the impaired extracellular matrix, and promoting the integration of the dissociated grafted myocytes . Zakharoin vitro and in vivo models and demonstrated that cardiac cell sheets express VEGF, Cox-2, and Tie-2 and exhibit endothelial cell organisation and microvessel formation [in vivo. Expression of these proangiogenic genes was further induced by preventing graft apoptosis with antiapoptotic gene therapy [To understand the molecular mechanisms of cell sheet angiogenesis Sekiya et al., studied both ormation . Kitabay therapy . Moreove therapy . Memon e therapy . Finally therapy . In thisDifficulties in reproducibility in cell injection therapy, including low survival and function of the cells, have led to search for more robust methods. Engineering of 3D cell constructs has currently been under extensive investigation. Preassembled cell constructs might provide effective tools for the future cell therapy research. Establishment of programmable materials used in the cell engineering technology has enabled the creation of scaffold-free cell sheets in a rather simple and inexpensive method. The main aspects of cell sheet construction that must be met for successful regenerative therapy are dynamic, electrical, and histological integration. Increased cell-to-cell communication and survival in cell sheets warrant further attention. The reviewed studies demonstrate the existing potential to produce viable, functional myocardial tissue implantable constructs well beyond the current diffusion-limited thickness regime.


Thus, targeting IAP proteins represents a promising molecular targeted strategy to overcome apoptosis resistance in childhood leukemia, which warrants further exploitation.Inhibitor of Apoptosis (IAP) proteins are a family of proteins with antiapoptotic functions that contribute to the evasion of apoptosis, a form of programed cell death. IAP proteins are expressed at high levels in a variety of human cancers including childhood acute leukemia. This elevated expression has been associated with unfavorable prognosis and poor outcome. Therefore, IAP proteins are currently exploited as therapeutic targets for cancer drug discovery. Consequently, small-molecule inhibitors or antisense oligonucleotides directed against IAP proteins have been developed over the last years. Indeed, IAP antagonists proved to exhibit  Cancer cells have typically acquired the ability to evade apoptosis, a form of programed cell death . In addic and second mitochondria-derived activator of caspases (Smac)  pathway and the mitochondrial (intrinsic) pathway . Signal s (Smac) . Smac fas (Smac) . By comptivation .The family of IAP proteins comprises eight human analogs . Among tExpression levels of IAP proteins are elevated in a variety of human malignancies including pediatric leukemia, which may be caused by genetic events as well as by transcriptional or posttranscriptional mechanisms. It is important to note that aberrant expression of IAP proteins was described to correlate with adverse patients’ outcome, suggesting that IAP proteins bear a prognostic impact.The prognostic significance of XIAP has been studied in childhood acute myeloid leukemia (AML). XIAP has been associated with adverse prognosis in pediatric leukemia by independent studies showing a correlation of high mRNA and protein expression levels of XIAP and several unfavorable prognostic parameters including high-risk groups for cytogenetics, immature morphology, poor treatment response to induction chemotherapy, and reduced relapse-free survival , 9. ThesIn childhood ALL, a large study comprising the analysis of 222 patients showed that high expression levels of ML-IAP mRNA correlated with a favorable rather than an unfavorable prognosis . In addide novo AML  or a locked antisense oligonucleotide was reported to induce apoptosis in leukemia cell lines and also potentiated the chemotherapeutic antileukemic effects –27. In aIAP proteins are promising novel targets for molecular targeted therapy in childhood leukemia. Agents antagonizing IAP proteins, including small-molecule inhibitors and antisense oligonucleotides, have been shown to trigger apoptotic and non-apoptotic cell death alone or in combination in preclinical studies in pediatric leukemia. Currently, IAP antagonists are under evaluation in early clinical trials in adult leukemia. Thus, IAP-targeting treatment strategies warrant further clinical investigation in childhood leukemia.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The authors present the endoscopic intranasal orbital decompression, one of the surgical techniques used for orbital decompression. It can be applied for various indications. The most common indications are: maxillo-facial trauma, orbital haemorrhage, subperiorbital abscess as the complication of sinusitis, optic neuropathy, thyroid-associated orbitopathy (Graves’ orbitopathy). The authors conclude that the endoscopic transnasal orbital decompression is a valuable and safe operational technique for patients requiring orbital decompression.


Physiologic (flexible) pes planus (flatfoot) is a descriptive term for feet that have a visually lowered medial longitudinal arch often in association with rearfoot eversion . ReporteA systematic review of randomised, quasi-randomised or controlled clinical trials comparing rigid or semi-rigid functional foot orthoses with: no orthoses or any other approach to managing symptomatic flexible pes planus in the adult. Relevant data bases were searched from inception to October 2011 with studies meeting the predetermined inclusion criteria retrieved and screened by two independent reviewers. No restrictions were placed on type of foot orthoses or alternative interventions. Included studies were independently assessed by two reviewers with risk of bias determined by the Cochrane criteria. Where feasible, meta-analysis will be undertaken.A narrative summary will be presented of the results with outcome measures to include: pain, gait changes , dynamic foot function or static foot posture changes.A determination of the current level/s of evidence for the use of foot orthoses in the adult with symptomatic pes planus.


Tau inclusions composed of tau fibrils are one of the key hallmarks of Alzheimer’s disease and other tauopathies. Studies from transgenic animal models and human AD pathological cases suggest that tau inclusions spread from the transentorhinal cortex to mono and transynaptically connected regions of the hippocampus and neocortical regions. This study examines cell-to-cell propagation of pathological tau in cell culture and in vivo animal models.To study transfer between donor and recipient cells, donor primary neurons isolated from human tau expressing mice (line rTg4510) were co-cultured in microfluidic(MF) chambers with recipients that were either GFP expressing tau knockout, or wildtype neurons (model one). In another model (model two) in which more aggregates were formed, fluorescently tagged pro-aggregating domains of tau (RD) were expressed in neurons using lentivirus; mCherry was used to label the recipient cell population. Immunofluorescence (IF) and live imaging were performed to examine transfer of tau between donor and recipient neurons. To further increase tau aggregate formation (model three), brain-derived tau filaments or full length recombinant tau were used as seeds to induce endogenous tau templating, and the effect on propagation was monitored. To gain insight into possible mechanism of tau transfer between entorhinal cortex (EC) and mono-synaptically connected hippocampal cells, immuno-electron microscopy (IEM) was used to examine tau distribution in donor and recipient cells.1. In both models one and two, endogenously produced tau transferred from donor to recipient cells. Live imaging and IF revealed that donor tau was localized, and accumulated into synapses derived from recipient cells.2. In model three, exogenous aggregated tau was taken up and induced templating of endogenous full-length tau or RD. These tau aggregates transferred from donor to recipient cells in MFs.3. Tissue IEM showed human tau in pre-synaptic terminals derived from EC neurons that express tau transgene, and in post-synaptic compartments derived from recipient granule cell dendrites in the hippocampus.in vitro and in vivo models. Future studies will elucidate the relevance of synaptic accumulation and the mechanism by which propagation occurs.Our data demonstrates that endogenous produced, physiologically relevant tau, aggregates derived from tau fragments and tau generated by templating transferred between neurons in culture. Current data implicates synapses as a point of accumulation for tau during propagation


