Traditional research in the health sciences has involved control and experimental groups of patients, and descriptive and inferential statistical analyses performed on the measurements obtained from the samples in each group. As the novel model of translational healthcare, which integrates translational research and translational effectiveness, becomes increasingly established in modern contemporary medicine, healthcare continues to evolve into a model of care that is evidence-based, effectiveness-focused and patient-centered. Patient-centered care and patient-targeted therapies require the timely and critical development and validation of a new research paradigm, individual patient research (IPR), as opposed to the customary group research approach. Here, we propose a model of individual patient research to define and characterize the effectiveness of a novel therapeutic intervention for temporomandibular joint disorder. The intervention must be tailor-made for each individual patient, and the data from each patient must be analyzed individually. We propose that this endeavor is best achieved by means of an adaptive cluster randomized stepped wedge blinded controlled trial, because it permit individual patient outcomes research and analysis, ensures equipoise, and maintains adequate power. The patient targeted therapies section of the Journal of Translational Medicine must endeavor to facilitate the dissemination of studies that focus broadly on translational research for the ultimate benefit of individual patients. The Affordable Care Act is the most important health care legislation enacted in the United States since the creation of Medicare and Medicaid in 1965. The law implemented comprehensive reforms designed to improve the accessibility, affordability, and quality of health care.” That is certainly true. It is also a fact that the Affordable Care Act leaves many important questions and issues unanswered and unresolved.Patient-centered therapies are at the heart of translational science in healthcare, which has gained considerable momentum from the Affordable Care Act-2010. In his recent paper [Translational research and translational effectiveness unquestionably signify together a positive future for patients and stakeholders across the health sciences. Translational research utilizes laboratory protocol of basic biology and physiology on specific biopsies to better define and characterize the pathological mechanisms that underlie the patient’s condition. Translational effectiveness utilizes the research synthesis, comparative effectiveness research and meta-analysis protocols and systematic review reports to craft and establish the consensus of the best evidence base (BEB) for electing the most appropriate mode of therapeutic intervention to treat the patient’s condition –8.Research synthesis, the chosen design for garnering BEB, is reported in the form of the systematic review. It is a systematic process of locating, and critically evaluating the body of research that addresses a particular clinical issue. Systematic reviews yield the highest level and quality of evidence, and the consensus of BEB for efficacy , or effectiveness . BEB can be expressed qualitatively, quantitatively, and statistically. Data extraction summarizes the salient evidence, sample size, nature of the individual studies, benefits and type and frequency of adverse events –10. WhatCase in point, translational science for healthcare consists of a continuum simply described as translational research (T1), that is the transfer of knowledge from patient-centered basic research to the patient-targeted therapies. Translational effectiveness T2), that identifies BEB from peer-reviewed clinical research, including clinical trials and observational studies, and disseminates BEB to practice settings and communities of stakeholders for the specific purpose of optimization of patient-centered, and patient-targeted interventions. This two-fold approach clearly demands increased emphasis on improving IPR, as well as optimizing patient-clinician communication and patient-tailored care delivery , that id. A thirdsine qua non for patient-targeted therapies is to obtain patient-centered outcomes of research and evaluation. That is to say, we must strive to tailor our research endeavors to the needs and characteristics of individual patients, rather than pursuing the traditional route of biostatistics that describes and makes inferences of group data. To foster patient centered research in healthcare, and as a direct product of the Affordable Care Act-2010, a novel Federal entity, the Patient-Centered Outcomes Research Institute (PCORI), was formed along side the existing National Institutes of Health (NIH) and the Agency for Healthcare Research and Quality (AHRQ). As it’s principal mandates, PCORI sets the methodological standards and guidelines in patient-centered outcomes research , prioritizes patient-centered outcomes research questions, obtains and disseminates BEB consensus, and responds to specific critiques, input and suggestions from the stakeholders.A One example of the use of IPR in translational healthcare is the model of temporomandibular joint disorder (TMJD). We outline here this timely and critical paradigm for patient-targeted therapies in evidence-based medicine and evidence-based dentistry.The arthrokinetic reflex describes the way in which a typical joint movement can reflexively cause neuromuscular activation or inhibition , 10. In With age and trauma, the disc may become thin and undergo change of cartilage in the central part, changes that may lead to impaired movement of the joint. Among the most common disorder of the jaw joint is disc displacement, which can lead to synovial inflammation, local pain and myalgias of the face, head, neck and shoulders as well as migraine-type headaches. From the viewpoint of translational research, jaw joint biopsies can be monitored for biomarkers of proximal  and distal inflammation  , and neurotransmitters of pain  , 13.Clinical research and observations have described the wide spectrum of the arthrokinetic reflex in TMJD, mediated largely by retrograde transport from the V3 terminal branch to the joint  and the central nervous system, and which can contribute and exacerbate neuro-muscular disorders, including tourette’s syndrome, cervical dystonia, complex regional pain syndrome, gait or balance disorders, Parkinson’s disease, middle and inner ear dysfunction, impaired eye movement, sleep disturbances, pain, and related neurological symptoms –15. The As proof of concept, the overarching arthrokinetic reflex in TMJD, the working hypothesis can be tested that by expanding the joint anatomical space the arthrokinetic reflex is reduced. In the context of patient-centered translational research, a broad spectrum of clinical independent patient data can be obtained from patients diagnosed clinically, by palpation as well as imaging  with mild-severe TMJD. Salivary and synovial levels of pro-inflammatory cytokines, replicate the findings reported in the literature , and areHeightPitchYawRollAnterior/posteriorThese observations strongly support the need to conduct patient-targeted therapy clinical trials to test the efficacy and the effectiveness of the intervention designed to expand jaw joint space as a potential treatment for TMJD, and more broadly for the plethora of pathologies related to the jaw joint arthrokinetic reflex. It is important to note that the intervention must be tailor-made for each patient along five principal criteria listed below and shown in Fig. We have proposed elsewhere , 18 the Individual patient outcome data could include salivary and synovial pro-inflammatory cytokines and pain peptides, as reported . RelatedRepeated individual patient outcome measures should be collected in the same manner as baseline every 3 months for 9–12 months, depending on individual patient’s clinical progress. At subsequent time points, clusters will switch over, following random ordering, and measurements would be obtained from each patient and analyzed as deltas (∆: difference from baseline). That is to say, the data of the proposed study would be—for each individual patient—the set of deltas for each variable repeated measures. Analysis of these data would follow the routine repeated measure ANOVA process, with Newman-Keuls post hoc comparisons and Bonferroni corrections for comparative purposes, and hierarchical multiple regression for predictive purposes integrating other individual patient characteristics. If the data were expressed as ratio change from baseline, then individual patient data meta-analysis could be projected with an approach similar to the present use of odds ratios in customary meta-analysis –8.This section on patient-targeted therapies of the Journal of Translational Medicine must redouble its focus on translational research  investigations, on studies that pertain to translational effectiveness , or on research that seeks to better define and characterize the T1–T2 transaction . Here, we proposed a model by discussing the use of an adaptive cluster randomized stepped wedge blinded controlled trial to test a patient-targeted intervention designed to ameliorate symptomatology and pathology derived from the arthrokinetic reflex of temporomandibular joint disorder.It is timely and critical that patient-targeted therapies be examined and tested through the critical lens of translational research, and of translational effectiveness. It is just as timely and critical that the best available evidence that derives from such translational science studies be efficiently disseminated to clinicians for the ultimate benefit of individual patient and of all stakeholders.


