This paper reviews the newest developments in computational cardiology. It focuses on the contribution of cardiac modeling to the development of new therapies as well as the advancement of existing ones for cardiac arrhythmias and pump dysfunction. Reviewed are cardiac modeling efforts aimed at advancing and optimizing existent therapies for cardiac disease  and at suggesting novel treatments, including novel molecular targets, as well as efforts to use cardiac models in stratification of patients likely to benefit from a given therapy, and the use of models in diagnostic procedures. The iterative interaction between experimentation and simulation has long played a central role in the advancement of biological sciences. Among computational models of the various physiological systems, the heart is the most highly advanced example of a virtual organ, capable of integrating data at multiple scales, from genes to the whole organ . State-oModeling arrhythmias in the whole heart to reveal mechanisms and suggest better treatments has become one of the most important hallmarks in the utilization of biophysically detailed computational modeling of the heart. A number of ventricular models have focused on arrhythmia dynamics, and specifically on the self-sustained reentrant propagation of complex 3D waves in the ventricles. Historically, these were the first applications of ventricular modeling. Ventricular modeling studies have revealed important aspects of reentrant arrhythmias, among which the dynamic characteristics of ventricular fibrillation (VF), and the role of alternans and restitution in arrhythmogenesis. Ventricular models have been used extensively in characterizing VF dynamics , 5. Part Recent years have witnessed revolutionary advances in imaging, including ex vivo structural and diffusion tensor (DT) magnetic resonance imaging (MRI) that facilitate acquisition of the intact structure of explanted hearts with high resolution. Leveraging on these advances, a new generation of whole-heart image-based models with unprecedented detail have emerged , 19. SucComputational modeling of the electrophysiology of the human atria is also becoming an important component in the evaluation and advancement of therapeutic strategies, as recent state-of-the-art biophysically detailed models can accurately simulate the complex spatio-temporal dynamics of atrial arrhythmias. Similar to ventricular modeling methodology, biophysically detailed atrial models are reconstructed from MRI  and CT  scans, a Atrial models have been used to determine the arrhythmogenicity of substrates due to ionic remodeling  or elect Contemporary atrial models allow for realistic simulation of ECG signals , monophaBiophysically detailed electromechanical models of the heart, which represent the most sophisticated models of the heart developed thus far , have al With the advancements of computational techniques and medical imaging and image processing, the groundwork for patient-specific modeling of electromechanics has also been laid. Similar to electrophysiological applications as described above, the first step in conducting patient-specific cardiac electromechanical simulations is to construct the computational model of the heart from the patient's medical images. In addition to the challenges in reconstructing heart geometry from in vivo clinical scans of low resolution for any other applications, a specific hurdle in constructing the geometric mesh of a patient's heart for electromechanical applications is defining the unloaded state of the heart, since the heart is constantly loaded during image acquisition. Aguado-Sierra et al.  used an Controlling the complex spatiotemporal dynamics underlying life-threatening cardiac arrhythmias such as fibrillation is extremely difficult because of the nonlinear interaction of excitation waves in a heterogeneous anatomical substrate. In the absence of a better strategy, strong electrical shocks have remained the only reliable treatment for cardiac fibrillation. Over the years, biophysically detailed multiscale models of defibrillation have made major contributions to understanding how defibrillation shocks used in clinical practice interact with cardiac tissue –76. Comp Recently, defibrillation modeling has focused on the development of new methodologies for low-voltage termination of lethal arrhythmias or for applying defibrillation in novel, less damaging ways. The study by Tandri et al.  was baseA major avenue of scientific inquiry in computational cardiology relates the binding/unbinding of drugs to molecular target(s) to the instigation, termination or prevention of cardiac arrhythmias. In this section we focus on examples where emergent behavior, resulting from integrations across the scales of biological hierarchy, has shed new light on existing or novel drug actions for treatment of arrhythmia.+ current, IKr [IKr. Perry et al. [IKr, represented by the KCNH2 isoform 1a current expressed in xenopus oocytes. Rate constants in a proposed modal gating scheme were determined to best fit the experimental data. The model revealed that IKr enhancement could be explained by dose-dependent loss of deactivation; point mutation analysis provided the structural mechanism behind this model prediction. Going a step further, Sale et al. [IKr in its open state in a use dependent manner [IKr in its open state, in a use-dependent manner [ At the level of the ion channel, Markov models with state specific drug binding/unbinding have been used to test hypotheses regarding the mechanisms of drug effects on macroscopic currents. Since the arrhythmogenic long QT syndrome (LQTS) type 2 is characterized by loss of repolarizing rapid delayed rectifier Knt, IKr , a straiy et al.  explorede et al.  simulatet manner  on the ht manner . Previou+ current (INa) [INa blocking drugs, lidocaine and mexiletine, revealing that mexiletine preferentially binds to the population of channels undergoing late burst opening; the latter events are dangerously common in LQT3, leading to arrhythmogenic early afterdepolarizations (EADs). By contrast, lidocaine preferentially binds to channels during the rapid activation/inactivation phase of INa. The model showed that there are mexiletine doses, which selectively remove late current and EADs without detrimental effect to excitability. Type 3 LQTS is brought on by enhancement of the noninactivating, or late Nat (INa) . Using Mt (INa)  comparedINa in atrial-selective fashion [INa Markov model. The effect of late INa block by ranolazine on tissue electrophysiology was examined by Morita et al. [INa block suppresses EADs that lead to focal reentry after hydrogen peroxide application, as observed in experiments. Importantly, ranolazine is a mild IKr blocker at clinical doses, an effect of major significance for drug safety. Since current FDA regulations require that new candidate drugs not block IKr, ranolazine would not have been approved if discovered today. Rodriguez et al. [IKr block, a phenomenon known as the “repolarization reserve” [ Nesterenko et al.  also dre fashion ; Nesterea et al. , who demz et al.  proposedz et al.  whose rereserve” . The artreserve”  and the reserve” , 97 alsoIKr blocker, and amiodarone, a complex multichannel effector, to arrhythmia formation in the heterogenous canine ventricular wedge. An emergent finding was the understanding of how the vulnerability window is enhanced by d-sotalol but reduced by amiodarone due to different effects of the drugs on different cell types. Whereas the drug models used by Benson et al. were implemented by simple conduction scaling, a new study by Moreno et al. has incorporated both state-dependent Markov modeling of drug effects and full integration to the human AP, human tissue, and finally realistic MRI image-based human heart [INa block are globally similar in response to dynamic protocols. However, clinical trials have shown previously that flecainide tended to be proarrhythmic at therapeutic doses, while lidocaine was not. Moreno et al. results make clear that neither simple reduction in sodium conductance nor single cell simulation can resolve this paradox. At the macroscopic scale, the vulnerable window was greater for flecainide than for lidocaine  and reentrant arrhythmia in the ventricle persisted , a century-old tool for assessing the electrical activity of the heart, is a global manifestation, on the body surface, of the electrical activity that takes place in the heart during the cardiac cycle. The electrical sources within the heart, separated by tissues from the body surface, are sampled on the body surface by only a few electrodes. This poses a challenge in the treatment of lethal ventricular arrhythmias. Thus, clinicians have sought to gain insight into the spatiotemporal patterns of electrical activation in the heart by interpreting other noninvasively recorded signals. Inverse electrocardiography represents the development on noninvasive methodology for assessing the spatiotemporal electrical activation in the heart, in which body surface electrograms and patient-specific anatomical data are combined with state-of-the-art computational techniques. From a mathematical standpoint, the reconstruction of signals in the domain of the heart from body surface measurements is ill-posed, in that it can easily be corrupted by low-amplitude electric noise or minute positional errors. Thus, the development of tools that can be implemented in clinical practice has been a long and arduous road. The application of inverse electrocardiography in humans has been led by the Rudy lab, whose electrocardiographic imaging (ECGI) method computes epicardial extracellular potential distributions from body surface potential maps. ECGI has been performed on Wolff-Parkinson-White (WPW) patients before and after accessory pathway ablation , to char Studies by the teams of He, Oosterom, Berger, and Kalinin –108 haveRobust methods for stratifying the risk of lethal cardiac arrhythmias decrease morbidity and mortality in patients with cardiovascular disease and reduce health care costs . The mosResearch has reported a strong correlation between increased arrhythmia risk and the presence of T-wave alternans , 128. InA recent study used MRI-based computational model of the human ventricles to demonstrate that detecting instabilities in the QT interval in the clinical ECGs can predict the onset of VT, particularly in patients with acute myocardial infarction . By haviModern cardiac research has increasingly recognized that computational models of the heart can help interpret an array of experimental data and dissect important mechanisms and relationships. This paper focused on another aspect of computational modeling of the heart: its translational potential. Computer simulations of the function of the diseased heart represent a profound example of a research avenue in the new discipline of computational medicine , aiming