Effective improvement in sorghum crop development necessitates a genomics-based approach to identify functional genes and QTLs. Sequenced in 2009, a comprehensive annotation of the sorghum genome and the development of functional genomics resources is key to enable the discovery and deployment of regulatory and metabolic genes and gene networks for crop improvement.Sorghum bicolor exons and UTRs. The genechip contains 1,026,373 probes covering 149,182 exons  across the Sorghum bicolor nuclear, chloroplast, and mitochondrial genomes. Specific probesets were also included for putative non-coding RNAs that may play a role in gene regulation , and confirmed functional small RNAs in related species (maize and sugarcane) were also included in our array design. We generated expression data for 78 samples with a combination of four different tissue types , two dissected stem tissues (pith and rind) and six diverse genotypes, which included 6 public sorghum lines  representing grain, sweet, forage, and high biomass ideotypes.This study utilizes the first commercially available whole-transcriptome sorghum microarray (Sorgh-WTa520972F) to identify tissue and genotype-specific expression patterns for all identified Here we present a summary of the microarray dataset, including analysis of tissue-specific gene expression profiles and associated expression profiles of relevant metabolic pathways. With an aim to enable identification and functional characterization of genes in sorghum, this expression atlas presents a new and valuable resource to the research community. Its unique and advanced ability to grow in regions of low and variable rainfall highlight its potential to impact agricultural productivity in widespread water-limited environments [Δ]Ct) [Δ]Ct) . Gene exhttp://affymetrix.com).The transcriptome dataset supporting the results of this article is available through NCBI's Gene Expression Omnibus (GEO) under accession number GSE49879, and the Sorghum Genome Array is available through Affymetrix . Common: genes expressed in all 78 tissue types .Click here for fileGene Ontology classifications in the biological processes category identified using the AgriGO Singular Enrichment Analysis (SEA).Click here for fileIdentification of stably expressed genes.Click here for fileList of small RNAs  included in microarray design.Click here for fileNumber of tissue-specific small RNAs across sorghum ideotypes. AR2400: biomass sorghum; Fremont: sweet sorghum; PI152611: forage sorghum; Common: number of genes in common among all three ideotypes.Click here for fileExpression of select sucrose metabolizing enzyme/transporter genes.Click here for fileExpression of select phenylpropanoid-monolignol biosynthesis pathway genes.Click here for file


Approximately one third of patients treated with cardiac resynchronization therapy do not derive any detectable benefit. In these patients, acute invasive hemodynamic evaluation can be used for therapy optimization. This report describes the use of systematic invasive hemodynamic measurements for clinical decision making in a patient who experienced severe ventricular arrhythmias and clinical deterioration following a biventricular upgrade. Cardiac resynchronization therapy (CRT) has been established as an effective treatment for heart failure patients with severe left ventricular (LV) systolic impairment and electrical dyssynchrony . UnfortuA 65-year-old male patient with non-ischemic dilated cardiomyopathy, left ventricular ejection fraction of 20%, intra-ventricular conduction delay with a QRS duration of 148 ms, and NYHA class 3 was scheduled for upgrade of an implantable cardioverter defibrillator (ICD) to a cardiac resynchronization therapy - defibrillation (CRT-D) system. The ICD had previously been implanted for primary prevention. Echocardiography prior to the BiV upgrade demonstrated myocardial scarring of the LV lateral wall and showed no evidence of mechanical dyssynchrony. Unfavorable coronary venous anatomy required epicardial LV lead placement in the lateral position via minimal lateral thoracotomy. Four weeks later, the patient was admitted with multiple ICD discharges due to incessant ventricular tachycardia (VT) . He was An invasive hemodynamic pacing study was performed to evaluate the hemodynamic effect of conventional BiV pacing and to explore whether LV endocardial pacing could effectuate hemodynamic improvement. For this purpose, a temporary pacing electrode and a RADI pressure wire were positioned within the LV cavity, another temporary pacing electrode was placed in the right atrium . The RADNeither LV, RV or BiV pacing with the implanted system nor LV endocardial pacing at different sites improved LVdP/dtmax as compared to baseline . FurtherPatient selection plays an important role in CRT response. According to the ESC heart failure guidelines available at the time of device implantation, our patient had a class I indication for CRT . HoweverThe presence of myocardial scar at the area targeted by the LV lead is an important determinant of CRT response . Lead poIn a small percentage of patients, CRT may potentiate ventricular tachyarrhythmias. The exact mechanisms of proarrhythmia remain largely unclear but our findings suggest that pacing in the region of myocardial scar may facilitate its development. This conception is supported by the morphology of the VT which suggested a lateral exit site close to the LV epicardial pacing lead. A suggested underlying mechanism is a potential increase in local myocardial oxygen demand by pacing, precipitating ischemia in the peri-infarct zone and making it vulnerable to re-entry ,9. The cThis case report illustrates the potential contribution of acute invasive hemodynamic evaluation to clinical decision making in CRT. Acute hemodynamic testing may also be considered as a step-up approach to justify implantation of a LV endocardial lead and to guide lead positioning optimization. Finally, this case underlines the importance of considering the possibility of CRT related proarrhythmia, whenever CRT treated patients develop new ventricular tachyarrhythmia's.


Nitric oxide (NO) is a potent biological mediator and plays an important role in cardiovascular homeostasis. Here it activates the soluble guanylyl cyclase (sGC) that synthesizes cGMP. The intracellular second messenger cGMP regulates vascular tone, vascular permeability, modulates inflammation and platelet reactivity. In platelets cGMP activates platelet inhibitory pathways via PKG and thereby inhibits platelet activation. Many cardiovascular diseases e.g. pulmonary arterial hypertension (PAH), are associated to a defective NO signalling. Therefore agents that stimulate the sGC are interesting therapeutic tools for the treatment of several cardiovascular diseases.Riociguat (Bay 63-2561) stimulates the sGC NO-independently without the risk of nitrate tolerance. Clinical Phase II and III studies determined the efficacy and tolerability in pulmonary hypertension patients. Riociguat was well tolerated and also significantly improved exercise capacity and hemodynamic parameters. To further analyse the effects of riociguat on platelet activation we tested the inhibitory effects on functions in isolated platelets and whole blood to elucidate additional applications of riociguat and to estimate adverse effects such as increased bleeding tendencies.In order to study the effects of riociguat on platelet sGC activity we monitored the VASP phosphorylation and cyclic nucleotides in washed platelets. Already low therapeutically relevant doses of 0.1 µM riociguat increased cGMP levels and VASP phosphorylation significantly. Consistent to these findings ADP induced platelet activation in washed platelets, as shown by platelet shape change, aggregation and integrin activation, was significantly impaired using low doses of riociguat. Additionally adhesion on collagen under shear conditions is significantly reduced in platelet riched plasma. In contrast to that one hundred times higher concentrations of riociguat were needed to obtain a significant increase of VASP phosphorylation as well as a significant inhibition of ADP induced aggregation in whole blood.Our results indicate that riociguat treatment will not lead to an increased bleeding tendency in pulmonary hypertension patients. Additional possible applications of riociguat, where targeting platelet function is beneficial, might be achieved using higher doses of riociguat.


People who have extremely high-arched feet or pes cavus often suffer from substantial foot pain. Custom-made foot orthoses have been shown to be an effective treatment option, but their specificity is unclear. It is generally thought that one of the primary functions of custom foot orthoses is redistribution of abnormal plantar pressures. This study sought to identify variables associated with pain relief after custom foot orthoses intervention.® in-shoe plantar pressure data from a randomised controlled trial of 154 participants with painful pes cavus were retrospectively re-analysed at baseline and three month post orthoses intervention. The participants were randomised to a treatment group prescribed custom-made foot orthoses or a control group given sham orthoses.Demographic, physical characteristics and Pedarp=0.03). Our final model predicted 73% of the variance in pain relief from custom foot orthoses and consisted of initial pain level, BMI, foot alignment, and changes in both Dynamic Plantar Loading Index and pressure-time integral. Results indicate that a primary function of effective orthotic therapy is redistribution of abnormal plantar pressures.No relationship between change in pressure magnitude and change in symptoms was found in either group. While redistribution of plantar pressure, measured with the Dynamic Plantar Loading Index, had a significant effect on pain relief (This study provides the mechanism by which custom-made foot orthoses reduce pain and disability in patients with painful pes cavus. The proposed model may assist in better designing and assessing orthotic therapy for pain relief in patients with a variety of painful foot disorders.