Arabidopsis thaliana. The transcriptional networks involved in this process, as well as the communication among the tissues that perceive the shade and the ones that respond to this stimulus will also be briefly commented.In high density of vegetation, plants detect neighbors by perceiving changes in light quality through phytochrome photoreceptors. Close vegetation proximity might result in competition for resources, such as light. To face this challenge, plants have evolved two alternative strategies: to either tolerate or avoid shade. Shade-avoiding species generally adapt their development by inducing hypocotyl, stem, and petiole elongation, apical dominance and flowering, and decreasing leaf expansion and yield, a set of responses collectively known as the shade avoidance syndrome (SAS). The SAS responses have been mostly studied at the seedling stage, centered on the increase of hypocotyl elongation. After compiling the main findings about SAS responses in seedlings, this review is focused on the response to shade at adult stages of development, such as petioles of adult leaves, and the little information available on the SAS responses in reproductive tissues. We discuss these responses based on the knowledge about the molecular mechanisms and components with a role in regulating the SAS response of the hypocotyls of  The optimum plant density of each plant species is determined by its peculiar set of requirements and the environmental factors that directly influence plant growth and, consequently, crop yield. However, in general, as planting densities increase so does the shade signals provided by plants and, hence, the activation of plant responses to vegetation proximity. For many plant species, perception of plant proximity results in a set of responses known as the SAS that strongly affects plant development and architecture. When activated, SAS results in a reduced seed set and altered fruit development. Crops are typically grown at high densities, and SAS responses, if activated, are generally detrimental to yield because they induce reallocation of resources into elongation growth at the expense of harvestable organs . Therefore, one key research challenge that will certainly have a major impact in agriculture is to identify the mechanisms that underlie plant development in response to vegetation proximity.Over the past few decades, improvements in crop yields have come largely through increasing planting densities. Under the current scenario of rapid population growth and limited amount of arable land on Earth  and FR (about 700–800 nm), as the influence of PAR (between 400 and 700 nm) and other environmental factors, such as green and blue light, ethylene production or mechanical stimuli have been reviewed recently  and low elongation response . By contplant proximity (without direct shading by neighboring plants) and direct plant canopy shade. Because vegetation is considered to preferentially reflect FR compared to other wavelengths, plant proximity generates an intermediate or moderate reduction in the R:FR. By contrast, under a plant canopy, photosynthetic pigments from green tissues specifically absorb light from the PAR region (between 400 and 700 nm) whereas FR, which is poorly absorbed by plant tissues, is reflected from or transmitted through vegetation. Consequently, under direct plant canopy shade both the amount of PAR and R:FR is strongly reduced (low and very low R:FR), the latter effect mostly due to the selective depletion of the R of the sunlight filtered by the leaves  is relatively constant in quality, and the R:FR is about 1.2–1.5. In environments of high vegetation density, two related but different situations that lower the R:FR can occur: e leaves .A. thaliana are encoded by a small gene family of five members (PHYA to PHYE). Whereas PHYA encodes the only photolabile phytochrome, phyA, the other PHY genes encode photostable phytochromes, phyB–phyE. Phytochromes exist in two photoconvertible forms, an inactive R-absorbing Pr form and an active FR-absorbing Pfr form. Consequently, in the light, the steady-state ratio of Pr and Pfr forms  depends on the R:FR. Indeed, there is a positive correlation between the R:FR and the Pfr/Ptot levels. Under high R:FR  the photoequilibrium is displaced toward the active Pfr form, the Pfr/Ptot is high (0.7 or higher), and the SAS is suppressed. On the contrary, under low R:FR the photoequilibrium is displaced toward the inactive Pr form, the Pfr/Ptot is low (0.6 or lower), and the SAS is induced . These are phenotypes very similar to those of wild-type plants growing under low R:FR . Therefore, the constitutive SAS phenotype of phyB mutant plants was taken as indicative that phyB is repressing SAS responses under high R:FR conditions, i.e., that responses to low R:FR are primarily mediated by phyB. Mutant analyses also showed that phyD and phyE act redundantly with phyB in controlling adult SAS responses, such as petiole elongation and internode elongation between rosette leaves  responses to low R:FR, which indicates that phyA and phyB have antagonistic actions in shade. This is particularly obvious when growing under deep plant shade. Whereas vegetation proximity (that results in moderate R:FR) promotes a similar hypocotyl elongation in wild-type and phyA seedlings, under deep and direct plant canopy shade (that results in low and very low R:FR) hypocotyls of wild-type seedlings tend to elongate significantly less than those of phyA mutant seedlings, which display an exaggerated elongation  simulated shade, to refer to any conditions that lower the R:FR and have not been defined by the authors as mimicking vegetation proximity or shade; (2) proximity shade, to those conditions that simulate plant or vegetation proximity; and (3) canopy shade, to those conditions that mimic natural direct plant shade. These treatments are obtained in the laboratory by applying increasing intensities of FR to a fixed intensity of white light (W), usually provided by fluorescent tubes: for a given amount of PAR, intermediate R:FR (about 0.50–0.30) results in proximity shade treatments, and low and very low R:FR (<0.29) results in canopy shade treatments .Laboratory conditions that mimic plant proximity, before actual canopy shading occurs, have been termed py shade . Severaleatments . These ROne might think that the very low R:FR of the canopy shade treatments rarely exists in nature: because the amount of FR employed in the laboratory to supplement the W is very high, it seems difficult to comprehend how nature can produce such as high proportion of FR simply by filtering and transmitting differentially the R and FR components of the sunlight. In that respect it is important to keep in mind that in chlorophyll-rich organs, such as leaves, light absorption from the ultraviolet to the R part of the visible region by chlorophyll leads to the emission of FR by fluorescence , a propeIn addition to supplementing W with FR, an alternative way to induce SAS responses is to treat plants with a pulse of FR for a few minutes at the end of the light period and immediately before starting the dark phase of the photoperiod. These are called end-of-day-FR (EOD-FR) treatments . Like loArabidopsis led to conclude that the SAS induction is regulated at least in part by the interaction of active phytochromes with the PIFs (PHYTOCHROME RAPIDLY REGULATED (PAR) genes, postulated to be instrumental for the implementation of the SAS responses. Because many of these PAR genes encode transcriptional regulators, it is considered that SAS responses are consequence of the phytochrome regulation of a transcriptional network, composed by several types of transcriptional regulators organized in partially redundant functional modules. Genetic analyses performed measuring the hypocotyl elongation demonstrated roles in the SAS regulation for several PAR genes. This is the case of members of the HD-Zip II, , bHLH  and B-BOX CONTAINING (BBX) families of proteins. Analyses of mutants with altered levels of these factors led to propose negative , positive  and complex (HD-Zip II) roles in the SAS regulation  response to simulated shade has been poorly studied, hypocotyl elongation has been most commonly and deeply studied. Analyses of the hypocotyl elongation responses to simulated shade in the PIFs , which rgulation . Furthergulation . PIF1, Pgulation . In contpression . It seemSAV3 encodes TAA1, an enzyme required for the shade-induced biosynthesis of IAA, a bioactive auxin  pathway , which produces IAA that is essential for plant development , indicating as well a possible involvement of PIFs in modulating auxin sensitivity  of cotyledons  combined with molecular or physiological analyses in the responding stems  and interorgan mechanisms, which involve the role of auxins and PIFs. Indeed, cotyledons are the major site of shade perception that controls several apex-responsive genes, including those that are auxin-responsive and/or PIF7-dependent. This is consistent with the known role of PIF7 predominantly regulating the seedlings SAS response by controlling auxin biosynthesis in cotyledons . However, the shade signal perceived in the shoot apex also controls gene expression in the cotyledons , providing evidence for an unexpected bidirectional communication between these seedlings parts , promotion of flowering and inflorescence stem length together with a suppression of axillary bud outgrowth  and a petiole . The petiole places the leaf blade in the position that is best suited for light reception. Hence, the regulation of petiole elongation seems important to maximize photosynthesis. One of the most studied SAS response of the rosette leaves of Arabidopsis is petiole elongation, which is promoted by light treatments that simulate