The most significant epigenetic alteration found in cancer cells is a global loss of DNA methylation. Recent analyses of cancer methylomes have suggested that methylation is specifically lost from Lamin-associated domains (LADs) which are associated with the nuclear periphery. This suggests that nuclear organisation is a key influence on epigenetic alterations in cancer but the relationship between nuclear organisation and demethylation has not been directly investigated.in-situ hybridisation (FISH) to determine how nuclear organisation in normal cells relates to alterations in DNA methylation levels in cancer.We have combined analyses of cancer methylomes with fluorescence Our analyses demonstrate that DNA methylation is lost from different regions of the genome in breast and colorectal tumours. Surprisingly, we find that the propensity to become demethylated in cancer is not correlated with localisation to the nuclear periphery in the corresponding normal cell types. While regions some breast cancer hypomethylated regions are localised to the periphery in normal breast epithelial cells, an equal proportion are found in the nuclear interior.Our observations decouple hypomethylation in cancer from a peripheral nuclear localisation and suggest that association with the nuclear lamina is not mechanistically involved in the loss of methylation in cancer.


Knee malalignment and variations in foot posture and function affect the forces transmitted through the knee joint and are associated with knee pain and medial tibiofemoral cartilage damage . HoweverNineteen patients  diagnosed with predominantly medial compartment knee OA who were scheduled for TKR surgery participated in the study, and were tested prior to and 12 months after TKR. Foot Posture Index (FPI) and arch index were measured as well as motion of the tibia, rearfoot and forefoot using a 3D motion analysis system incorporating a multisegment foot model (Oxford Foot Model).Significant increases in tibial external rotation  and tibial transverse plane range of motion (ROM)  were observed following the surgery. An increase in rearfoot ROM in the frontal plane  and a decrease in rearfoot transverse plane ROM  were observed. No significant differences were found between pre and post-surgery in the FPI and or the arch index.Following TKR, there is an increase in the ROM of the rearfoot in the frontal plane, but no change in static foot posture suggesting that rearfoot motion compensates for changes in the alignment of the knee.


Rare diseases are designated as affecting less than 200,000 individuals (US) and of the approximately 7000 designated rare diseases, the majority of these occur in pediatric patients, and across international boundaries. An example is pediatric ARDS (Acute Respiratory Distress Syndrome) which is not diagnosed until a previously healthy child presents in the pICU with severe symptoms and in which more children die each year than from cystic fibrosis and leukemia, combined. The Nathaniel Adamczyk Foundation (NAF) is focused on identifying risk factors and opportunities for prevention of this devastating disease. Boththe diagnosis and patient management are challenged by having to deal with a syndrome in a critical care situation in a heterogeneous patient population.NAF has undertaken the development of an (inter) national tissue and data repository to support both clinical research and enhanced clinical decision support for patient management. Creation of an analytical platform to integrate, access and analyze temporal clinical data ranging from the pICU to also incorporate neo-natal ICU and pregnancy history is underway with a prototype already in testing. Analytical methods are being evaluated in collaboration with Dr. Mike Quasney  and the Virtual Pediatric ICU and PALISI (Pediatric Acute Lung Injury and Sepsis Investigators). This effort is exploring expanded international partnerships in both Europe and China to increase the accessible data for analysis and to further participate in the development of better diagnostic standards.We will present the initial state of both the analytics and platform development to encourage extension of this international effort to interested clinicians and clinical researchers. We believe that this unique approach, which focuses first on addressing the critical need to improve patient management through disease stratification, will not only benefit pARDS but be extensible to many other pediatric rare disorders.


The UK Department for International Development (DFID) is committed to investing in research to combat poverty, reduce high mortality and morbidity in resource poor contexts and support progress towards meeting the Millennium Development Goals. Research helps us to identify what works, what does not work and how to understand the local context when introducing new ways of working. There is no point doing research if the findings do not get into policy and practice. DFID strongly encourages all research programmes to consider research uptake activities as an integral part of the research.This special supplement draws on the work of the Sexual Health HIV Evidence into Practice (SHHEP) initiative. SHHEP is a collaboration across four DFID Research Programme Consortia (RPC) that undertake research and action on HIV and Sexual and Reproductive Health in resource poor contexts. Each consortium consists of 5 or more research, advocacy or service provider institutions from the south and the north working together over a five year period on critical areas of sexual and reproductive health. The essence of SHHEP is to share learning on research uptake and research engagement in Sexual and Reproductive Health, including HIV. The group has formulated a range of targeted mechanisms to communicate health research to different audiences and spearhead change, and were finalists for the British Medical Journal 2010 Getting Research into Practice (GRiP) prize.The papers in this special supplement focus on lesson learning on getting research into policy and practice. They highlight the range of methodologies and approaches researchers and communication specialists have used in different contexts to try to ensure research does not simply gather dust on library shelves but feeds into and is relevant to policy and practice in different contexts  and on a diversity of topic areas .The work reported in this supplement provides examples of approaches that have been tried and from which other researchers can learn. They demonstrate that getting research into policy and practice is complex, dynamic and multi-faceted; and a wide range of context and issue specific conceptual and practical approaches have to be used. I hope that the innovative approaches and promising ways forward, presented in these papers, will inspire and motivate others.Professor Christopher WhittyDirector Research and Evidence DivisionDepartment for International DevelopmentDr Sue KinnHead of Health ResearchDepartment for International Development The authors declare that they have no competing interests.


The Pall Micro24 Bioreactor system is one of several microbioreactor systems that have been commercialised in recent years in response to the demand to reduce costs and shorten process development time lines.We have previously demonstrated that the Micro24 Bioreactor system can be integrated successfully into the later stages of cell line screening programmes and that the results correlate well with those from more conventional methods . FurtherThis work describes the use of the Micro24 Bioreactor system to identify improved process conditions for different cell lines and their subsequent validation in bioreactors.3.This system comprises 24 bioreactors (7 ml working volume) each capable of independent temperature, dissolved oxygen and pH control. The main limitation of the system is the lack of automation meaning that any feed additions or sample removal must be made manually and similarly, for mammalian cultures, upwards pH control is achieved by the manual addition of NaHCOEngineering characterisation studies carried out at UCL (data not shown) have shown how conditions within the individual Micro24 chambers compare with those in bioreactors and recent results also indicate that the selection of the Micro24 plate type is critical in ensuring good correlation with performance in traditional bioreactors.Within the Micro24 Bioreactor system cell cultures are carried out in presterilised polycarbonate mammalian cell culture cassettes which are inoculated manually in a laminar flow cabinet before sealing with Type A single use closures and incubation under experimental conditions.Chemically defined medium and feeds were used throughout this work. Unless otherwise stated standard experimental conditions were used. ). Viable cell numbers and viability were determined using a ViCell Cell Viability Analyser (Beckman Coulter) and antibody titres were determined using an Immage Immunochemistry System (Beckman Coulter).Typical process relevant factors that can be tested in the Micro24 include feed regime, pH, DO and temperature. The effects of these types of factors are best tested using a Design of Experiments (DoE) approach to assess the effects not only of different factors but also of the interactions between them. Such data can then be used to build predictive models of process performance to specify the appropriate operating conditions in larger scale bioreactors. We have already developed and are using a similar approach for microbial dAb processes.The data below shows examples of how we have used this system to identify improvements to platform processes for specific cell lines.In this experiment the effects of changes to the platform process pH and DO set points on the performance of a mAb producing cell line were assessed in the Micro24 using a DoE approach with different operating conditions in each well.This data demonstrated that although the dissolved oxygen level had little effect on viable cell numbers, titres and specific productivity, operating at a higher pH than the standard platform set point resulted in an increase in titre and in specific productivity. There was no significant interaction between the factors.The high pH process identified from the Micro24 was run in 2 litre bioreactors and compared to the standard platform process.At the high pH set point cell numbers during the later stages of the process were slightly reduced compared to the control and as in the Micro24 higher titres were produced under higher pH conditions. However, as in the Micro24 the greatest effect of increased pH was on specific productivity which in the bioreactors was increased by approximately 35% compared to the control.Similar results were achieved at the 50 litre scale for a different cell line running in the same platform process but producing a different molecule Figure . There wThe Micro24 can be used to investigate the effect of different feeding regimes on culture performance. We have already demonstrated that the effect of feed addition on culture performance in the Micro24 is similar to that in shake flasks ; the datOur previous work has demonstrated how the Micro24 system can be used for mammalian cell line selection  and the The validation of the Micro24 results in bioreactors suggests that the integration of this technology into mammalian process development could reduce significantly the numbers of bioreactors required to achieve process improvements which could result in reduced resource requirements and improved timelines.