Pleurobranchaea may closely resemble that upon which the more complex valuation and decision processes of the social vertebrates are built. The neuronal natures of the pathways in the connectionist model comprise classic central pattern generators, bipolar switch mechanisms, and neuromodulatory state regulation. Marked potential exists for exploring more complex neuroeconomic behavior by appending appropriate circuitry in simulo.A simple circuit for cost-benefit decision derived from behavioral and neural studies of the predatory sea-slug  Organisms are designed to engage three basic functions: resource acquisition, defense against accident , and reproduction. Their lifestyles represent behavioral economic strategies, and range in complexity from very simple solitary foraging to the complicated, multi-layered economies of the social vertebrates. The complexities of valuation, decision-making, and lifestyles are parallel over this range. What are the gradations of complexity in behavioral economy, and how are they traversed in evolution? Let’s begin by examining the simpler systems.In simple terms, goal-directed decision is regulated by an animal’s appetitive state, which is the summation of sensation, internal state, and learning. Operationally, the appetitive state itself is the likelihood that an animal will perform any of a repertory of goal-directed, homeostatic behaviors. The basic premise of behavioral economics is that decisions so made will, on average, optimize success in foraging and reproduction, and minimize accompanying risk. How these computations are effected at levels of neural networks and nerve cells is basic to understanding the genesis of behavioral economics in nervous system function.Pleurobranchaeacalifornica.For foraging animals, a most critical and simple behavioral decision regulated by appetitive state is that for approach or avoidance of a stimulus. The neuronal nature of appetitive state, and how it toggles decision, are problems that have been investigated in the predatory sea-slug, Pleurobranchaea’s simple economy of lifestyle. The sea-slug  from the activated motor networks. Thus, the network interconnections modify appetitive state, mediate reward, and direct behavioral choice.The model is built on an empirical approach to a general theory of cost-benefit decision. It is accessible to hypothesis testing and modifiable from the results of those tests. It represents three types of neuronal networks interconnected in feed-forward and feedback loops: (1) The goal-directed feeding network is regulated internally by satiation state, and externally by sensory inputs that include effects of odor memory  sums into appetitive state with the effects of sensation and learning. Both satiation and general arousal mechanisms entail serotonin (5-HT), a modulator of the feeding network . Thus, it is presently considered that peripheral ganglia may encode the memory of odors for transmission to the CNS in terms of secondary appetence and nociception in the relatively few sensory interneurons  cannibalism, and its larvae are left to find their own luck with myriad other plankton. Thus, the bare-bones model of the decision process is markedly amenable to in simulo experiment with modifications and add-ons that could bring the artificial entities toward social interactions characteristic of functional cognition and consciousness. Some logical add-ons that might be implemented in evolutionarily plausible ways to achieve social characters of higher vertebrates could be territoriality, social hierarchy formation, and altruistic partnering. Here, the building-from-the-bottom-up approach is a potent complement to the top-down, in which the truly intelligent animals are taken apart like one might analyze a complex electronic instrument. Modern computers and communication devices themselves were developed over time from very simple electronic circuits. Indeed, the training of our technicians begins with and builds on those simple circuits. The analogy is obvious for the comparative approach to understanding higher function. We look forward to future efforts in neuroscience and engineering aimed at moving back the borders of this frontier.What actual benefit is offered by the model of Figure cortical or cognitive components in motivation are clearest when we compare the behavior of higher and lower species. Application of a genuine comparative method is essential in the field of motivation as well as of intellectual functions.” It is timely that the comparative method finds fuller fruition now in parallel studies of self-awareness, cognition, and value assessment in species ranging across nematodes, rotifers, sea-slugs, cephalopods, leeches, arthropods, fish, frogs, birds, rodents, carnivores, and the varied species of primates.Interactions of appetitive state with neural bases of reward, learning, and cognition are also only beginning to be appreciated at the neuronal level (e.g., Tindell 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.


Mycobacterium immunologist at the Albert Einstein School of Medicine and is now dean of the Harvard School of Public Health. Dr. Lambert is a vaccine immunologist at the University of Geneva.Few fields in medical science involve as wide a range of specialties and expertise as vaccinology. It encompasses the research, development, and manufacturing processes of vaccines, their incorporation into immunization programs, and the logistic and clinical aspects of their use. Commissioning experts to write chapters with a minimum of jargon, minutiae, and redundancy for a book with a target audience of immunologists, microbiologists, clinical trial specialists, epidemiologists, economists, policy-setting public health officials, and practitioners who administer the resulting products and provide follow-up care, is challenging. But the experienced editors of this book have achieved this goal. Dr. Bloom was previously a ,The Vaccine Book first covers the impact of disease, including chapters on vaccine economics and finance policy, and the potential for widespread vaccination to change the epidemiology of the target disease. One example is the herd effect of childhood rubella vaccination, which postpones infection in nonimmunized women into their childbearing years. The next section reviews the immune system, and here lies the book's greatest disappointment. Its chapter on basic immunology is confusing and presumes familiarity with terms and concepts without antecedent explanation. It lacks a logical flow in describing what is yet known of the (infinitely?) complex immune system and its many "up-" and "down-regulating" feedback loops. Readers hoping for a chapter-length "Immunology 101" course would be advised to turn elsewhere (Leishmania as a case study.The phased stages of clinical trials are covered in excellent chapters by accomplished authors with practical insights. Another section shows how knowledge of microbial pathogenesis can affect vaccine design, including Rolf Zinkernagel's well-written chapter on immunologic memory. Another chapter on parasite pathogenesis, however, delves too deeply into the immunity of Stanley Plotkin's thoughtful overview of the 11 disease-specific chapters annotates new vaccine technologies as well as current issues of debate, such as replacing the live oral polio vaccine worldwide with injectable, inactivated polio vaccine once the eradication program breaks the chain of wild-virus circulation, to avoid reverse mutations and resulting vaccine-associated paralysis. Plotkin also provides a comprehensive table of vaccine types currently available or in active clinical development.Remaining sections of The Vaccine Book cover the ethics of research and use of vaccines, their safety and controversies, and their introduction into healthcare systems. The editors conclude with major future challenges, such as circumventing microbial escape, vaccines for chronic and autoimmune diseases, and maintaining public support of immunization in the face of anti-vaccine movements.The breadth of vaccinology inevitably requires leaving out some topics. There is no chapter on measles vaccines, used universally for a major cause of childhood death and disability. Manufacturing steps such as fermentation, purification, formulation, fill, and finish are not described. There is little on quality assurance and regulation, such as the investigational new drug application process and current good manufacturing practice, although good clinical practice is mentioned. Despite these gaps, compared to this field's authoritative encyclopedia (


Health care for women can be improved by strengthening adult health services, improving health awareness and community participation, decentralizing decision-making, and using epidemiologic surveillance. In the Americas, the Pan American Health Organization supports strategies for the appropriate control and elimination of vaccine-preventable diseases, especially if the strategies are designed to reduce health inequities, strengthen the political commitment for immunization services, and promote the culture of prevention. In September 2003, the 44th Directing Council of the Pan American Health Organization adopted a goal to eliminate rubella and congenital rubella syndrome by 2010. One of the main objectives of this initiative is improving women's health, consistent with achieving the Millennium Development Goals. An important component of rubella elimination is conducting vaccination campaigns for men and women of childbearing age to reduce rapidly the number of people susceptible to rubella infection. From 1998 to 2002, the English-speaking Caribbean, Chile, Costa Rica, Brazil, and Honduras conducted mass rubella vaccination campaigns aimed at adults. Vaccination coverage reached >95% in each country with an exception of the Caribbean, where the coverage was 80%. The Pan American Health Organization (PAHO) supports strategies that encourage political commitment, reduce inequities in health, and enhance the culture of prevention  in the Americas, launched in 1977, was to reduce illness and deaths from prevalent childhood diseases that could be prevented with vaccination , Costa Rica (2001), Brazil (2001–2002), Honduras (2002), and El Salvador and Ecuador (2004) have conducted mass rubella vaccinations among adults. They combined this strategy with the introduction of the rubella vaccine into their national childhood vaccination programs. This combination strategy is designed to rapidly reduce rubella virus circulation, while preventing a shift in the prevalence of the disease to susceptible young adults, especially women of childbearing age. The Caribbean, Costa Rica, Honduras, El Salvador, and Ecuador vaccinated men as well as women, while Chile and Brazil vaccinated only women of childbearing age. The countries that only vaccinated women have reported cases of rubella in 2004; the last congenital rubella syndrome case in Chile was in 2001 and in Brazil in 2004  in their national child vaccination program. The only remaining country, Haiti, should do so in 2005.The experiences of Cuba and the English-speaking Caribbean countries strengthened the commitment for rubella elimination in Chile, Costa Rica, Brazil, and Honduras before the regional elimination initiative was adopted by the directing council of PAHO. These experiences showed that implementing strategies and recommendations to eliminate rubella and congenital rubella syndrome was feasible. In addition, rubella elimination provided opportunities for strengthening the health system by building partnerships and involving national and local authorities In the English-speaking Caribbean, the cost-benefit ratio for vaccination was 13.3:1, and the cost-effectiveness was U.S.$2,900 per prevented case of congenital rubella syndrome. The comprehensive vaccination plan for adults included strategies for safe injections and monitoring adverse events during campaigns. In Chile, health promotion was well-planned, and awareness among women about their own health and their family's increased.In Costa Rica, the decision to conduct the campaign was based on epidemiologic information and cost benefit analyses. The president of the republic declared the event official by executive decree, which greatly facilitated intersectoral coordination of public and private institutions. The strategies to reach older populations in urban and rural areas differed. In urban areas, vaccination teams began with captive populations and ended with door-to-door "mop-ups." In rural areas, the campaign began in more isolated places and moved towards city centers with door-to-door "mop-ups" or micro-concentration. Enlisting the participation of medical societies and professional associations and the active involvement of health workers were essential. Blood banks had to be involved so that the nation's blood supply was not threatened. The monitoring of post-vaccination adverse events and immediate investigation of events was considered a top priority. Extensive follow-up studies of women who were vaccinated and not known to be pregnant demonstrated that an increased risk for adverse events did not exist.In Brazil, social mobilization was the key to the success of a vaccination campaign aimed at adults. Health professionals recognized as leaders and decision makers in the country were called upon to explain the campaign and clarify issues. A rapid response plan was put together in each state to deal with crises or adverse events of vaccination, and a telephone hotline was set up for the public. The most common questions were where to go to be vaccinated (36%), what to do if a pregnant woman had been vaccinated by mistake (14%), and other questions