vegetation proximity or canopy shade, such as low R:FR and EOD-FR . Genetic analyses indicate that leaf petiole elongation is regulated by photostable phytochromes: the phyB mutant has longer petioles than the wild type , and the phyAphyBphyD and phyAphyBphyE mutants have longer petioles than the phyAphyB double mutant  is up-regulated by shade. However, only the knockout mutants for XTH15 and XTH17 had reduced or absent petiole SAS responses. Together, these results confirm the functional role of some XTHs in the cell wall restructuration required for the cellular expansion that fuels rapid petiole elongation during the SAS . This suggests that when leaves are exposed to proximity or canopy shade, growth is invested in petiole elongation at the expense of blade expansion. The EOD-FR treatment promotes more strongly the elongation of the basal part of the petiole, although both the basal and apical part of this organ elongate. Similarly, the EOD-FR inhibited mostly the expansion of the middle portion of the leaf blades . At the leaf stage analyzed, both effects happened by differential control of cell elongation, with a negligible contribution of cell division  families, were up-regulated by EOD-FR in the leaf blade  and petiole , respectively. Genes that are dually controlled by auxin and BR were overrepresented in the EOD-FR-induced genes also in leaf blades and petioles , suggesting that these factors also have a regulatory role in the shade-induced leaf growth and expansion. Although there is not yet experimental evidence confirming this possibility, single or multiple PIF-deficient mutants, such as pif4 and the double pif4pif5 show small and compact rosettes; in agreement, PIF4 and PIF5 overexpressing plants display expanded rosettes with strongly elongated petiole leaves under a range of light conditions or temperatures  and of supportive organs . It is unknown whether the regulators of shade-induced hypocotyl elongation also control the shade-induced petiole elongation. Available transcriptomic data suggest the existence of some common regulators . Microarpetioles . Similarpetioles . Amongsteratures . Recent 7 mutant . These fArabidopsis, which have leaves close to the ground, usually results in a repositioning of the leaves, which helps to avoid shading imposed by neighboring plants. The upward bending of the leaves, caused by faster growth on their lower than their upper side, is called hyponasty. The hyponastic response to low R:FR is severely reduced in a range of auxin mutants, such as sav3, which encodes an enzyme involved in the rapid increase of endogenous levels of IAA required for the shade-induced hypocotyl elongation , and pin3, which encodes a protein that controls the direction and rate of cellular auxin eﬄux, indicating that the leaf hyponastic response to simulated shade requires an intact auxin signaling  and abaxial (lower) leaf sides, although no information is available about the effect of shade on the epidermal cell area on these sides of the leaves. It is intriguing to find that mutants with altered levels of response , do shown leaves . Since ledundant , might bFigure 1). The combination of these responses places leaf lamina away from the shade of neighbors, likely enhancing the photosynthetic activity of the plant. Current evidence supports that some regulators of these responses could be shared with those in seedlings, despite the structural differences between the involved organs. Very recently it has been also suggested that Arabidopsis plants reorient their leaves upon recognition of kin neighbors  and IAA6 (At1g52830), two auxin-responsive genes in the petiole identified previously as also being induced after EOD-FR treatment of the whole plant, showed that their expression was under the control of phytochrome in the leaf blade; i.e., the spotlight given on the leaf blade effectively induced gene expression not only in the leaf blade but also in the petiole. In contrast, petiole irradiation was not effective at all in inducing the expression of these two genes in the petiole itself. Together, these simple and elegant experiments indicated that phytochrome action in the leaf blade controls gene expression and elongation responses in the petiole  displayed reduced seed number per silique compared with wild-type plants, suggesting that some of these phenotypes are in part determined by phyB signaling. PhyB activity did not appear to play a significant role in the determination of other phenotypes examined, such as silique length and seed weight  to plant proximity or shade  is separated from the site of action , as it is known to happen in the photoperiodic-dependent flowering induction. However, there is no information about this aspect in the SAS responses of the reproductive tissues, although, as mentioned, inflorescence tissues perceive and respond molecularly to plant proximity (Arabidopsis when inflorescences are fully growing, rosette leaves are already senescing, it seems likely that – for these responses - the site of perception and action coincide. Thus, future research on the characterization of the SAS responses in adult plant stages, as well as on its spatial and genetic regulation, will greatly contribute to the understanding of this important adaptive trait with critical impact on crop yield.Despite the efforts made by many laboratories during the last decades to understand the SAS (reviewed in roximity . ConsideIR-V and JFM-G wrote the manuscript.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.


Ischemic cardiomyopathy is one of the major health problems worldwide,representing a significant part of mortality in the general population nowadays.Cardiac magnetic resonance imaging (CMRI) and cardiac computed tomography (CCT)are noninvasive imaging methods that serve as useful tools in the diagnosis ofcoronary artery disease and may also help in screening individuals with riskfactors for developing this illness. Technological developments of CMRI and CCThave contributed to the rise of several clinical indications of these imagingmethods complementarily to other investigation methods, particularly in caseswhere they are inconclusive. In terms of accuracy, CMRI and CCT are similar tothe other imaging methods, with few absolute contraindications and minimal risksof adverse side-effects. This fact strengthens these methods as powerful andsafe tools in the management of patients. The present study is aimed atdescribing the role played by CMRI and CCT in the diagnosis of ischemiccardiomyopathies. It is a condition characterized by thepresence of myocardial ischemia, either associated or not with fibrosis caused bymyocardial infarction. Myocardial ischemia only occurs in cases of imbalance betweenoxygen supply and demand, and the decreased blood flow is considered to be thephysiopathology in most cases of acute myocardial infarction and unstable anginaepisodes. Additionally, the synergism between the oxygen supply and demand is themain determining factor of ischemia in cases of stable chronic angina. In about 50% to 70% of patients, acute myocardialinfarction is the first manifestation of ischemic cardiomyopathy,3. The main etiopathogenic substrate of ischemic cardiomyopathiesis atherosclerosis. The riskfactors for development of atherosclerosis and subsequent ischemic cardiomyopathyinclude, besides age, systemic arterial hypertension, diabetes mellitus, smoking,dyslipidemia, sedentarism and obesity.The clinical presentation of the coronary disease ranges from stable chronic anginato sudden death. This spectrum includes acute myocardial infarction with ST segmentelevation, acute myocardial infarction without ST segment elevation, and unstableangina, currently catalogued as acute coronary syndrome.Currently, noninvasive cardiac imaging has been fundamental for the diagnosis andmanagement of patients with diagnosis or even suspicious of chronic coronarydisease. Mostfrequently, the following noninvasive methods are utilized in the diagnosis ofischemic cardiomyopathy: exercise stress test; pharmacological stress or exercisestress echocardiography; myocardial perfusion scintigraphy; cardiac magneticresonance imaging (CMRI); and cardiac computed tomography (CCT), with emphasis onthe two latter methods.The diagnosis is based on the patient's clinical history and presence of riskfactors. Electrocardiography and chest radiography may also be useful to clarifychest pain etiology. Cardiac catheterization, however, is the gold standard for thediagnosis of coronary artery disease (CAD), despite its invasiveness andexpensiveness,8. CCT is a more recent method with main clinicalapplication focused on the diagnosis of CAD, determining the Agatston coronarycalcium score (CCS) and the performance of noninvasive coronaryangiography,8.CMRI is extremely useful in the evaluation of CAD, both in the acute and chronicphases. Because of its high spatial resolution, this method can currently beconsidered as a reference standard for evaluation of the global and regionalmyocardial function and for detection and quantification of myocardial infarctionareasOn the basis of the above considerations, the present study is aimed at describingthe current concepts regarding the utilization of CMRI and CCT in ischemiccardiomyopathy, highlighting the diagnostic, therapeutic and prognostic impactscaused by the method. A systematic review was performed in the PubMed data basissources , utilizing the search terms "cardiac magneticresonance in ischemic cardiomyopathy" and "computed tomography in ischemiccardiomyopathy", as well as in themecorrelated books, consensus and societiesguidelines., III Diretriz Brasileira deInsuficiência Cardíaca Crônica and Diretriz de Doença CoronarianaCrônica - Angina Estável) were utilized. The present study was developed on thedata