In many countries around the world sex work is criminalised and its regulatory control is therefore often in the hands of the police. In addition to the impact of this criminalised legal environment, much literature describes the negative impact that certain police practices can have on the ability of sex workers and the programs that work with sex workers to access essential HIV prevention, treatment, care and support services. This situation has resulted in persistent concentrated HIV epidemics among sex workers in many countries of the world. The need for multi-sector partnerships between police and HIV programs is increasingly recognised in various UN declarations and resolutions yet descriptions of the process or key ingredients required to actually establish and sustain these necessary partnerships between police and sex workers [or the programs that provide essential services to sex workers] are sparse. The paper seeks to establish key considerations and critical processes that are required to foster partnerships that if further investigated and scaled up, could result in an enhanced enabling environment for the provision of essential HIV services for sex workers around the globe. This paper is based on a realist review that investigated isolated examples of partnership formation between law enforcement and HIV programs working with sex workers. This methodology research is designed to work with complex social interventions and is based on the emerging 'realist' approach to evaluation. A realist review methodology was chosen given the paucity of relevant literature in this vein and the authors’ familiarity with the grey literature and relationships with experts who work in this sphere. The review found that political and police leadership, civil society strengthening and police reform in relation to HIV, are critical factors and key ingredients in changing the enabling environment in which sex work takes place to ensure that HIV prevention, individual and public health as well as HIV prevention and the promotion of human rights are the number one priority. Further research into this relationship is needed to provide evidence for effective HIV programming with police. In many countries the buying and selling of sex is illegal and criminal law is enacted to control the industry. Regulatory control of the industry is therefore often in the hands of police. However, even where sex work is legal, street-based sex work is often conducted outside of the law. This situation makes it difficult to provide essential services to sex workers and ensures that in many countries concentrated epidemics of HIV among sex workers persist. Decriminalisation is widely regarded as the evidence-based model of sex industry regulation that best supports effective health promotion, public health outcomes, the human rights of sex workers and is the best practice model for the prevention of HIV and STIs. 2] 3]  [3] 2] [  [3] 2] Decriminalisation is also espoused by WHO, UNAIDS, UNFPA, UNDP, sex worker organisations and human rights groups.11] Desp Desp11] Given the prevalence of criminalisation, there is a growing political realisation of the need to promote partnerships between sex workers and police is also encouraged by various UN political declarations including UNESCAP Resolutions 66/10 and 67/9  yet therThe aim of this review is to identify and highlight examples of positive police partnerships that work with sex workers and sex worker organisations to prevent HIV transmission and to examine the aspects of these partnerships that contribute to success.To best source and analyse emerging examples of partnerships between sex workers and police a realistic review methodology was chosen. This qualitative approach was chosen for its aptness for in depth analysis of a small number of cases and its flexibility with regard to sampling and is a methodology designed to work with complex social interventions based on the emerging 'realist' approach to evaluation. It provides an explanatory analysis to explore what works, when and how. A realist review does not seek to find simple solutions to complex issues but can provide a more in depth understanding of how an intervention can be made more effective.  A small There is a significant amount of documentation that describes the barriers that various law enforcement cultures and practices can create for sex workers’ health and wellbeing, in particular the barriers they create for HIV prevention programs. These barriers are often compounded by the inherent legal environment in which sex work takes place but are also often the result of law enforcement cultures and practices that operate outside of legislated paradigms.The use of the threat of arrest and bribery by the police towards sex workers has been documented widely.18]19][[19][18][[[19][18]had the right to beat them. Thei Thei41] The harassment and arrest of peer educators and outreach workers by police, documented in India, Nepal and the Philippines severely compromises their ability to serve their constituency and provide condoms and safe sex information. IncarcerPolice harassment, violence and extortion have very real and serious consequences for the health and well being of sex workers. Violence is associated with unprotected sex and heightened risk of STI and HIV transmission. In many Despite criminalised environments, there are emerging examples of both sex worker programs working with police to create greater understanding of the sex industry within police ranks, to ensure better access to services and greater wellbeing for sex workers. In addition, there are also examples of police led interventions as well as reform measures taken by police institutions that are beginning to result in both better outcomes for sex workers and police. A selection of these programs are described in order to draw out the critical factors and key ingredients in changing the enabling environment in which sex work takes place to ensure that HIV prevention, individual and public health as well as HIV prevention and the promotion of human rights are the number one priority.Resourcing Health and Education in the Sex Industry (RhED) is a service for the sex industry in Victoria, Australia. RhED uses a social model of health that incorporates harm minimisation, health promotion, social inclusion and community participation approaches to promote physical, emotional and social health and wellbeing for sex workers. RhED’s UThailand’s Sex Workers in Network Group (SWING) provides services for male sex workers in Bangkok and has an intern program for police recruits that aims to build relationships of mutual respect to enable sex workers to access STI and HIV prevention and treatment without fear of arrest. Police cadets’ internship gives them first-hand knowledge of the working lives of sex workers. The police cadets study English and take part in other SWING program activities such as outreach. The program aims to sensitise future police officers to the needs of sex workers to foster supportive environments for sex workers and to create a cadre of police officers within the Bangkok police ranks that share an understanding and empathy for sex worker’s rights.Save the Children’s Poro Sapot program works with police liaison officers and conducts peer education amongst police in various sites in Papua New Guinea  of India decided to target local police stations to talk about HIV awareness with operational police. Informal meetings with sex workers and police were held which proved to be a beneficial way to communicate issues of concern for sex workers. The police constables were sensitized to the problems facing sex workers and devised steps to lessen the harassment. Peer educators were introduced to police so they recognized them as a part of the program. Police constables are now informing VJT as soon as any sex workers have been arrested. The GateKeeping Alive Societies Hope (KASH) has worked with sex workers for over 7 years in the Nyanza province of Kenya. In Kisumu, Nyanza’s largest city, 60% of sex workers are HIV positive. Police violence has been widely observed and documented as a determinant of HIV risk. In 2007, KASH initiated joint workshops for police and sex workers to discuss, share and learn about HIV and AIDS and Kenyan laws on sex work. KASH selected 10 police officers and 10 sex workers as peer educators. This core group developed a data collection system to document abuses against sex workers, held regular workshops for their peers, and reconvened bimonthly to discuss their findings and strategize on how to address emerging patterns of abuse. The programme is now supported by the provincial police administration who have made it an integral part of all police training programmes in Kisumu.55] Simi Simi55] The development of police strategy, instruction and standard operating protocols has been shown to have some impact in addressing HIV risk among key affected populations, including sex workers. In 2005 the Nepal Police released their HIV/AIDS Strategy and Work Plan that outlined the commitment of the Nepal Police to HIV prevention both among uniformed officers and the general population of Nepal including sex workers and other key affected populations. The document outlines the importance of collaborative partnerships between the police, public health and NGOs working with vulnerable groups. It also mentions the need for HIV training and sensitisation of high ranking police officers so that policy can translate to operational guidelines and practice on the ground.Specifically in relation to vulnerable groups, the overall objective of the Nepal police is to ensure the creation of an enabling environment for supportive behaviour with vulnerable groups. In addition to regular sensitisation meetings, internships and field visits, the HIV/AIDS Strategy of the Nepal Police also includes a joint monitoring mechanism between the police, civil societies and vulnerable groups to monitor the behaviour of the Nepal Police. Further supporting reforms from the Nepal Police included the establishment of a Human Rights Unit in 2003 in order to promote and protect human rights in Nepal by implementing a range of human rights promotion measures into the operations of the Nepal Police. The Human Rights Unit is represented in all levels of the Nepal Police to train police on relevant human right issues, to monitor Nepal Police in the maintaining of human rights standards and to investigate cases brought to their attention by individuals or members of a community or network.To the knowledge of the authors there are no rigourous peer reviewed studies that have examined the efficiency of police/sex workers collaborations or police led interventions or reforms on HIV risk behaviour or access to service. As a result there are limitations regarding the quality and quantity of data included in this review. While these programs are not extensively documented, a realistic review makes it possible to draw out common themes and key ingredients that can help foster better partnerships between police, sex workers and the programs that provide services to sex workers. It also highlights where research to further investigate this field is warranted. In promoting an environment where collaborations between police and sex workers can support enhanced HIV service provision it is clear that the following areas need to be considered.While political leadership at a national and international level is critical, many of the examples described have resulted from local level collaborations between police and sex worker groups. Inherent is the need to identify champions from both the policing and the civil society, community-based and non-government organisations. The pursuit of collaborative leadership efforts can bring a sense of ownership, responsibility and support for partnerships. The Australian Government’s former aid agency, AusAID, supported senior police officials from Vietnam and Cambodia to Australia to partake in a three-week training program designed to develop and promote police leadership in responding to HIV in Asia. Further efforts to develop police leadership include the formation of the International Police Advisory Group (IPAG) under the secretariat of Law Enforcement and HIV Network. An IPAG delegation recently presented at the 2013 UN Commission on Crime Prevention and Criminal Justice and launched an International Statement of Police in Support of Harm Reduction and other evidence-based HIV Prevention Strategies for Key Affected Populations. It is clear that as civil society organisations, NGOs and community based organisations and networks gain strength, they are more able to represent the needs of the people they work with and more able to engage in discussions and collaborative program design with police. The ongoing support for these organisations is critical as is their need to articulate and develop advocacy and program design strategies that describe and outline how they will engage and work towards partnerships with the police. This paper briefly described the positive impact of these efforts in India and Kenya.Across regions with concentrated epidemics of HIV among sex workers there exist numerous reviews of the legal and policy environment in which sex work takes place and the changes in legislation that are required. This paper highlights that without an equal examination of the culture and practice of law enforcement, addressing the legal and policy environment is self-defeating. PartnersThe example of the Nepal Police in designing and implementing their HIV/AIDS Strategy effectively outlines a best practice response of police when working with key affected populations including sex workers. While acknowledging the need for further legal reform, resources and high level political will, the Human Rights Cell of the Nepal Police has been an important platform and link between civil society groups and the Nepal Police. Police reform in the context of responding to HIV among sex workers is being seen through the efforts of the Ukrainian Police Training Institute  and the Police partnerships are not a substitute for law reform and should not preclude advocating for a more human rights based legal framework for the sex industry. However given that criminalization of sex work and sex work activities persists in a majority of countries in the world, creating police partnerships is a pragmatic option in support of the health and wellbeing of sex workers. The authors acknowledge that the examples of the programs described here warrant a more in depth analysis into the essential elements of HIV prevention programs that work with police in order to improve the health, wellbeing and quality of life of sex workers. Documenting these best practice examples and promoting further analysis begins to build an evidence base for the design of programs that can redress the barriers that law enforcement create and help contribute to greater access to services [especially HIV and STI prevention] and quality of life for sex workers and freedom from repeated incarceration and violence. Unfortunately these examples remain the exception rather than the rule.At the intersection of policing and sex work and in pursuit of a more enabling environment for the provision of HIV services for sex workers it is clear that interventions need to be multi-layered, multi-sector and designed so that they can be scientifically evaluated. While these intervention and study designs are more complex, the research community and the institutes that fund HIV prevention research need to move beyond single interventions and prioritise the design of multi-faceted structural interventions that require a greater level of complexity and indeed a greater level of community and government involvement. This is really the last frontier of HIV intervention science: the science of the enabling environment. The very process of this type of research will lead to program designs that if enacted will contribute to the scale up of access to HIV prevention, treatment, care and support for sex workers and other key affected populations around the globe. In addition, it will also lead to the development of more humane and professional police services.


