This article introduces the identification, prevention, and treatment of hereditary cancer as an important public health concern. Hereditary cancer research and educational outreach activities are used to illustrate how public health functions can help to achieve health benefits of genetic and genomic medicine. First, we evaluate genetic service delivery through triangulating patient and provider survey results which reveal variability among providers in hereditary cancer knowledge and genetic service provision. Second, we describe efforts we have made to assure competency among healthcare providers and to inform, educate and empower patients with regard to the rapidly evolving field of genomics and hereditary cancer. Lastly, key policy-issues raised by our experiences are discussed in the context of how they may help us to more effectively translate future genomic technologies into practice in order to attain population health benefits from genetic and genomic medicine. The National Human Genome Research Institute defines genetics as the study of genes and their role in inheritance . As an eGenetic and genomic medicine involves using genetic or genomic information as part of an individual’s clinical care  . SeveralGenomic medicine, however, is typically less focused on the inheritance of single genes that confer high risks for disease. An example of cancer genomics involves sequencing of tens or hundreds of genes in a tumor from a cancer patient to help in selecting cancer treatments. An important distinction here is that the gene mutations identified in most tumors are not the result of inherited mutations, but occur after conception and are typically only present in the tumor cells. Tumor sequencing is already being incorporated into clinical care at many cancer centers and hospitals across the U.S..The next challenge is going “beyond the bedside” to ensure that genetic and genomic tests are leading to sustained and wide-spread population health benefits while preventing adverse outcomes . We discBRCA1 mutation that confers increased risks for breast and ovarian cancers of up to 70% and 40%, respectively [Targeted therapies and cancer prevention or screening options may be refined based on inherited gene mutations ,5. One oectively ,7,8,9. Tectively ,11.As this real-world experience illustrates, identifying hereditary cancer predisposition is of critical public health importance because it changes cancer risk management options and enables patients and their at-risk family members to benefit from proven cancer prevention or early detection options, which can reduce risks to near that of the general population ,13. MoreEvidence supporting the health benefits of using genetic tests and family health history in clinical practice is reflected by the addition of genomics objectives to Healthy People (HP) 2020 . The firAchieving these HP objectives requires the effective translation of genetics and genomics into healthcare practice through engagement in public health functions at multiple levels, including the patient/family, healthcare providers, and healthcare system  see Fig. In the Ongoing efforts to evaluate genetic service delivery are critical in the context of hereditary cancer given the evolving landscape in which services are provided and the large variety of healthcare providers who offer these services. We have assessed service delivery through surveying Florida healthcare providers who order genetic testing for hereditary breast and ovarian cancer to determine their awareness, knowledge, and practices at two different time points . Overall, survey results were consistent across both time points in revealing significantly higher knowledge and greater awareness of recent changes in genetic testing and policies among those providers with a professional degree in genetics compared to those with little or no formal training in genetics . AdditioAlthough we recognize several limitations associated with self-reported data, the results are consistent with our research findings from surveys of patients who had genetic testing. Specifically, when a provider with a master’s degree in genetic counseling or a fellowship-trained MD in clinical genetics was involved, patients were more likely to recall having their family history taken, reviewing the possibility of uncertain results, and discussing insurance-related issues . TrianguRecognizing the need for educational outreach to practitioners who provide hereditary cancer services in Florida, we created a network of providers through our Inherited Cancer Registry (ICARE) initiative in 2010. Providers are based at centers across Florida and beyond ; and inchttp://inheritedcancer.net/newsletters) [Through our ICARE initiative, we have also established a research registry of high risk patients, to which over 1700 patients have been consented since 2010, including 945 BRCA carriers. Baseline data is collected on participants through a questionnaire, aimed at addressing our own research questions and contributing to the larger research mission through sharing de-identified data with collaborators to answer various clinical questions and perform genetic association studies. Registry participants are provided with clinical and research updates through a mailed bi-yearly ICARE newsletter (available at: letters)  and are Assuring genetic/genomic competency among healthcare providers will be an increasingly important public health function as testing expands because harms have been documented due to lack of access to appropriate genetic testing, inaccurate results interpretation, or failure to tailor recommendations based on the individual’s personal and family medical history ,23,24. TVariability we documented in genetic service delivery raises a key question regarding what constitutes quality in genomic services and who should make decisions about quality. Several organizations have developed professional guidelines for elements to include in a pre-test discussion related to hereditary cancer testing ,26,27,28As we have begun testing for more genes or even the whole exome , it is no longer feasible to present highly detailed information about each gene or all possible test results. Subsequently, even providers with formal genetics training are struggling to identify “best practices” for cancer genetic service delivery in this evolving landscape and there remains an unmet need to define quality genetic service delivery based on patient outcomes research rather than relying on anecdotal experience or expert opinions. Empirically determining what information people actually can and will benefit from in their decision making processes in various contexts will be critical for assuring population health benefits as genetic/genomic medicine expands.Genetic and genomic medicine entail performing appropriate risk assessment, genetic/genomic testing, results interpretation, and patient counseling, all of which are competencies included in accredited Master’s level genetic counseling training programs in North America. Although genetic counselors may be well equipped to help integrate genetic/genomic tests into practice, the majority of clinical testing for hereditary cancer within the U.S. is currently ordered in community settings by providers without a professional degree in genetics; and it is anticipated that this will be the case for other genetic and genomic tests in the future.The Commission on Cancer guideline indicates cancer genetic services may be provided by an informed health care provider with no special certification . HoweverPolicy makers have proposed that health care professionals should, at a minimum, possess the following genomics competencies: (1) a basic understanding of the rationale behind the genomic tests; (2) the ability to identify the limits of his/her genomic expertise; and (3) knowledge regarding where to go for information, resources, and referrals ,30. AddiEvaluating genetic/genomic test results within the context of family history, environmental, and lifestyle factors increases the complexity of prevention interventions and medical care. Recent advances in genetic testing technology have made the option of multi-gene and whole exome testing more financially feasible in clinical practice. Additionally, there are a growing number of genetic testing laboratories offering a variety of hereditary cancer testing options. As such, the increasing complexity of results interpretation that comes with broad-scope testing and the expanding options for hereditary cancer testing highlight the importance of ongoing patient and provider education. Our approach to building a network as part of ICARE is one model by which to discuss challenging cases and educate both providers and patients in the evolving landscape of genetics.i.e., familial and hereditary cancers) and cancer genomics (specific to tumors) will be needed to advance genetic and genomic medicine in the oncology setting.Amidst issues of quality and competency in genetic service delivery, there are also concerns that restricting genetic services to be delivered only by those with specialized training may further reduce utilization of genetic services . This raThis article provides examples of how we have applied a few of the public health functions to the identification and treatment of hereditary cancer to provide insights that may be useful for ensuring successful implementation of other genetic and genomic medicine applications. Although our examples focused on genetic medicine, many of the challenges and questions related to quality and access are applicable to other genomic medicine applications and public health functions are necessary to ensure that genomic technologies lead to population health benefits for all. As genetic/genomic medicine continues to evolve, ongoing evaluation will be needed to monitor dissemination and implementation in various contexts by various providers. Additionally, ongoing educational interventions are needed to assure healthcare providers are prepared and competent to implement genetic/genomic medicine. In conjunction, consideration should be given with regard to policies that that may be needed to define quality of genetic/genomic medicine, promote wide-spread dissemination of evidence-based practices, and assure a competent work force. Ultimately, it will be important to bring various stakeholders together to develop efficient identification and referral systems to facilitate appropriate utilization of genetic and genomic services.