collected in this review.The authors found 1319 articles and, among those, 43 articles published inhigh-impact journals were selected by consensus of the authors, Additionally onesocieties consensus and three guidelines   .. The evaluation oftransmurality of the regions with myocardial necrosis or fibrosis allows forpredicting, with excellent accuracy, the probability of regional myocardialfunction recovery after revascularization, either surgical orpercutaneous.As a function of its excellent spatial resolution, CMRI can diagnose,besides transmural infarction, small subendocardial infarctions. Cine CMRI allows for thesame type of analysis of segmental contractility than echocardiography.However, as such information is combined with the detailed evaluation of theinfarcted region provided by the delayed myocardial enhancement technique,CMRI allows for accurately determining what is stunned myocardial tissue andwhat is irreversible necrosis.In what concerns CAD, the presence and the pattern of delayed myocardialenhancement at CMRI in a patient with ventricular dysfunction allows for thediagnosis of ischemic or non-ischemic cardiomyopathy.Among the method limitations, there is the fact that coronary MRIangiography, employing several acquisition techniques, reveals moderatesensitivity (72-77%) and specificity (71-87%) values for detection ofcoronary stenosis as compared with invasive angiography,23. CMRI has modest spatial resolution in thedetection of coronary stenosis as compared with the high spatial resolutionprovided by CCT. It is possible that in the future coronary MRI becomes moreusual, but currently, coronary CT angiography is a more robust method, withhigher sensitivity and specificity as compared with CMRI.CMRI has some relative contraindications, namely, presence of pacemakers,implanted defibrillators, cerebral clips, cochlear implants and metalfragments in the eyes.The method limitations include systemic nephrogenic fibrosis, a disease thatcauses systemic tissue fibrosis and is associated with the use of gadoliniumin patients with chronic renal failure stages 4 and 5 and in patients withhepatorenal syndrome. It is important to highlight that such warning doesnot apply to patients with normal renal function. The systemic nephrogenicfibrosis physiopathogenesis is still to be understood, but it is known thatthere is an association between the development of the disease and use ofgadolinium, which was demonstrated by the detection of gadolinium inbiopsies of tissues of patients with systemic nephrogenic fibrosis, and bythe disease onset after a 2-12-week period after the use of gadolinium.Systemic nephrogenic fibrosis is a quick-onset and progressive condition,determining the onset of symptoms such as muscle weakness, arthralgia, skinhardening and contractures, which, in conjunction, lead to the patientimmobility. The risk for development of the disease increases at eachexposure to gadolinium. For this reason, the Food and Drug Administrationrecommends the calculation of the creatinine clearance in the patientspreviously to the gadolinium enhanced CMRI, and the indication of thisexamination for patients at risk only if strictly necessary, followed bydialysis, despite the absence of scientific evidence that dialysis preventsthe onset of systemic nephrogenic fibrosis.In the clinical practice, all the imaging studies for investigation ofischemia are performed with the patient under pharmacological stress, whichrepresents a partial limitation for the non-pharmacological evaluation, inspite of the fact that some studies have already demonstrated thepossibility of performing MRI with exercise stress. Such method presents a highnegative predictive value in the detection of CAD, and for this reason it may be utilized as analternative to cardiac catheterization to rule out CAD.CCT is a method that utilizes ionizing radiation and iodinated contrast agent,with the main clinical application focused on the diagnosis of CAD. The presence of calcium in the coronary arterieshave a strong predictive value for future cardiac events in asymptomaticpatients-30, considering the highprobability of obstructive coronary disease associated with the increase inthe amount of coronary calcium,31. Thusevaluation based on the CCS allows for the differentiation betweenasymptomatic patients and those under risk to develop CAD overtime. At theBethesda Conference, it was concluded that CCT and the CCS techniqueconstitute the most accurate method currently available for early detectionof coronary atherosclerosis.CCT detects and quantifies coronary artery calcium, a marker of the presenceand extent of atherosclerotic disease. Such process is explained by the Gagov'sphenomenonthat consists in the patency of the normal volume of the vessel, despite thepresence of an atherosclerotic process, which is called positiveremodelling. The evaluation of the CCS , with high sensitivity and specificity in thedetection of coronary stenosis. It is indicated principally for patients atintermediate risk for CAD and with dubious tests for ischemia, or inpatients with low clinical probability of CAD, but with positive test forischemiaplaques . In the ues , requiring theuse of beta-blockers during the scan. The use of sublingual nitrate, asindicated, might be considered as a limiting factor as it generates atendency to the CCTA overestimate the degree of coronary stenosisCMRI as well as CCTA are diagnostic imaging methods undergoing constanttechnological development..Undoubtedly this will reduce the acquisition time and will maintain orimprove the diagnostic potential of the method.The main future prospect for CMRI is related to the continuous improvement ofthe images quality, allowing for a more detailed understanding of themyocardial anatomy, function and perfusion, of the tissues characterizationand cardiac viability, besides representing an important tool for cliniciansand cardiologists-43. The high spatial and temporal resolution of this methodallows for images acquisition with a great anatomical detailing andnoninvasive evaluation of the spatial relation between adjacentstructures.The main prospects for CCT involve the reduction of the radiation doseaffecting the patient, reduction of the acquisition time and, consequently,of the breath hold time, reduction of the volume of contrast agent requiredfor the noninvasive acquisition of coronary arteries images, and reductionof the radiation dose. Another prospect involves the analysis of myocardialperfusion by means of dual energy CT apparatusesOver the last four decades, the analysis of the coronary anatomy to predictthe myocardial physiological status has ever been considered to beevidencing. However, it is currently believed that the isolated anatomicalanalysis cannot predict the physiological behavior of a single patient,since the biological variability is not taken into consideration. Anatomicalparameters such as percentage of stenosis in the coronary diameter are not avery useful tool to understand the physiological behavior in general. In thefuture, the tendency is the adoption of parameters capable of moreaccurately and less invasively predicting the physiological status.. The calculation of the fractional flow reserve hasalso been studied by means of CCTA. Although still undergoing improvements,it would be theoretically ideal for the management of patients with CAD,since a single scan would allow for the anatomical evaluation of adetermined stenosis and its functional, demonstrating if, in fact, there wasimpairment of the myocardium. However, data about clinical validation andcost-effectiveness are still limited,46.Such physiological parameters can be evaluated by means of noninvasiveimaging methods such as PET/CT or by invasive methods such as cardiaccatheterization and, recently, noninvasively by CCTA. PET/CT, because of itshigh spatial resolution, is capable of quantifying myocardial perfusion atrest and stress and determining the coronary flow reserve. Cardiaccatheterization allows for determining the fractional flow reserve that isdefined as the quotient between the pressure distal to a stenosis and theproximal pressure. Both physiological parameters allow for more accuratelypredicting the degree of ischemia caused by the CAD, because theseparameters are superior to evaluate diffuse, multisegmental coronarydiseases and those with heterogeneous remodelling. As compared with eachother, the coronary flow reserve is accurate to predict ischemia andsuperior in the evaluation of diffuse diseases, so there is a futuretendency towards the analysis of such parameter by PET/CT. The most relevantPET/CT clinical application in myocardial perfusion is the selection ofpatients with atherosclerosis who will benefit more from undergoingmyocardial revascularization-50.Another approach under study is the evaluation of myocardial perfusion understress by CT in association with CCTA. Such a technique evaluates themyocardial perfusion um stress and the coronary anatomy, providing dataabout a possible ischemia and coronary stenosis, thus evaluating both themyocardial anatomy and physiology. Since 1970, there have been attempts toimprove such technique, but only recently, with the technological evolutionof CCT, it was possible to perform a myocardial evaluation under stress.Preliminary studies have demonstrated an improvement in the diagnosticaccuracy when the techniques are utilized in combination as compared withCCTA alone. However, this technique still lacks further studies to establishimaging protocols defining contrast agents and radiation dosesCMRI and CCT are validated as highly sensitive and specific diagnostic tools, withfew contraindications and minimal risks of adverse effects, and should be utilizedby physicians as aid in the management of their patients.