Electronic data collection for randomised trials is attractive as it can, in theory, provide great financial advantages by reducing fieldwork costs and data inputting time, as well as increasing the accuracy of responses over and above paper based methods. For trials involving young people, electronic methods provide other advantages such as the ability to adapt questions to meet the needs of young people of differing ages and abilities. Researchers have also suggested that young people prefer electronic methods over traditional ones and have found equal validity across both methods. This presentation will discuss issues relating to the collection of sensitive information from young people in Northern Ireland, using electronic and paper formats. We will draw on experience gained across several research studies that have collected data on sexual risks and behaviours, particularly in school-based research; including a recent trial on adolescent pregnancy. We will examine the feasibility, reliability and validity of data collected along with an evaluation of the cost implications and ease of using both methods (including the merging of the resulting datasets if both methods are offered). The views of the researchers and participants will also be reflected upon.


Monogenic diabetes (diabetes caused by a change in a single gene) accounts for around 2% of all diabetes but is not well recognised and is initially misdiagnosed in 80-90% of cases. This frequently leads to inappropriate treatment and advice including unnecessary use of insulin injections. This presentation illustrates how nursing research has increased our understanding of the impact of a genetic diagnosis of diabetes and treatment change from insulin injections to sulphonylurea tablets for individuals and their families.Rapid advances in genetic technology have resulted in the identification of 30 genes causing monogenic diabetes. Identifying a means of effectively translating these genetic findings into diabetes clinical care was clearly needed. Training experienced Diabetes Specialist Nurses as Genetic Diabetes Nurses across the UK has increased awareness and recognition of monogenic diabetes, leading to improvements in clinical care. The role of the Genetic Diabetes Nurse, in the education of other health care professionals and aiding identification of patients with monogenic diabetes, and how this could be used as a model for other areas is discussed.


Thus, early reactivation might be necessary for Beyond clarification of neuronal mechanisms, the findings of Waldhauser et al. afford a number of future directions to strengthen the argument that extrastriate reactivation is functionally relevant to episodic memory. Extrastriate cortex has distinct upper visual field and lower-visual field representations that map onto more ventral and dorsal portions, respectively  from those that are familiar . Recollection and familiarity have unique neural correlates . SK is supported by the National Science Foundation Graduate Research Fellowship Program (NSFGRFP grant number DGE1258923).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.


Frontiers in Plant Science by Goolsby and Mason  acquired this property in the course of their evolution millions of years ago  most others growing in the same soil environment, and (ii) most others growing on less metalliferous soils. These concentration-based definitions serve the very useful practical purpose of drawing attention to a relatively rare plant response to particular elements. Identification of hyperaccumulator behavior in the natural environment can then lead to studies on plant physiology and molecular biology, and to practical applications in phytoextractive technologies. Next-generation sequencing can lead to a better understanding of the evolutionary path toward hyperaccumulation and extend knowledge to species other than model plants (Verbruggen et al., 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.


During the recent years, the scientific knowledge of the pathomechanisms and new therapeutic options in pediatric lung diseases has dramatically increased which is reflected by the more and more increasing number of publications in this important field. Additionally, major scientific efforts have been bundled within national and international research networks like the German Center for Lung Research (DZL), the platforms of the European Respiratory Society (ERS), and the different Cooperation in Science and Technology (COST) actions , 2. It wPediatric lung disease already starts early in utero when the highly orchestrated process of lung development gets disturbed –7. The bTo this end, the conclusions of the symposium pointed out that despite the heterogeneities between different pediatric lung diseases and even between different clinical phenotypes within one disease, the commonalities of major pathomechanisms highly encourage a comprehensive concept to elucidate the frontiers in science to the different pediatric lung diseases within a bundled interdisciplinary approach. Learning from the others’ cohorts and experimental results cannot only broaden the horizon but speed up the development and introduction of new and more specific therapies into the clinics to all children with pediatric lung diseases. We want to thank all speakers for their excellent presentations during the symposium and for their important contributions to this special edition.


The current research topic and eBook “Mechanisms of neuroinflammation and inflammatory neurodegeneration in acute brain injury” was initiated as a reaction to the rapidly expanding literature on inflammatory mechanisms in the pathophysiology of acute brain injuries. The scope of this compilation of reviews, opinion, and original research articles was to give a broad overview of the diverse cellular compartments and mechanisms involved in the inflammatory response to brain tissue injury.Although a specific aspect of the pathophysiology of acute brain injuries, the immune system interacts in highly complex as well as diverse mechanisms with the damaged brain.On one side acute brain lesions, such as brain ischemia, hemorrhage or traumatic injury, induce a local neuroinflammatory reaction, wherein microglial cells represent the local immune cells (Benakis et al., In addition to an overview and discussion of basic mechanisms and involved pathways in secondary neuroinflammation after acute brain injury, our research topic also contains several reviews and original articles on novel therapeutic approaches to modulate the immune response. Rissiek et al.  introducIn summary this research topic gathered contributions from the leading laboratories working in the field of secondary neuroinflammation after brain injury with nearly 100 authors from 4 continents. We are confident that this compilation covers most established and emerging research questions in this specific research field and presents an up-to-date overview on inflammatory mechanisms and drug targets in acute brain injuries.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 authors wish to amend the Competing Interests Statement for this article, which should have included additional information in relation to potential competing interests relevant to this work. The authors apologize for this omission and revise the Competing Interests Statement to read as below.The University of Pittsburgh Medical Center has received grants from the National Football League and the Pittsburgh Steelers. Dr. Joseph Maroon is an unpaid consultant for the Pittsburgh Steelers football club. He has been the team neurosurgeon for the Pittsburgh Steelers since 1981 and the medical director for World Wrestling Entertainment Corporation since 2008 for the management of spine and brain-related injury. He also has served on the National Football League's Head, Neck and Spine Committee since 2007 and is currently a consultant to the committee. Dr. Maroon is a founder and shareholder in ImPACT (Immediate Post Concussion Assessment and Cognitive Testing), and the WWE has partnered with ImPACT to provide concussion management. Dr. Maroon has served as an expert witness in medical legal cases involving concussions. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.In addition, the authors would like to correct statements in the published article and provide additional clarification regarding the searches underlying the systematic review:Figure 1 indicates that the authors conducted a meta-analysis on 40 studies, which is incorrect. The text in the last box of the flow chart should read "40 studies included in quantitative analysis." For the qualitative analysis of 58 studies, the authors gathered information on observed pathology, associated symptoms and suspected risk factors of chronic traumatic encephalopathy (CTE). The 18 qualitative studies that were excluded from the quantitative analysis did not present any pathologically confirmed case reports of CTE.The following statement in the third paragraph of the Discussion section is incorrect: "This is also true for athletes of contact sports with risk for head impact but with no confirmed CTE cases to date, such as rugby or soccer players." There are both rugby and soccer players included in the authors' dataset of pathologically confirmed cases of CTE (Table S1).The article reports a review of published data from 1954 to August 1, 2013. Because the review data collected did not have consistent demographic identifiers, each subject reported required an exhaustive process to cross-match the entire database to determine duplicate reporting and identify unique individuals. After the data collection, the analysis of the data and their preparation for publication took 12 months. Since the closing of the data collection in August 2013, there have been a number of additional reports documenting athletes and others with pathologically confirmed CTE. This includes an article by McKee and Robinson (2014) that reported on four US veterans from the recent wars who had a history of blast exposure and were found to have CTE at autopsy [A related publication by McKee et al. 2014) published after the closure of our data collection 014 publi and were