Hypoxia is a well-characterized driver of aggressive cancer phenotypes, including metastasis. Accumulating evidence suggests that, in addition to having local effects, the consequences of tumour hypoxia can be systemic, leading to the formation of pre-metastatic niches that can later foster metastatic colonization in distant organs. Recent findings have demonstrated that such niches can also form in the bone, possibly revealing new avenues for therapeutic intervention. Cancer metastasis is a complex process that consists of a series of biological phenomena that eventually leads to the formation of secondary tumours in distant organs. Even though often pictured as an orderly cascade of events akin to organismal development, at the cellular level metastatic tumours emerge from a disorderly process whereby the dissemination of millions of cells can eventually lead to the development of only few secondary tumours . Yet difThe molecular definition of a fertile metastatic soil remains in most cases elusive. It could consist of stem cell or other niches that provide cancer cells with the required survival signals in a tissue-specific manner . HoweverIn a recent study, Cox and colleagues  add a neThe pathobiology of osteolytic bone metastases has been widely studied, revealing a central role for the RANKL-RANK system that controls osteoclast maturation . SpecifiBased on initial bioinformatic analysis of clinical data sets, Cox and colleagues focus on ER– breast cancer in their experimental work. The data suggest, however, that many ER+ breast cancers also express high levels of LOX, even though this is not associated with bone metastases. Given the tendency of ER+ breast cancers to metastasize to the bone , it woulA conclusion highlighted by Cox and colleagues is that LOX expression in ER– breast cancer could be a useful biomarker for increased bone metastasis risk as well as for the identification of patients for bisphosphonate treatment in the adjuvant setting. The use of bisphosphonates in breast cancer patients has a long history, but the results have been inconclusive , 10. Mor


The activations associated with the traditional classes of goods replicate previous correlations between neural activity in valuation areas and behavioral preferences. In contrast, CV-elicited values for environmental proposals did not correlate with brain activity at either the individual or population level. For a sub-population of participants, CV-elicited values were correlated with activity within the dorsomedial prefrontal cortex, a region associated with cognitive control and shifting decision strategies. The results show that neural activity associated with the subjective valuation of environmental proposals differs profoundly from the neural activity associated with previously examined goods and preference measures.Environmental public goods—including national parks, clean air/water, and ecosystem services—provide substantial benefits on a global scale. These goods have unique characteristics in that they are typically “nonmarket” goods, with values from both use and passive use that accrue to a large number of individuals both in current and future generations. In this study, we test the hypothesis that neural signals in areas correlated with subjective valuations for essentially all other previously studied categories of goods  also correlate with environmental valuations. We use contingent valuation (CV) as our behavioral tool for measuring valuations of environmental public goods. CV is a standard stated preference approach that presents survey respondents with information on an issue and asks questions that help policymakers determine how much citizens are willing to pay for a public good or policy. We scanned human subjects while they viewed environmental proposals, along with three other classes of goods. The presentation of all four classes of goods yielded robust and similar patterns of temporally synchronized brain activation within  Environmental public goods—including national parks, clean air, and ecosystem services—provide substantial benefits on a global scale  and are stated preference approach, the CV procedure presents survey respondents with information on a nonmarket good  and asks questions that attempt to reveal the monetary values people place on these goods. This approach contrasts with revealed preference methods, which determine values based on observed and impactful behaviors, such as market transactions or consumer choices. Since revealed preference methods are tied to observable behaviors, it is not possible to use these methods for estimating passive-use values. These values, such as the existence value of a resource, represent a large component of the total value of many environmental public goods. Thus, the measurement of stated preferences is warranted in the assessment of total economic values of public policies and assets [Exxon Valdez’s 11-million-gallon oil spill in Alaska’s Prince William Sound. For such issues, stated preference surveys—most often in the form of CV—represent the only established approach to estimating the economic value at stake. It should be noted that despite its wide use, there is ongoing debate over the validity of the CV method for environmental goods [As a d assets . Indeed,al goods –6.all human valuations may be reflected in activity that can be measured in these two brain areas [all forms of valuation that have so far been studied. However, the neural representation of subjective values for environmental public goods has not been established. Further, the unique characteristics of these goods—such as the previously mentioned passive use component, and their status as non-marketed items—prevent obvious extrapolation from existing datasets. Here we compare the neural representation of subjective values for four classes of goods, including a set of environmental public goods behaviorally valued with a standard CV procedure.Across disciplinary lines, neurobiologists using functional magnetic resonance imaging (fMRI) techniques have discovered robust correlations between the values people place on goods and the blood-oxygen-level-dependent (BOLD) signal at two specific loci. These correlations ubiquitously connect brain activity within the ventromedial prefrontal cortex (vmPFC) and ventral striatum (VS) with estimates of how subjects behaviorally value goods using a wide range of preference-elicitation methods ,8. Notabin areas –21. In sin areas ,23 have One goal of this study is to determine whether the CV procedure—when used to value environmental proposals—also yields preferences that correlate with brain activity in established valuation areas. Put another way, all previously tested valuation procedures are associated with brain activation in the vmPFC and VS when subjects considered, valued, or chose between previously tested types of goods. Thus, we aim to compare this classical result with the subjective valuation of environmental goods and any of its associated neural correlates. We find that all four classes of goods examined yielded robust trial-related activation within attentional networks. Replicating previous studies, we also find that the average vmPFC and VS BOLD activations are associated differentially with the most preferred and least preferred goods for each of the traditional goods classes. Robust and replicated correlations are observed for the values individuals placed on daily activities, snack foods, and consumer goods. However, we find no evidence of a relationship between brain activity in these areas and CV-elicited valuations of environmental goods. Puzzlingly, we find that the neural activations elicited by the environmental goods in these areas are lower than the average BOLD activity elicited by snack foods. This is true despite the fact that the average monetary valuations elicited by the CV procedure for the environmental goods are greater than the valuations reported by our subjects for snack foods. These findings suggest that environmental valuations (as measured by CV) are associated differently to neural activity than previously examined valuation procedures and goods.This study was approved under the New York University Institutional Review Board University Committee on Activities Involving Human Subjects IRB# 13–9417. This submission was reviewed and approved following an Expedited Review at 45 CFR 46 110(b)[Thirty subjects  participated in a two-stage experiment with three goals aimed at allowing us to compare brain activations across types of goods and valuation procedures. Our first goal was to replicate three separate fMRI valuation studies to demonstrate that our procedures, subjects, and measured patterns of neural activity were well aligned with previous work and to provide a direct basis for comparison with the environmental proposals’ CV data. Second, we sought to measure the general pattern of brain activation associated with viewing environmental proposals. Third, we sought to test whether valuations for environmental goods are correlated with brain activations in areas specifically associated, in previous studies, with subjective valuation.In the first stage of our experiment, subjects in the scanner viewed four classes of goods in a randomly interleaved order: snack foods, consumer goods, daily activities, and environmental proposals. Following the procedure by Levy et al. , subjectAs a replication of the previous studies that involved these stimuli, snack foods and daily activities were presented as text , and conSnack foods were valued using the incentive-compatible Becker, DeGroot & Marschak (BDM) auction –25. BDM Consumer goods were valued using an incentive-compatible choice experiment . In thisDaily activities were rated for pleasantness using a non-incentive-compatible Likert-type scale . Here, sEnvironmental proposals were valued using the CV procedure utilizing a standard payment card format . The payIn the second stage of our experiment, subjects were taken out of the scanner and asked to place values on all four categories of goods using four different valuation procedures :Snack fAll trials belonging to each preference-elicitation procedure were randomly interleaved during the behavioral session, similar to the presentation of each good type during the scanning session. Trial order for goods was randomized across subjects.presentation of our four separate classes of “goods” . This allowed us to visualize the average pattern of BOLD activation under each of these four viewing conditions. As shown in First, we examined the trial-related activity belonging to the Our preference-elicitation measures yielded four different behavioral response types from which we could aggregate and associate with the neural data. To assess the reliability  with which subjects reported the values for the CV payment cards, we computed the probabilities of a “yes” response across each of the repeated presentations of each of the payment cards during the behavioral valuation session . Returning to our main experiment, the “yes” responses obtained from each payment card were used to compute a willingness-to-pay for each environmental proposal for each subject. The remaining preference procedures provided us with an ordered set of idiosyncratic preferences for each subject across each of the other three good types. This was achieved by computing the average auction bids for snack foods, computing the average pleasantness ratings for each activity, and by tallying the number of choices made toward each good . All four of our preference-elicitation measures successfully elicited a reliable set of idiosyncratic preferences within each subject