Nearly half of the malnourished population of the world lives in South Asia, and agriculture is the main source of livelihood of the people in this region. Many review exercises have analysed the available evidences to understand the ways in which agriculture can be leveraged to enhance nutritional status; however, very few of them have employed a systematic approach ensuring internal and external validity. The present paper seeks to fill this gap for strengthening the policy recommendations. It demonstrates an association between agricultural interventions and nutritional outcomes; and it shows that the production of targeted nutrition-rich crops, homestead gardens, and diversification of the agricultural production system towards fruits and vegetables and aquaculture can potentially improve nutrient intake and nutritional outcomes. The empowerment of women and nutrition knowledge play a crucial role in establishing linkage between agriculture and nutritional outcomes. In this region, food insecurity is high, with almost 23% of the population not having access to adequate calorie intake . Agricul1.Source of food: Agricultural produce by the farmers is also used for their own household food consumption.2.Source of income of households engaged in agriculture, for food and non-food expenses: Agricultural income may be earned either through wages earned as agricultural workers or through the sale of produce. The income spent on nutritious food may have impact on malnutrition.3.Agricultural policy and food prices: Agricultural policies can affect the relative prices and affordability of various marketed food and non-food crops.4.Women in agriculture and their socio-economic status: The socio-economic status of women in intra-household decision making and resource allocation may influence the nutritional status of the mothers and their children.5.Maternal employment in agriculture, child care and feeding: The involvement of mothers in agriculture may influence their ability to manage child care and feeding.6.Women in agriculture, maternal nutrition, and health status: The maternal nutritional outcomes and health may be compromised due to involvement in agriculture. The work-related energy expenditure may exceed the intake, or the dietary diversity may be compromised. Some of the agricultural practices may be hazardous to their health. These factors, consequently, affect the nutritional status of the children.There are multiple pathways through which agriculture can influence the nutritional outcomes . The UNIThese pathways are considerably influenced by different factors such as the type of agriculture, market and consumer demands, inequalities in the system, tastes and preferences, and nutrition-relevant policies and programmes. Therefore, the pathways from agriculture to nutrition are evolving and dynamic; and are not linearly associated .In the recent past, several studies have focused on leveraging or modifying agriculture to enhance nutrition. Many review exercises have analysed the available evidences on the linkages between agriculture and nutritional outcomes. Some of them are global in nature and others have country specific focus. In the SA region, women constitute approximately 35% of the agricultural workforce. In the rural areas of this region, 70% of the employed women are engaged in agricultural sector, indicating the importance of agriculture . HoweverThe studies on agricultural interventions, some of them based in the SA countries, have focussed on several factors including increasing production of micronutrient-rich food , diet diThe studies focusing on agricultural interventions to improve production of micronutrient-rich foods, through increased productivity, home gardening, bio-fortification, diversification, etc., have reported a significant impact on dietary diversity and micronutrient intake, through the first and/or second pathways. Policies which affect the relative price of staples (third pathway) may also have considerable effect on the nutritional intake. However, no conclusive evidence exists on the impact of these interventions on nutritional outcomes . It has The interventions directly affecting multiple pathways, through nutrition-education and multi-sectoral aspects of the involvement of women, considerably improved the nutritional outcomes . TherefoThe existing review papers show that agriculture does have the potential to promote nutritional outcomes, although the linkages are rather complex . The revSeveral reviews have reported the inter-linkages between agricultural interventions and nutritional outcomes; however, few have used a systematic approach . The sel2We analysed the studies on the impact of interventions in agriculture and allied sectors  on the nutritional outcomes for adults and children, published since the year 2000. The nutritional outcomes were captured through both intermediate outcome indicators such as dietary diversity, calorie intake and nutrient intake, and outcome indicators such as anthropometric factors and DALYs (Disability Adjusted Life Years). The process for selection of the published studies and the criteria adopted for assessment of the internal and external validities is given in the following two subsections.2.1The search was conducted for shortlisting the empirical studies with agricultural interventions or programmes as the central concern. A systematic literature search was carried out using several search engines and websites of relevant institutions: Google Scholar, AgEcon Search, CAB Abstracts, EconLit, Eldis-IDS, Food and Agriculture Organization (FAO), International Food Policy Research Institute (IFPRI), Government of India , Leveraging Agriculture for Nutrition in South Asia (LANSA), Ingenta Connect, Harvest Plus, United Nations Children’s Fund (UNICEF), and World Bank. We have not considered grey literature and the literature available in languages other than English. A wide range and combination of catch phrases, with terms ‘impact/effect’, ‘agriculture/agricultural’, ‘interventions/programmes’, ‘nutrition’, ‘nutritional outcomes’, and ‘South Asia’ were used, on the literature published during the period of January 2000 to July 2014. The term ‘health’ was not included in the search process as it resulted in an unmanageably large number of irrelevant results. To reduce the prospect of missing relevant publications on agricultural programme and policies due to limitations of the used search phrases, the search was repeated in many related publication databases. The search results from Google Scholar were scanned by using the advanced search with all words ‘agriculture nutrition South Asia’ and the exact phrase ‘agriculture nutrition’ until the relevance of the search title diminished. The search yielded in 2080 papers . On the 2.2For conducting a systematic review, a set of twenty-five studies were selected as described in the previous section. The set was not homogenous in terms of a common outcome indicator and the studies used different metrics for examining the linkage. Some studies analysed nutritional outcomes by examining the stunting and wasting of children and adolescent, whereas others analysed the Body Mass Index (BMI) for determining adult malnutrition or levels of micronutrients such as vitamin A and haemoglobin. Some studies used intermediate outcome indicators, such as changes in consumption patterns, dietary diversity, and intakes of certain foods. Such differences in techniques and indicators made comparisons across studies difficult and limited the scope of the aggregation of results into a single metric, as also indicated by Most of the included empirical studies analysed data from secondary datasets and had large sample sizes. Others were primary baseline surveys, with smaller sample sizes. None of the included studies used randomized control trials (RCT). The power test for sample size selection was not reported in these studies; and hence they could not be scored on the basis of their power calculations in our analysis. With the studies showing large variations in sample sizes and many not adhering to sampling procedures, a direct comparison of the results was not feasible. Based on our scoring criteria for counterfactual methods, only one study  was scorExternal validity  is estabThe reviewed empirical studies scored better on external validity than on internal validity. A large number of studies presented a sound programme theory in terms of conceptual frameworks. Some studies also analysed intermediate outcomes, making their external validity sound. In terms of heterogeneity of impact, many studies analysed causal effects of varying population characteristics, such as socio-economic conditions and regional variations, lending more credibility to their findings. Thus, the studies on linkages between agricultural interventions and nutritional outcomes have duly emphasised the underlying programme theory, analysing intermediate outcomes and heterogeneity of impact .3Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka constitute the SA region. Of the 25 studies selected in this review, 10 were based on India, six on Bangladesh, three on Nepal, and one on Pakistan. No study based on Afghanistan, Bhutan, Maldives, and Sri Lanka was shortlisted for the review. Moreover, we included one study based on Vietnam and four global studies covering South Asian countries. Therefore, there exists a regional imbalance in the coverage of the SA countries. Evidences in these studies for the different pathways are examined in the following subsections to understand how effectively agricultural interventions can be used to improve the nutritional outcomes.3.1Twenty-two