Adequate assessment of (un)consciousness is not only of theoretical interest but also has a practical and ethical importance, especially when it comes to disorders of consciousness (DOC). Accurately determining the presence or absence of consciousness in patients with DOC allows informed decisions to be made about long-term care support, referral for rehabilitation, pain management and withdrawal of life support.In spite of significant progress in neuroimaging and the introduction of clear-cut clinical diagnostic criteria, determining the (un)consciousness still presents an important clinical problem: errors are common and have been shown to be as high as 37–43%  or increased (more consciousness), and thus considered to be gradual  and high (like in seizure) levels of synchrony among neuronal assemblies result in a dramatic loss of consciousness Flohr,  Figure .High strength of default mode network synchrony is required to support representational content integrated within the first-person perspective  offer a unique opportunity to study the neural basis of (un)consciousness due to the fact that impairment in awareness of self and environment is dissociated in such patients from preserved and stable wakefulness. We believe that an appropriate level of consciousness description should articulate the operational level of brain organization where the phenomenal/conscious phenomena reside  differ considerably in their level of operational architectonic dysfunction and that in turn translates into different expression of consciousness (Fingelkurts et al., 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.


Just as John Snow used a branch of informatics, geospatial analysis, to identify the source of cholera in London and so prove the germ theory and revolutionise medicine in 1854, so too will the application of informatics and associated technology be instrumental to the next big change in healthcare. All countries with advanced economies are facing increased demand from ageing populations and increased chronic disease. Many also have shortages of skilled workers. Mounting evidence points to avoidable errors causing serious harm in health systems. Indeed optimal care only occurs about half the time in even the best performing health systems  that may


The ageing population is becoming a major concern in Hong Kong. According to population projections by the Census and Statistics Department , the numCustomer relationship management (CRM) is the strategic use of information technology and people to manage customers' relationships with companies  across the whole customer life cycle .Existing CRM technologies include databases, software  and security features . ResearcAn initial framework is developed by extensive literature review. The final framework is further supported and finalised by in-depth interviews with industry practitioners and academics. Content analysis is used to analyse the collected data.The results provide evidence that innovative technology  can reveal the business opportunities of the ageing population and provide better service to this segment. For example, the use of big data can provide a better understanding of the needs of the 'silver hair market' and the mobile business and online retail platforms can ease their purchasing processes.The research findings can be applied across a range of industries to improve CRM for the ageing population.


One of the main challenges in critical patient management is to assess the blood volume and determine which patients will benefit from volume expansion and which patients will benefit from support with vasopressor and/or inotropic drugs. It is known that 40-72 % of critical patients respond to volume expansion with increased stroke volume or cardiac index.To search the literature for methods assessing fluid responsiveness in spontaneously breathing critically ill patients.The present study is a systematic literature review. We searched randomized clinical trials through a blind search performed by two independent authors in any language in the National Library of Medicine from 2009 to 2014.We selected three articles for full review and analysis, totaling 116 patients. The results are shown in Table This systematic review supports the beneficial effects of adopting maneuvers that amplify the hemodynamic changes, increasing the accuracy of methods to predict fluid responsiveness in spontaneously breathing critically ill patients.


Translational research helps move basic science and clinical laboratory discoveries toward application in health and medicine. Through controlled experiments, basic scientists use animal models to reproduce disease characteristics caused by an agent—in this case, excessively high exposure to alcohol. Through systematic study and observation, clinical research scientists identify symptomatic and physiological characteristics that define a disease. These bidirectional, complementary approaches enhance basic and practical knowledge about the biological basis of disease and hold promise for creating thoughtful, scientifically motivated solutions for improving public health.More than a decade ago, the National Institutes of Health (NIH) recognized the need for accelerating translation of research findings. In 2003, NIH developed the “Roadmap for Medical Research,” a collection of initiatives designed to find ways of motivating the translation of basic science into practice with the goal of transforming health care and outcomes. That vision was further crystallized in 2011 with the formation of the National Center for Advancing Translational Sciences (NCATS), which creates integrated translational and clinical research programs and fosters collaborations with community partners.NIH’s attention to translational research demonstrates its quest to bridge the laboratory–clinic divide. In this issue, we examine how current research in the alcohol field is setting the stage for translating clinical research findings to alleviate physical damage and restore neuropsychological function in individuals with alcohol use disorder (AUD).A highly promising area is the translation of cognitive neuroscience discoveries to gain a basic-science understanding of behavioral and pharmacological treatment outcomes. Findings from structural magnetic resonance imaging (MRI) and functional MRI (fMRI) studies, both in active and in abstinent alcoholics, are leading to a better picture of cognitive pathways that underlie behavior change in AUD (see the article by Naqvi and Morgenstern). A more complete understanding might be achieved by tracking the condition of the brain’s communication networks through the cycle of alcoholism from sobriety to relapse and recovery. Indeed, anomalous brain circuitry is present in certain individuals with a genetic predisposition for alcoholism (see the articles by Kamarajan and Porjesz and by Cservenka and colleagues). Knowing more about these networks may enable us to identify people at high risk for developing an AUD. In earlier research, electrophysiological recordings obtained with scalp electroencephalography (EEG) first helped explain the genetic predisposition for AUD in individuals with a dense family history of alcoholism (see the article by Kamarajan and Porjesz). An extension of these studies could contribute to prevention and individualized treatment regimens.Research using fMRI to examine brain network connectivity suggests that alcoholism may be related to problems in maintaining balance between opposing networks. As Fein and Cardenas explain, it may be possible to treat AUD by altering selective brain network function with focused magnetic stimulation applied transcranially and with the use of neurofeedback. Neuroimaging studies also have identified neuronal changes that may be associated with drinking relapse. Underlying the chronic relapse risk may be negative neuroplastic changes in the brain, caused by the cycle of continued alcohol abuse, repeated brief alcohol abstinence, and alcohol withdrawal.In light of the multifactorial nature of AUD, we now know that factors such as stress affect brain circuitry in recovering alcoholics (see the article by Seo and Sinha). Hence, basic research through animal models of stress is critical for testing the effects of stress surmised from human studies. Lovinger and Kash review the effects of high alcohol exposure on two brain regions in a limbic pathway—the striatum and bed nucleus of the stria terminalis (BNST)—involved in long-term stress-related behaviors. This research should enhance our understanding of the mechanisms by which alcohol produces its long-lasting change in synaptic function  and their potential as new treatment strategies.Excessive alcohol consumption by pregnant women is particularly dangerous to the fetus. The timing of hazardous drinking occurring during fetal development dictates the locus and extent of neural and facial dysmorphology sustained, resulting in fetal alcohol spectrum disorders (FASD). Landmark studies of human FASD conducted by Riley and his colleagues and reviewed in their article  also demonstrate how animal models can enhance the role of neuroimaging in human studies and lead to advances in FASD diagnosis and treatment. Animal models of FASD have yielded essential information about normal brain development and the temporal and dosage parameters of alcohol exposure that produce significant dysmorphology (see the article by Wang and Kroenke). In turn, this knowledge has provided suggestions for treatment.Alcoholism is a complex human disorder with biomarkers for neural health dysfunction that are now detectable with neuroimaging methods. Clearly, alcohol researchers have led the way in applying these methods to identify—in the living brain—neural changes that occur with chronic, hazardous substance use. This accommodation of brain structure and function to the chronic presence of alcohol, that is neuroadaptation, seems to be either reversible or at least reduced with sustained sobriety. The promise of many of the functional imaging studies, then, is to identify neural circuits affected by and maladapted to alcohol, as well as those intact enough to undergo further neuroadaptation, but now in the direction of normalization. Knowledge about bidirectional neuroadaptation also might lead to the development of medications based on neural circuitry that expresses neuroplasticity (see the article by Johnson and Oslin) and identification of individuals with AUD who are treatment candidates because of their adequate neuroadaptive reserve. By fostering innovative collaborations across government, academia, industry, and the people we strive to treat, we can make the most of translational research findings and meet the growing need for specialized treatment (see the article by Batman and Miles). Research designs with both basic and clinical translational components hold promise for preventing and treating AUD and sustaining sobriety.