about adverse events (10%). Health authorities used the rapid evaluation tools to determine which groups of women had not been vaccinated and designed effective methods to reach them. In Honduras, adult men in marginal areas rarely seek health services, so the campaign served to increase health contacts.In El Salvador, vaccination methods implemented during the first 2 weeks were aimed at captive populations in work and study centers and in high-transit areas or areas with high populations. House-to-house vaccination was continued after normal work hours to ensure that the adult population was at home. In addition to promotion during the campaign, the plan for social communication and mobilization launched activities aimed at motivating blood donors and avoiding blood shortages before the campaign.In Ecuador, a presidential decree urging public and private sectors to participate was helpful. A total of 6,722 rapid coverage monitoring surveys were performed in 2,006 health units, and 75% of municipalities reported coverage >95%. When coverage was not recorded, the surveys helped to identify susceptible groups and implement "mop-up" activities. The social communication showed that the source of information from health units, TV, and radio was most effective. School source information was also helpful.To accelerate the strategies to eliminate rubella and congenital rubella syndrome, countries were challenged to improve surveillance of congenital rubella syndrome, while strengthening the already established integrated measles and rubella surveillance system. Improving congenital rubella syndrome surveillance required that health authorities more effectively identify and monitor women of childbearing age who may have contracted rubella during their pregnancy.The reporting network of Latin America and the Caribbean includes nearly 22,000 reporting sites. The network encourages collaboration between the public and private sectors. The network has contributed to the formation of trained epidemiologists with experience in surveillance, disease control, and operations research to respond to new, emerging, and reemerging infectious diseases, such as cholera, influenza, and yellow fever (Implementing congenital rubella syndrome surveillance is particularly important during the initial phase of elimination to monitor effectiveness of congenital rubella syndrome prevention. Moreover, all countries are setting up consultation teams in hospitals for congenital infections with the active participation of neonatologists. Well-baby check-ups are used to look for congenital malformations. As a by-product, national registries for identifying all congenital malformations and ensuring their follow-up are being strengthened.Strengthening health services by implementing high-quality congenital rubella syndrome surveillance, periodic well-baby check-ups, or setting up areas for consultations for congenital infections is essential for high-quality, comprehensive perinatal care. The use of these perinatal information systems improves the monitoring of children with congenital malformations and provides them with increased contact with rehabilitation and special education services. The by-product of such efforts is providing patients with better, more specialized care and referrals.Empowering women with the knowledge of prevention is a key strategy for improving the quality of health care for women (Regional perinatal information systems, such as the Latin-American Center for Perinatology and Human Development and the Congenital Malformation Latin-American Collaborative Study, help to improve surveillance and services for newborns (The rubella elimination initiative offers an opportunity to put adults in more frequent contact with the health services. In some communities, adult men also make key decisions affecting care-seeking for women and their newborns. Thus, men must be aware of women's needs, risks, and warning signs. Promoting men's roles as partners and fathers is essential for enlisting their participation and support, a message that is always conveyed during adult vaccination campaigns (A major challenge in women's and perinatal health care is ensuring universal access, which means bring healthcare services high-risk communities where poor and underserved groups live. Because the vaccination campaign is aimed at 100% of the population, inequities based on sex, ethnicity, social class, race, and geographic distribution are reduced. This experience also greatly contributes to the reduction of inequities of maternal health outcomes (To improve the health of all persons, scientists, health providers, administrators, business, media, and religious leaders, and all other sectors of society must be enlisted. The most fundamental challenges faced by the rubella elimination initiative are the mobilization and coordination of all sectors in a joint cause. Promoting women's health care and safe motherhood should be well grounded in a multisector approach that requires carefully building and maintaining partnerships.Immunization services aimed at protecting children have played a decisive role in improving childhood health in the Americas. The foundation for expanding vaccination to other age groups should generate opportunities for strengthening health services for adults. Countries in the Americas are working hard to extend the benefits in the fields of social mobilization, community participation, staff education, epidemiologic surveillance, and program management. Countries are also committed to ensuring that the rubella elimination initiative plays a major role in improving women's health care.


Although item response theory (IRT) appears to be increasingly used within health care research in general, a comprehensive overview of the frequency and characteristics of IRT analyses within the rheumatic field is lacking. An overview of the use and application of IRT in rheumatology to date may give insight into future research directions and highlight new possibilities for the improvement of outcome assessment in rheumatic conditions. Therefore, this study systematically reviewed the application of IRT to patient-reported and clinical outcome measures in rheumatology.Literature searches in PubMed, Scopus and Web of Science resulted in 99 original English-language articles which used some form of IRT-based analysis of patient-reported or clinical outcome data in patients with a rheumatic condition. Both general study information and IRT-specific information were assessed.Most studies used Rasch modeling for developing or evaluating new or existing patient-reported outcomes in rheumatoid arthritis or osteoarthritis patients. Outcomes of principle interest were physical functioning and quality of life. Since the last decade, IRT has also been applied to clinical measures more frequently. IRT was mostly used for evaluating model fit, unidimensionality and differential item functioning, the distribution of items and persons along the underlying scale, and reliability. Less frequently used IRT applications were the evaluation of local independence, the threshold ordering of items, and the measurement precision along the scale.IRT applications have markedly increased within rheumatology over the past decades. To date, IRT has primarily been applied to patient-reported outcomes, however, applications to clinical measures are gaining interest. Useful IRT applications not yet widely used within rheumatology include the cross-calibration of instrument scores and the development of computerized adaptive tests which may reduce the measurement burden for both the patient and the clinician. Also, the measurement precision of outcome measures along the scale was only evaluated occasionally. Performed IRT analyses should be adequately explained, justified, and reported. A global consensus about uniform guidelines should be reached concerning the minimum number of assumptions which should be met and best ways of testing these assumptions, in order to stimulate the quality appraisal of performed IRT analyses. Since there is no gold standard for the assessment of disease severity and impact in most rheumatic conditions, it is common practice to administer multiple outcome measures to patients. Initially, the severity and impact of most rheumatic conditions was typically evaluated with clinical measures (CMs) ,2 such aStatistical methods are essential for the development and evaluation of all outcome measures. By far, most health outcome measures have been developed using methods from classical test theory (CTT). In recent years, however, an increase in the use of statistical methods based on item response theory (IRT) can be observed in health status assessment -10. ExteAlthough IRT appears to be increasingly used within health care research in general, a comprehensive overview of the frequency and characteristics of IRT analyses within the rheumatic field is lacking. The Outcome Measures in Rheumatology (OMERACT) network recently initiated a special interest group aimed at promoting the use of IRT methods in rheumatology . An overFigure Only original research articles written in English were included. Articles were considered original when they included original data and when they performed analyses on this data in order to achieve a defined study objective. To be included, studies should present an application of IRT in a sample of which at least 50% had some kind of rheumatic disease. In cases where less than 50% of the study sample consisted of rheumatic patients , the study was only included when the rheumatic sample was analysed separately from the rest of the sample. Reviews, letters, editorials, opinion papers, abstracts, posters, and purely descriptive studies were excluded. No limitations were set for study design.The search strategy resulted in a total of 385 studies. After the removal of 189 duplicates, 196 unique articles were identified. Two reviewers independently screened all 196 studies for relevance based on the abstract and title identified from the initial search. If no evident inclusion or exclusion reasons were identified, the full-text was examined. In total, 103 studies did not meet inclusion criteria and were excluded. The main reasons for exclusion were: the study population , the statistical analyses (i.e. no IRT application), and the article type . Figure First, two reviewers independently evaluated a random sample of 15 articles. Both general study information as well as IRT-specific information were extracted, using a purpose-made checklist , publication year, study population, the populations’ country of origin, total number of participants (N), study design of the IRT analyses , type of outcome measure (PRO or CM), and main measurement intention .The purpose of the analyses was determined by the main goal the author(s) of the article pursued .Before a researcher can perform IRT analyses, an appropriate IRT model should be selected. Unidimensional models are most widely applied, the simplest being the Rasch model which assumes that the items are equally discriminating and vary only in their difficulty. The 2-parameter logistic model (2-PL model) extends the Rasch model by assuming that the items have a varying ability to discriminate among people with different levels of the underlying construct ,15,19,23The applied IRT software and the corresponding item and person parameter estimation method(s) should also be cited, since not all software packages report the findings in the same way  and becaTo make IRT results interpretable and trustworthy, three principal assumptions should be evaluated when applying a unidimensional IRT model ,23. The Other useful IRT applications include the evaluation of the presence of differential item functioning, the reliability and measurement precision, the ordering of the response categories or item thresholds, and the hierarchical ordering and distribution of persons and items along the scale of the underlying construct.Differential item functioning  is present when patients with similar levels of the underlying construct being measured respond differently to an item ,22. CommGlobal IRT reliability is equivalent to Cronbach’s alpha, with the difference that not the raw score but the IRT score is being used in its calculation. Which specific global