across each category of goods.all four categories of goods  were then used to generate parametric estimates of subjective value  to correlate with all brain activity measured during viewing of all of the goods. A whole-brain univariate regression analysis reveals that BOLD activity measured across all four categories of goods correlates with preference rankings in regions of the VS, ventromedial prefrontal cortex (vmPFC), and posterior parietal cortex (PPC)—all areas that have been implicated in subjective valuation meta-analyses [The set of behavioral valuations for analyses –23 as weanalyses ,12,26. Tanalyses ,22,23.each class of valuation procedure and object type to this overall correlation, and to allow comparison of the subjective value representations across good types, separate contrast maps  preceding each trial. In comparing the brain’s response within each trial type, we utilized an a priori—defined region of interest (ROI) for the vmPFC (see below), and a 3 mm sphere centered at the peak T-statistic of the value correlating region within the ventral striatum . The time courses for each trial type reveal a reduced level of activity for environmental trials for both of the investigated regions .Here, we focus our analysis on the vmPFC as a hypothesized region for common valuations . In order to examine a further property of valuation-associated BOLD signals, we tested for differential activity associated with high- and low-valued goods. Here, we used a spherical ROI with a 3 mm radius from the vmPFC decision contrast , for each subject within each good category  for each whole brain . Indeed, using the same percent change analysis employed earlier, the vmPFC signal for this sub-population did not yield significantly differential activity between most and least-preferred environmental goods (Md = 6.55 s) also yielded a similarly significant correlation between environmental valuations and activity in the dmPFC  for this sub-population. It is important to note, however, that this supplementary analysis was performed as a subsequent validation exercise and thus should not be interpreted as a second piece of independent evidence for a sub-population effect.To investigate more deeply the relationship between behavioral valuations elicited by the CV procedure and neural activity, we performed a within-subject regression on CV-elicited valuations and selected all subjects who showed a positive (though not necessarily significant) correlation le brain . Once thle brain . Surprisal goods . This fiattentional network [We measured the neural activity associated with a range of stimuli that included environmental goods, snack foods, daily activities, and consumer goods and examined how this activity related to series of behaviorally elicited valuations of these goods. Firstly, we found that the presentation of each class of goods produced identical activations throughout what has come to be known as the brain’s executive  network . Indeed,We also examined the behavioral valuations that subjects placed on these four classes of goods using four very different procedures. We examined the relationship between neural activity and the four different types of behavioral valuations we elicited. We examined this relationship in two ways: using a whole-brain analysis that searched for any correlation between preferences and the BOLD signal, and using an ROI-based approach that targeted valuation-associated areas. Both approaches revealed a previously documented correlation between brain activity in valuation areas and behaviorally elicited valuations for three classes of goods. These were the relationships between: i) snack foods and auction bids, ii) daily activities and pleasantness ratings, and iii) consumer goods and choice-based rankings. Surprisingly, we saw no significant correlations between activity in any valuation-associated area and the CV-elicited willingness-to-pay valuations environmental goods. We did, however, observe a limited correlation between the CV-elicited valuations and activity in the dmPFC (specific to a subset of subjects). However, this particular region has not been associated with subjective valuation in decision making; instead, it has typically been associated with the deployment of cognitive control, task switching, and shifting decision strategies.We take these results to indicate that the brain activity associated with the elicitation of environmental values by the CV procedure differs profoundly from the brain activity associated with all other known good-valuation relationships. Below, we highlight several possible explanations for this unexpected result. Broadly speaking, these possible explanations highlight: i) the distinctive nature of environmental proposals relative to other previously studied classes of goods, ii) possible heterogeneity across subjects in valuing the environmental proposals, iii) a substantial limitation in contemporary neuroimaging technology, and iv) potential limitations in the current experimental design.Without a doubt, environmental public goods possess distinct properties that make them difficult to appraise behaviorally using traditional methods. Previous studies of neural and behavioral valuation in experimental public goods games  as well Our failure to observe a clear correlation between the CV-elicited valuations for environmental goods and activity in valuation areas may be caused by a between-subject heterogeneity in strategies. It may be that different subjects employ different neural mechanisms for contingent valuation, and as a result, the aggregated data from a group of heterogeneous subjects lacks the statistical power to reveal these disparate valuation mechanisms. The sub-population (N = 12) isolated from our study group that exhibits correlations within the dmPFC  with CV-Another possibility is that the contingent valuation of environmental public goods does, in fact, correlate with activity in certain brain areas . However, the statistical power needed to detect this correlation might be far greater than that required for the other goods included in this study. Value signals for environmental goods may have been normalized during the experiment within a larger set of familiar private goods such that the value-related activations of the environmental goods were rendered undetectable by fMRI. Such contrast issues would, however, also suggest that environmental public goods are valued on a vastly different internal scale than what is elicited by traditional preference experiments. Our observation in Our efforts to study contingent valuation in a similar manner to the other valuation procedures impose several important limitations. It should be noted that making the trial durations, presentation formats, and other design parameters similar to other procedures used for other classes of goods may have inadvertently obscured a correlation between the CV derived environmental values and the brain activations we measured. Indeed, adjustments to the briefing procedure and presentation styles of CV visual aids have been studied with respect to CV’s validity . LikewisOur results indicate that no particular brain region exhibits significantly measurable correlated activity with the subjective values estimated via contingent valuation of environmental proposals using our procedures. This observation lies in stark contrast to all other known goods/valuation procedures for which such correlations have already been observed using these same approaches. This was true despite the fact that we briefed subjects on the environmental proposals, that the neural data indicates that our subjects were attentively viewing the stimuli, and that the behavioral survey elicited reliable responses. The absence of such a correlation is thus puzzling, especially given that this observation was made while successfully replicating, on randomly interleaved trials, three disparate classic valuation results ,12,26. NThis result may be of interest because CV is frequently used for informing public policy and litigation. External validity studies, where available, do suggest that the CV method is demand-revealing when conditions related to incentive compatibility are met . The curS1 FigAll six environmental proposals and their proposed payment vehicles that were presented to subjects before the fMRI scanning sessions and during the behavioral valuation task.(PDF)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


The inner membrane of mitochondria accommodates the oxidative phosphorylation complexes that are composed of subunits encoded and synthesized in two different cellular compartments, with most of the subunits expressed from nuclear DNA. Interestingly, mitochondrial gene expression provides only a handful of proteins that nevertheless represent the catalytic core subunits of the oxidative phosphorylation machinery, rendering mitochondrial translation a crucial process for cellular metabolism. Because mitochondria developed from a prokaryotic ancestor it has long been assumed that mitochondrial gene expression might employ similar mechanisms as found in bacteria. However, recent work has revealed many novel organelle-specific aspects that probably evolved to facilitate and optimize gene expression in the organelle.Mitochondria contain a full genetic system with DNA, mitochondrial ribosomes and all factors required to: A) replicate and transcribe the DNA, B) mature and turnover mRNAs, tRNAs and catalytic RNA, and C) assemble mitochondrial ribosomes. Moreover, mitochondria-specific ribosomes are responsible for the synthesis of the hydrophobic core subunits of the oxidative phosphorylation system. How all these factors are organized in time and space and coordinated with nuclear gene expression is a busy area of mitochondrial research. Indeed, recent work shows that the mitochondrial gene expression machinery is much higher organized than previously assumed. Studies in the mammalian system showed that factors involved in RNA metabolism and ribosome assembly are present in distinct foci, termed RNA granules, that are found in close proximity to the mtDNA –3, 5. ThThe organization of mitochondrial gene expression might extend far beyond these RNA granules. By developing a system allowing the purification of intact mitochondrial ribosomes, we could demonstrate that mitochondrial ribosomes in yeast form large expressosome-like assemblies that gather almost all factors involved in posttranscriptional steps of gene expression that we termed MIOREX complexes . Some ofOne hypothesis is that the peripheral-MIOREX complexes might help to coordinate translation with oxidative phosphorylation complex assembly in a system where gene expression is not regulated at the level of transcription. We and others have recently identified feedback loops operating in the mitochondrial matrix that connect translation of key respiratory chain subunits with the efficiency of their assembly , 7. In cThe careful organization and channeled transfer of mRNAs in the MIOREX complexes reflects a common theme in mitochondrial biology: Many processes are organized in large assemblies making subsequent biochemical reactions more efficient. Surely, it will be a long, challenging and exciting way to unravel the unique features that mitochondria evolved to express a handful of genes and to learn which other features mitochondria acquired in their journey from a prokaryotic endosymbiont to a “modern” organelle. Because most mitochondrial diseases arise from aberrant mitochondrial gene expression, insights into this fascinating system will allow to develop new therapeutic strategies for these often fatal diseases.