of the 25 reviewed studies examined the contribution of agriculture as a source of food for nutrition. The studies indicate strong evidence that the dietary intake of agricultural households largely depends on food supplies from their own farm , becauseAgricultural productivity can be improved by providing timely access to inputs, improvement of rural and marketing infrastructure , and adhThe increase in food production, particularly that of staple grains, pulses and vegetables, showed more conclusive evidence on improving the nutrient intake and nutritional outcomes, compared with the overall agricultural growth rates . HoweverIt has been observed that households having vegetable based production systems had a lower deficiency from Recommended Daily Allowance in the consumption of vitamin A, iron, and vitamin C for adults and for children vis-à-vis those having non-vegetable based production systems . The intAgricultural intensification, measured in terms of irrigation and improved seed or fertilizer use, showed a negative correlation with child nutritional outcome, particularly with respect to wasting and stunting .This mayAquaculture appeared as a crucial source of diet diversification leading to an improved intake of animal-based micronutrients . The farBio-fortification of staples has been reported to be more cost effective in reducing the burden of diseases resulting from deficiencies by combating micronutrient deficiencies, as compared with fortification and supplementation, especially in developing countries . However3.2Agriculture can be leveraged to improve the nutritional outcomes indirectly through the income and expenditure routes, as perceived in this pathway, and it has been examined by eight out of the selected 25 studies. A cross-country study by The household’s main occupation may also affect the nutritional status. Nutritional security was reported to be significantly influenced by the per capita agricultural income . The agrThe increase in household income through crop production at the household level had a significant positive effect on calorie intake because of the increased food expenditure . The incConsidering an increasing land fragmentation in the SA region, the diversification of agriculture towards high value crops, livestock, and aquaculture has been suggested for increasing the farm income. However, the size of landholding did not show significant impact on the nutritional status .3.3Five out of the selected studies have analysed the role of agricultural policies aimed at reducing relative prices or increasing the affordability of food on the nutritional status. Therefore, the evidence base is very small. Based on the representative sample for India, it was demonstrated that policy intervention for affecting food prices played an important role in diet diversification and nutritional outcomes . The pol3.4The importance of women empowerment in agriculture and its contribution to household food and nutritional security was addressed by eight studies. The nutritional status of the mothers, measured using the BMI, had statistically significant positive effects on HAZ scores and weight for age (WAZ) scores of their children aged less than three years . There iWomen empowerment influenced the quality of feeding practices for infants and young children, but was weakly associated with child nutrition status . AgriculAn index of ‘Women’s Empowerment in Agriculture’ (WEAI), combining five domains of empowerment sub-index and a gender-parity index, showed a significant and positive association with calorie availability and household dietary diversity . It had 4The set of studies selected for review, although heterogeneous in terms of agricultural interventions and nutritional outcomes, shows an association between various interventions and outcome indicators through empirical techniques. The review confirms that agricultural interventions targeted at nutrient-rich crops and diversification of agricultural production system towards fruits, vegetables, and aquaculture through women empowerment hold the potential to improve the nutritional outcomes in South Asia.The main feature of our review exercise is a systematic approach which involved assessing the internal and external validities of the studies under review. The quality of evidence constrained the exercise to 25 studies. Only one of these studies ranked high on the internal validity. None of the included studies used RCT for studying the effect of interventions. Hence, the existing indications cannot be interpreted as a concrete evidence of the nutritional impact of agricultural interventions . The gapThe studies on agriculture for improved nutrition in South Asia have generally focused on the first and second pathways. Very few of them have covered a relative price policy (pathway 3) and women empowerment (pathways 4–6). The studies typically included evaluations of specific agricultural interventions, analysis of different data sets for change in consumption pattern, and calorie and nutrient intake to capture the nutritional outcomes. The measurement of anthropometric factors and the micronutrient level as direct outcome indicators has been scanty, as also mentioned by The major pathways linking agriculture with nutrition and illustrating the evidences are shown in The review further shows that agricultural growth is not a sufficient condition for addressing the problem of malnutrition, because its impact is location specific and depends on the state of economy and other socio-demographic conditions. Income and under-nutrition are weakly associated, whereas non-income factors, such as child vaccination and women education, have strong and significant effects. The pathway of agricultural policies affecting the affordability has positive effect on food security at the household level; however, its effect on diet diversity and nutritional outcomes is not conclusive.The pathways of women in agriculture and their empowerment (pathways 4–6) have poor evidence base, but they bring out the importance of women employment, land rights and access to resources, for improving the nutritional status of the mothers and their children. The evidences are consistent across the studies included in the review. They show the benefit of reducing the gender gap and the empowerment of women for improving the nutritional status, as reported earlier . Our fin5The agricultural interventions have the potential to influence nutritional outcomes in the South Asia; however, the available evidence linking the agricultural interventions and their impact on the nutritional status of women and children is small. The findings, generally in concordance with those from the previous reviews, show that linkages between agriculture and nutrition are complex and require multi-sectoral and multi-dimensional approaches to tackle the malnutrition problem in this region. However, the findings clearly indicate the importance of the home production of nutrient-rich food crops for improving the nutritional outcomes. Bio-fortification of staples and homestead gardens can influence the intake of a micronutrient-rich diet and consequently nutritional outcomes. The diversification of agriculture towards fruits and vegetables and integrated agriculture-aquaculture can potentially promote dietary diversity and improve nutritional outcomes. With more favourable nutrition-sensitive agricultural policies and empowerment of women, it is possible to improve nutritional status.There exists a need for well-designed studies with sound methodologies and rigorous analytical techniques, as indicated in some earlier reviews . Such st


The kappa opioid receptor (KOR) and the endogenous peptide-ligand dynorphin have received significant attention due the involvement in mediating a variety of behavioral and neurophysiological responses, including opposing the rewarding properties of drugs of abuse including opioids. Accumulating evidence indicates this system is involved in regulating states of motivation and emotion. Acute activation of the KOR produces an increase in motivational behavior to escape a threat, however, KOR activation associated with chronic stress leads to the expression of symptoms indicative of mood disorders. It is well accepted that KOR can produce analgesia and is engaged in chronic pain states including neuropathic pain. Spinal studies have revealed KOR-induced analgesia in reversing pain hypersensitivities associated with peripheral nerve injury. While systemic administration of KOR agonists attenuates nociceptive sensory transmission, this effect appears to be a stress-induced effect as anxiolytic agents, including delta opioid receptor agonists, mitigate KOR agonist-induced analgesia. Additionally, while the role of KOR and dynorphin in driving the dysphoric and aversive components of stress and drug withdrawal has been well characterized, how this system mediates the negative emotional states associated with chronic pain is relatively unexplored. This review provides evidence that dynorphin and the KOR system contribute to the negative affective component of pain and that this receptor system likely contributes to the high comorbidity of mood disorders associated with chronic neuropathic pain. Chronic pain may be considered an epidemic in many westernized countries affecting 25% of the population, and where quality of life of chronic pain patients is reported to be lower than other disorders such as heart failure, renal failure and even depression . Pain isNeuroplasticity in brain regions important for the expression of affect may underlie the comorbidity between chronic pain and Axis I disorders of the DSM-V, including