reliability statistics are presented usually depends on the software package used. Contrary to CTT methods, IRT also provides information about the local reliability  and, relWith rating scale analysis, the ordering of the response categories or item thresholds can be checked, enabling the evaluation of the appropriateness or redundancy of the response categories . LikewisThe initial database search yielded a total of 93 eligible studies. Six additional studies were identified by manual reference checks of the selected studies. This resulted in a final selection of 99 studies  or osteoarthritis (OA).Outcome measures of overall physical functioning and quality of life were most frequently being analysed. To a lesser extent, studies applied IRT to PRO measures of specific functioning ,29-37, pMost common main goals for both the PRO- and the CM-studies were the development or evaluation of new measures, the evaluation of existing measures, and the development or evaluation of alternate or short form versions of an existing measure. In addition, several studies aimed to cross-culturally validate a patient-reported or clinical measure. IRT was rarely applied for the development of item banks ,58 or coThe vast majority of IRT applications within rheumatology involved Rasch analyses, although a clear specification and rationale of the applied Rasch model was not always given. Few studies used a two-parameter IRT model or Mokken analysis. Most analyses were carried out with the software packages Bigsteps/Winsteps or RUMM.A motivation of the model choice was only provided in 27.3% of the studies. Likewise, the item and person parameter estimation methods were rarely specified .The assumption of unidimensionality was tested in approximately three quarters of the studies. Methods used for this purpose mainly concerned some type of factor analysis  or the examination of specific IRT statistics . No studies were found where unidimensional IRT models were contrasted with multidimensional IRT models.A possible violation of the assumption of local independence was evaluated in only one of the CM studies, and in only 18.8% of the studies concerning a PRO. Evaluation of the studies also indicated there was no clear agreement on how to evaluate this assumption, given the variety of methods used.The assumption of the appropriateness of the model was evaluated by approximately 91% of the studies. When applied, roughly half of the cases evaluated overall fit , almost all evaluated item fit , but a much smaller percentage evaluated person fit statistics .More than half of the studies used IRT to examine DIF. When applied, analyses varied from cross-sectional DIF across gender , age , disease duration , countries/cultures/ethnicity , and disease type , to longitudinal DIF analyses over time .Other commonly performed IRT analyses included analyses of the global reliability, the hierarchical ordering and distribution of items and persons, and rating scale analyses (i.e. the ordering of the response categories or item thresholds). In addition, a small number of PRO-studies reported IRT analyses regarding the measurement precision of the scale, whereas only 1 of the CM studies evaluated this.IRT offers a powerful framework for the evaluation or development of existing and new outcome measures. This is the first study that systematically reviewed the extent to which IRT has been applied to measurements from rheumatology. Results showed a marked increase in IRT applications within the rheumatic field from the late eighties up to now. Even though most research focussed on PROs, IRT also appeared to be useful for application to CMs. Some opportunities for further IRT applications and improvements in the analyses and reporting of IRT studies were also pointed out.IRT can be applied for various purposes. First, IRT analysis is useful for the development and evaluation of new measures . For insIRT is also suitable for the evaluation of existing  outcome measures. For example, when evaluating an instrument’s included response categories it can be determined whether they perform as intended or whether categories should be collapsed into fewer options or expanded into more options . FurtherAnother favourable feature of IRT is that it is expressed at the item level instead of test level as in CTT . By evalAnother commonly used feature of modeling at the item level is the robust assessment of DIF, as reflected in the high proportion of performed DIF analyses. Nevertheless, the full potential of modeling at the item level is not yet being used, given the low percentage of studies evaluating the items’ performance  along the scale.When comparing the studies focusing on RA patients with those focusing on OA patients, the measurement intensions of the analysed instruments and the applied IRT models were highly comparable. However, a notable difference was found in the main goals of these studies. Where the RA studies pursued widely varying main goals, including the development of new instruments, the evaluation of existing instruments, the comparison of different instruments, and cross-cultural validation, the studies on OA patients generally focused on the evaluation of existing instruments only.There are several IRT applications which have not yet been (frequently) used within rheumatology. One IRT application which appears to be still in its infancy within rheumatology, but which is likely to gain importance in the future, is the development of computerized adaptive tests (CATs) . When teThe potential advantages of cross-calibration is another IRT application which has not yet been recognized within rheumatology. As opposed to CTT methods, the item responses are regressed on separate item and person parameters in IRT . This meAs discussed earlier, it is important to test the assumptions of unidimensionality, local independence, and model appropriateness when analysing data by means of IRT methods. Items which violate one or more of these assumptions should be combined, rephrased, or deleted ,23, sincThe results also showed room for improvement in the reporting of made choices and the rationale for specific decisions. For instance, the applied IRT model is often not specified and, if specified, the reasons behind the selected IRT model and used estimation methods are often not clearly motivated. This complicates the quality appraisal and replication of performed analyses.Where Belvedere and de Morton  examinedAlthough IRT is becoming increasingly popular in health status assessment, IRT is quite complex to understand and is not yet a main-stream technique for most researchers and rheumatologists. To increase common understanding and to improve the interpretation of outcomes resulting from the performed IRT analyses, (bio)statisticians, rheumatologists, and researchers should closely collaborate. Clear guidelines on the quality appraisal of performed IRT analyses might increase the use and understanding of IRT in rheumatology even further. Currently, there are no clear guidelines available for rating the methodological quality of the performed IRT analyses. Although standardized tools like the COSMIN  checklist  can be uThe formulation of such guidelines will provide a strong foundation to future IRT studies. Tennant et al. already provided such guidelines for performing Rasch analyses . HoweverA marked increase of IRT applications could be observed within rheumatology. IRT has primarily been applied to patient-reported outcomes, but it also appeared to be a useful technique for the evaluation of clinical measures. To date, IRT has mainly been used for the development of new static outcome measures and the evaluation of existing measures. In addition, alternate or short forms were created by evaluating the fit and performance of individual items. Useful IRT applications which are not yet widely used within rheumatology include the cross-calibration of instrument scores and the development of computerized adaptive tests which may reduce the measurement burden for both the patient and the clinician. Also, the measurement precision of outcome measures along the scale has only been evaluated occasionally. The fact that IRT has not yet experienced the same level of standardization and consensus on methodology as CTT methods stresses the importance to adequately explain, justify, and report performed IRT analyses. A global consensus on uniform guidelines should be reached about the minimum number of assumptions which should be met and best ways of testing these assumptions, in order to stimulate the quality appraisal of performed and reported IRT analyses.2-PL model: 2-Parameter Logistic model; CAT: Computerized Adaptive Test; CM: Clinical Measure; CTT: Classical Test Theory; DIF: Differential Item Functioning; HAQ: Health Assessment Questionnaire; IRT: Item Response Theory; OA: OsteoArthritis; PRO: Patient-Reported Outcome; RA: Rheumatoid Arthritis; SF-36: 36-item Short Form health survey.The authors declare that they have no competing interests.LS was responsible for the conceptualization of the manuscript. LS and PTK were responsible for the screening and identification of studies and the extraction of relevant data. PTK, ET, CG and MVDL supervised the whole study and the interpretation of the results. All authors critically evaluated the manuscript, contributed to its content, and approved the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/13/216/prepubChecklist. Both general study information as well as IRT-specific information were extracted, using a purpose-made checklist based on both expert input and important issues as mentioned in Tennant and Conaghan [Conaghan , Reeve aConaghan , and OrlConaghan .Click here for fileList of included articles. Literature searches in PubMed, Scopus and Web of Science resulted in 99 original English-language articles which used some form of IRT-based analysis of patient reported or clinical outcome data in patients with a rheumatic condition.Click here for file


We critically discuss the operationalization of motivation in current weight control programs, present a complementary approach to understanding motivation based on self-determination theory, and review empirical findings from weight control studies that have used self-determination theory measures and assessed their association with weight outcomes. Weight loss studies which used Motivational Interviewing (MI) are also reviewed, considering MI's focus on enhancing internal motivation. We hypothesize that current weight control interventions may have been less successful with weight maintenance in part due to their relative disregard of qualitative dimensions of motivation, such as level of perceived autonomy, often resulting in a motivational disconnect between weight loss and weight-related behaviors. We suggest that if individuals fully endorse weight loss-related behavioral goals and feel not just competent but also autonomous about reaching them, as suggested by self-determination theory, their efforts are more likely to result in long-lasting behavior change.This article explores the topics of motivation and self-regulation in the context of weight management and related behaviors. We focus on the role of a  More and better studies using MI in overweight/obese persons are also expected in the near future, to provide the needed experimental evidence that will definitively further our understanding of the role of motivation, and self-motivation, in long-term weight control.In conclusion, the current evidence is compatible with the notion that autonomous regulation is among the key predictors of successful weight outcomes. However, intervention research with obese individuals is still in the early stages. Meanwhile, the more abundant evidence for the role of autonomous and intrinsic motivation in exercise and physical activity adherence and studies that have analyzed autonomous eating self-regulation (both reviewed elsewhere , TeixeirThe authors declare that they have no competing interests.PJT led the writing of the manuscript and drafted the first version. DM led the writing of the section on Motivational Interviewing and revised the entire manuscript. JM, MNS, and ALP revised the entire text and made substantial contributions to subsequent versions. All authors read and approved the final manuscript.