Motor recovery after stroke involves developing new neural connections, acquiring new functions, and compensating for impairments. These processes are related to neural plasticity. Various novel stroke rehabilitation techniques based on basic science and clinical studies of neural plasticity have been developed to aid motor recovery. Current research aims to determine whether using combinations of these techniques can synergistically improve motor recovery. When different stroke neurorehabilitation therapies are combined, the timing of each therapeutic program must be considered to enable optimal neural plasticity. Synchronizing stroke rehabilitation with voluntary neural and/or muscle activity can lead to motor recovery by targeting Hebbian plasticity. This reinforces the neural connections between paretic muscles and the residual motor area. Homeostatic metaplasticity, which stabilizes the activity of neurons and neural circuits, can either augment or reduce the synergic effect depending on the timing of combination therapy and types of neurorehabilitation that are used. Moreover, the possibility that the threshold and degree of induced plasticity can be altered after stroke should be noted. This review focuses on the mechanisms underlying combinations of neurorehabilitation approaches and their future clinical applications. We suggest therapeutic approaches for cortical reorganization and maximal functional gain in patients with stroke, based on the processes of Hebbian plasticity and homeostatic metaplasticity. Few of the possible combinations of stroke neurorehabilitation have been tested experimentally; therefore, further studies are required to determine the appropriate combination for motor recovery. Advances in non-invasive brain imaging technologies have increased our understanding of neural plasticity, which induces the functional and structural changes in the central nervous system after stroke and rehabilitation  techniques, which can change cortical excitability  and tDCS, to prime cortical stimulation because there is strong evidence that this can change cortical excitability -triggered neuromuscular electrical stimulation to induce motor recovery after stroke as combined sensorimotor stimulation synchronizes with muscle activity  techniques that can monitor brain activity in real time. Brain state-dependent stimulation using a BCI typically utilizes robot-assisted movement execution that is synchronized with brain activity during voluntary movement intention. It is postulated that the re-establishment of the disrupted sensorimotor loop by integrating movement intention and passive limb movement, assisted by a robot, will strengthen the associative connection, following the principles of Hebbian plasticity. Ramos et al. investigated whether robotic orthosis feedback using an electroencephalograph (EEG)-based BCI could improve physical therapy  BCI coupled with robot-assisted hand grasping has an additional effect on therapist-assisted arm mobilization (Ang et al., tDCS has an advantage in that it can be simultaneously performed with other interventions, as it is not limited by movement. Therefore, many researchers have explored simultaneous tDCS and physical therapy to improve motor function in stroke patients (Lindenberg et al., In addition to physical therapy, several studies have reported that the use of tDCS during neurorehabilitation procedures such as peripheral nerve stimulation, robot-assisted arm training, virtual reality training, and CIMT, facilitates motor recovery after stroke (Celnik et al., Thus, many studies have reported positive synergic effects of combined neurorehabilitation therapies in both different and simultaneous timing strategies; however, the outcome of these combination-based strategies is influenced by several factors. At the present, there have been many reports of the use of neurorehabilitation combinations that include NIBS. NIBS combination strategies use the interhemispheric competition model after stroke as rationale; however, applying this theory to all patients with stroke is oversimplified or even incorrect (Di Pino et al., The synergic effect of combined neurorehabilitation therapies will vary according to the type and timing of the neurorehabilitation used. To facilitate this synergic effect, it is important to predict its effect by confirming the mechanism involved, in addition to improving new technologies. We have mainly discussed peripheral sensorimotor feedback as a brain-state dependent stimulation, but simultaneous cortical and peripheral stimulation using BCI technologies could provide a novel neurorehabilitation strategy for stroke patients. Preliminary work decoding brain signals of motor imagery has shown that synchronous TMS with haptic feedback assisted by a robot facilitated the induction of associative plasticity (Gharabaghi et al., The synergic effect might be facilitated when it is combined with multisensory simulation, such as motor imagery, action observation, mental practice, mirror therapy, training in virtual reality, and music-related therapies (Johansson, If associative plasticity between multiple regions and M1 is important for the synergic effect of combined neurorehabilitation, direct brain stimulation outside M1 may also enhance the neurorehabilitation. Although we have primarily discussed M1 as the brain stimulation site for neurorehabilitation, several studies have shown neuroplastic changes induced by stimulating other areas of the brain that are functionally connected to M1, such as the somatosensory (Bliem et al., In this regard, functional and structural connectivity neuroimaging information will be helpful in better understanding the heterogeneity of associative plasticity and to allow the individual design of combined neurorehabilitation programs based on preserved and undamaged brain connectivity (Rehme et al., Plasticity outside the brain is of interest in future studies using combined neurorehabilitation, as plasticity may occur in the spinal cord (Taylor and Martin, Although meta-analysis and systematic reviews have investigated these therapies, there is a lack of convincing evidence to support any motor stroke neurorehabilitation approach as being more effective in recovery than any other approach (Langhorne 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.


Patients with non-small cell lung cancer frequently demonstrate differing clinical courses, even when they express the same tumour stage. Additional markers of prognostic significance could allow further stratification of treatment for these patients. By generating quantitative information about tumour heterogeneity as reflected by the distribution of pixel values within the tumour, CT texture analysis (CTTA) can provide prognostic information for patients with NSCLC. In addition to describing the practical application of CTTA to NSCLC, this article discusses a range of issues that need to be addressed when CTTA is included as part of routine clinical care as opposed to its use in a research setting. The use of quantitative imaging to provide prognostic information is a new and exciting development within cancer imaging that can expand the imaging specialist’s existing role in tumour evaluation. Derivation of prognostic information through the application of image processing techniques such as CTTA, to images acquired as part of routine care can help imaging specialists make best use of the technologies they deploy for the benefit of patients with cancer. Lung cancer remains the leading cause of cancer death in Western societies, with more than 75 % of cases comprising non-small cell lung cancer (NSCLC). Tumour stage is the most important prognostic variable for survival, and this parameter makes a major contribution to clinical decisions concerning the benefits of surgery, chemotherapy and/or radiotherapy for individual patients. However, patients with the same tumour stage frequently demonstrate differing clinical courses. Hence, there is a need for additional markers of prognostic significance that could for example, identify those patients with the highest likelihood of post-surgical recurrence who might benefit most from adjuvant chemotherapy Fig. , or alteComputed Tomography (CT) plays a key role in staging of NSCLC, either as a stand-alone technique or during Positron Emission Tomography, and the use of CT to provide additional prognostic markers can form a natural extension to this role. Deriving markers of prognosis from existing CT images avoids the cost and radiation exposure associated with techniques such as perfusion CT that require specialised data acquisitions. CT texture analysis (CTTA) is an image processing method that can be applied to routinely acquired images to provide additional quantitative information about tumour heterogeneity as reflected by the distribution of pixel values within the tumour. Tumour heterogeneity is an important biological characteristic related to tumour aggression and response to treatment. There is an increasing body of evidence demonstrating the ability of CTTA to provide prognostic information for patients with NSCLC and other tumours –5.At present, none of the currently available image viewing or Picture Archiving and Communication software packages has integrated CTTA into their products. A stand-alone software that implements the filtration/histogram method is available commercially Fig.  but needAlthough any CT image can in principle be analysed using CTTA, at our institution we currently restrict analysis to the low-dose CT (LDCT) component of Positron Emission Tomography (PET)/CT examinations for the following reasons: Firstly, the prognostic value of CTTA in NSCLC has been more extensively clinically validated for LDCT than for diagnostic CT images, including derivation and testing of cut-off values from separate patient cohorts . SecondlThe single CT slice that displays the largest cross-section of the tumour is selected for analysis and displayed in soft-tissue windows. When constructing the tumour region of interest (ROI), automated segmentation procedures should be used wherever possible to optimise consistency in analysis between operators. Computer automated segmentation of tumour relative to aerated lung is straightforward. When a tumour is completely surrounded by aerated lung, segmentation tools allow the operator to construct a ROI beyond the tumour edge within which the precise tumour margins are defined by the software algorithm Fig. . HoweverCTTA software typically returns a range of texture parameters for the constructed tumour ROI. For the filtration-histogram CTTA approach, these parameters characterise the histogram of pixel intensity values within the ROI for a series of filtered images highlighting features of a specified size. Each parameter has a different relationship with the size, number, brightness and variability of features in the original CT image . A choicCTTA parameters reflect variations in x-ray attenuation (measured in Hounsfield Units) within the tumour. The accuracy of CT attenuation values is checked as part of the routine quality procedures recommended by the equipment manufacturers. Nevertheless, the potential sources of variability in CTTA values between different sites have not been fully characterised. It is therefore essential to audit the prognostic performance of results acquired locally before full implementation of CTTA as a biomarker in clinical practice. If the audit indicates that selection of different CTTA parameters and/or adjustment of cut-off values is required to optimise prognostic performance, new cut-off values should be determined from one patient cohort and tested in another. Alternatively, a cross-validation procedure may be used . AuditinAcceptance of prognostic imaging biomarkers by clinicians is an essential pre-requisite to adoption into clinical practice and communication of a convincing case for the use of CTTA as a marker of prognosis is important for achieving clinical engagement. A “black box” approach which fails to enunciate the biological basis of the imaging biomarker values is unlikely to be successful even in the presence of compelling data linking the measurements to prognosis. In NSCLC, emerging evidence that points to the intra-tumour heterogeneity reflected by CTTA as being a phenotypic consequence of activation of the MAPK tumour pathway provides a clinically and therapeutic relevant foundation for CTTA as a prognostic indicator. Studies have shown CTTA values in NSCLC to be related to hypoxia, mutations in EGFR and KRAS genes, and ALK gene re-arrangements , 5, 9–12The use of quantitative imaging to provide prognostic information is a new and exciting development within cancer imaging that can expand the imaging specialist’s existing role in qualitative and semi-quantitative assessments of prognosis such as TNM staging and changes in tumour appearances during serial imaging. Parallel developments are occurring, or have already emerged, in other areas of imaging such as CT coronary calcium scoring for risk-assessment in patients with coronary artery disease. Cancer patients often need to undergo a range of investigations and there is a responsibility to maximise the clinically relevant information obtainable from these procedures, particularly when they entail ionising radiation. Derivation of prognostic information through the application of image processing techniques such as CTTA, to images acquired as part of routine care can help imaging specialists make best use of the technologies they deploy for the benefit of patients with cancer.