Abdominal wall defects repair using prosthetic material is currently considered as the best available solution for most incisional hernias. Postoperatory suppuration remains the most frequent and fearful complication after this kind of intervention therefore imposing prevention methods. The aim of our study was to evaluate this serious yet controllable complication in the situation of a known pathogenic agent.This retrospective case series was carried on in the Surgery and Emergency Clinic III of the University Emergency Hospital Bucharest. It includes 14 cases of suppuration after abdominal wall reconstruction using prosthetic material during the last 15 years.In the situation of specific pathogenic agent, the use of specific antibiotic therapy and certain rather simple surgical techniques could guarantee therapeutic success for the doctor as well as the patient. A very good collaboration between the surgeon and the infectious disease physician was the key to therapeutic success.


Translational research to discover therapeutic targets for stroke has not fared well in developing new treatments for patients. The three most pressing issues are the choice of therapeutic target, animal model, and timepoint of administration of treatment. This manuscript “Different immunological mechanisms govern protection from experimental stroke in young and older mice with recombinant TCR ligand therapy” provides a fresh approach toward developing stroke treatments (Offner et al., For a number of years, researchers have reported the entry of immune cells into the area of the infarct, which leads to further neurodegeneration. However, targeting this immune response as a treatment for stroke remains elusive (Iadecola and Anrather, This treatment reduced infarct volumes in both age groups by altering the immune response to this neurological insult. Most interestingly, the recombinant TCR ligand differentially affected components of the immune response in the elderly and young mice but still resulted in a blunted immune response reducing neurodegeneration. This study illuminated differences in the immune cell composition and inflammatory expression between these two age groups in response to stroke. This is one of the few studies that enlists elderly animals which begins to provide insight into the differences in the physiological responses to stroke between young and the aged animals. Such differences in young and elderly could be responsible for the failure to translate findings at the bench to those in the clinic since the vast majority of studies use greatly cheaper young ones. More studies using elderly rodents will further supply additional insight in translating stroke treatment from the preclinical research to the clinical setting. This study sets the basis for future ones to develop new therapeutic approaches for a treatment for stroke.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.


Anorexia Nervosa is a devastating disorder with the highest mortality in mental health. For some, it becomes a life long struggle with immense personal and social consequences and premature death. Severe and enduring anorexia is often synonymous with intractable disorder.This presentation challenges the common definition of treatment resistant disorder. It presents the case of a 60 year old woman who has lived with the disorder for over 30 years. The treatment went beyond weight restoration and resolution of the anorexic thinking; the main focus was on minimising harm and focusing on best possible quality of life as defined in a collaborative therapeutic relationship with the client. The presentation is not only about what went well but also trial and error and learning to be flexible and inventive rather than being stuck with pre-conceived ideas of ‘successful’ treatment goals.


Given the characteristics of VR, we have to admit that imagery of “rotated head” generated the same neural conditions associated with real head rotation, despite the subjects could not predict which neural circuits should be activated/inhibited and the studied reflex could not be voluntarily controlled. In other words, highs can transform into appropriate neural activations not only the mental images of voluntary movement and of selected perceptions  of the brachial artery (Green et al., highs and lows may exhibit NO-dependent different activation of sensory and associative regions such as those belonging to the salience and executive circuits, cerebellar inhibition of the motor cortex, internal model for postural control.In the cerebellum NO acts also as a negative regulator of granule cell precursor proliferation, promotes survival and differentiation of these neurons and regulates bidirectional plasticity at parallel fiber-Purkinje neuron synapses (Contestabile, In conclusion, our findings allow to include hypnotizability among the individual traits responsible for part of the variability in postural control and indicate that it may be involved in the construction of individual sensorimotor selves. They suggest a key role of the cerebellum in hypnotic responding and go beyond psychological theories by suggesting that the involuntariness in action reported after a few sensori-motor suggestions can be real rather than merely experienced.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.


Mental retardation (MR) is frequently the result of genetic mutations. Syndromic mental retardation is intellectual deficits associated with other medical and behavioral signs and symptoms. Non-syndromic mental retardation refers to intellectual deficits that appear without other abnormalities. The newly identified ARX  gene consists of five exons and encodes 562 amino acid proteins and is thought to regulate brain development. Mutations in the ARX gene are associated with a diverse spectrum of phenotypes ranging from severe developmental abnormalities of the brain to syndromic and nonsyndromic forms of X-linked mental retardation (XLMR) syndromes that can be associated with normal or abnormal brain morphology. Mutations in the human ARX gene are the major cause of developmental and neurological disorders.The present study was focused on screening of exon 2 of ARX gene in Indian families with mental retardation in order to obtain the relative prevalence of ARX mutations. Method adapted in present study was amplification of target exon by using polymerase chain reaction, qualitative conformation of amplicons by agarose gel electrophoresis and their use for conformation sensitive gel electrophoresis to find heteroduplex formation which is followed by sequencing.In present study we have found insertion mutation at genomic position 25031668, this change leads to loss of homeobox, OAR domains of ARX protein. The other mutation obtained was substitution of C to A/G is observed and does not affect protein functioning.


The dataset originally included as The Data Availability statement for the article is revised to read: The authors have prepared a dataset that fulfills requirements in terms of anonymity and confidentiality of trial participants, and which contains only those variables which are relevant to the present study. Data are available as Supporting Information.S1 Dataset(DTA)Click here for additional data file.


The interesting comments of Assistant Professor Cakir et al.  highlighOur study showed a relatively high incidence of mild forms of depression in both groups of patients (patients with diabetic foot versus diabetic controls ). SevereBased on our data, we will support further investigation of psychosocial assessments in patients with the diabetic foot to improve their standard of living and therefore their quality of life.