Environmental Health Perspectives (EHP) established the Paper of the Year in 2008  mouse as an epigenetic biosensor to demonstrate that genistein, the major phytoestrogen in soy, increases DNA methylation of the Agouti gene, resulting in population-level decreased incidence of adult-onset obesity, diabetes, and cancer. At the inception of this study, epidemiological data suggested that increased dietary genistein plays a role in decreased incidence of cancer in Asians compared with Westerners. Thus, they hypothesized that early dietary exposures, including genistein, might be linked to adult health status via epigenetic mechanisms. These authors demonstrated that maternal dietary genistein supplementation of mice during gestation at levels comparable to humans consuming high soy diets shifted the coat color of heterozygous viable yellow agouti (Avy/a) offspring toward pseudoagouti. This phenotypic change was significantly associated with increased methylation of six cytosine–guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. A significant finding was that genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from adult-onset obesity.in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome. They also established the framework for future studies by showing that both genistein and methyl donors, such as folic acid, betaine, and choline, counteract DNA hypomethylation caused by bisphenol A, an endocrine-active agent used to make polycarbonate plastic. Their results showed that simple dietary changes can protect against the deleterious effects of environmental toxicants on the fetal epigenome (pigenome .EHP congratulates Dolinoy and colleagues for their contribution to the environmental health science literature. In addition to demonstrating that single-nucleotide polymorphisms can affect environmentally responsive genes, they demonstrated that early nutritionally and environmentally induced epigenetic modifications may be an alternative mechanism underlying individual susceptibilities to environmental agents.


Insecticide Treated Nets (ITNs) remain an important tool for sustained malaria control and play an integral part in malaria elimination strategies. As malaria incidence decreases in holodemic areas, however, proactive and regular use of ITNs may simultaneously decline if risk perception diminishes.In Summer 2012, we conducted a cross-sectional survey of three communities in Vanuatu: i) where malaria has been locally eliminated (Aneityum), ii) where malaria remains present but with rapidly declining incidence (Ambae), and iii) an urban area where malaria transmission may or may not occur (Efate). Respondents were asked a battery of questions regarding knowledge of malaria, ITN possession and use, and compliance with other anti-malaria interventions. Information on basic demographics, education levels, dietary habits and household economic activities were also recorded.Residents of Aneityum  reported near universal use of ITNs, but uneven knowledge of malaria, particularly in younger individuals born around the time of malaria elimination. Residents in the other communities reported less consistent, though high levels of ITN use despite past individual malaria diagnoses.Results indicate that achieving sustained high levels of ITN use in near- and post-elimination contexts is possible, but that maintaining awareness could present a long-term challenge to prevent reintroduction and recrudensence. Sustained local community cooperation will be essential to maintaining elimination efforts worldwide.


Implantable cardioverter defibrillator (ICD) is the currently accepted treatment for prevention of sudden cardiac death (SCD). Left ventricular ejection fraction is the only useful tool currently available to risk stratify patients at risk of SCD. Several other parameters have been studied for further risk stratification of SCD. Selection of appropriate subjects will improve the efficacy of treatment and also avoid unwanted ICD implantations in low risk patients. Role of QRS duration, QT dispersion, signal-averaged ECG, heart rate variability, ambulatory ECG monitoring, heart rate turbulence, T wave alternans, baroreceptor sensitivity and heart rate recovery have been investigated to identify patients at higher risk of arrhythmia and sudden cardiac death. However, none of these non-invasive tests could reliably stratify patients at risk of sudden cardiac death .Fragmented QRS complex (fQRS) has been identified as one of the non-invasive markers of mortality and sudden cardiac death . fQRS haIn this issue of the journal Apiyasawat et al  have repThus based on the available data in the literature, fQRS cannot be reliably used for risk stratification of SCD currently. More understanding is needed on the relation between fQRS, scar burden and arrhythmia inducibility  before i


Myocardial PVM may be used to assess peak velocities and the times to those peaks (TTP) in order to characterise healthy and pathological regional heart motion . HoweverAn efficient navigator-gated spiral trajectory PVM sequence  was used to scan basal, mid-ventricular and apical short-axis slices in ten healthy volunteers on two separate occasions. Retrospective cardiac gating was implemented, allowing analysis of all major velocity peaks throughout the cardiac cycle, including atrial systole. The reproducibility of peak velocities and their TTP values was assessed by Bland Altman analysis. Analysis of TTP vales was repeated after normalisation to a fixed systolic and diastolic length.Reproducibility data are shown in Table High temporal resolution myocardial PVM with retrospective cardiac gating is a highly reproducible technique for measuring all peak velocities in the cardiac cycle, including those in atrial systole. Absolute and normalised systolic TTP values have comparable reproducibility. However the reproducibility of diastolic TTP values is improved following normalisation to a fixed systolic and diastolic length. This is particularly apparent for the late diastolic peak representing atrial systole.The authors acknowledge the support of Heart Research UK, Imperial College London and NIHR Royal Brompton Cardiovascular Biomedical Research Unit.


Many drugs are characterized by polypharmacological mechanisms of action. Thus, prospective drug discovery studies often start by testing large compound libraries in multiple and diverse High-Throughput Screening (HTS) assays. These large heterogeneous data collections pose numerous computational challenges concerning processing, curation, and analysis of untreated output files generated by plate readers. We have developed the freely-accessible HTS Navigator software to enable and facilitate the processing and analysis of polypharmacological HTS data. We report on the capabilities of Navigator and present several case studies where we employed cheminformatics approaches embedded within the Navigator to curate and analyze large datasets of compounds tested toward different panels of targets. Examples include libraries of compounds tested for their inhibition potencies across several CYP450; or for their inhibition of multiple protein kinases; or their binding profiles against multiple GPCRs. We show how to quickly identify and highlight compounds with unique mono- and dual- selectivity for certain targets in the curated HTS matrix. We discuss the problem of experimental variability in HTS data and its consequences for molecular modeling and emphasize the synergistic potential of different cheminformatics approaches to detect both false-positive and false-negative compounds using neighborhood analysis and target baseline correction factors. Finally, we describe the Chemical−Biological Read-Across (CBRA) approach  also imp


Migraine attacks originate in the meninges which are densely innervated by trigeminal nerve fibers. Stimulated endothelial cells of dural blood vessels secrete nitric oxide, where neuropeptides are released from trigeminal nerve fibers. This, in turn, leads to meningeal Plasma Protein Extravasation (PPE), serving as an established indicator for migraine attacks in animal models. In our mouse migraine model, we sensitized mice against the 5-HT2B receptor agonist meta-chlorphenylpiperazine (mCPP). Mice kept under hypoxic conditions for four weeks displayed significantly elevated PPEs in the dura mater upon mCPP injection. Tissue accumulation of the tracer Evans Blue was measured to quantify the extent of the PPE. In this study, several histological tracers were employed to identify the part of the vasculature where PPE occurs and the cellular mechanism associated with it. Injections of BSA-FITC  verified the mCPP induced PPE in the dura mater. After leaving the blood vessels, the tracer was incorporated into perivascular, CD68-positive macrophages. With electron microscopic studies using the tracer HRP (horse radish peroxidase) we demonstrated that the PPE is associated with increased transcytotic transport. After 5-HT2B receptor activation, HRP escapes from capillaries and venules of hypoxic mice via an increased transcytotic transport in the endothelium. The hypoxic treatment itself increases transcytosis in arterioles, which may be indicative of a proinflammatory state of the endothelium. HRP was also detectable in intercellular clefts, but was always retained at tight junctions In summary, we demonstrated that in mice hypoxic treatment induces dural PPE via increased transcytotis at arterioles and that this is elevated to capillaries and venules after mCPP-injection.