Similar to the descending serotonergic system, the dopaminergic system may serve as a potential target to promote recovery of locomotor function following spinal cord injury (SCI); evidence suggests that dopaminergic agonists can promote recovery of function following SCI. We discuss pharmacogenetic and optogenetic approaches that could be deployed in SCI and their potential tractability. Throughout the review we draw parallels with both noradrenergic and serotonergic modulatory effects on spinal cord networks. In all likelihood, a complementary monoaminergic enhancement strategy should be deployed following SCI.The spinal cord contains networks of neurons that can produce locomotor patterns. To readily respond to environmental conditions, these networks must be flexible yet at the same time robust. Neuromodulators play a key role in contributing to network flexibility in a variety of invertebrate and vertebrate networks. For example, neuromodulators contribute to altering intrinsic properties and synaptic weights that, in extreme cases, can lead to neurons switching between networks. Here we focus on the role of dopamine in the control of stepping networks in the spinal cord. We first review the role of dopamine in modulating rhythmic activity in the stomatogastric ganglion (STG) and the leech, since work from these preparations provides a foundation to understand its role in vertebrate systems. We then move to a discussion of dopamine’s role in modulation of swimming in aquatic species such as the larval xenopus, lamprey and zebrafish. The control of terrestrial walking in vertebrates by dopamine is less studied and we review current evidence in mammals with a focus on rodent species. We discuss data suggesting that the source of dopamine within the spinal cord is mainly from the A11 area of the diencephalon, and then turn to a discussion of dopamine’s role in modulating walking patterns from both  Neuromodulators are the key ingredient allowing motor networks the flexibility to produce multiple patterns of output. When one considers a task such as stepping, a number of patterns need to be produced to run, walk, hop, go up and down inclines and walk in a circular pattern. While we focus on stepping in this review, neuromodulators contribute to the rhythmic operation of most, if not all, biological networks. A complete understanding of the role of neuromodulators in motor control must take into account the combinatorial effects of the complement of transmitters released both synaptically and extrasynaptically. This is an immense challenge for the field of motor control, especially when small invertebrate motor circuits are compared directly with their larger, less accessible and more complex mammalian cousins. However, in the last decade new genetic tools have become available that allow spinal circuits that compose a motor network to be identified  , consists of 26–30 neurons that generate a pacemaker-driven higher frequency pyloric rhythm and a conditionally active and lower frequency gastric mill rhythm. Neuromodulation profoundly reconfigures this small circuit, biasing individual neurons to participate in the different motor behaviors. Within even the simplest of nervous systems rhythmic behaviors are not hard-wired, and neuromodulation imbues networks with the flexibility to generate multiple patterns of motor output Marder, . DopaminHirudo Medicinalis) illustrates that dopamine has a profound effect on locomotor behaviors, highlighting its ability to bias the network toward a particular motor output or reinforce an ongoing behavior. Specifically, dopamine acts as a command signal to elicit crawling along with suppression of swimming  where it also acts to bias locomotor activity to a crawl pattern of activity over swimming  and reducing the late component of the AHP in neurons such as edge cells, dorsal cells and giant interneurons, although these cells are not strong contributors to rhythmogenesis. It is more likely that the influence on rhythm frequency is due to a reduction in inhibitory drive from inhibitory commissural interneurons  on inhibitory commissural interneurons that generate left-right alternation of swimming by reducing the calcium conductance through the CaV1.3 channel  neurons of the midbrain forming the dopaminergic diencephalospinal tract (DDT) that send descending projections to the spinal cord  becoming less potent by 5 dpf  and promotes locomotor activity at higher concentrations (10–50 µM) via D1-like mechanisms  and phenylethanolamine-N-methyl-transferase  versus Kv1.2 respectively) and some TH+ neurons may not even express them at all  and the D2-like receptors . Generally, activation of the D1-like receptor subfamily elicits excitatory effects through a stimulatory G-protein (Gsα) interacting with adenyl cyclase, subsequently increasing intracellular cAMP levels. In contrast, activation of the D2- receptor subfamily hyperpolarizes the cell membrane through an inhibitory G-protein (Giα) to close calcium channels, open potassium channels and reduce intracellular cAMP levels  were particularly successful in producing locomotion that resembled normal stepping in spinalized rats, supported by data from in vitro preparations  are constitutively expressed for months following a SCI in rodents and upregulation of these receptors may contribute to functional improvement in locomotion following injury  combined with apomorphine reliably elicited locomotor activity in mice with a complete spinal transection  for activation or proton pumps  for silencing of neuronal activity that can be expressed based on cell-specific transcription factors or promoter regions (for review see: Aston-Jones and Deisseroth, This review has focused on the role of dopamine in modulating locomotor centers in the spinal cord. Our knowledge of dopamine’s contribution to monoaminergic locomotor drive in mammals is in its infancy. However, parallels to other vertebrate systems, such as the lamprey, clearly exist.Tools to specifically target dopaminergic and other monoaminergic descending populations now exist. Data from behaving animals suggests that while monoamines generally act to increase tone, they can act to promote specific patterns on their own. While the temptation is to examine each monoaminergic system in isolation, it will be necessary to examine combinatorial actions to start to understand the state-dependent role of monoamines in the freely moving animal.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.


Reassortment is an evolutionary mechanism of segmented RNA viruses that plays an important but ill-defined role in virus emergence and interspecies transmission. Recent experimental studies have greatly enhanced our understanding of the cellular mechanisms of reassortment within a host cell. Our purpose here is to offer a brief introduction on the role of reassortment in segmented RNA virus evolution, explain the host cellular mechanisms of reassortment, and provide a synthesis of recent experimental findings and methodological developments. While we focus our discussion on influenza viruses, wherein most of the studies on reassortment have been carried out, the concepts presented are broadly applicable to other multipartite genomes.Virus reassortment, or simply reassortment, is a process of genetic recombination that is exclusive to segmented RNA viruses in which co-infection of a host cell with multiple viruses may result in the shuffling of gene segments to generate progeny viruses with novel genome combinations  1]. Rea. Rea1]. In contrast, recombination occurs through a template switch mechanism, also known as copy choice recombination. When two viruses co-infect a single cell, the replicating viral RNA-dependant-RNA-polymerase can disassociate from the first genome and continue replication by binding to and using a second distinct genome as the replication template, resulting in the generation of novel mosaic-like genomes with regions from different sources ,8 such aEssential prerequisites for reassortant include the entry of more than one virus particle into a single host cell, followed by the concomitant production of genome segments within the host cell. Experimental systems have revealed a high frequency of multiple infections ,14, althUltimately, the definitive formation of viable infectious reassortants is dependent on the incorporation of one copy of each segment into a virus particle. Two alternative mechanisms for reassortment within the host cell have been proposed. The random packaging model ,17 positThe identification of reassortment is important to detect novel reassortants with increased transmissibility, increased pathogenicity, or those that escape antibody recognition or are resistant to antivirals. Reassortment is most commonly detected through incongruencies in phylogenetic relationships among the different segments of a viral genome –26, as gInfluenza exhibits high levels of mixed infections in all major hosts –42, withThe tremendous genomic novelty generated by reassortment confounds all current methods of virus control. Evolutionary studies indicate an advantage for gene lineages with reassorting backgrounds. Specifically, a significant increase in transient amino acid mutations is observed following reassortment , primari


We describe the kinetics of Zika virus (ZIKV) detection in serum and urine samples of 6 patients. Urine samples were positive for ZIKV >10 days after onset of disease, which was a notably longer period than for serum samples. This finding supports the conclusion that urine samples are useful for diagnosis of ZIKV infections. Flaviviridae, genus Flavivirus) that was isolated in 1947 from a rhesus monkey in the Zika forest in Uganda  is an emerging mosquito-borne pathogen ; arthralgia, notably of small joints of hands and feet; myalgia, headache; retroorbital pain; conjunctivitis; and cutaneous maculopapular rash. ZIKV infection is believed to be asymptomatic or mildly symptomatic in most cases . Although IgM against ZIKV can be detected by ELISA, few laboratories have this ability. Thus, in addition to the nonspecific clinical features of infection with ZIKV, laboratory diagnosis is challenging because of low viremia and cross-reactivity of ZIKV antibodies with other flaviviruses (including dengue), which require confirmation by neutralization assays , we used both sets of primers/probe specific for ZIKV . Urine s,Partial sequences of the gene for ZIKV nonstructural protein were obtained  after onset of symptoms, which was >7 days after it was not detected in serum samples.Other groups have reported that other flavivirus genomes, such as those of dengue virus . However, urine was preferred for virus detection. We observed a slight increase in ZIKV RNA from urine over the first few days after disease onset and rash . We therThis study investigated the diagnostic utility of urine as a source for detection of ZIKV RNA by real-time RT-PCR. Results suggest that urine might be useful for confirmation of ZIKV infection because virus was detected at higher titers and for a longer period in urine samples than in serum samples. Although these results need confirmation in larger cohorts, they strongly suggest the suitability of urine as a specimen for ZIKV detection and screening in large-scale investigations or other epidemiologic contexts .Ae. albopictus mosquitoes are a competent vector for ZIKV (In industrialized regions, where local transmission of arboviruses, such as dengue virus or chikungunya virus has been reported, physicians should test patients who return from tropical regions for ZIKV when a case of dengue-like infection is suspected. Travelers might be a source of local transmission because