Sodium channel blockers are used to control electrical excitability in cells as a treatment for epileptic seizures and cardiac arrhythmia, and to provide short term control of pain. Development of the next generation of drugs that can selectively target one of the nine types of voltage-gated sodium channel expressed in the body requires a much better understanding of how current channel blockers work. Here we make use of the recently determined crystal structure of the bacterial voltage gated sodium channel NavAb in molecular dynamics simulations to elucidate the position at which the sodium channel blocking drugs benzocaine and phenytoin bind to the protein as well as to understand how these drugs find their way into resting channels. We show that both drugs have two likely binding sites in the pore characterised by nonspecific, hydrophobic interactions: one just above the activation gate, and one at the entrance to the the lateral lipid filled fenestrations. Three independent methods find the same sites and all suggest that binding to the activation gate is slightly more favourable than at the fenestration. Both drugs are found to be able to pass through the fenestrations into the lipid with only small energy barriers, suggesting that this can represent the long posited hydrophobic entrance route for neutral drugs. Our simulations highlight the importance of a number of residues in directing drugs into and through the fenestration, and in forming the drug binding sites. The treatment of cardiac arrhythmia, epilepsy and pain usually involves blocking the protein channels responsible for initiating electrical activity in nerves and muscles. Current drugs block all such channels, but improved medication requires compounds that can differentiate between the channels present in different parts of the body. Achieving this goal calls for a better understanding of the interactions of current drugs with the proteins. Here we use computer simulation to understand where a local anesthetic and an anti-epileptic bind to a bacterial sodium channel and how they find their way to this position, helping to uncover ways to selectively target different human channels. Voltage-gated sodium channels (Navs) are transmembrane proteins that initiate action potentials in excitable cells by responding to small depolarizing signals to allow the rapid influx of Sodium channel inhibitors exhibit a wide range of chemical moieties, but common to most of them is the presence of a phenyl ring connected to a basic nitrogen, with some combination of aromatic and aliphatic decorations Humans have nine different types of voltage-gated sodium channels, which are preferentially expressed in different tissue Arcobactor Butzleri, called NavAb, shows the protein is a tetramer of four identical subunits, with the pore axis running down the central axis While there are no atomic resolution structures of eukaryotic voltage gated sodium channels (eNavs), the recent publication of a number of structures of homologous channels from bacteria (bNavs) Despite the similarities between bacterial and eukaryotic voltage gated sodium channels that may make bNavs good models for studying tonic block, there are also functional and structural differences. NaChBac exhibits far slower gating kinetics than eNavs In order to better understand the mode of action of sodium channel inhibitors, here we use molecular dynamics simulations to examine the route of entry and mechanism of binding in NavAb of two channel-blocking drugs: the local anesthetic benzocaine, and the anti-epileptic phenytoin. Both are small, neutral drugs that bind inside the pore of eNavs As described above, mutation studies strongly support the notion that local anesthetics bind to residues in the central cavity. For this reason we limit our search for possible binding sites to the channel cavity and fenestrations in order to more extensively sample potential binding pockets (meaning that we will not pick up any sites on the exterior of the protein.) To gain a first appreciation of where the drugs might interact with the protein and to observe drug behaviour inside NavAb, we start our investigation by placing phenytoin or benzocaine in the middle of the central cavity of both the closed and inactivated conformations and allow them to explore the interior of the pore without external influence. Although the size of the cavity is small and the drugs rapidly move about in this region, the timescale of our simulations is shorter than the typical time taken for drugs to block the channel, so it is possible that the drugs will not find their way to the most likely site in the pore. However, this approach does enable us to make a first identification of potential binding pockets which can be verified with the more exhaustive metadynamics search described below. As will be described later, the same binding positions found in these equilibrium simulations are found in two additional independent methods, lending support to them representing likely binding positions in the bacterial channel NavAb.One of the most commonly occupied sites is formed by the hydrophobic pocket above the intracellular activation gate, created by the confluence of the four S6 segments at the pore axis  are shown in Since both drugs are uncharged and there are no aromatic residues available for pi-pi stacking or cation-pi interaction in the NavAb channel lumen, nonspecific binding based on van der Waals attraction to hydrophobic pockets seems to be the dominant force behind drug association in our simulations. Both the identified binding sites involve significant interactions with residues at positions previously shown to be important for block in eukaryotic channels To assess the strength of binding relative to bulk in each of the two sites identified in the unbiased and metadynamics simulations we employed the method of free energy perturbation. Using this, the binding free energy of each drug in each site was determined, from which the dissociation constant was calculated for comparison to experimental measurements. As shown in For benzocaine, published values for the dissociation constant in closed eukaryotic channels range from 0.3–1.2 mM Experimental dissociation constants for phenytoin binding to the closed channel are rare, due to its low solubility and affinity to this state. In eukaryotic channels, phenytoin has been shown to bind to inactivated channels with a dissociation constant in the range of 4 – 9 μM, with affinity up to 100-fold weaker in the closed state Drug passage through a hydrophobic pathway has long been hypothesized in sodium channels As shown in Movement of benzocaine and phenytoin through the fenestration is associated with extension of water chains from the channel lumen into the fenestration and possible retraction of resident lipid tails. Without the drug present, lipids extend into each fenestration for the majority of our simulations eg  as suspeMoving from the bulk lipid into the fenestration requires the drugs to move into the hydrophobic core of the membrane, something previously shown to be unfavourable Accurately converging the right hand side of the free energy profiles is difficult. Once the drug leaves the fenestration it can sample more positions at the given coordinate value and there are a number of slow motions that are hard to sample in the 30 ns of simulation we allow for each drug position. These slow motions include lipids entering/leaving the fenestrations, the drug moving between leaflets of the bilayer and the formation and breakage of water chains. Although the PMF does not change significantly when we extend our simulations  we have Using molecular dynamics simulations we have characterised the likely binding sites for benzocaine and phenytoin inside the central cavity of NavAb, with 3 independent simulation methods yielding consistent results. Both drugs are found to bind either in the hydrophobic pocket formed by the activation gate or at the entrance to the hydrophobic fenestrations. In both cases, the drugs interact with residues found to be important in binding in eNavs. But, we find this association is due to non-specific hydrophobic interactions meaning that binding occurs due to the overall architecture of the central cavity rather than interactions to specific residues. Although our simulations clearly identify the likely drug binding sites in the channel, it is not yet clear if the binding of more than one drug is necessary to occlude the pore or prevent channel opening. Our simulations also provide a plausible rationalisation for the differences seen between tonic and use dependent block, as interaction of cationic drugs with aromatic residues are essential in the use dependent case but not for resting state block Our results also show that the hydrophobic fenestrations seen in NavAb can serve as conduits for benzocaine and phenytoin to enter the central cavity and thus can form the long hypothesised hydrophobic entrance route The large degree of sequence similarity in the pore forming regions of eNavs makes the design of subtype selective channel blockers a difficult goal. Elucidating the mode of entry and binding of existing channel blockers is an important step toward achieving this aim. Here we have been able to do this for benzocaine and phenytoin in a bacterial channel, but it is not clear how much about binding in eukaryotic channels can be inferred from this given the significant differences between these families of proteins. For example, the nature of binding seen here is likely to be less specific than that in the eukaryotic homologues. Additional functional studies of drug block in bacterial channels, increased availability of structural information about the different functional states of bacterial channels, reliable models of eukaryotic channels and detailed investigations of specific drug-residue interactions in tonic and use-dependent block will all aid progress toward the design of subtype selective channel blockers.Two simulation systems were set up based on the NavAb sodium channel with coordinates obtained from the protein database: a closed/pre-open channel; PDB accession code 3RVY In order to gain a first idea of the likely position of drug binding in the central pore cavity, three simulations lasting 125 ns each were run for each protein/drug system . In each of these the drug was placed in the center of the cavity with a different random orientation. Once complete, the first 25 ns was excluded from further analysis to allow for equilibration of the drug in the channel, and the three trajectories for each protein/drug system were combined. Cluster analysis was performed on the drug position in the combined trajectory  using the quality threshold algorithm to locate the most commonly occupied drug positions. For this purpose we clustered according to RMSD of the drug coordinates using a cutoff of 3 Å. To determine which residues the drug interacts with in potential binding sites, the NAMDEnergy plugin was used to measure the interaction between the drug and chosen residues for selected subsets of the trajectory corresponding to each cluster.To better assess if the equilibrium simulations had sampled the most likely drug binding poses, metadynamics Free energy perturbation The equilibrium constant of the drug binding to each site were calculated using the following relation The energy profile for drugs to pass through the lateral fenestrations from the channel cavity into the lipid bilayer was determined using umbrella sampling Figure S1Orientations of the drugs as a function of time during the metadynamics simulations.(PDF)Click here for additional data file.Figure S2Representative snapshots of the binding poses of benzocaine phenytoin.(PDF)Click here for additional data file.Figure S3Drug-protein interaction energy decomposition. The interaction energies for benzocaine and phenytoin and residues in NavAb are decomposed into van der Waals and electrostatic components.(PDF)Click here for additional data file.Figure S4Snapshots from umbrella simulations. These show benzocaine and phenytoin occupying a hydrophobic fenestration at the same time as a lipid molecule from the bilayer.(PDF)Click here for additional data file.Figure S5Convergence of the potentials of mean force (PMF).(PDF)Click here for additional data file.Figure S6Cross-section of the simulation system used in this study.(PDF)Click here for additional data file.


Since the middle 1990s biologics have been available for rheumatic diseases. The initial experiments showed efficacy for symptoms and signs but concern was expressed about tachyphylaxis and absence of a true DMARD effect. Combining the antibodies with methotrexate answered some of these criticisms and since that time the number of agents available for rheumatoid arthritis, psoriatic arthritis and spondyloarthropathy has grown.It is clear these agents work, what is less clear is how they should be used to produce optimum cost benefit. The ever expanding market has attracted a large number of pharmaceutical players to this area and this shows no sign of abating. Also there are number of new drugs including oral synthetic DMARDs becoming available.None declared.


Breast cancer is the commonest malignancy of women in many parts of the world and comprises 18% of all female cancers. There is one million new cases in the world each year. Neopterin which is a pteridine produced by activation of monocytes by IFN-γ may be used as a marker of immune system activation. The biological function of neopterin is still largely unknown and certain patho-physiologic roles have only recently been elucidated. Therefore, the aim of this work was to investigate the role of neopterin in females with primary and metastatic breast cancer. The obtained results were correlated with different clinicopathological data of those patients. The study population included females with primary and metastatic breast cancer as well as healthy age matched females were taken as a control group. Peripheral blood mononuclear cells were separated from each subject under study by Ficoll-Hypaque density gradient centrifugation technique. The isolated cells were cultured with and without PHA and neopterin levels were measured in serum and culture supernatants by ELISA technique. The results showed that neopterin levels were lowest in serum, followed by culture supernatants without PHA and highest in culture supernatants with PHA in each studied group. The mean neopterin values in serum and culture supernatants with PHA of metastatic breast cancer patients were significantly higher than in the primary breast cancer patients and the control group. Our results also indicated that neopterin levels positively correlated with the tumor grade, tumor stage and the presence of metastasis. From all mentioned data it is clear that, measurement of neopterin either in serum or in culture supernatants with or without PHA can give an indication about immunological status of breast cancer patients' response to therapy and early detection of metastasis. It gives an important and valuable prognostic information before surgical intervention is performed.