Paradoxical embolus through a patent foramen ovale is a well-reported phenomenon. Clinical consequences include stroke, intestinal infarction, lower limb ischaemia, and even acute myocardial infarction (MI), via embolisation to the coronary arteries. We present a case of acute MI, cardiogenic shock, and cardiac arrest caused not by this mechanism, but by embolisation of thrombotic material to the aortic root with transient complete occlusion of the left main stem (LMS) coronary artery. During percutaneous coronary intervention to treat this occlusion the thrombus became lodged at the aortic bifurcation causing lower limb ischaemia. Despite successful treatment of this via bilateral groin exploration and thromboembolectomy the patient became increasingly acidotic and an abdominal and pelvic CT scan was performed. This revealed the source of the thrombus to be the patient's congested and compressed pelvic veins which were the result of a large, previously undiagnosed ovarian malignancy with metastatic spread. Although very unusual we feel this case highlights an important differential in the diagnosis of anterolateral MI and images similar to those presented here are previously unreported in the literature. Paradoxical embolus through a patent foramen ovale is a well-reported phenomenon. Clinical consequences include stroke, intestinal infarction, lower limb ischaemia, and even acute myocardial infarction (MI), via embolisation to the coronary arteries. We present a case of acute MI, cardiogenic shock, and cardiac arrest caused not by this mechanism, but by embolisation of thrombotic material to the aortic root with transient complete occlusion of the left main stem (LMS) coronary artery.A 57-year-old woman presented acutely to the primary percutaneous coronary intervention (PCI) service at our institution with a history of indigestion-type symptoms for several hours followed by acute shortness of breath, back, and chest pain. She was previously fit and well with no personal or family history of cardiac disease. Her electrocardiogram (ECG) showed typical changes of anterolateral ST elevation myocardial infarction (STEMI) and she was transferred immediately to the catheterisation lab. The patient was haemodynamically unstable with signs of cardiogenic shock; femoral arterial and venous sheaths were inserted on arrival. Initial coronary angiography revealed a large irregular mass in the aortic root  causing 1) branch consistent with microembolisation. These findings were confirmed on transoesophageal echo (TOE) which also demonstrated anterior wall akinesis (as expected) and a patent foramen ovale with a small left-to-right shunt. However, an angiogram of the distal aorta revealed occlusion of the left common iliac artery with compromised lower limb circulation evident both angiographically , aortic root thrombus, or possible dissection. On return of cardiac output (within minutes) a repeat aortogram via the coronary guide-catheter was performed . Surprisphically  and clinAt this stage a vascular surgery opinion was sought and the decision made to perform urgent open groin exploration with thromboembolectomies bilaterally in the cardiac cath-lab. The patient remained critically unwell and required an intra-aortic balloon pump as well as increasing inotropic support to augment cardiac output. Successful catheter trawl proximally and distally restored lower limb perfusion and embolic material was sent for emergent histology, whilst four-compartment calf fasciotomies were performed to prevent the development of subsequent compartment syndrome. Despite this acute management the patient's clinical state continued to deteriorate with worsening metabolic acidosis, rising lactate levels, and falling blood glucose.An urgent CT scan was undertaken to exclude significant mesenteric ischaemia, however, this revealed the presence of a huge ovarian tumour with pelvic venous congestion, thrombus, and evidence of widespread metastatic spread or “omental cake”. There was no evidence of bowel, renal or liver ischaemia however the patient continued to deteriorate and ITU support was sadly withdrawn after consultation with the patients' family and clinical team. Blood tests taken prior to deterioration did not reveal any evidence of thrombophilia although routine clotting parameters were deranged due to the patient's poor clinical state. A postmortem examination reinforced the clinical and radiological findings Figures  and 5 anAlthough a sad and thankfully rare case, we feel this paper illustrates an important differential in the cause of acute myocardial infarction. Paradoxical embolus through a patent foramen ovale is a well-reported phenomenon. Clinical consequences include stroke, intestinal, or renal infarction, and lower limb ischaemia. Paradoxical embolism to the coronary arteries has been previously proposed as a cause of MI  and bothTo our knowledge this is the first report of a venous thromboembolism causing complete coronary artery occlusion and subsequent iliac obstruction after entering the arterial circulation via PFO. As such this is a novel condition which highlights many learning points in terms of diagnosis and management, not least the importance of multidisciplinary team working between surgical, radiological, cardiological, and anaesthetic colleagues.


Macropus and Wallabia) exhibit more expansive areas of high radiodensity in the distal tibia than arboreal  or terrestrial quadrupeds , which may reflect the former carrying body weight only through the hind limbs. Arboreal quadrupeds exhibit smallest areas of high radiodensity, though they differ non-significantly from terrestrial quadrupeds. This could indicate slightly more compliant gaits by arboreal quadrupeds compared to terrestrial quadrupeds. The observed radiodensity patterns in marsupial tibiae, though their statistical differences disappear when controlling for phylogeny, corroborate previously documented patterns in primates and xenarthrans, potentially reflecting inferred limb use during habitual activities such as locomotion. Despite the complex nature of factors contributing to joint loads, broad observance of these patterns across joints and across a variety of taxa suggests that subchondral radiodensity can be used as a unifying form-function principle within Mammalia.Joint surfaces of limb bones are loaded in compression by reaction forces generated from body weight and musculotendon complexes bridging them. In general, joints of eutherian mammals have regions of high radiodensity subchondral bone that are better at resisting compressive forces than low radiodensity subchondral bone. Identifying similar form-function relationships between subchondral radiodensity distribution and joint load distribution within the marsupial postcranium, in addition to providing a richer understanding of marsupial functional morphology, can serve as a phylogenetic control in evaluating analogous relationships within eutherian mammals. Where commonalities are established across phylogenetic borders, unifying principles in mammalian physiology, morphology, and behavior can be identified. Here, we assess subchondral radiodensity patterns in distal tibiae of several marsupial taxa characterized by different habitual activities . Computed tomography scanning, maximum intensity projection maps, and pixel counting were used to quantify radiodensity in 41 distal tibiae of bipedal (5 species), arboreal quadrupedal (4 species), and terrestrial quadrupedal (5 species) marsupials. Bipeds ( Dendrolagus; Dendrolagus), in that the former are able to decouple speed and cost of transport Eutherian and metatherian  lineages diverged approximately 160 million years ago Eutherian mammals and marsupials Compressive strength of subchondral bone is determined by mineral content and porosity Primates and xenarthrans exhibit subchondral radiodensity patterns that corroborate theoretical expectations of limb loading according to their habitual activity patterns . Human distal radii exhibit lower weight-bearing (compressive) loads compared to suspensory and quadrupedal primates, as would be expected since human forelimbs no longer have an active weight-bearing role in locomotion Mammalia. In order to achieve these aims, we test two predictions. First, bipedal marsupials should exhibit significantly more expansive high radiodensity area in the distal tibia compared to quadrupedal marsupials because of the unique mechanics of their hopping gait, and because they carry body weight only through the hind limbs rather than all four limbs . Second, high radiodensity area in distal tibiae of terrestrial quadrupedal marsupials should exceed high radiodensity area in distal tibiae of arboreal quadrupedal marsupials because the latter may systematically adopt a more compliant gait, and/or systematically use more compliant arboreal substrates . If observed relationships between high radiodensity patterns and limb use in marsupials are consistent with previously documented relationships in eutherian mammals , it would be reasonable to elevate these relationships to unifying form-function principles throughout Mammalia.The goals of this study are two-fold. First, we aim to document whether a form-function relationship exists in radiodensity patterns in subchondral bone of marsupial distal tibiae. Second, we evaluate whether radiodensity patterns of subchondral bone exhibit a unifying form-function principle within The study sample consists of data derived from 41 marsupial tibiae housed in collections curated at the: Australian Museum (AM), Australian National Wildlife Collection (ANWC), Queensland Museum (QM), and Tasmanian Museum (TM)  maps from the standard reconstructions and fitted them to 3D renderings of distal tibiae generated from the bone reconstructions Following field observations and locomotor descriptions Ratio distributions for gait groups did not differ significantly from normal distributions according to a series of Kolmogorov-Smirnov Tests (p>0.05). Thus, we applied a series of one-way ANOVAs in order to statistically evaluate observed differences between gait group means . Gait grphytools package In our sample, some marsupial taxa representing gait groups are also closely related . In order to tease apart the extent to which observed gait group differences may have reflected phylogeny and function, we performed a second set of ANOVAs in which we accounted for phylogenetic effects (pANOVAs). We constructed a phylogenetic tree with known divergence dates  for taxaDendrolagus) has a comparatively low mean ratio of 0.017 (n = 2). When accounting for phylogeny, the comparison of species means eliminates statistical significance  again has a comparatively low mean ratio of 0.300 (n = 2) compared to other macropods. When accounting for phylogeny, the comparison of species means eliminates statistical significance , the ankle was observed to be the greatest contributor to whole limb work and power over a range of accelerations and decelerations The distinctiveness of distal tibiae of bipedal marsupials corroborates findings of others who have noted distinctiveness of the calcaneus of bipedal marsupials It was unexpected that mean radiodensity ratios of arboreal and terrestrial quadruped marsupials did not differ significantly. Arboreal quadrupedal primates exhibit gait compliancy compared to terrestrial quadrupedal primates, and thus limbs of the former experience lower peak vertical components of SRFs A second potential explanation for the unexpected non-significant difference between arboreal and terrestrial marsupial quadrupeds could be related to the application of such rigid gait and substrate use categories in the first place. There are a wealth of primate observational data on locomotor activities and substrate use Vombatus and Lasiorhinus) and non-fossorial terrestrial quadrupeds  would facilitate another potentially interesting comparison within marsupials. Wombats are described as emphasizing forelimbs during digging, while their hind limbs are primarily relegated to clearing accumulated sediment Expanding samples of fossorial , the observed trend exhibited by bipedal and quadrupedal marsupials adds to the accumulating evidence suggesting that the relationship between relative area of maximum radiodensity and joint compressive loads in limbs may be a unifying form-function principle amongst eutherian and metatherian mammals. By demonstrating how behavior influences morphology in a variety of mammals, these unifying principles support the existence of form-function signals in skeletal tissues that often elude comparative functional anatomists.Table S1Specimen information and raw data used in analyses.(XLS)Click here for additional data file.Table S2Nexus tree file used in the pANOVA. The phylogenetic tree with known divergence dates for taxa in the sample is based on recent molecular studies of marsupials (NEX)Click here for additional data file.