The meaning of correlated neural activity for the processing and representation of information in cortical networks is still not understood, but evidence for a pivotal role of correlations increases . Recent


Multiple sources of influenza surveillance data are becoming more available; however integration of these data streams for situational awareness of influenza activity is less explored.We applied multivariate time-series methods to sentinel outpatient and school absenteeism surveillance data in Hong Kong during 2004–2009. School absenteeism data and outpatient surveillance data experienced interruptions due to school holidays and changes in public health guidelines during the pandemic, including school closures and the establishment of special designated flu clinics, which in turn provided ‘drop-in’ fever counts surveillance data. A multivariate dynamic linear model was used to monitor influenza activity throughout epidemics based on all available data. The inferred level followed influenza activity closely at different times, while the inferred trend was less competent with low influenza activity. Correlations between inferred level and trend from the multivariate model and reference influenza activity, measured by the product of weekly laboratory influenza detection rates and weekly general practitioner influenza-like illness consultation rates, were calculated and compared with those from univariate models. Over the whole study period, there was a significantly higher correlation  for the inferred trend based on the multivariate model compared to other univariate models, while the inferred trend from the multivariate model performed as well as the best univariate model in the pre-pandemic and the pandemic period. The inferred trend and level from the multivariate model was able to match, if not outperform, the best univariate model albeit with missing data plus drop-in and drop-out of different surveillance data streams. An overall influenza index combining level and trend was constructed to demonstrate another potential use of the method.Our results demonstrate the potential use of multiple streams of influenza surveillance data to promote situational awareness about the level and trend of seasonal and pandemic influenza activity. Many public health agencies routinely monitor influenza virus activity to facilitate situational awareness of the degree of disease activity in the community During the 2009 influenza pandemic, situational awareness was hindered by the introduction of new ‘drop-in’ surveillance systems and potential changes in behavior in pre-existing systems The local Department of Health conducts influenza-like illness surveillance among a network of 50 private-sector sentinel general practitioners (GP) and 62 public-sector sentinel general outpatient clinics (GOPC) who report weekly proportion of outpatients fitting the surveillance definition of ILI  and trend (decreasing/stable/increasing) of the underlying influenza activity representing different phases of influenza epidemics.For each week since 2004, we estimated the latent level and trend, and calculated the overall influenza activity index based on all available GOPC, GP ILI, school absenteeism and DFC fever counts surveillance based on data available up to that week. The data along with the scaled inferred influenza level and trend from the dynamic linear model, and the reference influenza activity are shown in We fitted dynamic linear models to the individual surveillance data streams, and estimated the correlation of these individual models versus influenza activity. We compared this with the correlation between the multivariate models using all available data versus influenza activity . While tWe have demonstrated the use of a multivariate method to integrate information from multiple streams of influenza surveillance data to improve situational awareness of the current level of influenza activity, and how a combined use of both the inferred influenza level and trend or an integrated index that can be potentially used to indicate overall influenza activity currently. Our study showed the advantage of a multivariate model-based approach especially if some surveillance data streams are interrupted or supplemented by additional systems during certain critical periods such as the 2009 influenza pandemic. During the whole study period, the estimated influenza level from the multivariate model showed higher correlation with influenza activity and the estimated influenza trend stably reflected the change in influenza activity as good as the best individual surveillance data streams from which it was derived  & 2. In A potential caveat of the method is that historical data are needed to parameterize the model prior to estimation of the overall influenza activity. The statistical time series model may not be able to fully describe the evolution of an infectious disease such as influenza. In this study we did not try to optimize the parameters for combining the level and trend into the overall influenza index nor validate the index with respect to an objective function. The level or trend may have different importance in various contexts which can be easily adjusted according to specific purpose, and compared to the simple average there may be superior combinations of these two parameters to provide a single prospective estimate of the degree of influenza activity currently and in the short-term future. We used the product of laboratory influenza isolation rate and GP ILI rate as a proxy measure for the reference influenza activity, which may partly explain the high correlation between GP ILI and influenza activity during the pandemic with particularly high proportion of medical consultations due to influenza. While we have taken into account the elevated ILI consultations during the pandemic which may have affected the laboratory isolation rate, change in healthcare consultation behavior was not accounted for due to limited data.Text S1Description of the multivariate dynamic linear model.(DOC)Click here for additional data file.Text S2Example syntax for estimation of the latent level and trend by the multivariate dynamic linear model.(DOC)Click here for additional data file.Table S1Test of differences in correlations with influenza activity, between surveillance data and inferred influenza level from the multivariate models.(DOC)Click here for additional data file.Table S2Test of differences in correlations with changes in influenza activity, between surveillance data and inferred influenza level from the multivariate models.(DOC)Click here for additional data file.


Bracovirus and IchnovirusTextbooks define viruses as infectious agents with nucleic acid genomes (RNA or DNA), which replicate inside living host cells to produce particles (virions) that can transfer the genome to other cells To appreciate the conceptual challenges PDVs present requires first an understanding of their life cycle. In wasps, PDVs persist in the germ line and somatic cells as an integrated provirus. Replication, in contrast, only occurs in pupal/adult stage females in the nuclei of specialized calyx cells that are located in the ovary . In the Recent studies show that BV genomes exhibit organizational and functional features unlike any other virus group, while also providing important insights into why the activity of PDVs differs between wasps and the hosts wasps parasitize So when did PDVs evolve? In the case of BVs, all associated wasps reside in a single family named the Braconidae and form a monophyletic assemblage named the microgastroid complex Insights into what BVs evolved from derive from comparing the conserved core genes of their proviral genomes to other viruses. This exercise reveals homologies with the core genes of another group called nudiviruses The organization of nudivirus genomes and the core genes they encode suggest three features of likely importance in the evolution of BVs into beneficial symbionts. First, nudiviruses package their genomes as a single circular dsDNA into virions, while integrating as a single large linear DNA into the genome of host cells Polydnaviridae because they both package multiple circular dsDNAs into virions and exhibit similar life cycles, albeit the former are associated with braconids and the latter are associated with wasps in another family named the Ichneumonidae BVs and ichnoviruses (IVs) were assigned to the Returning to the definition of what a virus is, PDVs clearly replicate inside living cells and produce particles that transfer genes to other cells. Similar to other families of large dsDNA viruses, like the Baculoviridae and Poxviridae, BV genomes also encode a conserved set of replication genes plus other virulence factors from diverse sources that vary among genera and species


The introduction of Highly Active Antiretroviral Therapy has transformed HIV-infection from an inevitably lethal disease to a chronic condition with a life expectancy comparable to that of people with diabetes mellitus.In recent years it has become evident that people living with HIV/AIDS have an increased risk of developing cardiovascular disease and it is expected that the prevalence of chronic kidney disease will rise accordingly. To investigate the prevalence of chronic kidney disease in patients with HIV we conducted a retrospective observational analysis using the clinical database of a large centre  in the urban area of Antwerp, Belgium. The prevalence of chronic kidney disease among HIV infected subjects was found to be 3.0%. The development of chronic kidney disease was associated with age above 50 years, lower CD4 cell counts and Caucasian origin. Screening for chronic renal disorders and prevention of evolution toward chronic renal failure is a crucial challenge in the management of people living with HIV/AIDS.