Mesenchymal stem cells (MSCs) are adult multipotent cells that give rise to various cell types of the mesodermal germ layer. MSCs are of great interest in the field of regenerative medicine and cancer therapy because of their unique ability to home to damaged and cancerous tissue. These cells also regulate the immune response and contribute to reparative processes in different pathological conditions, including musculoskeletal and cardiovascular diseases. The use of MSCs for tissue repair was initially based on the hypothesis that these cells home to and differentiate within the injured tissue into specialized cells. However, it now appears that only a small proportion of transplanted MSCs actually integrate and survive in host tissues. Thus, the predominant mechanism by which MSCs participate in tissue repair seems to be related to their paracrine activity. Indeed, MSCs provide the microenvironment with a multitude of trophic and survival signals including growth factors and cytokines. Recent discoveries suggest that lipid microvesicles released by MSCs may also be important in the physiological function of these cells. Over the past few years the biological relevance of micro- and nano-vesicles released by cells in intercellular communication has been established. Alongside the conventional mediators of cell secretome, these sophisticated nanovesicles transfer proteins, lipids and, most importantly, various forms of RNAs to neighboring cells, thereby mediating a variety of biological responses. The physiological role of MSC-derived vesicles (MSC-MVs) is currently not well understood. Nevertheless, encouraging results indicate that MSC-MVs have similar protective and reparative properties as their cellular counterparts in tissue repair and possibly anti-cancer therapy. Thus, MSC-MVs represent a promising opportunity to develop novel cell-free therapy approaches that might overcome the obstacles and risks associated with the use of native or engineered stem cells. Over the last decades, adult stem cells have been extensively studied with regard to their potential implications in regenerative medicine. The multipotent precursors of the bone marrow stroma were the first adult stem cells to be identified  in their niche  subpopulations that display the same multipotent potential of adherent MSCs. Moreover, the non-adherent MSCs present the same ability to migrate to damaged tissues The surface antigen pattern is also an aspect of MSC characterization to be carefully considered because the expression of markers changes depending on the surrounding environment, during culture and upon exogenous stimuli  production , nerve growth factor (NGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), indeed Finally, MSCs are able to reverse acute kidney injury in mouse models. Also in this case the precise mechanisms by which MSCs protect from tissue damage is not understood. While initial studies demonstrated that trans-differentiation of the administered MSCs into tubular epithelium cells was responsible for the structural and functional repair of the kidney vesicles (50–100 nm) that are derived from specialized intracellular compartments known as late endosomes or Multi-vesicular bodies (MVBs). Many other types of vesicles exist that presumably derive from the plasma membrane and consensus has been reached to collectively name these extracellular membrane vesicles. Exosomes are released from most cells constitutively, but following activation their release is significantly increased. They were first implicated in reticulocyte maturation and later shown to have an important role in immune responses. More recently exosomes have been found in different biological fluids such as urine, plasma, malignant and pleural effusions of ascites and synovial fluid, and, because of their specific content, have been proposed as suitable biomarkers of different diseases  RNA and protein content of these vesicles.in vivo , and protect from lethal cisplatin-induced AKI, most likely by inhibiting apoptosis of tubular epithelial cells  degeneration MSCs have been demonstrated able to restore the normal disc structure. Since IVD degeneration seems to depend on alterations of nucleus pulposus (NP) cells, Strassburg et al.  investigThe potential use of MSC-MVs for the treatment of cardiovascular diseases has recently been reviewed by Lai et al. . The autIf the beneficial and protective effects of MSC-MVs in tissue repair have been reported in different pathological conditions, their use for cancer therapy needs careful consideration.Bone marrow MSC-derived exosomes have been shown to support tumor growth and angiogenesis in a mouse xenograft model of gastric carcinoma, and the pro-angiogenic effect has been ascribed to the increase of VEGF expression in tumor cells (Zhu et al., While the use of MSCs in regenerative medicine and anti-cancer treatment raised high expectations, concerns about safety and tight regulations hampered their practical use in clinical settings. However, the use of MSC-derived secretome and, in particular, of the vesicles released by these cells may have many advantages compared to a cell-based approach.The increasing interest around this strategy of intercellular crosstalk adopted by MSCs relies on the ability of these vesicles to condition and reprogram the surrounding microenvironment, thereby influencing a variety of biological responses, in particular in injured tissues and cancer.in vivo.MVs function primarily in cell–cell communication, which is, as discussed above, highly relevant in the biology of MSCs. The significant contribution of MSC paracrine activity, rather than their ability to differentiate, to the reparative process has already been established. It will now be of importance to decipher the exact role of MSC secretome and vesicles, since it is likely that in parallel to soluble factors as growth factors and cytokines, MVs strongly contribute to the paracrine effects of these cells. Indeed MVs present a complex composition that mirrors that of the parental cells and seems to have similar properties Therefore, the use of MSC secretome-derived vesicles represents an interesting alternative for tissue repair that might overcome the limitations and risks associated to cell-therapy approaches. Concerning the potential applications for cancer therapy, exosomes released by opportunely engineered MSCs may still retain the ability to home to tumor site and, at the same time, mediate anti-proliferative or pro-apoptotic effects, relieving the concerns related to the genetic manipulation of stem cells for cell-therapy.Evidently, crucial questions need to be answered before the objective described above can be satisfactorily fulfilled. First, it is necessary to verify to which extent MSC micro- and nano-vesicles contribute to the beneficial effects mediated by MSCs; second, the content of these vesicles, in terms of proteins and, in particular, small RNAs, needs to be thoroughly characterized; and, finally, it is essential to uncover the effect of the genetic content of MSC-MVs on recipients cells and determine which cellular pathways may be affected.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.


Atherosclerosis is a chronic inflammatory disease of the arteries. Clinical consequences of the atherosclerotic process occur in the adult population, however atherosclerotic process begins in childhood. The classic risk factors for atherosclerosis include obesity, dyslipidaemia, age, gender or family history. In recent years, attention has been drawn to the similarity between atherosclerotic inflammatory processes and inflammatory changes in the course of systemic connective tissue disease, in particular systemic lupus etythematosus (SLE) or rheumatoid arthritis (RA). There is also observed the similarity of the pathogenetic background of development of atherosclerosis and juvenile idiopathic arthritis (JIA). Elevated levels of pro-inflammatory cytokines are observed in the course of juvenile idiopathic arthritis. Also homocysteine concentrations, which may play a significant role in the development of atherosclerotic lesions, are observed higher in patients with JIA. Some studies revealed higher carotid intima-media thickness (IMT) index values in children with JIA. In view of the fact that atherosclerotic process begins as early as in childhood, the introduction of appropriate preventive measures in children is a matter of utmost importance. Elevation of the concentrations of acute phase proteins, such as CRP, is also a reflection of the inflammatory process. An elevated homocysteine concentration also increases the risk of developing cardiovascular diseases. Awareness of the fact that initiation of the atherosclerotic process takes place very early in life underscores the need for identifying these changes as early as possible despite the absence of clinical symptoms. Special attention must be given to children belonging to the risk group for cardiovascular disease, which includes children with the following medical problems: familial hypercholesterolaemia, diabetes, chronic kidney disease, a past history of neoplastic disease, Kawasaki disease, congenital heart disease, history of a heart transplantation, and chronic inflammatory diseases. Chronic inflammatory diseases include juvenile idiopathic arthritis (JIA); typically, this disease begins before the age of 16 years and has several clinical presentations, of which the most common is the oligoarticular-onset JIA, affecting 1 to 4 joints, and less common subtypes: polyarticular-onset JIA (inflammation of 5 or more joints), systemic JIA and psoriatic arthritis, enthesitis-related arthritis, and forms that do not meet the criteria for the abovementioned subtypes or comprising features of more than one of these subtypes [Atherosclerosis is a chronic inflammatory disease of the arteries. Clinical consequences of the atherosclerotic process, in the form of ischaemic heart disease, disorders of cerebral circulation, or