Osteonecrosis after craniofacial radiation (ORN), osteomyelitis and bisphosphonates related necrosis of the jaw (BRONJ) are the predominant bone diseases in Cranio- and Maxillofacial surgery. Although various hypothesis for the pathophysiological mechanisms including infection, altered vascularisation or remodelling exist, the treatment is still a challenge for clinicians. As the classical pharmacological or surgical treatment protocols have only limited success, stem cells might be a promising treatment option, indicated by recently published data. In maxillofacial surgery clinicians face three diseases of the jaws predominantly: osteonecrosis after craniofacial radiation (ORN), osteomyelitis and bisphosphonates related necrosis of the jaw (BRONJ). Numerous reports exist suggesting various pathological mechanisms and treatment modalities for these diseases ,2. Altho


Transcranial direct current stimulation (tDCS) is a promising tool for cognitive enhancement and neurorehabilitation in clinical disorders in both cognitive and clinical domains . Here we suggest the potential role of tDCS in modulating cortical excitation/inhibition (E/I) balance and thereby inducing improvements. We suggest that part of the mechanism of action of tDCS can be explained by non-invasive modulations of the E/I balance. Cognitive enhancement is a popular topic in the neuroscience community. Non-invasive neuromodulation methods, such as transcranial direct current stimulation (tDCS) can either increase  or decrease  cortical excitability  studies have shown that anodal tDCS reduces local concentrations of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), whereas cathodal tDCS reduces excitatory glutamate levels  receptors and brain-derived neurotrophic factor (BDNF) in the synaptic potentiation of the motor cortex after anodal tDCS  balance, measured by ratios of glutamate/GABA, may provide more meaningful interpretations of individual cognitive performance and deficits than glutamate or GABA alone. GABA and glutamate contribute in a complementary fashion to high-level prefrontal cognitive performance in healthy adults  and transcranial alternating current stimulation (tACS) is currently unknown and requires further exploration.Roi Cohen Kadosh filed a patent for an apparatus for improving and/or maintaining numerical ability.


RPE65) gene. Tremendous challenges still lie ahead to extrapolate these studies to other retinal disease-causing genes, as human gene augmentation studies require testing in animal models for each individual gene and sufficiently large patient cohorts for clinical trials remain to be identified through cost-effective mutation screening protocols.Retinal dystrophies cause severe visual impairment due to the death of photoreceptor and retinal pigment epithelium cells. These diseases until recently have been considered to be incurable. In the last two decades genetic studies have shed light on the molecular causes of several of these diseases, which has opened new avenues to develop therapeutic approaches. The mammalian eye has been at the forefront of therapeutic trials based on gene augmentation in humans with Leber congenital amaurosis, an early-onset recessive retinal dystrophy, due to mutations in the retinal pigment epithelium-specific protein 65 kDa (Pharmacological approaches to antagonize retinal degeneration are also under development, including modulation of the immune system.


While the effects of hypoxia on stem cells have been examined under in vivo hypoxia on a recently characterized population of pluripotent stem cells known as very small embryonic-like stem cells (VSELs) by whole-genome expression profiling and measuring peripheral blood stem cell chemokine levels.We investigated the effects of We found that exposure to hypoxia in mice mobilized VSELs from the bone marrow to peripheral blood, and induced a distinct genome-wide transcriptional signature. Applying a computationally-intensive methodology, we identified a hypoxia-induced gene interaction network that was functionally enriched in a diverse array of programs including organ-specific development, stress response, and wound repair. Topographic analysis of the network highlighted a number of densely connected hubs that may represent key controllers of stem cell response during hypoxia and, therefore, serve as putative targets for altering the pathophysiologic consequences of hypoxic burden.A brief exposure to hypoxia recruits pluripotent stem cells to the peripheral circulation and actives diverse transcriptional programs that are orchestrated by a selective number of key genes. Hypoxia is a pathophysiologic condition commonly seen in lung diseases and in many other disorders such as tissue ischemia and cancer . In the et al isolated a homogenous population of rare, small stem cells from adult murine BM mononuclear cells that expressed embryonic lineage markers, and were thus named very small embryonic-like stem cells (VSELs) .Click here for fileGene product interaction network of differentially expressed genes in VSELs. This file contains two figures depicting a gene product interaction network of differentially expressed genes in VSELs after in vivo exposure to hypoxia. Panel (A) highlights up and downregulated genes (red and green respectively). This network has 424 genes (nodes) and 604 connections (edges). Note that each connection represents a known direct interaction between two gene products. Panel (B) demonstrates that the topology of this network is scale-free because it follows a power law distribution. Nk, degree distribution; k, nodal connectivity.Click here for file


The great importance of cytological examination in diagnostic procedures of thyroid gland pathological lesions is widely known. Unfortunately, cytology as a diagnostic method presents many limitations due to possible presence of elements abnormal for thyroid gland physiology and histology. Especially difficult in cytological diagnosis appear: among non-neoplastic lesions - dyshormonogenetic and amyloid goiter and Riedel disease and among neoplastic lesions - rare microscopic variants of tumours, neoplasms arising from ectopic tissues and nonepithelial tumours.


Human monoclonal antibodies have been characterized recently that potently neutralize HIV-1 isolates across all clades. These exciting new antibodies (PGT series) were derived from direct functional screening of B cells from IAVI protocol G donors (Theraclone/Monogram) and are unusually potent with binding predicted to be to novel glycan-dependent epitopes on Env.Structures of these new PGT antibodies are being determined by x-ray crystallography and electron microscopy with further characterization using binding and mutagenesis assays.The crystal and EM structures so far have been elucidated for many of these antibodies. Work on the others are in progress, focusing on Fab complexes with glycans, gp120 core and fragment constructs, as well as Env trimers.Structural characterization and biochemical analysis of these antibodies have uncovered novel specificities to new glycan-dependent epitopes and reveal further mechanisms for viral neutralization. These new epitopes provide additional insights for neutralization of HIV-1 and how antibodies can bind and penetrate the glycan shield, a novel framework for structure-assisted vaccine design.This study was supported by the International AIDS Vaccine Initiative (IAVI), Ragon Institute of MGH, MIT and Harvard, and NIH AI84817.