Community Advisory Boards (CABS) have played an important role in ensuring community oversight of AIDS vaccine trials and are an accepted part of the ethical conduct of AIDS vaccine trials. China's political system limits community engagement in trial communities and wholesale application of western CAB approaches does not accomplish the intent of a CAB. We adapted the CAB concept to China's political system through a multi year process of research and pilot testing in collaboration with six provincial CDCs conducting AIDS prevention research studies.Using questionnaires developed by IAVI for a global CABS study, we carried out an assessment of existing CABS in six provinces in China. The questionnaire examined membership, process, and governance along with other aspects of CABS operations. The results were used to revise standard CABS guidelines developed by IAVI for use in Africa and India. The revised guidelines were pilot tested in three sites, in Yunnan, Guangxi, and Shanxi. In depth interviews were also conducted with CAB members and local CDCS.A revised version of Chinese CABS guidelines was published in October 2011 and publicized at China's AIDS Prevention Conference by China's AIDS Ethical Review Board and IAVI. The CABS guidelines are now being promoted as part of the ethical requirements for AIDS prevention clinical trial research by China's National Center for AIDS Prevention and Control.Developing and adapting ethical tools for ensuring community input and oversight of clinical trial research in China is necessary given China's political system. These newly adapted CABS guidelines provide a mechanism to accomplish the intention of a CAB even while different in form and governance from standard CABS elsewhere.


The authors of guidelines provide 100 recommendations describing many intensively discussed issues. Among them is hepatotoxicity of PTU and limitation of PTU treatment mainly to the first trimester of pregnancy. Methimazole becomes first line ATD for patients with new onset of Graves’ disease. Graves’ orbitopathy (GO) is classified according to its clinical activity and severity. Deterioration of GO after radioactive iodine (RAI) treatment and beneficial effects of steroids to prevent RAI induced exacerbation of GO are described. All patients with subclinical thyrotoxicosis who are older than 65 years and those who are below age 65 and have risk factors or hyperthyroid symptoms should be treated. It is proposed to measure TSH receptor autoantibodies in pregnant women with a previous history of autoimmune thyroid disease. The information about thyroid ultrasonography with the colour-flow Doppler for the rapid differentiation between the two main types of amiodarone-induced thyrotoxicosis, and its help for accurate treatment of these conditions is provided.


About 15 % of patients who have been undergone to a laparotomy may develope abdominal wall hernia and the risk increases with age. In last years the Laparoscopic treatment of ventral hernia (LVHR) is becoming increasingly widespread in surgical community thanks to the good outcomes of this technique . The aimBetween January 2001 and March 2013, 523 patients were admitted to the Specialistic Surgery Centers  and treated for abdominal wall hernia. Two groups (Open and Laparoscopic Repair), each one of 100 patients, with similar characteristics have been selected from these presents more advatages compared to Open procedures related to reduced global complications and hospital stay with better comfort of patients.


It is now widely accepted that insects encode odor identity in terms of the stimulus specific rate patterning observed in the projection neurons of the antennal lobe (AL). Several studies have explored nonlinear dynamical frameworks in order to gain general insights into the mechanisms underlying the observed dynamical phenomena. The currently most popular framework is the heteroclinic orbit (HO) developed by Rabinovich and collaborators -3. This Despite its obvious appeal there has been little work on applying the HO framework to more detailed conductance based models of olfactory dynamics even though it is in principle possible to obtain HO dynamics from biologically plausible neurons . HoweverHere we describe an alternate nonlinear dynamical framework which provides an appealing account of both the origin and function of rate patterning dynamics. We start by analytically reducing a biologically plausible conductance based model of the AL to a quantitatively equivalent rate model and construct conditions such that the rate dynamics are well described by a single globally stable fixed point. We then straightforwardly describe the AL's response to an odor stimulus as rich transient trajectories between this stable baseline state and an odor specific fixed point. We show how this framework can account for a disinhibitory period observed immediately after the stimulus is removed, for the qualitative differences between the dynamics in the presence and the absence of odor and for the invariance of odor identity to both the duration and intensity of an odor stimulus, as reported in . We comp


Current cognitive models of social phobia converge on the view that negative imagery is a key factor in the development and maintenance of the disorder. Research to date has predominantly focussed on the detrimental impact of negative imagery on cognitive bias and anxiety symptoms, while the potential benefit of promoting positive imagery has been relatively unexplored. Emerging evidence suggests however that positive imagery could have multiple benefits such as improving positive affect, self-esteem and positive interpretation bias, and enhancing social performance. The present article defends the view that combining bias induction with a repeated practice in generating positive imagery in a cognitive bias modification procedure could represent a promising area for future research and clinical innovation in social anxiety disorder. People with social anxiety disorder (SAD) frequently report experiencing negative self-imagery of how they think they appear to others in feared social situations  may have favored the generation of observer perspective imagery. Encouraging the use of field perspective imagery  is likely to produce stronger effects on negative and positive emotions, and counteract the natural tendency among socially anxious individuals to imagine themselves from an observer perspective. A second caveat with regards to the methodology used is that it may be too challenging for individuals with clinical levels of social anxiety to recall and elaborate on a time when they had experienced a positive social situation. This possibility is supported by recent evidence showing that social anxiety is associated with an impairment in generating detailed imagery of past positive events  for people with high levels of social anxiety (Murphy et al., The present article defends the view that combining a repeated practice in generating positive imagery with a CBM-I intervention may be a helpful component in future treatment of SAD. A similar hypothesis has been suggested in the context of depression (Holmes et al., The effects of imagery-focussed CBM on depression have been tested using analog and clinical samples of depressed participants (Blackwell and Holmes, Lang et al.  addresseSAD is a highly prevalent condition that causes considerable distress and significant functional impairments (Kessler et al., 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.


Despite the huge progress in the understanding of the pathomechanism of thyroid orbitopathy (OT) done during recent years this extrathyroidal manifestation of Graves’ disease still remains one of the most complex problems of clinical endocrinology. The outcome of the management is not satisfying neither for patient nor for physicians. Some likelihood of the improvement of the results may be expected from innovative treatment options basing on the progress in understanding of mechanisms of autoimmunity and inflammation. On the other hand an effort must be done for the progress in the existing treatment regimes.Glucocorticoids have been used in the treatment of severe OT for over 50 years but irrespectively of therapeutic regime any improvement in eye changes may be achieved only in ca. 70% of patients. Numerous schemes of glucocorticoid use should be validated, optimized and meet an individual approach as well as adhere to the local capabilities.The common adjuvant treatment with selenium in Graves’ disease patients may prevent from a development of eye symptoms and possibly will improve the quality of life.The mode of management of hyperthyroidism has an influence on OT. Medical and surgical therapy seem not to deteriorate the course of OT while radioiodine therapy may worsen eye symptoms. OT patients at high risk should get the preventive glucocorticoid treatment.The access to a surgical treatment procedures as orbital decompression and rehabilitative surgery must be assured for OT patients and techniques of surgical procedures should be developed.The results of anticytokine therapy are promising and the progress in this field may be expected while the value of newly developed TSH receptor blocking molecules needs further observations.The frequency of circulating CD40(+) fibrocytes is markedly increased in patients with OT, suggesting that this receptor might represent a therapeutic target for OT.An increase in a local steroidogenesis documented within orbital tissues in an active phase of OT rises the idea of the use of 11β hydroxysteroid dehydrogenase-1 inhibitors in OT patients. These drugs are under intensive clinical investigation for the treatment of type 2 diabetics.Since recommendations basing on EBM according to the pivotal problems of the management OT are still lacking, the system of care for OT patients should be based on centres of excellence with proper experience and multidisciplinary approach.