Undeniably, acoustic signals are the predominant mode of communication in frogs and toads. Acoustically active species are found throughout the vast diversity of anuran families. However, additional or alternative signal modalities have gained increasing attention. In several anurans, seismic, visual and chemical communications have convergently evolved due to ecological constraints such as noisy environments. The production of a visual cue, like the inevitably moving vocal sac of acoustically advertising males, is emphasized by conspicuously coloured throats. Limb movements accompanied by dynamic displays of bright colours are additional examples of striking visual signals independent of vocalizations. In some multimodal anuran communication systems, the acoustic component acts as an alert signal, which alters the receiver attention to the following visual display. Recent findings of colourful glands on vocal sacs, producing volatile species-specific scent bouquets suggest the possibility of integration of acoustic, visual and chemical cues in species recognition and mate choice. The combination of signal components facilitates a broadened display repertoire in challenging environmental conditions. Thus, the complexity of the communication systems of frogs and toads may have been underestimated. A great diversity of signalling strategies and behaviours can be observed during animal communication shaped by sexual selection and the environmental constraints  prefer advertisement calls in addition to the visual cue of a pulsating vocal sac over the call alone under low sound pressure levels. However, when the visual stimulus is presented with a less attractive slow call rate, females rather choose the attractive unimodal call, which emphasizes that vocalizations are necessary for mate attraction ) demonstrated that a pulsating white vocal sac increases the frequency of response behaviours in conspecific males and elicits an agonistic visual display response  was able to elicit territorial aggression in the opponent male, only temporally overlapping dynamic bimodal cues evoked fighting behaviour  perceive plant-borne vibrations indicating a conspecific intruder, they in turn shake branches as an agonistic display  do not form fixed-composite signals (sensu Partan and Marler Hyla squirella) and Túngara frogs (E. pustulosus) . The temporal blue nuptial colouration in males was suggested to be a visual signal promoting instantaneous mate recognition and allowing males to quickly move between rivals while scrambling for females  are attracted to the male by “splendipherin”, an aquatic pheromone produced by males in glands on the head , females tested in Y-maze experiments showed a clear preference for water containing homogenized male post-axillary breeding glands or water previously containing live males . Recording interactions over large spatial  scales was too technologically challenging, labour intensive, or both. New technological advances promise to change all this by enabling researchers to explore the complexity of chorus organization in ways only imagined in the late 1970s” (Bee et al. As aforementioned, similar technical and conceptual advances in studies on visual and olfactory signals start to promote the research field Cummings . AnswersThe degree to which individual and/or combined components influence receivers in multimodal communication still remains difficult to generalize across species (Taylor et al. We advocate that the natural history and habitat conditions of the respective study species are of utmost importance for understanding the evolution of signal design. Similarities in communication strategies do not necessarily indicate the same underlying mechanism, but could be of convergent origin and could have developed under related or different selection pressures. Interactions between sender and receiver under natural conditions could eventually help to understand the success of a certain signal and modality in the sense of signal efficacy and sensory drive.


Stem cells are considered as new implement for tissue regeneration. Several niches in adult human body are colonized by multipotent stem cells but access to these potential reservoirs is often limited. Although human dental pulp stem cells isolated from healthy teeth have been extensively characterized, it is still unknown whether stem cells also exist in reactive lesions of oral cavity such as pyogenic granuloma and peripheral ossifying fibroma which are deliberated as inflammatory proliferation of different cell families.The aim of this study was to explore for clues to see whether pyogenic granuloma or peripheral ossifying fibroma contain dental mesenchymal stem cell (DMSC). Four pyogenic granuloma and four peripheral ossifying fibroma specimens were collected by excisional biopsy and preserved in PBS-EDTA at -86 °C. Then we cut them in 5µm diameter using Cryostat. Having been rinsed with PBS, the samples were stained with a primary mouse anti-human STRO-1 monoclonal IgM antibody. Afterward, a secondary goat anti-mouse IgM-FITC antibody was applied to detect STRO-1+ cells as probable stem cells by immunofluorescence technique. Immunofluorescence microscopy revealed presence of STRO-1+ cells in these lesions, particularly localized on perivascular zone. The negative control group was not glowing. Based on these results, it was found that reactive lesions of pyogenic granuloma and peripheral ossifying fibroma have STRO-1 positive cells, which raises the possibility that these cells may be DMSCs. Stem cells are promising tools for tissue regeneration. Their remarkable ability in proliferation and differentiation enables them to restore the structures of impaired tissues. The needThe application of adult stem cells (ASCs) in tissue engineering is not followed by legal and ethical issues. Recently, most of ASCs are multipotent mesenchymal stromal cells (MSCs) that havThe major source of ASCs is the bone marrow; however, they can be obtained from other reservoirs such as adipose tissue and dentDental pulp and its supportive tissues are derived from a sort of tissue called ectomesenchyme, which is produced by interaction of neural crest cells and mesenchyme in embryonic period. Hence, dental stem cells are likely to have properties identical to mesenchymal stem cells such as those of bone marrow. Despite the similarities, these two cell groups have some differences. For instance, stem cells of dental tissue are more differentiated, undergo fewer changes, and can help more in development and progression of odontogenic rather than osteogenic differentiation. In recenThe aim of this study was to find clues on presence of dental mesenchymal stem cell (DMSCs) in these lesions, using an immunofluorescent technique to detect DMSC marker STRO-1. deceleration of Helsinki, the lesion were cut under sterile conditions, immersed in PBS-EDTA solution which was made up of 1% penicillin/ streptomycin  and 1% fungizone  and then placed in embedding matrix for frozen section  and was rapidly frozen in Cryostat. Then several 5-µ sections were cut from the middle of the samples and were placed on slides.Eight patients with pyogenic granuloma and peripheral ossifying fibroma who had referred to Shiraz School of Dentistry were examined and their diagnosis was confirmed by an expert pathologist. Four pyogenic granulomas and four peripheral ossifying fibromas were recruited as samples in this study. After getting informed consent according to The slides were immersed in phosphate buffered saline (PBS) for 5-10 minutes. Then, they were placed in 1% peroxidase for 5 minutes to ensure the peroxide inside the tissue had gone away and that non-specific reactions have been prevented. The samples were again rinsed with PBS for 5 minutes and 10% horse or goat serum was poured on them to inhibit the non-specific immunoglobulins.The primary antibody, STRO-1  with dilution of 1:50 remained on samples for 2 hours and the secondary antibody, goat anti–mouse IgM-FITC  with dilution of 1:50 remained on samples for 45 minutes. Having been rinsed with PBS, the samples were placed in a container wrapped in aluminum, and were transferred to be assessed through immunofluorescence microscopy . The primary antibody was replaced by PBS as negative control and sections of pulp tissues were used as positive control. In this study, four pyogenic granulomas and four peripheral ossifying fibromas were studied. It should be noted that the fluorescence intensity was lower in those slides that have been prepared sooner; and that negative control group showed no sign of presence of these cells. This study experienced the presence of STRO-1 positive cells within reactive oral pathosis. It may raise the hope of stem cell presence within these tissues which would be a new source of multipotent mesenchymal stem cells expecting them to be used for regenerating purposes in future, at least in dentistry. Markers of STRO-1 and CD146 are the most frequently used markers in studying stem cells. They areDue to the high power of proliferation and differentiation, adult stem cells have been introduced as a promising tool in tissue engineering that are followed by less ethical and legal issues., 22 The in vitro; and in vivo. They had the ability to transform to mature lamellar bone just like new cells. It is not completely known how much the inflammation affects the differentiation potential of stem cells, however, it is recognized that mild inflammation improves the differentiation of odontoblasts and osteoblasts and increases the formation of matrix; while severe inflammation increases the apoptosis of stem cells. in this reactive lesion, the properties of these cells like cultivation capability, phenotypic features, colony forming ability, the number of stem cells, their proliferative rapidity , and the differentiation potential of the approved categories must be studied and compared with healthy dental pulp stem cells. Also the right panel of cell surface antigen markers must be checked for them using flow cytometry so that their position would be clarified in the International Society for Cellular Therapy. The results of this study revealed that reactive lesions of pyogenic granuloma and peripheral ossifying fibroma had mesenchymal STRO-1+ cells that would raise the possibility of the presence of stem cells within these tissues. Thus, since oral reactive lesions may serve as new possible stem cell reservoirs, their specific features and differentiation potentials should be evaluated.