Self-organized criticality refers to the spontaneous emergence of self-similar dynamics in complex systems poised between order and randomness. The presence of self-organized critical dynamics in the brain is theoretically appealing and is supported by recent neurophysiological studies. Despite this, the neurobiological determinants of these dynamics have not been previously sought. Here, we systematically examined the influence of such determinants in hierarchically modular networks of leaky integrate-and-fire neurons with spike-timing-dependent synaptic plasticity and axonal conduction delays. We characterized emergent dynamics in our networks by distributions of active neuronal ensemble modules  and rigorously assessed these distributions for power-law scaling. We found that spike-timing-dependent synaptic plasticity enabled a rapid phase transition from random subcritical dynamics to ordered supercritical dynamics. Importantly, modular connectivity and low wiring cost broadened this transition, and enabled a regime indicative of self-organized criticality. The regime only occurred when modular connectivity, low wiring cost and synaptic plasticity were simultaneously present, and the regime was most evident when between-module connection density scaled as a power-law. The regime was robust to variations in other neurobiologically relevant parameters and favored systems with low external drive and strong internal interactions. Increases in system size and connectivity facilitated internal interactions, permitting reductions in external drive and facilitating convergence of postsynaptic-response magnitude and synaptic-plasticity learning rate parameter values towards neurobiologically realistic levels. We hence infer a novel association between self-organized critical neuronal dynamics and several neurobiologically realistic features of structural connectivity. The central role of these features in our model may reflect their importance for neuronal information processing. The intricate relationship between structural brain connectivity and functional brain activity is an important and intriguing research area. Brain structure  is thought to strongly influence and constrain brain function . Concurrently, brain function is thought to gradually reshape brain structure, through processes such as activity-dependent plasticity . In this study, we examined the relationship between brain structure and function in a biologically realistic mathematical model. More specifically, we considered the relationship between realistic features of brain structure, such as self-similar organization of specialized brain regions at multiple spatial scales  and realistic features of brain activity, such as self-similar complex dynamics poised between order and randomness . We found a direct association between these structural and functional features in our model. This association only occurred in the presence of activity-dependent plasticity, and may reflect the importance of the corresponding structural and functional features in neuronal information processing. The temporal and spatial statistics of EEG, ECoG, MEG and fMRI signals likewise show power-law scaling Self-organized criticality is increasingly postulated to underlie the organization of brain activity Brain dynamics are thought to be strongly influenced by neuroanatomical connectivity The presence of an intuitive association between self-similar brain structure  and self-similar brain dynamics , has not been previously examined. The relationship between brain structure and dynamics is reciprocal: while the structure strongly constrains the dynamics, the dynamics continuously modify the structure through mechanisms such as activity-dependent synaptic depression A number of modeling studies recently reported self-organized critical avalanche dynamics in neuronal networks with nontrivial topology and activity-dependent plasticity The fundamental organizational unit of our network model is a densely connected 100-neuron module The studied leaky integrate-and-fire neuron evolves according toormation .For a postsynaptic neuron Synaptic weights changed at every spike of a neuron incident to the synapse, according to a spike-timing-dependent plasticity (STDP) rule . The STDibutions . The uniParameter values of the model were adapted from the Thivierge and Cisek Each network comprised l levels . The denff rates . SynapseThe wiring cost associated with each scaling function was computed by estimating the number of synapses in each hierarchical level for that function, equating the cost of each synapse with the number of its hierarchical level  to other meaningful changes in neurobiologically relevant parameters, such as changes in external current, changes in conduction delays, changes in the postsynaptic response, presence of neuronal inhibition, changes in the STDP rule and changes in network size . Theoretvity see , but begweakened , top, buweakened , bottom.in vivo each neuron is thought to have thousands of synapses. We compensated for the small number of connections in our model by setting the postsynaptic-response magnitude of each neuron to a value which could theoretically exceed the neuron spike threshold and by using an instantaneous STDP learning rate that substantially exceeds empirically observed values  and self-similarity of dynamics . We now discuss the mechanisms behind this association, and the implication of our findings for empirical research.We found that despite seemingly stable neuronal activity, spike-timing-dependent plasticity enabled coherent within- and between-module neuronal activity. Furthermore, we showed that two variations of the STDP rule produced distinct weight distributions, but enabled a broad critical regime on conducive network topologies. In contrast, fixed or randomly altered synaptic weights were associated with subcritical dynamics and negligible module spike rates. STDP may facilitate coherent within-module activity by intermittently potentiating and depressing synapses between reciprocally connected neurons. In small networks, simulations showed that intermittent synaptic potentiation and depression was associated with pairwise neuronal synchrony, fluctuations of synaptic weights and continuous reversal of phase differences between reciprocally connected pairs of neurons (results not shown). In our networks, within-module weights were potentiated during module spikes, and depressed between module spikes . These aRecent studies have shown the importance of short-term synaptic depression in self-organized critical dynamics in networks of spiking neurons, but have not concurrently considered the effects of STDP Modular networks with low wiring cost showed a broad critical regime. Modular networks with high wiring cost showed a narrow critical regime, possibly due to high numbers of costly long-range connections, which enabled a rapid onset of globally synchronous, supercritical dynamics. Lattice networks with low wiring cost showed a narrowed critical regime due to uncoordinated inhibition and a consequent loss of coherent ensemble dynamics. Modularity and low wiring cost were hence simultaneously required for self-organized criticality to emerge. This simultaneous requirement is notable, as both properties are thought to be ubiquitously present in neuroanatomical organization.In an early comprehensive exposition, Jensen We found that inhibitory neurons in our model did not explicitly enable a broad critical regime. In contrast, recent network simulations of simple stochastic neurons by Benayoun et al. Our findings may be used to generate empirically testable hypotheses of the relationship between anatomical connectivity and emergent network dynamics. For instance, we hypothesize that self-organized critical dynamics in dissociated neuronal cultures emerge on a low-cost modular neuroanatomical connectivity. Recent studies show that dissociated neuronal cultures self-organize towards a critical state, via subcritical and supercritical states Our findings may hence be used to explicitly compare structure and dynamics of dissociated neuronal cultures, throughout this period of self-organization. A recent study found that functional activity patterns of dissociated neuronal cultures constitute a small-world network A clear limitation of our study is the oversimplified symmetric hierarchical organization and the relatively small size of our model. Substantial increases in the number of modules, and in the number of neurons within modules, are required to make realistic inferences about neuronal dynamics at larger scales. The study hence sets the groundwork for simulations of large networks of spiking neurons and for characterization of spatiotemporal activity patterns emergent on these networks. Such simulations may be conducted on increasingly detailed maps of large-scale anatomical connectivity in healthy subjects Studies of neuronal dynamics often employ numerical integration schemes (such as the Euler method), and manually store all previous spike times to compute synaptic currents. An advantage of the integrate-and-fire neuron model is the ability to integrate subthreshold activity exactly and incorporate effects of all previous spikes without the need for explicit summation at each step Despite growing empirical evidence for self-organized criticality, several important studies argue against this evidence, by either noting the potential for spurious reports of power-law scaling, or by attributing such scaling to simpler mechanisms, such as diffusive processes In conclusion, we show an association between modularity, low cost of wiring, synaptic plasticity and self-organized criticality in a neurobiologically realistic model of neuronal activity. Our findings theoretically reinforce the reciprocal relationship between connectivity and dynamics on multiple spatial scales.Text S1Supporting information code.(PDF)Click here for additional data file.Text S2Supporting information code.(TXT)Click here for additional data file.Text S3Supporting information code.(TXT)Click here for additional data file.Text S4Supporting information code.(TXT)Click here for additional data file.Text S5Supporting information code.(TXT)Click here for additional data file.Text S6Supporting information code.(TXT)Click here for additional data file.Text S7Supporting information code.(TXT)Click here for additional data file.Text S8Supporting information code.(TXT)Click here for additional data file.Text S9Supporting information code.(TXT)Click here for additional data file.Text S10Supporting information code.(TXT)Click here for additional data file.Text S11Supporting information code.(TXT)Click here for additional data file.Text S12Supporting information code.(TXT)Click here for additional data file.Text S13Supporting information code.(TXT)Click here for additional data file.Text S14Supporting information code.(TXT)Click here for additional data file.Text S15Supporting information code.(TXT)Click here for additional data file.Text S16Supporting information code.(TXT)Click here for additional data file.Text S17Supporting information code.(TXT)Click here for additional data file.