DACS  was developed to design a HTS collection or focused libraries for the FMP Screening Unit. But the dramatically increase of unique compounds of one order of magnitude from less than 10 to around 30 to 40 million compounds currently and approximately hundred million compounds in the next years requires a reorganization and redevelopment of the storage and searching strategy. To manage such a massive amount of data a relational database for registration and normalization of vendor catalogs was developed. This database contains the highly redundant data of the vendor catalogs and is converted in a second step into the non-redundant Unique Structure Database which represents a data warehouse combining vendor data, structural descriptors and in-house classification tools including our earlier developed ADMET- and reactivity filters as well as our in-house fragment-based fingerprints used for library design tasks [


The current study by Won and colleagues concluded that patients undergoing revision ACL surgery have a greater incidence of significant varus alignment compared with patients undergoing primary ACL reconstruction. The authors also observed that this varus alignment was associated with meniscal pathology and degenerative changes of the knee. The report of varus alignment provides an interesting observation that goes a step beyond the findings of the Multi-center Anterior (C)ruciate Revision Study (MARS) , but leaThe strength of the manuscript is that it reminds us that varus malalignment is a potential variable to be mindful of. It also serves to warn surgeons they should be aware of possible failure of the graft, and continuing pain related to medial compartment degeneration. Won and colleagues’ attention to detail in establishing an effective protocol for the long-leg films is important because standing long-leg radiographs are fickle in terms of being able to demonstrate consistently the true amount of coronal plane alignment.Kim and colleagues  reportedAnother MARS study  indicateWe need to perform a large prospective case-control study observing primary ACLs over a long period of time, and separately analyzing those who have initial varus with intraarticular pathology from patients who do not. We need to conduct followup analysis to determine whether the varus indeed increases the risk of ligament failure. Such a study should also observe the progression of osteoarthritis and secondary development of varus deformity so we could get a better picture of the natural history.Another study that would help fill in our current knowledge gap would be examining the existence of medial compartment osteoarthritis in an ACL deficient knee that has already had a failure of a primary ACL surgery. It should be determined, in the setting of a large randomized controlled trial, whether those patients who undergo a high tibial osteotomy at the same time as ACL revision surgery will fare better than those who have an ACL revision without an osteotomy.This should be a very well-defined study group with radiograph-based alignment protocol similar to the one used in the current study. How much varus is necessary to change the odds ratio for ACL revision alone? Is varus thrust indeed the only game changer? Will staging the stabilization and the realignment procedure provide the patient with a greater number of years of satisfactory function? These important questions remain unanswered.


Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant, rare familial cancer syndrome in which affected individuals develop diffuse gastric cancer at a young age. Mutations in the E-cadherin gene (CDH1) have a 70% lifetime risk of becoming gastric cancer and women with the gene have a 20-40% risk of developing lobular breast cancer.This paper will report on a series of young adults who have undergone predictive genetic testing and been identified as carrying the CDH1 mutation known to be present in their family. The majority of these patients have been diagnosed with gastric cancer at their first screening gastroscopy.Individuals who are known to carry the mutation are provided with a personalised cancer risk management plan with the aim of reducing morbidity overwhelmed by the number of appointments they receive and by the variability of information given to them, as care often moves from and between several teams. A care pathway has been developed by the oncology/genetics nurse to ensure optimal communication between the genetics and oncology treatment team, to ensure the best outcome for the patients. The oncology/genetics nurse coordinator with her specialist knowledge of genetics plays a vital role in facilitating ongoing follow up of these individuals, coordinating screening, educating patients and their family on risk management strategies.This paper will provide a clinical update on this rare familial syndrome will describe the needs of patients and families affected by this condition and illustrate the contribution that expert nursing care makes to the outcomes of people affected by HDGC.


SweTree Technologies is a plant and forest biotechnology company providing products and technologies to improve the productivity and performance properties of plants, wood and fiber for forestry and fiber related industries.Eucalyptus and Populus elite clones. Another crucial part of a practical tree biotechnology program is to test the GM trees with commercially interesting genes under field conditions. We have initiated field trials and plan to have over 35 different types of transgenic trees in field trials by the end of this year. These field experiments are performed by SweTree or in collaboration with academic partners. The importance and requirements for elite clone transformation and field trials will be discussed in the presentation.In the area of Biotech Trees, we have been testing and developing genes and biotech trees. Since 2002 we have successfully screened well over one thousand genes in our gene testing program. The program has been mainly directed towards increased growth, improved wood properties and stress tolerance. The current outcome of this program will be presented. The primary gene developing program is performed in hybrid aspen for which we have a very efficient transformation protocol. However for practical tree biotechnology the genes and DNA constructs have to be transformed into the best commercial clones. Therefore we have been setting up efficient transformation protocols for both


Atrial fibrillation (AF) is the most common arrhythmic complication in the postoperative period, occurring in about a third of patients undergoing coronary artery bypass graft surgery ,2. It isPharmacological interventions have been the mainstay of preventive therapy. Beta blockers have been shown to be the most effective preventive therapy and it is recommended now to continue or initiate beta blocker therapy for all patients in the perioperative period . AmiodarAtrial pacing is an attractive non-pharmacological intervention for the prevention of atrial fibrillation. Pacing in the postoperative period is easy to implement since it is only required for a short period and can therefore be performed using epicardial temporary pacing wires placed by the surgeon. The mechanisms by which atrial pacing is postulated to reduce the incidence of atrial fibrillation include reduction of bradycardia induced dispersion of atrial repolarization and overdrive suppression of atrial premature beats. Dual site atrial or biatrial pacing may result in additional benefit by promoting more synchronised atrial depolarization which results in reduced dispersion of atrial refractoriness and by altered atrial activation patterns that may prevent the development of intra-atrial reentry . ProphylIn this issue of the journal, Chavan et al  report o


Glyceryl trinitrate is a substance that causes vasodilation by donation of nitric oxide which causes relaxation of the endothelium of blood vessel walls. The vasodilatory effect of this substance has been known since 1870 and it has been used extensively in the treatment of angina via transdermal patches, sublingual tablets and sprays. Studies involving normal vasculature as well as diseased vascular states have been promising in terms of demonstrably consistent and significant vasodilatory effects on both systemic and peripheral systems. Podiatric application for this pharmacologic intervention seems to have received little attention in the literature to date. Its efficacy in equine treatment of laminitis, an ischaemic condition of the horses hoof has been well established and researched. It has been applied to other clinical problems involving perfusion of the extremities, such as treatment of inability to achieve penile erection and use in treatment of anal fissures. A literature search has produced information on this drug which suggests potential for greater application in clinical podiatry. This includes positive effects in digital perfusion, which holds promise for wound healing and shows potential for reducing amputations associated with peripheral vascular disease (PVD). This novel therapy has the potential to be useful in cases with borderline vascular supply that require a boost to perfusion to trigger the healing process and/-or relieve other symptoms of ischaemia. It has also been found to be of assistance in the management of painful diabetic neuropathy (PND). This finding is of particular interest as an adjunct to treatment for the prevalent and difficult clinical challenge of PND. The literature regarding its use in musculotendinous applications such as for Achilles tendinopathy will also be covered in this review. Potential issues with this drug including side effects and tolerance will be addressed. Further study of this treatment modality would be beneficial in terms of determining specific indications and limitations of its use, particularly for vascular insufficiency of the feet and healing of foot ulceration.