circulatory disorders of peripheral arteries occur in the adult population; however atherosclerotic changes have their beginning in childhood. The severity of atherosclerosis correlates with the number and intensity of risk factors such as body mass index (BMI), systolic and diastolic arterial blood pressure, total cholesterol, LDL, HDL, triglyceride concentrations, and passive and active cigarette smoking. At present, much significance is attached to the inflammatory aetiology of atherosclerosis, which makes it an inflammatory disease, a vascular wall response to injury. Proinflammatory cytokines, such as IL-1b, IL-6, IL-8, or TNF-n = 35) and preterm newborns who had died soon after birth (n = 47). The mean age of the examined foetuses was 6.2+/− 1.3 months. Some of the mothers of the examined foetuses had a history of hypercholesterolaemia prior to and during the course of their pregnancy, some only during pregnancy, while others had no history of hypercholesterolaemia. Atherosclerotic lesions were present in 60–80% of the examined aortas, irrespective of whether the mothers of these foetuses had normal cholesterol concentrations or hypercholesterolaemia, and the rate of progression of these changes corresponded to the severity of hypercholesterolaemia. The atherosclerotic process begins in childhood, and even in utero. Evidence of this was found in studies by Italian pathologists, headed by Napoli and Palinski –4. They In the FELIC (Fate of Early Lesions in Children) study, Napoli et al. assessed the aortas of 156 children, aged 1 to 13 years, who had died as a result of trauma or other sudden causes. The children were stratified according to maternal cholesterol status (normocholesterolaemic or hypercholesterolaemic) during pregnancy. All of the children had normal serum cholesterol concentrations. Nonetheless, atherosclerotic lesions in the abdominal aorta and the aortic arch, whose progression advanced with age, were present in all the children; moreover, the rate of progression of these lesions was higher in children of hypercholesterolaemic mothers versus that in children whose mothers were normocholesterolaemic [The Bogalusa Heart Study was an extensive epidemiological study evaluating cardiovascular risk factors in both African Americans and Caucasians, conducted in Louisiana (USA) in the years 1972–2005. In 1998, autopsy reports of 204 individuals who had died from sudden causes were published as part of this study. Fatty streaks were present in all the examined aortas. The presence of fatty streaks in the coronary arteries increased with age and was seen in 50% of children aged 2–15 years and in 85% of individuals in the 26- to 39-year age group. These studies also revealed an association between the extent of atherosclerotic lesions and the presence of risk factors for atherosclerosis  [The prevalence of atherosclerotic lesions in young individuals was also assessed in the multicentre Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. The study group consisted of approximately 3,000 individuals who had died aged 15 to 34 years as a result of accidents, suicide, or homicide. Fatty streaks were present in all the adolescents. The degree of progression of atherosclerotic lesions increased with age. Lesion size and the degree of progression were higher in men than in women. The risk factors for developing atherosclerotic lesions were obesity, smoking, and arterial hypertension. Ten percent of the examined young individuals were found to have very advanced atherosclerotic lesions and 80% of them were cigarette smokers [The presented studies, which were based on autopsy results, reveal not only the presence of atherosclerotic lesions, but also a correlation between these changes and the established risk factors for cardiovascular disease: BMI, arterial hypertension, serum lipoprotein concentration, and cigarette smoking. The earliest possible identification of increased-risk groups that should receive particular preventive care becomes of utmost importance. In December 2006, the American Heart Association (AHA) published guidelines endorsed by the American Academy of Pediatrics. Children with the following diseases were identified as being at high risk for cardiovascular disease: familial hypercholesterolaemia, diabetes, chronic kidney disease, a past history of neoplastic disease, Kawasaki disease, congenital heart disease, history of a heart transplantation, and chronic inflammatory diseases. The abovementioned diseases were then divided into 3 groups according to the level of risk. Chronic inflammatory disease was classified as a moderate-risk disorder . March 2The classic risk factors for atherosclerosis have been well known for years. They include both factors that are amenable to modification, such as obesity or dyslipidaemia, which allow for the introduction of appropriate preventive measures, as well as factors that are not amenable to modification, such as age, gender, or family history, which makes it possible to establish the group at high risk for cardiovascular disease. α, play a significant role in the development and progression of atherosclerotic lesions. The inflammatory process is also reflected by an increase in the concentration of acute phase proteins, such as C-reactive protein (CRP).In 1999, Russell Ross presented his ground-breaking hypothesis of an inflammatory aetiology of atherosclerosis . AccordiChronic inflammatory diseases are rheumatic diseases—such as rheumatoid arthritis or juvenile idiopathic arthritis, diseases with multifactorial aetiology and pathogenesis. In recent years, attention has been drawn to the similarity between atherosclerotic inflammatory processes and inflammatory changes in the course of systemic connective tissue diseases, in particular systemic lupus erythematosus or RA. Persistently elevated CRP values in the course of RA increase the risk of death due to cardiovascular disease . CRP detCardiovascular disease is the main cause of mortality in patients with RA . CompareAt the same time, attention is being drawn to the similarity of the pathogenetic background of development of atherosclerosis and JIA. Children with JIA are seen to have lipid metabolism dysfunction. A study by Urban et al. in 25 children with JIA, with early-phase disease and an absence of clinical signs of obesity, revealed increased concentrations of total cholesterol, LDL, and triglycerides; decreased concentrations of HDL; as well as correlations between homocysteine and total cholesterol concentrations, and homocysteine and LDL .Studies by Gonçalves conducted in a group consisting of 28 children with the polyarticular subtype of JIA revealed decreased HDL concentrations in the serum of 57% of patients with polyarticular JIA and elevated LDL values in 18%; 14% of the children had elevated triglyceride levels while 7% had elevated total cholesterol values. There was no association between reduced HDL concentrations and disease activity, the duration of the disease or the treatment administered . StudiesHomocysteine is a sulphur-containing amino acid produced in the body in the course of methionine conversion, obtained from food. An increase in homocysteine concentration may be caused by a genetically determined deficiency or absence of enzymes involved in the metabolism of homocysteine, a deficiency of coenzymes participating in the conversion of homocysteine, and medications, among them methotrexate, which is the dihydrofolate reductase inhibitor. Methotrexate is the drug most commonly used to treat juvenile idiopathic arthritis. Regarding genetic influence, it is known that a genetic polymorphism—MTHFR 1298 A/C—associated with changes in the levels of homocysteine was also found to influence the development of endothelial dysfunction and increased risk of cardiovascular disease in adults with RA . PostmorProinflammatory cytokines play a significant role in the development of atherosclerotic lesions . ElevateThe problem of finding noninvasive methods of assessing the risk of developing atherosclerosis in children with risk factors for atherosclerosis, including children with JIA, is answered by carotid intima-media thickness (IMT) assessment via ultrasonographic imaging. A rent meta-analysis confirmed that IMT is increased in adults with RA . This isCarotid intima-media thickness represents the combined thickness of the intimal and medial layers of carotid artery. The method showing changes in the microcirculation is the capillaroscopy, a simple, safe, and easy technique. It is a good method for detecting microvascular abnormalities in disorders associated with Raynaud's phenomenon. The presence of microangiopathy, ascertained using this technique, appears to be associated with endothelial dysfunction, the earliest form of the atherosclerotic process. However, definitive conclusions regarding the usefulness of capillaroscopic examination requires further studies .At present, there are many known risk factors for developing atherosclerosis. Some of them are amenable these may be modified, while some are nonamenable, these cannot be modified; however, they make it possible to identify groups at increased risk for cardiovascular diseases. The list of new factors is constantly growing. In view of the fact that clinical consequences of the atherosclerotic process manifest themselves in the adult population while the atherosclerotic process itself begins as early as in childhood, the introduction of appropriate preventive measures in children, particularly children belonging to the risk group for cardiovascular disease, including children with JIA, is a matter of utmost importance. These measures may halt the development of the atherosclerotic process at a very early stage. However, further studies are required that would enable assessment of the risk of early development of atherosclerosis in children, including children with JIA, particularly since attention is being increasingly drawn to the similar pathogeneses of atherosclerosis and JIA.