Reducing human infectivity of malaria parasite through early and effective treatment amongst under-five children is a major concern of WHO & MDGs 4 & 6. Getting mothers to bring their children to the nearest facility early for malaria treatment remains a major challenge.To explore health seeking behaviours and cultural attitudes of mothers of under five children suffering from malaria in Ile Ife using moderate interviews and providing recommendation to the Ministry of Health of Osun State to serve as knowledge basis for developing appropriate intervention.The study employs a qualitative research with the aid of purposive sampling, 16 women who brought their under five children to hospital for malaria treatment were recruited. A moderate interview was used to explore the experiences of the mothers and the data generated was subjected to thematic content analysis.Five themes emerged from the study. All respondents recognized fever as the major feature of malaria but their knowledge of what causes it, symptoms and sign was poor. They all perceived malaria as a simple disease for which mothers should be comfortable to apply home based remedies such as herbal concoctions. Religious beliefs did not prevent mothers from seeking hospital care but some are aware of mothers that rely on Holy water and prayer to treat malaria. Poverty is seen as an impediment to seeking treatment mostly by women in a polygamous relationship. Fear of use of injection to treat malaria in hospital coupled with perceived poor attitude of hospital staff was considered by some mothers.The study observed that mothers had poor knowledge of malaria; cultural beliefs in home remedies and poverty are issues that affect malaria outcome. Health education of the malaria life cycle, treatment and prevention is necessary for mothers as well as empowerment of women.


NZ is considered a bicultural society; Maori make up approx 15% of the population (NZ census 2013). Maori have strong cultural traditions and beliefs around food, with food not only determining physical health but also emotional, psychological and spiritual wellness (HRC report). Food is also strongly linked to customs and cultural values. The implications and understanding of eating disorders in this group are therefore complex.Mental Health services traditionally struggle to both engage and treat the Maori population. Eating disorders rates are low overall in the general population; research suggesting that there was a very low prevalence overall for eating disorders in Te Rau Hinengaro. However, the highest prevalence of eating disorders, particularly bulimia, was in Māori (BPJ 2010).With this in mind there are several challenges to consider when planning and offering services to treat eating disorders in this population.The CMDHB covers an area with high Maori population and provides a culturally specific service for both adults and young people. The rates of referral of Maori to the CMDHB Eating Disorders Service are low overall, despite this there is a recognised unmet need in terms of recognition and support for these difficulties. Often young people present with complex needs with eating issues part of this presentation. Traditional treatments pose dilemmas when considering the cultural aspects of engagement and working with maori families; as well as the explanatory models used to think about eating issues. This presentation will consider these challenges and use a case example to support ideas to improve services and outcomes in this population.


Drosophila melanogaster and human cells. They also reported that Rab5 is required for the correct alignment of chromosomes at the metaphase plate, an important step for the proper segregation of chromosomes.Mitosis is a crucial event that controls the equal partitioning of the genetic information between the two daughter cells. Failure in this process can cause various human genetic diseases and can contribute to cancer onset and development. For many years cell division studies focused on the identification and analysis of the mechanisms and signaling pathways that control microtubule dynamics and chromosome behavior, however in recent years other important cellular and regulatory processes have been implicated in various aspects of cell division and our traditional view of mitosis has changed. In particular several studies have highlighted the importance of membranes   , the Drosophila counterpart of the nuclear mitotic apparatus protein (NuMA) (Bowman et al., Drosophila, human Rab5 was found to be required for chromosome alignment, but interacted with a different mitotic player, CENP-F required for chromosome congression (Liao et al., During mitosis, RNAi-mediated depletion of Rab5 induced chromosome alignment defects at the metaphase plate and delayed mitotic progression both in s Figure  and it wDrosophila and human cells employ Rab5 proteins to direct membrane trafficking involved in the regulation and transport of key mitotic regulators important for the fidelity of chromosome segregation (Lanzetti, Together, the findings of these papers indicated that incomplete disassemble of the nuclear envelope affected the release and localization of important proteins for spindle assembly and maintenance. They also showed that both In conclusion, these findings indicate that mitosis requires more than just microtubules and chromosomes, and increasing evidence over the last years has pointed out that a membranous system surrounding the mitotic spindle is important not only to confine important mitotic proteins around the spindle (Capalbo 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.


Very few qualitative studies on cluster headache have been conducted. As a result we have little in-depth understanding of the perceptions and experiences of cluster headache patients and the health professionals who treat them. With this research we aim to rectify that gap.The overall objective of the project is to gain insight into the perceptions, experiences and understandings of cluster headache from the perspective of three key stakeholder groups: the cluster headache patients, GPs and neurologists. We present here the findings of our literature study and identify the emergent themes which we will use during the interview studies for this project.A qualitative study using semi-structured interviews with the three participant groups. A systematic qualitative methodology is applied to the transcribed interviews.This study runs from August 2014 to June 2015 and data collection is currently in process. Therefore all results are tentative. Early findings show that this study sheds new light on the following aspects: early detection and diagnosis; health education and promotion; effective treatment and management of cluster headaches.This study will identify the particular challenges for each stakeholder group—patients, general practitioners and neurologists—with respect to early detection of cluster headaches and ways in which treatment and management can be facilitated. We envisage this study will raise awareness about the importance of early diagnosis, health education and the need for effective treatment pathways for cluster headaches.


The Micro Cellular Rubber (MCR) unit established in Vizinagaram, Andhra Pradesh in India by The Leprosy Mission Trust India (TLMTI) caters to the need of poor Leprosy affected patients with neuropathic feet within India and to countries nearby India. The MCR Unit till date has provided over a million pairs of MCR insoles to all with anaesthetic feet and still continues to do so.The MCR sheets manufactured with a shore hardness of 15' Shore 'A', has helped prevent high pressure points and thus avoid plantar ulcers in anaesthetic feet. Natural Rubber along with several other chemicals is used in optimum quantities to manufacture MCR. The unique manufacturing process gives MCR the ability to spring back to original shape when pressure is released while walking.The larger size (24” X 20”) coloured MCR sheets with 10mm thickness has become an ideal rubber to prevent stigma for deformed anaesthetic feet. The cost effectiveness in the production of the MCR rubber has helped the poor leprosy patients afford and use the MCR insoles for their footwear. Association and constant interaction with various shoe and footwear companies have led to experimentation and development of newer designs in MCR sandals. High quality and standards of the MCR insoles are maintained through periodic standardised quality tests carried out both within and outside the organisation.Although the initial purpose of the MCR unit was to cater to the needs of Leprosy affected people, in course of time, various Orthotic & Prosthetic centres realized the value and have started using MCR in their products, especially for Diabetic foot care. Since patients use and prefer protective MCR footwear to prevent ulcers, protect and cover their anaesthetic and deformed feet, it is essential for MCR production units to constantly upgrade and develop newer designs and give the patients and opportunity to choose. At present TLMTI uses 50% of its annual MCR production and the rest is used by other NGOs and Orthotic centres.With time there has been a rapid change and development in the design and manufacture of footwear, however there has been no alternative to MCR insole footwear. The constant strive of introducing and making use of MCR footwear in other general disabilities have reduced the stigma of MCR’s in leprosy to a great extent.


Disorders of consciousness (DOC) present a clinical challenge in diagnosis, prognosis and defining appropriate treatments that aim at improving the patient's care and quality of life. As there is no universally accepted definition of consciousness, DOC are difficult to define, elucidate and diagnose  have facilitated the integration of structural and functional methods enabling a greater understanding of the variation in different states and transitions of a DOC, as well as some individual differentiators within the spectrum (Laureys et al., EEG can measure brain signals of neuronal activity over bandwidths of frequency ranges recorded with dozens or hundreds of scalp locations over different timescales; it has particular relevance when considering brain dynamics and the mesocircuit model in DOC. Brain dynamics are measured through signal oscillations which act as communication connections integrating brain functions. They are important for the mediation and distribution of higher functional and synchronized processes in the human brain (Sauseng et al., The most accepted measure of interaction and connectivity is that of coherence, a generalization of correlation to the frequency domain. Coherence is used to study the relationship and interactions between EEG channels and between brain regions (Nolte et al., In DOC, coherence is used to study connectivity and synchronization between brain regions. Correlated activities amongst brain areas or electrodes can determine patterns of functional connectivity, which is known to be impaired in DOC (Noirhomme and Laureys, One of the main limitations of this approach is that coherence values must be interpreted carefully, as they can be contaminated by artifacts between electrodes caused by reference and by volume conduction which is pertinent to the DOC population. Volume conduction can impact interelectrode connectivity results due to the spatial autocorrelation between electrodes which measures connectivity between the two brain regions where the electrodes are placed, this is further impacted by skull injury and craniotomy following a TBI Cohen, . This haResearch using the modified imaginary coherence across difference frequency ranges and brain regions in DOC using resting state and diverse stimuli has expanded significantly over the last few years (e.g., Leòn-Carriòn et al., EEG studies of coherence can be used to assess the effects of auditory stimuli in DOCs. One of the most reliably tested methods is using salient auditory stimuli either through music therapy or music intervention that is meaningful or personal to the patient. DOC studies have identified that auditory stimulus with personal and/or emotional meaning produces meaningful results compared to unrelated auditory stimuli (e.g., O'Kelly et al., Music therapy is an established rehabilitation intervention in DOC (Magee et al., More research is needed on the mesocircuit model and thalamocortical synchronization to develop an EEG regional coherence methodology in order to analyse and compare cortical regional connectivity in response to rehabilitation interventions, including music therapy. The application of these models in a clinical setting could help develop an EEG regional coherence methodology to analyse and compare cortical regional connectivity in response to music rehabilitation interventions.It is important to understand if an increase in connectivity across the mesocircuit pathways could be an indicator of the conscious state and neuroplasticity, and whether such a change could monitor the functional recovery in line with the earlier works Schiff, . This apThe application of the mesocircuit and thalamocortical connectivty models using EEG coherence measures could lead to a more objective determination of the state of consciousness in patients with DOC and any transitions that may happen across the continuum within the different states through the trajectory of rehabilitation with the contribution of music therapy. It is hoped that the development and adoption of such clinically applicable and complementary tools across DOC patient populations will enhance the existing practizes to provide more translational and differential evaluation of post-injury diagnosis and throughout rehabilitation.VL is the lead author. Both VL and JO contributed to the conception and design of this work. VL drafted the manuscript and JO revised it critically for intellectual content. Both authors approved the final version of manuscript. Both VL and JO agree to be accountable for all aspects of the work.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.