Flexible bell margins are characteristic components of rowing medusan morphologies and are expected to contribute towards their high propulsive efficiency. However, the mechanistic basis of thrust augmentation by flexible propulsors remained unresolved, so the impact of bell margin flexibility on medusan swimming has also remained unresolved. We used biomimetic robotic jellyfish vehicles to elucidate that propulsive thrust enhancement by flexible medusan bell margins relies upon fluid dynamic interactions between entrained flows at the inflexion point of the exumbrella and flows expelled from under the bell. Coalescence of flows from these two regions resulted in enhanced fluid circulation and, therefore, thrust augmentation for flexible margins of both medusan vehicles and living medusae. Using particle image velocimetry (PIV) data we estimated pressure fields to demonstrate a mechanistic basis of enhanced flows associated with the flexible bell margin. Performance of vehicles with flexible margins was further enhanced by vortex interactions that occur during bell expansion. Hydrodynamic and performance similarities between robotic vehicles and live animals demonstrated that the propulsive advantages of flexible margins found in nature can be emulated by human-engineered propulsors. Although medusae are simple animal models for description of this process, these results may contribute towards understanding the performance of flexible margins among other animal lineages. Medusae are thought to be the first metazoans to evolve muscular swimming. The simplicity yet functionality of the biomechanics of their swimming make them an ideal organismal model for studying fundamental mechanisms of animal propulsion. Many medusan species swim using rowing propulsion Existing literature provides a conflicting picture of the potential interactions between propulsor flexibility and swimming thrust production. Empirical An important reason for the absence of design criteria guiding application of flexible propulsor tips or margins is that, despite an extensive body of work on flexible propulsors, the mechanistic basis for thrust augmentation by flexible propulsor margins remains unclear A recently developed robotic jellyfish vehicle  has provOur approach to determining the mechanistic basis of thrust augmentation by flexible propulsor margins was to compare propulsion by robotic jellyfish vehicles with and without flexible bell margins to each other and to live medusae . With thAurelia aurita. The other was modified to represent the Cyanea capillata morphology by excising portions of the bell to form gaps along the bell margin  to quantify vehicle kinematics as well as fluid motions x and y coordinates of the apex of the vehicle bell and the tips of the bell margin over time. Swimming speed was calculated from the change in the position of the apex over time ash/d where h represents bell height and d represents bell diameter.Swimming kinematics were quantified by using ImageJ software (NIH) to track the u is the Eulerian velocity field.Pressure field data was inferred from the measured velocity fields by numerically integrating the inviscid Navier-Stokes equation, or Euler equation:u. The pressure term was then determined to within a constant of integration by integrating The material acceleration term To reduce errors in the numerical integration of the measured velocity data, the procedure of Liu and Katz kt and subsequently advected to new positions kt+1. The initial velocity of each fluid particle is given by the measured DPIV velocity field at time kt . The velocity of each fluid particle at time kt+1 depends on the measured DPIV velocity field at time kt+1 and on the position of the fluid particle at the same instant in time. To determine the position of each fluid particle in the flow at time kt+1, we defined an advection velocity field in which the fluid particles are carried. The advection velocity field was taken to be the average of two successive DPIV velocity fields:ua was assigned to the first time instant kt by the present convention. The positions of the advected data grid points at time kt+1 are therefore estimated asi and j are unit vectors in the x- and y-directions, respectively. The material acceleration was then estimated asThe input to the version of the code used presently (kindly provided by X. Liu) took as input a time series of DPIV data on a 128×128 grid. Preprocessing of the DPIV data was completed in MATLAB to compute the material acceleration As a check of the dependence of the results on viscous stresses, which are neglected in The output of the code was a time series of pressure fields with scalar pressure computed at each of the 128×128 nodes of the corresponding DPIV fields.Live medusae originated from cultured collections of the New England Aquarium, Boston, MA. Video and DPIV methods were the same for both live animals and medusan vehicles except that the live medusae were video recorded in filtered seawater.Aurelia and Cyanea vehicles. While we did not treat the two vehicles as replicates, because of their different bell configurations, the flap and no-flap versions of each do provide repeatable validation of the effects of a flexible propulsor on the fluid interactions and swimming performance of the vehicles. Means and variability estimates on figures with error bars were calculated by averaging over three consecutive swimming cycles.Due to the intensive effort involved in manual manufacturing of robotic vehicles we were limited in terms of number of the Aurelia aurita and Cyanea capillata. The proficiency of swimming was quantified as the diameter-normalized swimming speed to account for differences in size between the live and robotic jellyfish, U/D where U is medusa velocity and D is relaxed bell diameter Cyanea flap version was less than that of both Aurelia versions (flap and no-flap).Biomimetic robotic jellyfish vehicles closely replicated the morphology  and apprAurelia robot during bell contraction demonstrates how the flexible margin contributed to the differences we observed in wake circulation and swimming performance. During bell contraction there were two sources of fluid momentum that contributed to the starting vortex circulation, the flow that was expelled, or pushed, from the subumbrellar volume and the flow that was entrained, or pulled, from outside the bell by the contracting bell margin  was strongly related to the distance between the tip of the bell margin and the inflexion point . Furthermore, the enhanced performance was due to both thrust augmentation during bell contraction and to more optimal spacing between consecutive starting and stopping vortex rings during bell expansion. The strong resemblance of vorticity patterns generated by the robotic vehicles with those of living medusae supports the notion that the flexible bell margins of medusae function to enhance thrust similarly to the flaps of the robotic vehicles. These observations enable us to suggest some mechanisms by which thrust augmentation by flexible propulsors may guide future studies on this topic.The utilization of robotic vehicles to examine biological propulsion has provided insight into just how important flexible propulsors are for some swimming animals. These vehicles, in combination with the simple body plan of medusae, have also enabled us to visualize the structural differences in the fluid interactions of flexible and rigid propulsors. Visualizations are necessary to begin to understand the mechanistic basis of the enhancement in propulsion provided by flexible propulsors and begin applying these principles more generally. To summarize what can be taken away from these more or less preliminary observations of propulsion by robotic jellyfish, we found that flexibility significantly enhances the swimming performance of both the robotic vehicles examined (Much of the performance differences between the flap and no-flap vehicles can be attributed to the higher vortex circulation generated by flexible bell margins during bell contraction. Higher circulation is expected to augment performance because thrust production of a propulsor is proportional to the circulation generated at the propulsor margin Rather than the previously reported explanations, we suggest that increased circulation characterizing flexible bell margins was more likely due to unique hydrodynamic forces generated by bending at the inflexion point connecting the flexible margin to the more rigid actuating structure of the vehicle's bell. During bell contraction, a low pressure region extended along the exumbrellar surface from the bell margin to the inflexion point of the flap vehicles. This low pressure region was larger and lower in magnitude in the flap vehicles than the pressure along the bell margin of the no-flap vehicles. Consequently, entrained flow in this low pressure region at the inflexion point initiated vortex formation and merged with flow expelled from the inside the bell at the margin edge. The larger volume and velocity of this flow is directly related to the low pressure field and resulted in larger starting vortex formation at the bell margins, and hence, greater overall thrust production by vehicles with flexible margins. Although we have focused on empirical visualization and quantification of fluid flows surrounding vehicle margins, these results are consistent with computational fluid dynamic models describing pressure gradients surrounding swimming bells of oblate medusae. Swimming by oblate medusae generates pressure differences at the bell margin due to formation of a high pressure region within the medusa bell and a lower pressure region outside the bell margin at the region of greatest bell displacement Aurelia aurita are consistent with the proposed mechanism by which flexible margins enhance swimming performance. Other mechanisms likely contribute to this simple pressure mechanism such as the angular motions associated with flexible flapping which may facilitate vortex formation These observations lead us to suggest that one way that flexible propulsors enhance performance of swimming jellyfish is by intensifying the low pressure region associated with the propulsor thereby increasing fluid flow and therefore overall thrust . The relIn addition to enhanced thrust generated during bell contraction, performance of the flap vehicles was also better during bell expansion. Vortex interactions during bell expansion appear to largely influence the overall swimming performance of the vehicles. The collision of the stopping vortex of the no-flap vehicle with the oppositely spinning starting vortex cancelled out the overall circulation in the wake and stopped the vehicle's forward progress. This observation suggests two things, first, that interactions between starting and stopping vortices play important roles in determining the medusan swimming performance. Consequently, adequate spacing of these vortices by propulsor kinematics appears to be essential for swimming. Second, the flexible propulsor spaced the vortices more optimally than the rigid propulsor. By increasing the spacing between the two vortices, the starting and stopping vortices did not cancel each other out and the circulation in the wake dissipated slowly due to viscous dissipation. Consequently, the flap vehicles continued their forward progression during bell expansion. Numerical simulations of other flexible propulsors support the notion that flexibility increases spacing between shed vortex rings by increasing the downstream advection of the vortices The absence of complicating fluid interactions, such as with additional fins or appendages, makes the simple morphologies of medusae useful for exploration of essential fluid interactions between a propulsor margin and surrounding fluids. Despite their simplicity, the fluid mechanical basis of enhanced vortex production by flexible medusan margins may have wider application to other biological propulsors. The suitability of the medusan bell margin model for comparison with other flexible propulsors is influenced by the extent to which a propulsor margin's bending creates an inflexion point near the margin. A variety of biological propulsors such as wings and fins fit these conditions and fundamental relationships between actuator force, margin dimensions, and flexural stiffness distributions may be important factors influencing the role that flexible margins play in propulsive force generation by propulsors of both natural and man-made design. A more full understanding of these interactions will allow us to appreciate the means by which animals convert the energetic liability that tip vortices present for fixed wing aircraft


Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) as a disturbance in attention and awareness according to several criteria  and the fact that the cytokine response can be confounded by many factors   is protective for the development of delirium while genetic polymorphisms in the receptor DRD2 and dopamine transporter genes, were associated with delirium   when nervous system damage occurs as a result of cerebral damage  has been reported to regulate differentiation of neural progenitor cells  and butyrylcholinesterase (BuChE) are involved in the production of inflammatory cytokines, and are hypothesized to play a role in PD development through this mechanism. One study found significantly decreased activity of these enzymes both preoperatively and postoperatively in patients experiencing PD (Cerejeira et al., The pathogenesis of PD is still poorly understood. Further elucidation and refinement of biomarkers to track the risk and progression of this disorder would help in the identification and treatment of patients at risk for this devastating disorder. Future research should focus on both identifying serum markers of delirium and understanding the genetic basis behind these processes. Hopefully, these efforts will make important strides in improving outcomes of patients experiencing delirium.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The trend towards universal access for HIV prevention and treatment that was initiated at the beginning of the 21st century  has been threatened by the 2008–9 economic crisis which currently translates in a fiscal crisis for most developed countries . Other advances such as the drastic drop in ARV drug prices are also threatened . The presentation will discuss the negative consequences of slowing down and delaying universal access on macro-economic growth in the most affected countries and suggest alternative sources of funding such as the financial transaction tax recently introduced by the French Parliament.


Following SCI activated ependymal cells generate progeny cells which migrate to the injury site but fail to produce the appropriate type of cells in sufficient number to limit the damage, rendering this physiological response mainly ineffective. Research is now focusing on the manipulation of ependymal cells to produce cells of the oligodendrocyte lineage which are primarily lost in such a situation leading to secondary neuronal degeneration. Thus, there is a need for a more focused approach to understand the molecular properties of adult ependymal cells in greater detail and develop effective strategies for guiding their response during SCI.Spinal cord injury (SCI) is a major health burden and currently there is no effective medical intervention. Research performed over the last decade revealed that cells surrounding the central canal of the adult spinal cord and forming the ependymal layer acquire stem cell properties either  Neural stem cells (NSCs) are specialized progenitor cells that can self-renew and generate both neurons and glia in the central nervous system (CNS). The first isolation of NSCs from adult brain lunched a new field of studies in neuroscience  of the forebrain  are produced from OL progenitors (OLPs) scattered throughout the parenchyma Miller, . SeveralWhile all NSCs in the SVZ of the forebrain express the stem cell markers Nestin, Sox2 and GFAP, in the spinal cord only dorsally situated ependymal cells express Nestin/GFAP, while Sox2 is expressed in all ependymal cells . It is also intriguing that the Gata3 gene has never been found to be expressed in any CNS progenitors but only in some differentiated neurons. In the spinal cord, Gata3 is expressed in V2b interneurons and its expression is regulated by Notch signaling , an agent that promotes axonal regrowth, possibly by recruiting myelinating OLs [reviewed by Weishaupt et al. ]. More rIn parallel to pharmacological manipulation of specific type of cells to limit functional impairment, the modulation of endogenously recruited ependymal-derived cells toward the OL lineage either using genetic engineering or by pharmacological means has not yet been reported. The fast-growing knowledge on glial cell specification during embryonic development should aid in this direction. For instance, the study of the regulation of the expression of the transcription factor OLIG2 in adult spinal cord could prove very useful in this regard. OLIG2 is not expressed in ependymal cells but only in OLPs scattered throughout the parenchyma (Meletis et al., In summary, several studies on the properties and behavior of ependymal cells in models of SCI have converged on to a number of findings that could pave the way for more effective therapies. Of major importance is the recruitment of a large number of ependymal-derived cells at the injury site while at the same time maintaining the ontogeny of the canal. Equally important is the fact that the astrocytes produced are positioned in the center of the glial scar opening the way for a more targeted approach to manipulate the fate of activated ependymal cells. Crucial in these efforts is to develop strategies for initiating remyelination at the injury site by manipulating the fate of cells produced from activated central canal stem cells. Forcing these cells to initiate a pro-oligogenic pathway of glial specification should be at the center of future experimentation. Such effort should be aided through combined approaches using knowledge from embryonic development and cellular responses following tissue damage in SCI conditions. It is likely that in the next few years we will be confronted with exciting developments that will open the way for clinical trials to treat SCI.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Detrended fluctuations analysis (DFA)  is a tecWe derived analytical formulations for the bias and variance of the error committed when using the scaling exponent obtained by DFA on a given time-series to predict the scaling exponent of the same time-series but shifted by one sample . These results make it possible to define a Kalman filter for tracking fluctuations in scaling exponents over a longer time scale. Estimates for the measurement noise of the filter are obtained by pooling DFA estimates of the signal across a small number of time shifts. Robust estimates of the state vector are obtained by augmenting the filter with a smoothing procedure.Simulation results with surrogate time series demonstrate that this technique makes it possible to accurately recover changing scaling exponents even in the presence of rapid fluctuations (see Figure