The visual cortex has been traditionally considered as a stimulus-driven, unimodal system with a hierarchical organization. However, recent animal and human studies have shown that the visual cortex responds to non-visual stimuli, especially in individuals with visual deprivation congenitally, indicating the supramodal nature of the functional representation in the visual cortex. To understand the neural substrates of the cross-modal processing of the non-visual signals in the visual cortex, we firstly showed the supramodal nature of the visual cortex. We then reviewed how the nonvisual signals reach the visual cortex. Moreover, we discussed if these non-visual pathways are reshaped by early visual deprivation. Finally, the open question about the nature (stimulus-driven or top-down) of non-visual signals is also discussed. The visual cortex has been traditionally considered as a stimulus-driven, unimodal system with a hierarchical organization, in which the early visual areas V1, V2) tune to general features while the higher-tier ones  respond selectively to the specific features of a visual stimulus , V2 tune. Two parThe structural and functional organization of the visual areas is supposed to develop through a combination of genetic instruction –11 and eHowever, the notion of the visual cortex as a unimodal system molded only by visual experience has recently been challenged because the visual cortex of both the sighted controls (SC) and the CB responded to a variety of nonvisual perceptive stimuli, including tactile, auditory, and olfactory. Furthermore, the visual cortex of the CB was also involved in cognitive processes, such as linguistic processing, working memory, and attention. Although the extent and magnitude of the activation in the visual areas depend on the tasks and subjects' characteristics , 38, theThe main topic of this review is to elucidate how the nonvisual signals recruit the visual cortex. We firstly provide evidence if the visual cortex is supramodal in nature, and then we reviewed how the nonvisual signals reach the visual cortex. Next, we discussed if these nonvisual pathways are reshaped by early visual deprivation. Finally, we also discussed about the nature (stimulus-driven or top-down) of nonvisual signals.Unimodal theory supposes that the visual cortex is specifically allocated to process visual stimuli in sighted people; however, this hypothesis has recently been challenged. Using the positron emission tomography (PET), Sathian et al. first reported that the extrastriate area close to the parietooccipital fissure (V6) was activated during discrimination of grating orientation compared with discrimination of grating groove width, suggesting this visual area is recruited in the processing spatial information of tactile signals . To furtThe cross-modal recruitment of the visual cortex has also been reported in auditory domain. As early as 1972, Morrell found that up to 41% of recorded neurons in extrastriate cortex of adult cats were modulated by both visual and auditory stimuli and that the receptive fields for both responses typically overlapped in space . Recent Relative to the sighted subjects, cross-modal processing of nonvisual signals in the visual cortex has been more extensively reported in the CB and EB subjects when they perform nonvisual perception and high-order cognitive tasks. Numerous studies reported that the visual cortex was recruited during diverse tactile tasks, such as the early and higher visual areas were activated in vibrotactile frequency discrimination , the hMTSimilar with the tactile perception, the activation of the visual cortex by auditory perception was also frequently reported in CB subjects , 65, 66.In the CB, besides auditory and tactile perception, the visual cortex was also recruited in olfactory processing . In thisThe visual cortex in EB subjects is not only involved in nonvisual perception, but also takes part in the process of higher-level cognitive tasks, such as language, attention, and working memory. Converging evidence supports the involvement of the visual cortex in language processing in the CB or EB subjects. The medial visual cortex was recruited during Braille reading –85 and t Besides the language processing, the visual cortex that normally subserves vision is activated in the CB subjects when performing nonvisual attention-demanding tasks, such as spatial attention discrimination , 35, 36.The visual cortex can also be activated by memory task with nonvisual stimuli or without any sensory input –101. TheTwo neural mechanisms have been proposed to explain the involvement of the visual cortex in the processing of nonvisual stimuli. One hypothesis holds that the visual cortex is supramodal in nature, which means that an occipital area relies on a common, abstract representation of the perceived stimuli irrespective of the sensory modality. Another hypothesis is the cross-modal plasticity. In the CB or EB, the visual cortex that normally serves to process visual input shifts to cross-modal process nonvisual information via plastic reorganization of the inner structure and function. However, the two mechanisms are not mutually exclusive, and they might coexist in the EB. As discussed above, many pieces of evidence that showed the involvement of the visual areas in processing nonvisual inputs in both the SC and EB may support the supramodal hypothesis , that is, involved in processing both visual and tactile motion, and a posterior part , which is only involved in processing visual information. In the EB, however, the entire hMT+ is involved in the representation of tactile motion, suggesting the coexistence of the supramodal (anterior part) and plastic (posterior part) mechanisms in this region. These results represent competitive interactions between visual and nonvisual inputs in the reshape of hMT+ complex , 116. It should be noted that the improved nonvisual perception performance in the early blind subjects can also be the consequences of the experience-dependent plasticity of their auditory or somatosensory related cortices. For example, the mice that are binocularly enucleated from birth demonstrate remarkable expansion of their barrel cortex, which may be interpreted by increased usage of the whiskers after visual deprivation . Cats thAs discussed above, much evidence supports the cross-modal processing of nonvisual signals in the visual cortex. It is then important to understand how the nonvisual sensory information reaches the occipital areas, especially in the CB subjects who have no visual experience about the external world. The candidate pathways include the thalamooccipital and corticooccipital pathway, which is categorized in Figures The thalamus is an important relay that receives afferents from different sensory organs and sends efferents to the primary sensory cortex. Under normal condition, the thalamic nuclei are relay stations via which sensory information from the peripheral sensory receptors can reach the primary sensory cortex. For example, the lateral geniculate nucleus (LGN), the “visual” thalamic relay, mainly transfers visual signals to the primary visual cortex (V1); the medial geniculate nucleus (MGN) is the “auditory” thalamic relay that connects the inferior colliculus (IC) and the primary auditory cortex (A1); and the ventral posterior nuclei (VP) is the “somatosensory” thalamic relay that receives tactile signals and transmits them to the primary somatosensory cortex (S1) , 121. FuRecent findings have shown that the LGN and its output projections to the V1 are atrophied in early blind subjects , 26, 27,An alternative pathway is that the visual areas receive nonvisual sensory information through corticooccipital connections between these sensory modalities , 153. ThThe corticooccipital pathway hypothesis is also supported by task-based fMRI studies , 172 andIt should be noted that these two pathways cannot be absolutely segregated in the brain network. They are interacted with each other by feed forward and feed back projections. For example, the auditory signals can first feed forward to the A1 for initial processing, and then feed back to the MGN and multimodal thalamic nuclei  , and finThe existing thalamo-cortical and corticooccipital pathways found in the normal adult animals and humans provide anatomical evidence of the supramodal nature of the visual cortex. Auditory and tactile information can be conveyed to the occipital areas through the direct and indirect connections. This anatomical connections pattern can explain the cross-modal involvement of visual cortex by nonvisual sensory tasks; furthermore, it can explain the development of a portion of the visual areas does not depend on the visual experience because inputs from other sensory modalities are sufficient to support the development of these functional patterns.in vivo evidence. In contrast, there are considerable studies showed that the whole segments of retinofugal pathway, including the optic tract, the LGN, and optic radiation, suffered atrophy and loss of integrity in humans after early visual deprivation [Two competing hypotheses have been proposed to explain the neural mechanisms of cross-modal plasticity after early visual deprivation. According to the rewiring hypothesis, cross-modal brain responses are mediated by the formation of new pathways in the sensory deprived brain. For example, after experimental destruction of the superior colliculi and the visual cortex in neonatal hamsters, the authors observed a strong projection from the retina to the A1, which can “perceive” the visual information , 179. Strivation , 23, 27.The unmasking hypothesis proposed that the loss of a sensory input induces unmasking and/or strengthening of the existing neural pathways. As discussed in Sections As shown in The following evidence supports stimulus-driven nature of the nonvisual signals that reach the visual cortex. These nonvisual signals can be conveyed from sensory organs to the visual cortex via rewired thalamic-cortical pathway –139 and According to the top-down mechanism, the peripheral auditory/tactile signals are firstly modulated and refined by the higher-level cortical regions, such as the multisensory associate areas , and then feed back to the visual cortex through the indirect corticooccipital pathway and cortico-thalamooccipital pathway . The exiVisual imagery mechanism supports the hypothesis of top-down recruitment of the visual cortex because the mental progress can recruit the visual cortex –108. ForTop-down attention may be the most extensively studied cognitive process that can modulate the activation of the visual cortex –208. It In the CB subjects, electrophysiological or neuroimaging studies have revealed that the top-down attention modulation was strengthened when they performing tactile/auditory attention-demanding tasks , 212–215In summary, the nature of the nonvisual signals to the visual cortex may be either stimulus-driven or top-down, or both. Indeed, effective connectivity analysis offers evidence for the coexistence of both bottom-up and top-down information flows during nonvisual perception –223. in vivo evidence for the former. Further studies with more advanced in vivo imaging techniques should be implemented to clarify this issue. Finally, the nature of the nonvisual signals to the visual cortex may be either stimulus-driven or top-down, or both. Further understanding the issue may help us to design appropriate interventions to improve the adaptive capacity of blind subjects to the external environments.The cross-modal processing of nonvisual signals in the occipital areas in both sighted and EB subjects suggests that the functional organization of the visual cortex is supramodal in nature. The cross-modal plasticity can also account for parts of the findings in the EB subjects. The normally existing thalamo-cortical and corticooccipital pathways provide anatomical evidence for the supramodal nature of the visual cortex. The cross-modal plasticity in the EB might be driven by two neural mechanisms: rewiring and unmasking, although there is lack of


Eukaryotic adaptation pathways operate within wide-ranging environmental conditions without stimulus saturation. Despite numerous differences in the adaptation mechanisms employed by bacteria and eukaryotes, all require energy consumption. Here, we present two minimal models showing that expenditure of energy by the cell is not essential for adaptation. Both models share important features with large eukaryotic cells: they employ small diffusible molecules and involve receptor subunits resembling highly conserved G-protein cascades. Analyzing the drawbacks of these models helps us understand the benefits of energy consumption, in terms of adjustability of response and adaptation times as well as separation of cell-external sensing and cell-internal signaling. Our work thus sheds new light on the evolution of adaptation mechanisms in complex systems. Adaptation is a common feature in sensory systems, well familiar to us from light and dark adaptation of our visual system. Biological cells, ranging from bacteria to complex eukaryotes, including single-cell organisms and human sensory receptors, adopt different strategies to fulfill this property. However, all of them require substantial amounts of energy to adapt. Here, we compare the different biological strategies and design two minimal models which allow adaptation without requiring energy consumption. Schemes similar to the ones we proposed in our minimal models could have been adopted by ancient protocells, that have evolved into the pathways we now know and study. Analyzing our models can thus help elucidate the advantages brought to the cells by consumption of energy, including the bypassing of hard-wired cell parameters such as diffusion constants with increased control over time scales. Dictyostelium discoideum chemotaxis The ability to adapt to different environmental conditions is a hallmark of any living organism, allowing sensory systems to adjust their sensitivity to changes in nutrient availability, stress, and other stimuli et al.In light of such complexity, the “physicist's approach” may help guide the identification of common principles among the different pathways. Recently, Lan Escherichia coli, known for amplifying weak signals by cooperative receptors and precise adaptation . The excitation of the receptor catalyzes the production of GTP and the dissociation of the G-protein. GTP then binds to the DictyosteliumDespite these similarities, eukaryote's most striking feature is the staggering complexity, often relying on long, multistep signaling cascades in parallel scoideum , and phoscoideum  and olfascoideum  in mammaAll bacterial and eukaryotic adaptation pathways share the consumption of energy by hydrolysis of fuel molecules, including S-adenosyl methionine (SAM) in bacterial chemotaxis, and cyclic adenosine and guanosine monophosphate (cAMP and cGMP) in eukaryotes Here, we present two minimal models in which a protocell exploits the non-equilibrium aspect of the changing external environment to respond and adapt to a stimulus without consuming (dissipating) energy itself. The first model contains only one component, represented by a receptor on the cellular membrane , left. TIn case the external stimulus cannot be used to mediate adaptation, e.g. for photo-transduction, a second model with two components is needed , left. Toff (inactive) state (with ligand dissociation constants on (active) state , which allows cells to interpret chemical gradients irrespective of scale Another important feature of adapting systems is on to off. When the ligand enters the cell, even a small concentration is enough to bind intracellularly the receptor in the on-state, turning it on. Therefore adaptation is fast, and the adaptation time decreases with increasing input steps due to the increased ligand gradient and flux. On the contrary, after a negative step, the state of the receptor is on with a high intracellular concentration of ligand, and thus for the receptor to switch off, the intracellular concentration has to decrease below the  intracellular Dictyostelium chemotaxis has the opposite trend The experimental adaptation times behave very differently  in response to an extracellular stimulus. A direct activation of this kind is similar to the conformational change-based mechanism in the bacterial chemotaxis pathway. In contrast, metabotropic receptors are more sophisticated: triggering of the receptor activates a cascade, usually a G-protein, leading to a change of second messenger concentration. This often involves complex feedback mechanisms Dictyostelium cells and to the inflow of Dictyostelium pathway this ligand is responsible for both sensing and adaptation. cAMP is not only outside and inside the cell, but also follows the external stimulus Click here for additional data file.