The role of cortical feedback in thalamo-cortical processing loop have been extensively investigated over the last decades. In general, these studies focused on cortical feedback exerted over lateral geniculate nucleus (LGN) principal cells, only in several cases the effects of cortical inactivation were investigated simultaneously in both thalamic relay cells and perigeniculate nucleus (PGN) inhibitory neurons. In the previous study  we showeTo identify network mechanisms underlying such functional changes we conducted a modelling study in NEURON on several networks of point neurons with varied model parameters, such as membrane properties, synaptic weights and axonal delays. We considered five network topologies of the retino-geniculo-cortical pathway -6.All models were robust against changes of axonal delays except for delay between LGN feed-forward interneuron and principal cell when this connection was present. In all such cases the models were found to be very sensitive to this delay. To reproduce the experimental results  the mode


Pulmonary tumor thrombotic microangiopathy is a rare complication of malignant diseases. The diagnosis is extremely difficult and is most often performed after death. Invariably, patients develop acute pulmonary hypertension causing right heart failure, shortness of breath and death in a few days. We describe the clinical and radiological findings of a patient who presented with this complication.A 28-year-old Caucasian woman with a previous history of pelvic tumor resection two months previously, suggestive of metastatic adenocarcinoma, presented with intense shortness of breath. A computed tomography scan showed signs of acute cor pulmonale and diffuse nodular opacities associated with a tree-in-bud pattern disseminated through her lungs, suggestive of bronchiolitis. Our patient's condition worsened and she underwent a surgical biopsy. Pathologic analysis of the biopsied specimens revealed pulmonary tumor thrombotic microangiopathy. Our patient's tumor evolved from a gastric origin (Krukenberg tumor). She underwent progressive clinical deterioration and died less than 24 hours after the biopsy. None of the cases described previously in the literature had diffuse centrilobular nodular opacities associated with a tree-in-bud pattern disseminated through the lungs, as in our case.Pulmonary tumor thrombotic microangiopathy should be considered in cancer patients with rapidly progressing dyspnea, chest computed tomography findings compatible with pulmonary hypertension and typical findings of inflammatory bronchiolitis. Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare complication of malignant diseases. The diagnosis is extremely difficult and is most often performed after death . InvariaA 28-year-old Caucasian woman presented to our hospital with a previous history of abnormal vaginal bleeding and abdominal pain that had begun four months prior to her initial presentation. A transvaginal ultrasound was performed at that time and demonstrated solid lesions in her left adnexal region, confirmed two weeks later with magnetic resonance imaging. She then underwent an exploratory laparotomy with a bilateral anexectomia. A pathological examination diagnosed a solid poorly differentiated adenocarcinoma, with signet ring cells diffusely infiltrating the ovaries and fallopian tubes bilaterally, compatible with a metastatic pelvic tumor of probable gastric origin, traditionally known as a Krukenberg tumor. After surgery, during the staging and treatment planning, our patient presented to our Emergency Room complaining of dry cough and shortness of breath of recent onset, with intense and progressive worsening. She had no other complaints and no fever. On examination, she was in generally poor condition, malnourished, dehydrated, with tachycardia and dyspnea; pulmonary auscultation revealed decreased breath sounds and mild wheezing in both lungs. Her leukocyte count showed no signs of infection; a blood test revealed the presence of mild anemia and a chest X-ray showed no abnormalities. Due to clinical suspicion of a pulmonary thromboembolism, our patient underwent a computed tomography (CT) scan of her chest, pelvis and thighs. Although the angiographic phase did not present any signs of pulmonary thromboembolism, the CT scan showed signs of acute cor pulmonale characterized by increased right heart chamber dimensions, slight interventricular septum deviation and a right ventricular to left ventricular ratio greater than 1.5 Figures , 4 and 5Laboratory investigations were remarkable for microcytic anemia  and a strongly positive D dimer (1100 ng/mL). Her arterial blood gas examination breathing room air showed hypoxia with respiratory alkalosis . Our patient was admitted with a presumptive diagnosis of pulmonary thromboembolic disease.PTTM is a rare complication of malignancies commonly detected after death. It was first described by von Herbay and colleagues as a diffuse intimal myofibroblast proliferation that causes pulmonary hypertension, leading to cardiopulmonary failure and death . This diDistinguishing between the clinical presentation of lymphatic and microvascular disease can be challenging, and many authors do not distinguish between these two. Soares and colleagues evaluated a series of 222 patients who had undergone autopsy, including 19 with microvascular pulmonary arterial embolism and 44 with lymphangitic carcinomatosis . AlthougOn histopathological investigation, pulmonary tumor thrombotic microangiopathy is characterized by widespread fibrocellular intimal hyperplasia of small pulmonary arteries, also called carcinomatous endarteritis induced by tumor microemboli . DiffuseNone of the cases described previously in the literature had diffuse centrilobular nodular opacities associated with a tree-in-bud pattern disseminated through the lungs, as in our case.PTTM should be considered in cancer patients with a rapidly progressing dyspnea, chest CT compatible with pulmonary hypertension and typical findings of inflammatory bronchiolitis.Written informed consent was obtained from our patient's next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.All the authors contributed to the writing of the paper. The original manuscript was written by MFA and AB, and the final version by MDG. RC and JLG contributed the CT images and additional references. All authors read and approved the final manuscript