Inflammation at both systemic and local intraperitoneal levels commonly affects peritoneal dialysis (PD) patients. Interest in inflammatory markers as targets of therapeutic intervention has been considerable as they are recognised as predictors of poor clinical outcomes. However, prior to embarking on strategies to reduce inflammatory burden, it is of paramount importance to define the underlying processes that drive the chronic active inflammatory status. The present review aims to comprehensively describe clinical causes of inflammation in PD patients to which potential future strategies may be targeted. Peritoneal dialysis (PD) is a form of home-based renal replacement therapy for patients with end-stage kidney disease (ESKD) that uses a patient's peritoneum as a dialysis membrane across which water and solutes  are exchanged between dialysis fluid and blood. PD has several advantages including greater ease of technique to master, greater preservation of residual renal function (RRF), early survival advantage, and superior cost effectiveness compared to haemodialysis –3. GreatDespite these benefits, the outcome of PD patients remains poor and cardiovascular events (CVE) continue to be the leading cause of death in PD patients . Higher Inflammation can be defined as a localised protective response elicited by injury or destruction of tissues that serves to destroy, dilute, or sequester both the injurious agent and injured tissue. Hence, it is a physiological response and in the form of an acute response to infections, trauma, or toxic injury, it helps the body to defend against pathophysiological insults. However, if inflammation becomes prolonged and persistent in the form of the so called chronic acute-phase reaction, it may lead to adverse consequences, such as decline in appetite, increased rate of protein depletion in skeletal muscle, hypercatabolism, endothelial damage, and atherosclerosis –19 Figu.There are several markers that can be measured to gauge the level of inflammatory burden, such as C-reactive protein (CRP). CRP levels can rise rapidly and markedly in response to acute inflammatory stimulus from increased synthesis by hepatocytes to contribute to host defense and innate immune response . Its indIn PD patients, inflammation can be broadly compartmentalised into two types, systemic and local intraperitoneal inflammation. As recently reported by the GLOBAL fluid study, these two represent distinct underlying processes that likely require different preventative or therapeutic approaches . The repInterest in inflammatory markers as targets of therapeutic intervention has been considerable as they are recognised as predictors of poor patient outcomes . However, prior to embarking on strategies to reduce inflammatory burden, it would be of paramount importance to define the underlying causes that drive the chronically inflamed state. The present review aims to comprehensively describe clinical causes of inflammation in PD patients at which potential future therapeutic targets may be aimed.A number of studies have reported an association between lowered RRF and higher systemic inflammatory burden in predialysis  and dialβ (NF-κβ) 2) when c < 0.05) . At presn = 76) from single-centres and their results have not been validated by others.Beyond the aforementioned possible interventions for reducing inflammation in PD patients , there hInflammation is a common complication of PD patients at both systemic and local  levels. Chronic inflammatory status is associated with a number of clinically significant adverse patient outcomes, including malnutrition, peritoneal membrane dysfunction, and cardiovascular events. Although there are a number of potentially modifiable clinical causes of inflammation, a limited number of intervention studies to date have not been able to successfully identify effective strategies to lower inflammatory burden in this patient group. Future studies should focus on better defining of the pathogenic mechanisms underlying peritoneal and systemic inflammatory cascade in PD patients and evaluating the efficacy of interventions targeting these identified factors.


Lice are socially-transmitted ectoparasites. Transmission depends upon their host’s degree of contact with conspecifics. While grooming facilitates ectoparasite transmission via body contact, it also constrains their spread through parasite removal. We investigated relations between parasite burden and sociality in female Japanese macaques following two opposing predictions: i) central females in contact/grooming networks harbour more lice, related to their numerous contacts; ii) central females harbour fewer lice, related to receiving more grooming. We estimated lice load non-invasively using the conspicuous louse egg-picking behaviour performed by macaques during grooming. We tested for covariation in several centrality measures and lice load, controlling for season, female reproductive state and dominance rank. Results show that the interaction between degree centrality (number of partners) and seasonality predicted lice load: females interacting with more partners had fewer lice than those interacting with fewer partners in winter and summer, whereas there was no relationship between lice load and centrality in spring and fall. This is counter to the prediction that increased contact leads to greater louse burden but fits the prediction that social grooming limits louse burden. Interactions between environmental seasonality and both parasite and host biology appeared to mediate the role of social processes in louse burden. Many parasites, i.e. organisms that live and feed exclusively within or on other living organisms (hosts), are socially-transmitted, either directly through contact between individuals or indirectly through spatial overlap and resource sharing3From this perspective, social network analysis (SNA) provides a useful tool that captures such heterogeneity by taking into account direct and indirect connections (edges) between individuals (nodes), allowing for multilevel analyses from individuals to populations32One common type of network relevant to social animals derives from social grooming . Grooming is often highlighted as a mechanism of establishing and maintaining group cohesion and social bonds7911121415161719Rickettsia prowazekii, Bartonella quintana, and B. recurrentisRickettsia, Anaplasma, and Bartonella spp. in various animals2025One common ectoparasite of mammals is the louse, which feeds on blood and requires a host during each stage of its life cycle. Adult lice typically lay one to several eggs (nitts) every few days, which are glued to the base of a hair. Like many organisms, lice respond to environmental conditions . In ungulates, for instance, adult louse populations peak in spring and drop in summer202122Lice and their mammalian hosts are thus a good host-parasite system to study the likelihood or risk of disease/parasite transmission within host social networksMacaca fuscata fuscata) is a social primate species living in multi-female multi-male groups, where individuals form linear dominance hierarchies and differentiated affiliative social relationshipsPedicinis obtusus and P. eurygaster). Based on quantification of egg and nymphal/adult stages of lice detected on culled macaques, it was estimated that an average-sized macaque could harbour up to 550 louse eggs17In this study, we investigated the risk of louse infestation within Japanese macaque social networks. The Japanese macaque . Because body contact provides a transmission opportunity for lice, and thus an infection risk for hosts, yet grooming may constrain louse density through parasite removal, we made two opposing predictions: compared to less central females, 1/ more central females will be most infested with lice due to their higher diversity of interacting partners or their higher frequency of body contact in the network; or 2/ more central females will be least infested with lice because they have their louse eggs removed through grooming by a higher diversity of partners and/or more frequently. Evidence for a positive relationship between centrality and lice load would indicate that despite increasing exposure risk to potentially deleterious parasites, being central still presents advantages. Conversely, a negative relationship would speak in favour of social grooming as an efficient antiparasite strategy that can be exploited by females through their grooming networks. To test prediction 1, we investigated the relationship between estimated lice load and centrality measures based on undirected weighted networks of body contacts, including grooming. To test prediction 2, we looked at whether lice load was related to in-centrality measures derived from directed weighted networks of grooming received. Testing different centrality measures allowed us to investigate whether it is the actual number (or diversity) of partners and/or the actual amount of social contact a female has that influences lice load. First, grooming skills and thus louse egg-picking efficiency significantly vary across individualsGrooming represented 27%  of all activity scans of female Japanese macaques of Koshima during this study. Body contact without grooming represented only 9%  of all scans with body contact. Females were in contact with other adult females in 48% of all scans with body contact , with males in 6%  and sub-adults, juveniles and infants in 41% . Total louse egg-picking events averaged 129 events per female over the whole study period , which represented less than one event per grooming minute-scan .The modularity Q of social networks, representing the extent to which a network is partitioned in smaller units, shifted between seasons especially before and after summer where it was highest . RandomiLice load also varied across seasons, being higher in summer and fall compared to spring and winter ; Fig. 2.obs < βrand = 0.043, Overall, only one of the centrality measures from contact networks was related to lice load and only through an interaction with season , 4, 5: fobs < βrand p = 0.087, Models with grooming received centrality measures showed a tendency towards lice load being related to in-degree through an interaction with season and reproductive state separately , 4, 5: fIn animal groups, increased centrality in social networks is often linked to increased parasite load and disease risk151920It must be stated up front that our measure of lice load is indirect, observational and dependent upon observing individuals grooming. Capturing monkeys and marking/collecting lice provides a direct estimate of lice loads and allows testing whether lice actually carry pathogens, but this approach is inconvenient and often impossible to implement in wild populations. That said, Japanese macaques are very conspicuous when picking items from the hair or on the skin of their grooming partners, and 98.9% of what is picked and consumed has been demonstrated to be louse eggs17The study of this louse egg-picking behaviour led researchers to discover that macaques groom for demonstrably longer durations if they find many louse eggs to pick and eat , irrespective of the relationship between groomer and groomee151730Tamias striatus) and mouse lemurs (Microcebus rufus), presumably because of the concomitant increase in both contact between individuals and host reproductive activity2821Spilopsyllus cuniculi), in which the