We report a case of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) which illustrates the natural progression of disease in the absence of availability of an implanted cardiac defibrillator (ICD). Electrocardiograms and cardiac imaging show the progress of ARVC and these clinical milestones of disease are presented herein. ARVC is a largely inherited cardiomyopathy that affects mostly young otherwise healthy individuals and is associated with an increased risk of sudden death . The morAn 18-year-old Chinese man was sent to the hospital after suffering syncope while playing basketball. After a 12-lead ECG revealed ventricular tachycardia  and a suThe deterioration of parameters on ECG and ECHO indicates a poor prognosis. Such clearly illustrated progression from diagnosis to SCD on clinical testing allows for better visualization of disease progression and may heighten clinician suspicion of disease and recognition of an ominous course. The lifesaving therapy for ARVC is ICD placement and this case corroborates the diminishment of the prognosis in its absence.


To the Editor: We would like to add some specification and clarification to the discussion regarding the diagnostics and case definitions for urinary schistosomiasis in travelers to Corsica, France  exhibited atypical morphology  that S. haematobium uses  is safe. Epidemiologic analyses should take into account the role of zoonotic S. bovis infection and supplement parasitological investigations with molecular analyses (We recommend that clinicians treat any suspected case of


In this study, we investigated the gene expression profiles between female and male mice using the sfx mouse model and BXD RI strains. The objective of this study is to identify sex differentially expressed genes in bone using the sfx model and BXD RI strains.Geber and Murphy  found thx) mouse  which lasfx mice. We then analyzed the potential gene network among those differentially expressed genes with whole genome expression profiles generated using spleens of female and male mice of a total of 67 BXD (C57BL/6J X DBA/2J) recombinant inbred (RI) and other strains.We first identified the genes that are differentially expressed in the femur between female and male sfx mice from either female or from male mice than we found previously using RNA of a mixture of female and male mice. It is obvious that the skeletal system is different between female and male. The female and male skeletal system is most likely to react to the VC deficiency in sfx mice differently. The comparison between disease and control samples using data of sex mixture suffers from neutralization of gene expression levels between the female and the male. This result suggests that in the study of genes that are potentially affected by the sex or the gender, data from female and male individuals should be analyzed separately. Many reports have been using the sex balanced data of mouse strains.By analyzing the female and male mice separately, we found many more differentially expressed genes between wild type and Our data posed a question about whether the balanced data should be used without understanding of the sex differences.


Due to high resolution cytogenetic microarray (CMA) has replaced traditional karyotyping for evaluation of individuals with intellectual disability, autism and congenital malformations. The diagnostic yield of CMA is 10 to 12 % and is more than any other investigation for evaluation of developmental disabilities. Due to its high resolution CMA is also being used as a prenatal test for chromosomal anomalies. The diagnostic yield is about 3% whatever may be the indication. The yield is higher in cases with fetal anomalies. The main concern with CMA is its ability detection of copy number variations of unknown significance. This is a major problem in prenatal diagnosis and is a challenge for the counselor and dilemma for the family in concern. With accumulation of more and more data of pathological and polymorphic variations in genome the variations of unknown significance will decrease. CMA is also useful in delineating abnormalities picked up by karyotyping. Some cases with double segment rearrangement may point towards familial chromosomal rearrangement and hence, CMA is indicated in familial cases with developmental disabilities and birth defects.Cost and availability of clinical cytogeneticists for appropriate interpretation of CMA results are important concerns for wider application of the technique.


The traThe unexplained repeated implantation failure (RIF) is still another unsolved and one of the principal problems to affect the outcome of assisted reproductive technology (ART). The successful embryo implantation requires accurate temporal regulation of maternal immune function  and endocrine system . The pasThe “best viable” embryo selection and also the optimal implantation regulation, both are going to be solved by new diagnostics and treatment methods based on personalized omics profiling . MoleculThe goal of our effort is to point out new and potentially useful biomarkers that can be used for the improvement of pregnancy rates after the assisted reproduction techniques (ART) in near future and also to emphasize some of the novel molecular targets and biomarkers that have been reported recently and might contribute to new strategies of infertility management that will return a hope of natural conception for selected couples.Evaluation of such markers may help clinicians to predict pregnancy outcome and detect occult implantation deficiency. Moreover, these novel molecular targets are expected to apply to the clinical practice from bench to bedside and improve the implantation efficiency in ART.


It has been proposed that one of the causes of stuttering is a deficit in brain timing networks Alm, . In stutNeural oscillations in the beta frequency band (15–30 Hz) are classically related to motor activity , are more likely to reflect anomalies related to the cause of stuttering rather than consequences of stuttering (see for review Chang and Zhu, If abnormal beta power arising from the striatum is causally related to stuttering, then fluency inducing manipulations should normalize beta power. This contention is supported by functional neuroimaging and electrophysiological studies. The finding that putamenal beta band oscillations are biased toward internal timing (Bartolo et al., hypoactive beta oscillations in the basal ganglia. DAF may have normalized the beta band oscillations in the basal ganglia thereby reducing the need for compensation via hyperactive beta in the cortex. This idea suggests both AWS and CWS should exhibit reduced beta band responses in the putamen when internalizing rhythms. The fact that fluency-inducing mechanisms reduce the hyperactivity of the beta band in the cortex has major implications for stuttering. Firstly, it implies that without regular external stimulation, AWS have abnormal beta oscillations in the cortex and possibly the striatum. Secondly, normalizing compensatory hyperactivity in the cortex as well as temporarily alleviating stuttering implies that DAF may act to normalize hypoactive oscillations in the striatum.It is unclear whether the hyperactivity of the beta band activity in stuttering (Rastatter et al., In summary, if stuttering is a disorder of internal timing and internal timing is represented by modulations of oscillatory power within the beta band in the striatum, then it is likely that the cause of stuttering is reflected in abnormal beta band oscillations in the putamen. This is consistent with the structural and functional abnormalities in CWS (Beal et al., 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.