In the past two decades, significant advances have been made in understanding the structural and functional properties of biological networks using graph-theoretic analysis. In general, most graph-theoretic studies are conducted in the presence of serious uncertainties, such as major undersampling of the experimental data. In the specific case of neural systems, however, a few moderately robust experimental reconstructions do exist, and these have long served as fundamental prototypes for studying connectivity patterns in the nervous system. Here, we provide a comparative analysis of several "historical" graphs, including areal connectivity graphs of the cat and macaque monkey cortex -3, as weWhile it is a common practice in applying graph-theoretic measures to empirical data to symmetrize the connectivity matrix prior to analysis, here we work with the graphs both in their unmodified directed, and symmetrized undirected forms, focusing on simple structural characterizations of their connectivity. This characterization includes the node degree distributions, the structural equivalence of graph nodes, as well as a nearest neighbor degree and assortativity analysis. All utilized measures are defined for directed graphs, but yield their forms known from the literature when applied to undirected graphs ,7.We find that the investigated networks share a strong component of randomness in their structural makeup, suggesting a mechanism of their formation which is much less constrained than that required for scale-free graphs. Specifically, fits of the node degree distributions are in accordance with a gamma model, supporting the idea of a simple local mechanism responsible for generating neural graphs. Secondly, the Euclidean distance of node adjacencies and node degree correlations are consistent with a independent random distribution of node connections for different nodes, but with strong correlations between in-coming and out-going connections for the same node. Finally, we find a weak disassortative tendency in the considered graphs, suggesting that in biological neural graphs nodes tend to be connected with nodes of higher average node degree.In conclusion, our results suggest that the structural makeup of biological neural graphs has a very strong random component, in contrast to previous studies promoting the view of dominant structural features such as scale-freeness. However, the observed graph structures differ from that of the Erdos-Renyi random graphs most widely used in the computational literature, by their specific node degree distribution and strong correlations of in-coming and out-going connections for individual nodes.


In the last years, medicine has seen a shift from a depersonalized towards a patient-centered individualized medicine. This, on the one hand, is based on the achievements in the field of genetics and molecular science fostering an individually designed drug therapy and treatment tailoring . On the The most common and comprehensive definition up to now has been given by the Consortium of Integrative Medicine in 2005. It describes integrative medicine as “the practice of medicine that reaffirms the importance of the relationship between practitioner and patient, focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic approaches, healthcare professionals, and disciplines to achieve optimal health and healing” . It therIn the last decades, several hospitals have adopted this concept of integrative medicine for the treatment of chronic and acute states of illnesses in an inpatient treatment. For instance, Sendelbach et al. (2003) describe the development of an inpatient integrative therapies program in a cardiovascular tertiary care center . Ernst aIn almost all cases, these hospitals have integrated one or more complementary disciplines as naturopathy, anthroposophical medicine, homeopathy, or traditional Chinese medicine. While, in the USA integrative medicine has emerged towards a marker for innovative quality patient care within the last two decades, other countries have a longer tradition in this field . In GermOf note, whole-systems evaluation of integrative in-patient treatment might also benefit from a systematic analysis of the patient characteristics of clinical pathways and flow processes between in- and outpatient treatments, which has been described .Finally, concepts of combining education, teaching, and in-patient integrative treatment can be seen as an important milestone for the development of integrative medicine. If only students are able to discover and get some first insight into the potential different perspectives of medicine and healing, they might be able to argue open-mindedly about the best fitting therapeutic strategy for the individual patient to regain his optimal health .Despite these current achievements, evaluations of the approach of integrative medicine as a whole system and its interactions with other services of patient care have only been seen marginally. Thus, the cutting edge for the future development of integrative medicine now is to close the “evidence gap”  and to sThis special issue tries to step into this direction by bringing together evidence from different perspectives. Apart from whole-systems evaluations of hospital programs, cost studies, and findings on educational aspects of integrative medicine, this issue also covers historical aspects of the development of integrative medicine and presents the meta-analyses of integrative approaches. Hopefully, science-driven implementation of integrative medicine into hospitals and patient care can improve the 21st century medicine.Thomas OstermannThomas OstermannAndre-Michael BeerAndre-Michael BeerVassya BankovaVassya BankovaAndreas MichalsenAndreas Michalsen


The application of emerging nanotechnology to the practice of medicine represents a frontier of nanomedicine. Nanomedicine has been defined as a science which emphasizes the use of nanoscale tools in conjunction with background knowledge of the human body for medical diagnosis and treatment. Application of nanomedicine in EM may give EM providers the opportunity to diagnose and treat life-threatening diseases in a shorter period of time. These applications include diagnostic utilities, preventive medicine, targeted pharmacotherapy, and tissue regeneration. The concept of nanotechnology arose in the 1950s with Feynman’s vision that engineering could occur on an atomic level . PresentThe application of emerging nanotechnology to the practice of medicine represents a frontier of nanomedicine. Nanomedicine has been defined as a science which emphasizes the use of nanoscale tools in conjunction with background knowledge of the human body for medical diagnosis and treatment . By operPoint-of-care testing: EM providers use point-of-care testing to promote rapid clinical decision-making and appropriate triage, thereby increasing emergency department (ED) throughput. These include tests for glucose, electrolytes, renal function, blood gas, pregnancy, cardiac biomarkers, and infectious diseases. Nanoscale technology allows for the development of highly sensitive point-of-care detection devices. For example, a recently developed microfluidic device with a surface plasmon resonance system demonstrated considerable sensitivity in its ability to measure a B-type natriuretic peptide concentration of 5 pg/mL . FlorianNeurologic disease: Magnetic resonance imaging (MRI) is a powerful tool for diagnosis of structural central nervous system pathology . A nanopCardiovascular diseases: Applications of nanomedicine in cardiovascular diseases include diagnosis and treatment of atherosclerosis and decreasing re-stenosis rates after stenting. An advantage of using a nanoscale agent is early detection of disease . AlthougNanomedicine offers several strategies for improving the efficiency of pharmacotherapy. Encapsulating relatively insoluble pharmaceuticals in liposomes or micelles enhances drug solubility in the bloodstream ,16. ThesThese numerous benefits are evident when applied to the treatment of ischemic CVA in the ED. Ischemic CVA is a source of significant morbidity and mortality in the United States . To restMorrow et al. have anticipated the concept of a nanomachine, nanoscale technology which would target lesions  within a patient to modify pathophysiology at the molecular level . In patiThe future may see the synthesis of novel nanomaterials for acute management of trauma  in the ED. Being biologically inert and hence less antigenic, use of these nanomaterials in tissue regeneration may eliminate the need for organic grafts and transplants, which are subject to compatibility and supply limitations . In a haApplications of nanomedicine in EM may give physicians’ opportunity to detect and treat life-threatening diseases in short period of time. These applications include diagnostic utilities, preventive medicine, targeted pharmacotherapy, and tissue regeneration. -It is worthwhile to mention that there are still some concerns regarding nanoparticles' functionality and their characteristics in vivo versus in vitro.The authors have no commercial associations or sources of support that might pose a conflict of interest.All authors have made substantive contributions to the study, and all authors endorse the data and conclusions. All authors read and approved the final manuscript.