reproductive cycle is triggered by pregnancy and parturition of the host doe. The fleas then migrate en masse to the nest to breed on the immunologically-naïve young50One ecological factor that clearly affects numerous behavioural outcomes is seasonality. We considered seasonality of the environment as well as host and parasite biology, as it is generally highly relevant to infectious disease dynamics3334sensu the effect of shearing on louse density in domestic sheepThese synergies between host and parasite biology also explain the results of this study. Lice load was highest in summer during the periparturient period. Females thus seemed more vulnerable to louse infestation at this time. This was particularly the case for reproductively active females, especially those that were less central in the social networks. This pattern could be due to the combination of several factors, also linked to the effect of environmental seasonality on host and parasite biology. First, the surge of sex hormones in the host around birth could have triggered louse reproductive activity and proliferation202122At Koshima, mean centrality indices generally seemed to vary in the opposite direction of mean lice load across seasons; the season in which mean centrality was lowest corresponded to the season in which mean lice load was highest. However, network modularity did follow somewhat closer to the pattern of mean lice load in that the season in which mean lice load was highest was also the season in which modularity was greatest. Greater modularity in a network means that the network decomposes into more modules than in a network with lower modularity. Greater modularity is hypothesized to negatively impact transmission of infectious agents throughout social groups by breaking down the chain of transmission5355Suricata suricatta)But if the network reflects pathways for parasite transmission, centrality indices such as degree and strength measuring risk of exposure are expected to be positively related to parasite infection patternsIn this evolutionary arms race, parasites effectively use their hosts’ behaviour to increase their own fitness6264In conclusion, our study shows that variation in contact and grooming network centrality in terms of number of connections explains variation in lice load in female Japanese macaques in that less central females have higher lice burden, providing further evidence of grooming as an efficacious anti-parasite strategy. However, our study also demonstrates that this relationship is dependent upon ecological and biological conditions, such as less central females have higher lice burden only during winter  and summer . Our study is the first to estimate lice load from direct observation of wild animals and to link this estimate to the centrality status of individuals in their contact networks. This study also highlights the importance of seasonal variation both in parasite intensity and in host behaviour in explaining variance in infection risk and exposure from socially-transmitted external parasites.2 and covered by evergreen broadleaved forestWe studied Japanese macaques on Koshima islet, Miyazaki prefecture, Japan . The region has a warm-temperate climate with monthly mean temperatures ranging between 9.3 °C in January and 27.2 °C in August, and monthly mean precipitation between 35 mm in January (humidity 60%) and 730 mm in June . Koshima is approximately 0.3 kmWe observed the 19–20 adult females (>7 years old) of the Main group. We focused on females because, in macaque societies, they form the core of the group and dominate dynamics of social networks, males are often few and not very social, and juveniles are difficult to recognise, often have their own subgroup, and usually engage in different age-typical activities than the adults6970Research adheres to the ASAB/ABS guidelines for the use of animals in research and was approved by the ethic committee of Kyoto University Primate Research Institute.ad libitum.Data were collected from January to November 2014  along the length of the hair, and eat itWe divided our dataset in four parts to account for seasonal variations biologically relevant to the studied host-parasite system. The winter dataset included observations between January and March and corresponded to the macaques’ mating seasonTo compute lice load, we used minute-scans of grooming received, the focal female being either the groomer or the groomee, and minute-scans of self-grooming per female as well as minute-counts of louse egg-picking gestures across all grooming received bouts per female. Lice load was then calculated per female as follows:where n is the total number of grooming or self-grooming bouts.undirected weighted networks of body contacts We used SNA to investigate the risk of exposure to louse infestation of females within their social network of female group members. First, we calculated the modularity Q of the contact and grooming received networks  based on eigenvector centrality, which provides a descriptive statistic of detection and characterization of community structure in networkscontacts . The secreceived . Althougad libitum. As there was no change in female hierarchical order across seasons, but individual normDS varied in magnitude, we finally assigned females an ordinal rank with 1 being the highest and 20 the lowest.To assign dominance rank, we calculated normalised David’s scores  while accounting for potential confounding factors, we built General Linear Mixed Models (GLMM) with Gaussian distributions and identity link functions using the function lmer from the lme4 packaged season . In modeTo assess the variability present in host sociality and lice load that may affect the relationship between the two, we built GLMMs with each centrality measure as the response variable, season, reproductive state and rank as predictors, and individual identity as random effects. Variation in lice load was assessed from the null model that was built to test predictions 1 and 2 and that included season, reproductive state, treatment status and individual identity as well (see below).lice load as the response variable, centrality index as the main predictor, season, reproductive state, rank, and treatment status as confounding factors and individual identity as a random effect.To address our main question concerning the relationship between measures of centrality and lice load, we built GLMMs with We also included a three-way interaction between centrality, season, and reproductive state, and its associated two-way interactions . The effect of centrality on lice load could indeed depend on seasonal variations in both lice load and centrality, and lice load could also be differentially influenced by some stages of host reproduction , and these stages depend on season. Thus, it may be that the effect of the interaction between centrality and season on lice load varies according to female reproductive state, such as females more central in the network have more lice in winter and summer but only if they are reproductively active . We usedHow to cite this article: Duboscq, J. et al. Network centrality and seasonality interact to predict lice load in a social primate. Sci. Rep.6, 22095; doi: 10.1038/srep22095 (2016).


Despite the well-documented improved survival of coronary heart disease with the use of statins, their effects on atherosclerotic plaques are not yet fully understood. While some studies suggest statins may reduce plaque volume, the reduction is small even with the use of high-dose statins. Due to this small change in plaque volume, other effects of statin therapy on plaques have been proposed. A large meta-analysis by Banach et al. explored statin effects on plaque composition detected by intravascular ultrasound (IVUS). We discuss the mechanisms of plaque composition modification demonstrated in their study and its implications on atherosclerotic plaque stabilization.http://www.biomedcentral.com/1741-7015/13/229.Please see related article:  Since the landmark publication of the 4S trial, which demonstrated improved survival with the use of statins , a serieInitial magnetic resonance imaging (MRI) studies of the aorta suggested that statin use might result in atherosclerotic plaque regression as early as 6 months after initiation of therapy . These fSome of this excitement slowly faded away due to two important pieces of evidence. First, the association between plaque burden and incident cardiovascular events did not prove to be true for other classes of drugs. For example, while niacin effectively reduced the carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis , this waBMC Medicine. The authors included nine studies with more than 830 individuals in whom virtual histology data was available. This study supported previous findings that higher statin doses result in significant plaque volume reduction, while lower statin doses does not. More interestingly, the pooled virtual histology data demonstrated that this small change in plaque volume is a poor summary of plaque composition change. On the one hand, the fibro-fatty and necrotic core volumes remained unchanged with statin use; and on the other hand, a significant fibrous plaque volume reduction accompanied a significant increase in the dense calcium volume. The data also suggests that there is a direct correlation between statin intensity used in each study and the effects on fibrous plaques and on dense calcium volumes, despite the limited power of subgroup analysis. Another very recent meta-analysis reached similar conclusions using different analytical techniques [A new meta-analysis by Banach et al.  reinvestchniques .in vitro studies indicate that calcium location may better explain the difference in plaque rupture risk [An interesting aspect of plaque composition derived from the study by Banach et al. is the role of coronary calcification in the atherosclerotic process and its implications on cardiovascular risk assessment. While some authors propose that calcium formation is part of the healing and stabilizing process of atherosclerosis, other ure risk . In facture risk  indicateure risk  demonstrure risk .Collectively, these results indicate that instead of regression, the use of statins can lead to plaque healing and stabilization. The “healed” plaque is only discretely smaller, although it has better structure and is less prone to rupture. Even so, the occurrence of cardiovascular events despite optimized treatment in a significant proportion of patients receiving statins, the so-called “residual risk”, suggests that the healing process is incomplete. In fact, it has been proposed that statins and other preventive measures alter the mechanisms leading to acute coronary syndromes. Instead of plaque rupture, acute coronary syndromes in those “healed” plaques are more likely to occur by erosion. This change is thought to be related to the improved plaque structure associated with the change in its components.In light of the evidence from the study by Banach et al., future clinical studies using invasive and non-invasive techniques should move forward, with a deeper evaluation of drug effects on atherosclerotic plaques. Instead of absolute quantification of plaque and its components , we should focus on the identification of plaque characteristics or changes in the distribution of plaque components , as plaques are much more likely to heal and stabilize than to regress.