We report the results of a simulation study in which we explore the joint effect of group absorptive capacity  and cognitive distance  on the emergence of collective rationality in groups. We start from empirical results reported in the literature on group rationality as collective group level competence and use data on real-life groups of four and five to validate a mathematical model. We then use this mathematical model to predict group level scores from a variety of possible group configurations . Our results show that both group competence and cognitive distance are necessary conditions for emergent group rationality. Group configurations, in which the groups become more rational than the most rational group member, are groups scoring low on cognitive distance and scoring high on absorptive capacity. As groups become ubiquitous information processing units in modern organizations, emergent group level cognitive properties received considerable attention in the literature Of particular interest for research advancement and practice is strong cognitive/rational synergy, reflecting the extent to which the group as a whole is more rational than the most rational member of the group. Previous research pointed towards the fact that strong synergy is not easily achieved An important antecedent of emergent group rationality is the initial configuration of group members’ individual rationalities. Cognitive distance as reflected by the detachment of the most rational group member from the rest of the group has a nonlinear association with both weak and strong group synergy Therefore, average individual rationality is a form of group absorptive capacity likely to be beneficial for strong cognitive synergy. The concept of absorptive capacity originates in the general management literature and describes a social system’s  capacity of acquiring, assimilating, generating and transforming knowledge in order to achieve a competitive advantage Groups composed of members varying in their task-related knowledge and cognitive competencies often face the issue of bridging these differences in order to reach consensus on a decision or problem solving approach. For disjunctive tasks, in which the task accomplishment depends on the most knowledgeable or competent group member, groups often have to bridge the cognitive gap between the most knowledgeable group member and the rest of the group. Previous empirical research tested models that predict a non-linear association between cognitive distance (defined as the cognitive gap between the most knowledgeable group member and the rest of the group members) and cognitive synergy Building on the above mentioned arguments, Meslec and Curşeu Meslec and Curşeu We argue here that groups with high absorptive capacity are better equipped to integrate effectively the knowledge shared by the most knowledgeable group member and as such they are more likely to successfully bridge the cognitive gap that separates the best performing individual in the group from the rest of the group. Such a claim is very difficult to test in real life settings, because it is extremely challenging to find enough groups to cover all possible group configurations in which both cognitive distance and absorptive capacity to vary. We therefore set out to develop a simulation model and test the effects of the interplay of cognitive distance and absorptive capacity on strong and weak cognitive synergy. Computational experiments can capture, starting from existing relations as identified in the empirical studies with real-life groups, relationships between variables and then extrapolate these relations for all possible configurations of the two variables explored. As argued, this extrapolation will never be possible in real life as it is close to impossible to gather data on groups that cover all the spectrum of possible combinations between cognitive distance and absorptive capacity. Starting from real life data reported in previous studies Specific approval from the university ethics review board was not required since this study reports a simulation based experiment and it did not involve additional data collection from human or animal subjects. Data for testing the mathematical model used in the simulation was obtained from previously published studies.With the consent of the authors we used real life data from previously published papers on group rationality The group data is split up by group size, and then groups of different sizes are treated separately in order to control for the co-varying of cognitive distance measure with group size. If we were to investigate groups of all sizes simultaneously, we would have had to contend ourselves with only averaged individual performance and the within group standard deviation, and perhaps the best individual performance in the group to ensure model fit – therefore rely on much less data than in the current approach. Afterwards, the columns for each group are sorted according to the individual performance. We then performed a linear regression of the group score based on the sorted individual scores. For a group of size five, we get five individual coefficients: Group absorptive capacity and cognitive distance were the independent variables in our simulation study. We used the average individual rationality within groups as a measure of groups’ absorptive capacity and we used a heuristic method of computing cognitive distance. Based on the guidelines reported in Meslec and Curşeu Our simulation was programed and ran in MATLAB version 8.1.0.604 (R2013a). In the supporting information folder  we preseAs illustrated in both figures, our simulation study replicated the empirical results presented in Meslec and Curşeu Although common in behavioral ecology, simulation studies starting from real life data According to our simulation results, a necessary condition for achieving strong cognitive synergy is that individual group members score high on rationality. If groups are composed of irrational individuals, they do not have the potential to become more rational than their most rational member. This finding is somehow at odds with studies on animal collectives showing that groups composed of irrational agents can in fact make rational choices Another important result of our simulation study, refers to the association between cognitive distance and group rationality (as strong cognitive synergy). At very low levels of cognitive distance, there is a small positive association between group competence and strong synergy. This pattern of results suggests that low cognitive distance is yet another necessary condition for achieving strong cognitive synergy. To conclude, our simulation study identified two necessary conditions for reaching strong synergy in groups. One of the necessary conditions is high group competence (absorptive capacity) and the other is low cognitive distance. When at least one of these conditions is not fulfilled, groups have little chance of achieving strong synergy that is, becoming more rational than their most rational group member. Yet another configural characteristic conducive for strong synergy is group size and according to our simulation results, at high levels of group absorptive capacity, groups of five have a higher chance of reaching strong cognitive synergy than groups of four. Availability of cognitive resources varies with group size and it is possible that groups of five with high absorptive capacity have more cognitive resources they can use to achieve strong synergy as compared to groups of four. This pattern of results comes at odds with previously reported negative association between group size and strong synergy File S1In the supplementary material folder labeled (ZIP)Click here for additional data file.


The earliest application of evolutionary theory, although unknowingly at the time, was artificial selection of crops and animals for food production. Ever increasing technical advances in breeding, genetic engineering and comparative genomics have since led to a rapid acceleration in the rate of such selection, although many of the basic principles underlying the process have remained the same over time. For example, whereas we used to inter-breed among genotypes and even species to generate standing genetic variation upon which to select, we can now introduce specific genes of interest directly into the preferred genetic background.Much of crop domestication historically has involved increased yield and size (for example of fruit or seed), and this has resulted in parallel and often convergent selection upon traits and even genes of interest. Recent work by Dorian Fuller and colleagues used archaeological plant remains from around the world to examine the parallel acquisition of so-called “domestication syndrome traits” across both plant species and regions (Fuller et al. Improved understanding of the evolutionary process as well as major technological advances means the pace of artificial selection has intensified and our ability to respond to changes in both the abiotic and biotic environment has improved greatly. Our ability to translate understanding of plant genetics and genomics into meaningful applications in crop science is discussed in a new piece by Pamela Ronald Ronald . The worArabidopsis thaliana in order to determine the specificity and consequences of evolution on one host to infectivity on another. They use experimental evolution to show rapid increases in infectivity and virulence on the host background in which the virus has been adapted, but also demonstrate that some host types select for viral populations that are more generally infective to other types (Hillung et al. Given the rapid potential for adaptation, many predictions regarding pest or pathogen evolution can be directly tested in the laboratory in order to inform better disease management. Recent work by Julia Hillung and colleagues examined the adaptation of a plant RNA virus to various ecotypes of Importantly, the utility of evolutionary theory for agricultural practice is not limited to pest and pathogen interactions. The increasingly clear role of the microbiomes across the rhizosphere and phyllosphere suggest great potential for application of both community ecological and evolutionary thinking. Suzanne Donn and coauthors examined the changing soil microbiome of intensive wheat crops across years and found that, relative to soil in the absence of plants, rhizosphere communities changed substantially over time in the presence of plant roots and these temporal dynamics could be explained well based on the stage of plant development (Donn et al. Overall, although artificial selection has been central to agricultural practice since its dawn, we are still constantly improving our ability to speed up the selective process, incorporate adaptation across heterogeneous environments, and allow for a more responsive management program in the face of coevolving enemies and mutualists. As such, there remains great promise in our ability to increase crop yield and decrease the use of pesticides and fertilizers through the application of evolutionary thinking.


Pathology of posterior horn of medial meniscus is common and often presents a difficult approach during arthroscopy for various reasons. We describe an easy maneuver to facilitate “delivery of the medial meniscus” during arthroscopy. Treatment of medial meniscus pathology is one of the most commonly performed arthroscopic and often presents difficult access during arthroscopy , 2. TherWe describe a technique to improve medial meniscus posterior horn accessibility without use of additional portals or tools.Standard anterolateral and anteromedial portals are used to enter the knee joint. Lateral compartment procedures are completed as it can be easily enlarged by conventional techniques. Medial compartment is assessed and configuration of medial meniscus tear is established through the anterolateral portal. The degree of opening of the medial joint is assessed by valgus stress in extension and slight internal rotation of the knee. If the standard 4 mm shaver can enter the posteromedial corner of the knee the space is usually adequate to access the posterior horn. Stable flap tears in the posterior horn can easily be resected using a cutting punch and oscillating shaver. The peripheral portion or unstable flaps become difficult to reach due to “posterior slipping away” of the posterior horn of the meniscus especially in cases of menisco-capsular separation. In this scenario we use the technique of “meniscus delivery”. With the knee in 20–30 degrees of flexion, valgus stress is applied and the medial joint is allowed to open as much as possible, then the assistant places the middle or index finger on the posterior knee surface just medial to the semimembranosus tendon at the level of the joint line, and applies anteriorly directed pressure towards the centre of knee joint . This deIt is often difficult to visualize the posterior horn of the medial meniscus during arthroscopy and struggling to enter this part of the compartment may lead to iatrogenic cartilage injury and/or instrument damage. The maneuver we describe uses routine tools and allows easy access to the posterior horn without the need for additional portals or special tools. The push to the posteromedial aspect of joint must be done in the valgus opened knee and this allows delivery of the posterior horn into view for easy accessibility. This technique takes no extra time and is especially helpful in tight knees and osteoarthritic knees. It is described for the medial meniscus only as the lateral meniscus is usually easy to approach by conventional methods.The authors declare no conflict of interest in relation with this paper.


There is a lack of experience in implementing clinical guidelines in Norway and most guidelines are put into practice without an implementation plan. This presentation is part of a project dealing with developing strategies for implementing a clinical guideline for persons with concurrent mental disorders and substance use disorders. Purpose To describe the different tools that have been developed to implement the guideline and thereby bridge the gaps between current practice and clinical guidelines.We have put an emphasis on leaders, patients/ families and service providers. For leaders we have established a toolbox for managers including equipment for doing clinical Audits and a practical guide for how to change practice. Representatives from patients organizations have selected and promoted the 10 most important recommendations. An electronic version of the guideline has been developed which in addition to the national dual diagnosis competence training program, are important tools for service providers.The national training programme has gathered around 200 to 300 service providers, leaders and users on 17 locations in Norway. Unfortunately, mental health workers and leaders are more absent from the seminars than addiction workers. One important objective of our implementation efforts is that health care workers should participate in continuous training using our internet-based educational training packages like video lectures, instruction videos, screening tools etc. The 10 user selected recommendation have been widely distributed and might also be downloaded as Apps. The clinical Audits have been used in several institutions and departments and we are now developing a community and user Audit. We will present some finding on the use of our net tools and Apps during the presentation.In an effort to bridge the GAP between the guideline recommendations and current practice, several measures have been put in place targeting leaders, service providers and users. One of the hurdles we have faced in the implementation is security systems and data programs used by the health authorities making access to our net based tools difficult.