depression, anxiety disorders, bipolar disorder, and ADHD. Comorbidities with each of these disorders in chronic pain patients have has been well documented, where depression is the most common comorbidity, with some studies finding a prevalence rate approaching 100% among clinical chronic pain samples . It has been demonstrated that rewarding stimuli such as food and pleasurable music decrease pain sensitivity , whereasOpioids and their receptors play a central role in various physiological effects throughout the peripheral and central nervous systems. In addition to their ability to modulate the sensory component of pain (the intensity), opioids also modulate the emotional, aversive component of pain . For example, a patient being treated with opioids for post-operative pain may still feel the sensory component of pain, but it no longer bothers them. There is strong evidence that release of dopamine within the ventral striatum is responsible for the mood altering properties of opioids. However, opioid-evoked release of dopamine also contributes to their abuse potential, where an allostatic shift in reward signaling leads to the pathological state of addiction. Mu opioid receptor (MOR) agonists positively modulate mood and are the predominant opioid drugs used for clinical and recreational purposes. However, both delta (DOR) and kappa opioid receptors (KORs) also modulate mood and emotion, but in opposite directions . ActivatA decrease or suppression of mesolimbic dopaminergic transmission that originates in the VTA is one mechanistic commonality between a stress response, the precipitation of an aversive state, and chronic pain. Salience is one of the key functions of the mesolimbic dopaminergic circuitry that is encoded via interactions between tonic and phasic spikes in dopamine neurons . The ‘paFigure 1). These brain structures include the habenula, rostromedial tegmental nucleus (RMTg), and ventral pallidum. The habenula is a small brain structure located near the pineal gland and the third ventricle, sometimes called the tail of the VTA. Recent reviews highlight the critical role this brain structure has in influencing the brain’s response to pain, stress, anxiety, sleep, and reward .Gamma-aminobutyric acid is the primary neurotransmitter in RMTg neurons that project to the VTA . ActivatOne prominent feature of the habenula is that it is involved in the processing of aversive information, including pain. In addition, repeated or continuous stress can lead to expression of depression-like behavior and exacerbate chronic pain. Importantly, sensitization of the LHb-dopamine circuitry occurs in depressive states . Indeed,Because the habenula is such as small brain structure, imaging studies to examine changes in activity within this region are challenging. Nevertheless, the habenula circuitry is proposed to undergo neuroplastic changes in chronic pain , where tIt cannot be assumed that the inputs to the VTA discussed above result in modulation of the dopaminergic projections to the NAc implicated in reward. The VTA-NAc projection is also implicated in the pathogenesis of stress-related behaviors. Dopaminergic neurons within the VTA project to various brain structures, including the medial prefrontal cortex (mPFC), amygdala, and hippocampus, as well as the NAc. Importantly, there is evidence that discrete subpopulations of VTA dopaminergic neurons exclusively project to only one of these regions and that they are engaged by different stimuli and inputs . It is wOther brain structures that either directly or indirectly modulate VTA dopaminergic circuitry are the NAc, amygdala, and the bed nucleus of the stria terminalis (BST). Medium spiny neurons within the NAc are GABAergic neurons that comprise the striatonigral (direct) and striatopallidal (indirect) cortico-basal ganglia pathways. There are two subtypes of medium spiny neurons within the NAc that respond to different patterns of dopaminergic firing patterns . A burstN-methyl-D-aspartate (NMDA) receptors has been shown to play a critical role in these aversive responses. The amygdala sends projections to, among other areas, the hypothalamus, VTA, and the cortex, making it a neuroanatomical structure well positioned to mediate the negative affect (aversiveness) associated with chronic pain . The selectivity and distribution of the opioid peptide and receptor systems suggests enkephalin and beta-endorphin act through the MOR and DOR, and dynorphin via the KOR. A fourth opioid receptor family, nociceptin, is distinct from the classical opioid receptor family, in that the endogenous opioid peptides do not bind to it with high affinity . Rather,The opioid receptors and their peptides are distributed throughout the central and peripheral nervous system in a distinct but overlapping manner . The MORWhile some studies implicate a positive role for the dynorphin/KOR system in anxiety-like behavior , other sChronic pain produces anxiety and dysphoria that suggests the engagement of the dynorphin/kappa opioid system . In the in vivo . In fact, development of biased agonists for these pharmacological effects has the potential to mitigate some of the side effects associated with KOR activation . It has What remains unclear, and difficult to ascertain, is whether KORs modulate mesolimbic circuitry and drive the emotional, aversive nature of pain. KOR agonists have dysphoric and psychotomimetic properties in humans and will mediate place aversion in rodents . These eEvidence for a role of dynorphin in linking the depression of both behavior and dopaminergic transmission in chronic pain states remains sparse. It is recognized that acute pain (like euphorogenic drugs) activates dopaminergic transmission in brain reward circuitry including the NAc , whereasThe perception of pain and processes of reward and aversion are complex, multifaceted phenomena manifested through extensive processing in and between multiple brain structures. Of note, these networks exhibit extensive anatomical overlap with several major brain structures are important nodes in pain, pleasure and aversion processing. The mesolimbic system is one point of convergence that lends credence and consilience to the extensive evidence for interactions between pain, reward, and aversion.The aforementioned studies provide evidence for the role of KOR in modulating dopaminergic neurotransmission in reward circuitry and the influence of dopamine in the transduction and generation of pain processing. Pharmacological manipulation of KOR can be used to modify dopamine transmission and negative affect. An engaging hypothesis holds the upregulation of dynorphin/KOR in chronic pain states to be causal in the generation of concomitant depression and mood disorders. This remains to be fully tested, however supporting evidence includes upregulation of dynorphin following chronic drug use and in post-mortem suicide patients where stress, depression, and anxiety disorders have developed.There is a clear a role for the dynorphin/KOR system in modulating the interplay of pain and reward processing. Through modulation of limbic neurotransmission, this system produces aversion, stress affect, and depression. The manifestation of these processes as corresponding psychiatric disorders is highly comorbid with chronic pain and suicide is exceedingly prevalent in chronic pain patients. These linked conditions have profound and severely deleterious effects on patients’ quality of life. Despite the implication of the KOR system in this progression, accepted treatments targeting it are lacking, thus manipulation of the KOR system may prove valuable in ameliorating chronic pain-induced negative affect.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.


Brain Imaging: What It Can (and Cannot) Tell Us About Consciousness with anticipation.From the height of his 90 years of experience, Robert G. Shulman is not just a veteran of World War II, but a world-class biophysicist with a distinguished research career spanning the California Institute of Technology, Bell Labs, and Yale University. A forerunner in the use of nuclear magnetic resonance, Shulman contributed to the study of biochemical processes, founded the Yale Magnetic Resonance Research Center, and shepherded functional Magnetic Resonance Imaging (fMRI) as a dominant tool of cognitive neuroscience. Together with Gregory McCarthy et al., Shulman authored several of the earliest fMRI studies, including the first to explicitly manipulate cognitive processes  to support his ideas. Despite this description, he defines these acts of consciousness (and consciousness itself) by observable behaviors and physical brain correlates (see p. 22) rather than by the capacity to recognize or decide. This conundrum rekindles the issue of reverse inferences , we may discern the study of consciousness from the study of biophysics. Novel neurophenomenological frameworks are rising to the challenge, helping scientists map cognition using experiential reports, psychoanalytical methods, and hypnotic suggestion , serve as fodder for neuroskeptics Uttal, . In the Regardless of how cognitive science relates to phenomenology and behaviorism, this worthwhile read will likely inspire continued discussion. Perhaps unknowingly, Shulman and his peers juxtapose phenomenology with empirical science. Whether or not readers find such concurrence palatable, Shulman presents a well-articulated account of behaviorist brain imaging. Our reservations hinge less on his advocacy for empirical and inductive science, and more on his presupposition that phenomenal and empirical evidence remain mutually exclusive.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.