Ungulates exert a strong influence on the composition and diversity of vegetation communities. However, little is known about how ungulate browsing pressure interacts with episodic disturbances such as fire and stand thinning. We assessed shrub responses to variable browsing pressure by cattle and elk in fuels treated  and non-fuels treated forest sites in northeastern Oregon, US. Seven treatment paddocks were established at each site; three with cattle exclusion and low, moderate and high elk browsing pressure, three with elk exclusion and low, moderate and high cattle browsing pressure, and one with both cattle and elk exclusion. The height, cover and number of stems of each shrub species were recorded at multiple plots within each paddock at the time of establishment and six years later. Changes in shrub species composition over the six year period were explored using multivariate analyses. Generalized Linear Mixed Models were used to determine the effect of browsing pressure on the change in shrub diversity and evenness. Vegetation composition in un-browsed paddocks changed more strongly and in different trajectories than in browsed paddocks at sites that were not fuels treated. In fuels treated sites, changes in composition were minimal for un-browsed paddocks. Shrub diversity and evenness decreased strongly in un-browsed paddocks relative to paddocks with low, moderate and high browsing pressure at non-fuels treated sites, but not at fuels treated sites. These results suggest that in the combined absence of fire, mechanical thinning and ungulate browsing, shrub diversity is reduced due to increased dominance by certain shrub species which are otherwise suppressed by ungulates and/or fuels removal. Accordingly, ungulate browsing, even at low intensities, can be used to suppress dominant shrub species and maintain diversity in the absence of episodic disturbance events. Both livestock and wild ungulates commonly occupy high elevation pastures during the summer months in many parts of the globe. In the western United States, most ranchers bring their livestock to high elevation summer pastures that are located within public forest lands Considerable research has been conducted on the separate impacts of fires Odocoileus virginianus) led to loss of preferred woody species which in turn resulted in increased abundance of less palatable understory plants such as sedges Both episodic disturbances The response of vegetation diversity to ungulates can also vary depending on browsing frequency and intensity We measured the compositional and diversity responses of native forest shrubs  to variable browsing pressure over several years from dominant ungulate herbivores, cattle and elk, at sites where fuel loads were mechanically removed and followed by prescribed fire, and at sites with no history of fire or fuels removal for 40 years (referred to fuels treated and non-fuels treated respectively from here on). We hypothesized that vegetation responses to browsing would vary between fuels treated and non-fuels treated sites, and that the greatest level of diversity would be achieved at moderate levels of browsing pressure, particularly at non-fuels treated sites where shrub cover and dominance is high.Research was conducted under approval and guidance by an Institutional Animal Care and Use Committee (IACUC 92-F-0004), as required by the United States Animal Welfare Act of 1985, following the IACUC protocol for conducting cattle, elk, and mule deer research in our study area. Permission to perform the study was given by the USDA Forest Service Pacific Northwest Research Station.Our study was carried out within the Starkey Experimental Forest and Range (SEFR) in the Blue Mountains Ecological Province of northeast Oregon , approxiPseudotsuga menziesii) and grand fir (Abies grandis) Conditions at SEFR are typical of montane forest types of interior western North America Pinus ponderosa), western larch , lodgepole pine (Pinus contorta), and Englemann spruce (Picea engelmannii). Common understory grass and grass-like species include Idaho fescue (Festuca idahoensis), elk sedge (Carex geyeri), pinegrass , western fescue , Kentucky bluegrass (Poa pratensis), and annual bromes (Bromus spp.). Common forbs include lupine (Lupinus spp.), strawberry (Fragaria spp.), tall annual willowherb (Epilobium paniculatum), and western yarrow (Achillea millefolium). Common shrub species include bearberry (Arctostaphylos uva-ursi), big huckleberry (Vaccinium membranaceum), grouse huckleberry (Vaccinium scoparium), rose (Rosa spp), snowberry , shinyleaf spiraea (Spiraea betulifolia lucida), twinflower , sticky currant (Ribes viscosissimum), prickly currant (Ribes lacustre), raspberry (Rubus spp.), Saskatoon serviceberry , black hawthorn (Crataegus douglasii), snowbrush (Ceanothus velutinus), willow , oceanspray (Holodiscus discolor), wax currant (Ribes cereum var. cereum), orange honeysuckle (Lonicera ciliosa), Scouler's willow , elderberry (Sambucus spp.), mountain ash (Sorbus scopulina), black cottonwood , and boxleaf myrtle (Paxistima myrsinites).In addition to Douglas-fir and grand fir, other canopy tree species present in these stands include ponderosa pine (Fuels reduction treatments were applied to grand fir and Douglas-fir stands (between 10 and 50 ha in size) in SEFR between 2000–2003 Stands were mechanically thinned with a feller-buncher to reduce fuel loadings to <35 tons/ha, compatible with fuel loads considered unlikely to carry stand-replacement fires Following fuels reduction treatment, exclosures ranging in size from five to seven hectares were established at five mixed Douglas-fir and grand-fir forest sites in the SEFR: Half Moon (HM), Louis Spring (LS), Bally Camp (BC), Doug Prairie (DP), and Bee Dee (BD) . Three . The othThe exclosures were established at each site by constructing a fence eight feet in height that excluded all ungulates , but allowed for other wildlife to pass under, over, or through. The exclosures were constructed in the year following the fuels treatments. The size and shape of each exclosure varied with site conditions, including topography, slope, forest structure, and the shape of the forest patch to minimize site variation within and among exclosures. The ungulate exclosures were divided into seven, roughly equal-sized paddocks  in which seven different levels of cattle and elk herbivory treatments were randomly assigned and implemented . The levBrowsing intensity for each treatment level was defined in terms of the number of days per ha that elk and cattle use Douglas-fir and grand fir habitat types in the interior northwestern United States, broken down into three levels of forage utilization: high—45% utilization; moderate—30% utilization; and low—15% utilization. These levels typify the range of grazing and browsing use established for cattle on summer ranges in Douglas-fir and grand fir habitat types on public lands like those at SEFR Stocking density  for each type of ungulate was then calculated using standard forage allocation procedures The calculated stocking densities were then refined so that the final number of cattle days per ha and elk days per ha for each treatment level corresponded to what was logistically feasible to implement with the tractable animals. Moreover, the number of animals must be compatible with each ungulate's group behavior for foraging and the need to complete the trials in as few days as possible to minimize changes in forage availability and phenology. Consequently, we used 4 elk and 6–8 cattle per trial to most efficiently approximate the calculated stocking densities. The diets of elk and cattle tend to converge during late summer in grand fir and Douglas-fir forests 2 plots (4×10 m) were systematically established in each paddock. Due to differences in paddock size and layout, the number of plots per paddock varied (from 12–18), though the percent of each paddock sampled remains similar (7–9%). Plot locations were determined using real-time differential global positioning system placed in a geographic information system (GIS). Plots were located 15 m apart along transect lines, with each transect line spaced 15 m apart from one another within each paddock. Edges of paddocks were excluded from sampling with a 5 m buffer, and a random starting point was used to determine the starting point of each transect (ranged from 5–10 m from the outer edge of exclosure).Permanent 40 mdiversity function in the vegan package The absolute and relative cover of shrub species were estimated using the line-intercept method, with transects running along the center of each 4×10 m plot. Within each 4×10 m plot, all shrub stems ≥1 m in height were identified, counted, and their height measured to the nearest cm. Due to their high abundances, stems <1 m in height were identified, enumerated, and their height and cover measured in a smaller 2×10 m plot through the center of each permanent 4×10 m plot. Shrub abundances were adjusted by dividing the number of stems by the area of the sampling plot area prior to analyses. Sampling occurred in July just before implementation of the browsing treatments, and again in July, after six years of the browsing treatment. Shrub diversity and evenness were calculated for each plot using all species with Simpson index using the The overstory has a strong influence on understory vegetation dynamics in western coniferous forests metaMDS function in the R package vegan Multivariate analyses were carried out to compare the relative changes in shrub species composition  across un-browsed paddocks and paddocks under differing levels of browsing pressure by elk and cattle separately. A Non-metric Multidimensional Scaling was conducted using the glmmPQL function of the MASS package plot function in R Because of the nested structure of our sampling design, ungulate treatment effects on vegetation structure were assessed with Generalized Linear Mixed Models GLMM;  with theInitial mean shrub cover and height were higher at paddocks within non-fuels treated sites than paddocks within fuels treated sites . Mean shAt non-fuels treated sites, the change in shrub composition was much greater at un-browsed paddocks compared to browsed paddocks, regardless of browsing intensity or ungulate type . The comIn contrast, un-browsed paddocks showed minimal change in shrub composition at fuels treated sites . The amoShrub species diversity and evenness were strongly affected by the interaction between fuels treatment and browsing at all three levels  indicatiIn non-fuels treated sites, shrub species diversity and evenness generally did not change over the study period in browsed paddocks regardless of ungulate type or browsing pressure . HoweverOur results demonstrate that ungulates have an important role in maintaining plant diversity in western forest ecosystems in the absence of episodic disturbance events such as fire and/or mechanical fuels removal. This finding agrees with Rambo and Faeth Episodic disturbances provide new growth that is often highly preferred by ungulates While we hypothesized that diversity would be highest at moderately browsed paddocks, shrub diversity was consistently higher at all three levels of browsing pressure compared to ungulate exclusion, and no differences were observed among paddocks under different levels of browsing pressure. This suggests that relatively little browsing, 8 and 10 days per hectare annually for elk and cattle respectively, is needed to suppress dominant shrub species and maintain shrub diversity in this ecosystem. Furthermore, diversity is not reduced under higher levels of browsing pressure, of up to 32 and 30 days per hectare annually for elk and cattle respectively. It has been suggested that reduced diversity occurs once browse-tolerant species become dominant Furthermore, because we conducted our browsing treatments towards the end of the summer when the diet of elk and cattle converge, we cannot conclude from our findings that perennial understory vegetation in western conifer forest is insensitive to browsing pressure or ungulate type. Cattle and elk may have different effects on shrub dominance and diversity patterns at the beginning of the growing season, particularly with high browsing pressure. Accordingly, browsing effects at different times of the year need to be determined to assess how much browsing pressure is required to maintain diversity when herbivory occurs during the spring, early summer, late summer/fall, or a combination of the three with some browsing in each season. The latest scenario is the most realistic since elk and other wild ungulates are likely to visit these sites several times over the growing season.Our findings have important implications for both livestock and wild ungulate management in dry forests of the western United States. First, management decisions to modify ungulate densities on the landscape will result in changes in abundance of different shrub species that could be based on a priori designs to meet vegetation management objectives for other resources, such as the desire to increase abundance of certain shrubs as habitat for wildlife. Second, while specific shrub responses may vary by type of ungulate and by the background site conditions in which herbivory occurs, either cattle or elk can be used to maintain shrub diversity in the absence of episodic disturbances. Consequently, management decisions that alter ungulate browsing patterns should take into consideration other current forest management activities and disturbances that may alter inter-specific interactions, such as prescribed burning and fuels removal. These considerations are particularly important to sustaining biodiversity in seasonally arid and fire-prone forest ecosystems of the Western United States where natural and human-induced disturbances exert strong control on vegetation.