Since mid 2011 the tragedy unfolding across the Horn of Africa following prolonged drought in the region has been a major focus for international relief operations and emergency aid. However, the most effective strategies for mitigating the effects of the drought have not been given sufficient media coverage or discussed critically enough in the public arena. Instead, while important and necessary, the focus has largely remained on emotive pleas for increased aid. This unfortunately, detracts from a considered discourse on the most effective interventions in the current circumstances and reduces scrutiny on performance of the primary agencies and bodies responsible for coordinating the relief effort. The authors present a personal perspective having recently returned from the Dadaab refugee camps where much of the relief effort has focused. The Dadaab refugee camps, located in the North Eastern Province of Kenya approximately 60 miles from the Somalia/Kenya border and about 320 miles from the capital, Nairobi highlight concerns around the delivery and distribution of relief and aid. The three original camps, Ifo, Dagahaley and Hagadera were established in the early nineties following the onset of inter-clan conflict in Somalia. The vast majority of refugees present are Somalis from Central and Southern regions of Somalia. While the populations in the camps remained relatively stable from 1994 to December 2006, this year in particular has seen hugely increased numbers of refugees arriving over the border as a result of the drought. With over 160,000 new refugees having arrived in the first eleven months of 2011 alone, the camp complex now (as of November 2011) holds in excess of 460,000 refugees in total according to UNHCR - the primary agency mandated with coordinating relief activity within the camps.Using a combination of focus group discussions and one to one interviews with refugees and members of the host community and following detailed discussions of comprehensive assessments carried out by NGO service providers within and outside the camps the authors conducted a rapid needs assessment over July 2011. The following discussion draws from those results as well as from more recent assessments and developments in the months since.The paediatric age group continues to be the most badly affected in terms of severe acute malnutrition and global acute malnutrition rates amongst newly arriving refugees.Another major area of concern in Dadaab is equity in the distribution of relief aid and service provision within refugee camps and adjacent areas. In the surrounding districts of Dadaab, Liboi and Fafi, the Host Community has also been suffering the consequences of the same drought plaguing the rest of the Horn. They, however, do not have equal access to services and relief routinely available to refugees. Healthcare services in the region exemplify these inequalities in aid provision. The three main camps are serviced by three hospitals with a total of 320 inpatient beds, 3 operating theatres, specialist outpatient services manned by doctors and visiting specialists. A structured referral system for specialized surgery and medical care in Garissa-the provincial capital, and Nairobi is also available to refugees. The Host Community which is approximately 150,000 strong and of a similar ethnic background to the majority of refugees only have access to outpatient health facilities within the camps. The only in-patient hospital service the Host Community has access to is a 30 bed district hospital (open to both the Host and refugee community) with 1 operating theatre. The most senior routine medical staff providing clinical care at this hospital are 2 clinical officers . A single Kenya Red Cross ambulance serves all three districts. These disparities are mirrored across other service sectors with old and new refugees having access to free food rations, water, sanitation and housing in an impoverished area where host communities are not routinely provided any of these services by the government or the NGOs.A perversely functioning artificial city-state has thus developed supported entirely by international Non- Governmental Organizations (NGOs) where older refugee camp residents after years of free utilities and services have developed successful businesses and even rent out their refugee shelters to newer arrivals or Host Community members and who can undercut any Host Community business with lower overheads. Host Community Kenyans often register as refugees themselves in order to avail improved healthcare services and obtain rations when necessary. A jointly commissioned report by the Danish and Norwegian Embassies and the Government of Kenya in 2010 estimated that at least 40,500  host community members hold refugee ration cards.The long term key to resolving the situation in Dadaab lies in recognizing that pastoralist Somalis have ancient patterns of movement which involve crossing to and fro across the artificial line that divides Kenya and Somalia and that services designed to cater for this group should facilitate and take account of their nomadic lifestyle. NGOs, local or otherwise able to operate on both sides of the border should thus be supported in their efforts to provide this service. UNHCR itself should be encouraged to view the situation holistically and look beyond its remit of catering specifically to refugee needs by partnering with organizations with a wider mandate that includes the Host Community. This will ensure that Somalis that cross into the territory of Kenya are both willing and able to cross back into bordering Somali provinces and obtain equitably provided services there as well. The authors would like to thank the team at Doctors WorldWide in Kenya for facilitating the field assignment to the Dadaab camps in July 2011. N/A The authors have declared that no competing interests exist.


Plants are constantly exposed to potential pathogens in their environment. The intimate associations involved in plant-microbe interactions have influenced the evolution of a multi-faceted surveillance system to detect and respond to both the presence of microbes at the cell surface as well as the presence of pathogenic effectors inside the cell. Here, we bring together 11 reviews that discuss current concepts in plant innate immunity with a focus on protein biology and proteomics  is closely connected to defense responses, both as a large intracellular store of calcium and as the site of immune receptor biogenesis. Eichmann and Schäfer  review tAdapted pathogens must evade or suppress host immune responses in order to colonize tissues and cause disease, and they deploy numerous effector proteins to secure this objective. Wirthmueller and Banfield  focus onProteomic methods have facilitated the identification of key players involved in plant immunity and have shed light on the significance of post-translational modifications and protein interactions in the regulation and transduction of immune signaling. In future, the use of large-scale and highly sensitive quantitative proteomics in combination with emerging transcriptomic and imaging technologies will play a central role in uncovering the kinetics of immune signaling pathways, which currently remains a challenge. This is an exciting time to be involved in plant immunity research and we hope that this collection of reviews will inform and inspire our readers.


Pharmaceutical industry consolidation and overall research downsizing threatens the ability of companies to benefit from their previous investments in translational research as key leaders with the most knowledge of the successful use of biomarkers and translational pharmacology models are laid off or accept their severance packages. Two recently published books may help to preserve this type of knowledge but much of this type of information is not in the public domain. Here we propose the creation of a translational medicine knowledge repository where companies can submit their translational research data and access similar data from other companies in a precompetitive environment. This searchable repository would become an invaluable resource for translational scientists and drug developers that could speed and reduce the cost of new drug development. There is a well known problem in big pharma, low productivity despite high costs. It has become clear that the pharmaceutical industry's business model is broken . ResearcCompanies have consolidated through mergers and acquisitions resulting in lay-offs for thousands of researchers and the closing of hundreds of laboratories to avoid perceived redundancies, focus on what is considered to be more productive or lucrative therapeutic areas and save costs . Just coTranslational Medicine and Drug Discovery was to provide a guidebook for current and future translational medicine scientists and to clearly describe successful strategies for early drug development that utilize biomarkers and state of the art technologies. This book partially addresses the issue described above. It includes sections and chapters describing successful translational strategies for early drug development, principles of biomarker qualification and utilization in drug discovery and development, in-depth examples of translational research in six different therapeutic areas, translational imaging technologies, modeling and simulation and examples of pre-competitive collaborations between companies in many areas including biomarkers and drug safety [Biomarkers in Drug Development, also attempts to serve as a "handbook of practice, application and strategy" for translational researchers [One of the reasons Littman and Krishna decided to create a textbook entitled g safety . Anotherearchers . HoweverWe believe that companies and other institutions involved in translational drug research need to foster the discipline of translational medicine, maintain a knowledge base of their work and, when it is not proprietary, share that knowledge through publication and pre-competitive collaborations. It is often easier to find the published results of translational research performed by others than it is to find the unpublished results of translational research done within your own institution, especially if the drug projects the research supported were discontinued. For this reason we advocate the creation of a searchable knowledge repository for human translational research. This database could be maintained by a consortium of drug companies that voluntarily submit data and it would include human biomarker data, translatable human pharmacology models and other types of clinical methods that have been used in humans to measure drug responses. A structured database like this could be initially populated by data from failed drug projects with no significant loss of competitive advantage to contributing companies and institutions. Also, time is not on our side. The opportunities to capture this type of information decreases almost monthly as companies continue to reorganize, downsize and consolidate. It can only happen if those involved in these projects are still employed and have access to their companies' data.Imagine the benefits if this human translational medicine database existed today and could be searched by drug target, pathway, biomarker, disease, therapeutic area, challenge agent and translational pharmacology model name or description. It would become the first place to look when developing a translational research plan for a new drug project. It could potentially prevent reinventing proven clinical methods and replicating past biomarker and human model qualification efforts. Often there are multiple choices for achieving proof of mechanism for new drugs and this database would simplify the choice when an acceptable existing method or biomarker can be easily found. Use of the database could also translate into reduced costs and reduced time for drug development and enable the comparison of results from newer drugs with those from past drug projects. These comparisons will also aid decision-making based on the data from existing projects compared to older failed or successful projects. We urge companies to strongly consider adopting this recommendation and finding a home for the database perhaps under the auspices of an existing consortium such as The Biomarker Consortium managed by the Foundation for the National Institutes of Health (FNIH) .


Journal of the American Heart Association (JAHA), the American Heart Association's new Open Access journal. The Scientific Publishing Committee created JAHA to align the American Heart Association with recent trends in the publishing industry as readers have moved away from the print version of journals and increasingly seek rapid electronic access to scientific articles. In addition, JAHA was conceived as a novel publication forum to represent the collective interests of the 16 Scientific Councils .6 This paper is important because of the need for more comparative effectiveness research to guide the management of peripheral arterial disease and the importance of publishing both positive and negative studies. Fonarow et al showed that the National Institutes of Health Stroke Scale (NIHSS) provides strong prognostic information about 30-day mortality risk in Medicare beneficiaries with acute ischemic stroke.7 The forthcoming editorial by Dr Edward Jauch, Chair of the American Heart Association Stroke Council, explains how these findings may be used to better evaluate the performance of centers that manage patients with ischemic stroke.8 Finally, Barkoudah et al provide an interesting analysis of published clinical trials in patients with Type 2 diabetes mellitus providing new information about the increasingly recognized links between renal disease and cardiovascular mortality.9Our launch includes a number of outstanding papers that exemplify our goal to publish a broad range of cardiovascular science. A translational study by Ammirati et al links a specific T-lymphocyte subset to the extent of atherosclerosis in human subjects and a murine dyslipidemia model.JAHA. The editors believe that the open access format represents the future of scientific publishing and we are excited and honored to oversee the American Heart Association's first open access journal. We look forward to working with our authors to speed the dissemination of high-quality science to our readers with the ultimate goal of increasing our understanding of the underlying mechanisms and improving the management of patients with cardiovascular disease and stroke.Our first articles and editorials demonstrate our commitment to publish a wide range of cardiovascular science in


Regulatory guidelines for assessing the safety of new food crops developed using biotechnology were published in the early 1990s, before the introduction of genetically modified (GM) crops. Many GM crops are now widely adopted as 77% of global soybean and 26% of maize production is from GM varieties. The early safety assessment guidelines seem to work as there are no proven cases of harm from these products. The greatest potential risk of food allergy would be the transfer of a gene encoding an allergen or protein sufficiently identical to an allergen to a different food crop so that unexpected reactions might occur upon ingestion. These risks can be evaluated using sera from subjects allergic to the source or with a sequence matched to an allergen based on FASTA or BLASTP. Some potential risk is also possible due to de novo sensitization as nearly every food may cause occasional allergies, yet only a few foods and proteins present great risk. The current paradigm considers stability of the protein in pepsin under fixed conditions, abundance of the protein in foods and the potential impact of heating and processing, features common to some major allergens. Those methods are not fully predictive and will likely be improved through experience. However, proposed revisions by the European Food Safety Authority (EFSA) as well as demands from some regulators to include the use of short-amino acid sequence matches, animal models and evaluation of potential changes in endogenous allergen expression using proteomics approaches could reduce the effectiveness of the assessment. The value of new tests should be rigorously tested. It is clear that absolute safety is not possible and that demands for these tests have never been applied to new crop varieties derived through inter-specific hybridization, mutagenesis or the introduction of a whole new food crop.


Jim McCambridge and colleagues analyze industry submissions to a Scottish Government consultation on whole-population approaches to alcohol policy. We examine how research evidence is used in alcohol industry submissions made to a Scottish Government consultation in 2008 to advocate policies in line with their commercial interests.Industry actors consistently oppose the approaches found in research to be most likely to be effective at a population level without actually engaging with the research literature in any depth.Strong evidence is misrepresented and weak evidence is promoted. Unsubstantiated claims are made about the adverse effects of unfavoured policy proposals and advocacy of policies favoured by industry is not supported by the presentation of evidence.The potential for corporations with vested interests to interfere with the evaluation of scientific evidence by policy makers needs to be restricted for effective policies to be designed.Studies of the nature of alcohol industry and other corporate influences on public policies can be informed by work already conducted on the tobacco industry.Like tobacco, alcohol is responsible for approximately 4% of the global burden of disease Alcohol industry actors, defined as all those involved with the production, supply, or sale of alcohol We examine formal submissions to the Scottish Government's 2008 consultation on “Changing Scotland's relationship with alcohol" We retrieved 27 separate submissions by industry actors made during the public consultation process from the Scottish Government's website . We extrThe views articulated on the nature of the alcohol problem facing Scottish society and appropriate policy responses are consistent across submissions. This position is encapsulated in the Executive Summary produced by the Wine and Spirit Trade Association (WSTA) Commitments to the use of evidence in policy making are often articulated. For example, the Portman Group . Pre–post comparison of 335 antisocial behaviour incidents in August to 196 in February yielded an overall reduction in antisocial behaviour incidents described as 42%. A decrease in alcohol-related litter at the skate park from 21 bottles and 86 cans on the first weekend of the project to 1 bottle and 8 cans on the final weekend produced a 92% decrease (the time periods differ from previously cited outcome measure).A community partnership in the small market town of St.Neots in Cambridgeshire was widely cited as a model initiative, for example being described as successful or effective by three of the four main supermarkets. The WSTA provided a detailed account of the initiative and evaluation data provided by the local police and trading standards officers. The project “aimed to improve recognition amongst enforcement authorities and the wider community that retailers are in fact often the victims of attempted under-age purchasing and should be seen as the front line of enforcement rather than the cause of the problem" [WSTA  pages 34The attention-grabbing percentage decreases are provided as evidence of benefits, and cited elsewhere, for example by SAB-Miller [paragraph 18 in The submission documents contain a number of unsubstantiated claims about adverse, unintended consequences of the proposals. These claims are frequently repeated and are by their nature difficult to evaluate. ASDA Sainsbury's Portman Group SBPA WSTA SAB-Miller Industry actors present targeted harm reduction measures as the preferred alternative to the whole population approach. The latter is presented as being too simplistic and blunt an instrument. This is a false dichotomy, as these approaches are complementary and the actual evidence in favour of some targeted measures ASDA Diageo Portman Group SAB-Miller Tesco The policy preferences of industry actors, with the interesting exception of greater law enforcement, are for policies such as industry self-regulation, public information, and education, which are the least likely to be effective There are few studies of alcohol industry documents in the public domain, with the exception of investigation of ICAP Investigations of the strategies of alcohol industry actors may benefit from comparisons with other industries, and particularly with the tobacco industry. Access to internal tobacco industry documents offers researchers extensive knowledge of the political goals, strategies, and tactics of transnational tobacco companies In addition to co-ownership of alcohol and tobacco corporations Click here for additional data file.Text S2Twenty-seven alcohol industry submissions.(DOCX)Click here for additional data file.Text S3All sources cited in industry documents.(DOCX)Click here for additional data file.