Current management of retinitis pigmentosa (RP) includes an attempt at slowing down the degenerative process through therapies that use either Western or traditional Chinese medicine (TCM). Novel therapies in Western medicine (WM) include use of tailor-made gene therapy, transplantation of stem cells, or neuroprotection treatment. TCM treatment includes two major approaches. These are orally applied herbal decoctions and acupuncture. In fact, all TCM treatments are based on the differentiation of a symptom-complex, which is the characteristic essence of TCM. Thus, diagnosed RP may be treated via the liver, the kidney, and the spleen. The principle behind these treatments is to invigorate the blood and brighten the eyes by toning up the liver and the kidney. Also treatments to cope with deficiencies in the two concepts that are unique and fundamental to TCM are considered: Qi or “vital energy” and Yin and Yang or the harmony of all the opposite elements and forces that make up existence. In particular, the Qi deficiency that results from blood stasis is addressed in these treatments. This paper also puts forward the existing problems and the prospect of the future development on integrating TCM with WM. Retinitis pigmentosa (RP) is a group of inherited degenerative retinal diseases, involving progressive degeneration of the retina, typically starting in the midperiphery and advancing toward the macula and fovea . It is aVarious types of stem cells have been isolated from a variety of tissues including preimplantation embryos, fetuses, birth-associated tissues, and adult organs. Based on the source, these cells can be broadly classified into embryo-derived stem cells (ESCs) and adult tissue-derived stem cells. And based on biochemical and genomic markers, these stem cells can be broadly classified into embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), hematopoietic stem cells (HPSCs), and induced pluripotent stem cells (IPSCs). Stem cell therapy is a novel approach for vision restitution in retinitis pigmentosa . TransplCell replacement: transplanted stem cells can differentiate into retinal cells and integrate into the retina of patients, and the differentiated stem cells replace the apoptotic or injured retinal cells .Nutritional support: the function of transplanted cells is to release diffusible factors and nutritional substances which act as a local cell delivery system for trophic factors and can promote photoreceptor cell survival –10.Protection of the retinal blood vessels and cones: bone marrow derived stem cells contain endothelial precursors. Through significant upregulation of many antiapoptotic genes, these stem cells can rescue retinal blood vessels that would ordinarily degenerate completely , 12. ResPromotion synaptic connections: many studies have shown donor cells taken from developing mouse retina at a time coincident with the peak of rod genesis can blend in with cells in a normal adult or a degenerating mouse retina and subsequently build synaptic connections with the remaining retinal cells and, thus, effectively improve visual function . DespiteIn recent years, stem cell transplantation therapy in RP has made progress. The mechanisms of stem cells therapy for this disease include the following.The mechanism in gene therapy is the transfer of a therapeutic gene by use of viral or nonviral vectors and requires genetic modification of the ocular cells to produce its therapeutic effect. There are two methods to replace or correct abnormal genes: (1) gene augmentation therapies, where a normal gene is inserted into the genome to replace nonviable or diseased genes using a carrier vector; (2) gene silencing therapies, in which the expression of the mutated gene is inhibited by use of ribozyme or RNA interference .Successful augmentation therapies are dependent on efficient transduction of the target cell by Adeno-associated virus (AAV) and sustained expression of the recombinant virus at a sufficient level. To date, more than 30 patients have so far received the gene therapy, ranging in follow-up from 90 days to 1.5 years and no major side effects have been reported , 17. TwoNeuroprotection provides a sympathetic environment to prolong the viability of the photoreceptors by their effect on the secondary biochemical pathways. It is a therapeutic strategy which can be achieved either by delivering neurotrophic growth factors, on the one hand, or inhibiting proapoptotic pathways on the other. It can also be delivered by the implementation of viability factors such as the rod-derived cone viability factor for the treatment of retinal neurodegenerative disease that is independent of the etiology of the degeneration. A number of neurotrophic growth factors that slow photoreceptor death in animal models have been identified: basic fibroblast-derived growth factor (bFGF), brain-derived neurotrophic factor (BDNF), cardiotrophin-1, nerve growth factor (NGF), fibroblast growth factor (FGF), and CNTF.The final common pathway of all types of RP is photoreceptor cell death. Leonard et al.  reportedTCM therapy is based mainly on the practice of Chinese medicine and is constantly enriched and developed by practical experience. In ancient times, Chinese people discovered that certain foods reduced or eliminated certain diseases. This became the basis of Chinese herbal medicine. It is thought that ancient peoples discovered that fomenting a painful area of the body with the warmth of a fire or the use of warm leather or bark bags or hot stones or sand eliminated the discomfort caused by pain. While using stone as a production tool, people discovered that after a certain part of the body being stabbed, the pain in another part could be relieved, thereby creating treatment methods of using stone and bone needles, which was developed into acupuncture and therefore the formation of meridian. Taiping-sengxian Prescriptions in 992 AD for the first time. This classical work recorded more than 16,800 prescriptions and was descended to later generations popularly. Treatment determination based on syndrome differentiation is an essential principle in TCM in understanding and treating disease. It is a specific research and treatment method of disease in TCM and also one of the essential characteristics of TCM. TCM believes that the congenital deficiency with debilitation of the life gate fire is the main reason that causes RP. Other pathogenic factors of RP in TCM include liver and kidney deficiency with essence and blood insufficiency, or spleen and stomach deficiency with Qi and blood insufficiency. Finally, these elements can result in blood stagnation and vessel insufficiency, leading to a loss of nourishment to the eyes, and these will whittle down the spirit light of the pupil, narrow of the visual field, and nocturnal blindness. In TCM, this condition is referred to as high-altitude wind internal obstruction or high-altitude wind sparrow's vision. In recent years, many TCM ophthalmologists conducted further study of the pathogenesis of this disease. For example, Peng [Retinitis pigmentosa (RP) belongs to the high-altitude wind sparrow's vision category in TCM. High-altitude wind sparrow's vision was described in the bookle, Peng  proposedle, Peng . This stOrally applied herbal decoctions and acupuncture treatment have a role in relieving symptoms and improving visual function in patients.All TCM treatments are differentiated on the symptom-complex seen. This is the essence of TCM therapy. High-altitude wind sparrow's vision can be treated from the liver, the kidney, or the spleen. TCM differentiates the pathogenesis of this disease into four different syndromes, including deficiency of the liver-Yin and kidney-Yin, deficiency of the spleen and Qi, insufficiency of the kidney-Yang, and deficiency of the Qi and blood stasis. Among these multifaceted symptom complexes, deficiency of the liver-Yin and kidney-Yin is the most common clinical pattern observed. Different syndromes are prescribed very different treatments. For example, deficiency of the liver-Yin and kidney-Yin is treated by modified Ming Mu Di Huang decoction, which nourishes and tones the liver and the kidney and leads to invigorating the blood and brightening the eyes. In this formula of modified Ming Mu Di Huang decoction, the Chinese herbal drugs, Shudihuang, Danggui, Wuweizi, and Gouqizi, work on supplementing liver and kidney. The Chinese herbal drugs, Danpi, Danshen, Yemingsha, and Chongweizi, can also clear heat and invigorate blood. Chinese herbal drugs Shan Zhu Yu and Shen Di Huang reinforce the kidney, which may improve eyesight by replenishing vital essence. The formula achieves the purpose of seeking Yang within Yin, bringing true Yang back to its origin and unblocking the vessels and collaterals. So the actions of this formula are nourishing and tonifying liver and kidney. And they can invigorate blood and brighten the eyes. A recent study  in ChinaAcupuncture has been applied as a therapeutic medical technique in China since at least 2,000 years ago, when stone knives and other sharp instruments were used. The term itself is derived from Latin “acus” meaning needles and “punctura” meaning puncture. In this form of treatment, some diseases of the body can be treated by puncturing the points on the body surface to regulate the meridians, Zang-Fu organs, and the circulation of Qi and blood. Acupuncture treatment in RP cases often takes the acupoints such as BL1 (Jing Ming), EX-HN7 (Qiu Hou), GB20 (Feng Chi), LB18 (Gan Shu), LB20 (Pi Shu), ST36 (Zu San Li), and SP6 (San Yin Jiao). The therapist selects 1-2 local points along with two distal acupoints each time. The points should be made with the reinforcing method of needle, which is thought to invigorate the body's healthy Qi and to strengthen weakened physiological function. The filiform needle should be kept for 20–30 minutes in place insertion. For patients who are chronically Yang deficient, one should apply the moxibustion on the distal points or use both needling with moxa. Moxibustion is a therapy in which burning moxa is used to produce a heat stimulation to the human body. It affects the function of the meridians and points to treat or prevent diseases.Acupuncture may improve the activities and speed of the rod and cone cells of retina, enhance the neural networks and biological activity of the retina cells, and improve the inner circulation, the metabolic activities of retinal epithelium-photoreceptors complexes, and the damages to visual function. Ma et al.  used acuHowever, one problem of acupuncture therapy is that there is no uniform standard and parameters on acupuncture point selection, needling techniques, depth and angle of piercing, gas-getting status, needle retention time, and stimulation methods.Some common clinical patterns and clinical treatments in traditional Chinese medicine is summarized in There are many topics in clinical studies on RP. The current approaches against RP include the Chinese herbal medicine, acupuncture, moxibustion, gene therapy, neuroprotection therapy, neurotrophic growth factors, antiapoptotic agents, ribozyme therapy, RNAi, retinal transplantation, dietary supplementation, retinal prostheses, stem cell therapy, and so on. However, due to the complexity of RP pathogenesis, multiple risk factors, long cycle of RP prevention and control, and the overall prognosis of severe RP remains dismal. There are some obstacles: the success of these treatments depends on proper patient selection; how to successfully translate new therapies in the animal models of the disease; how to effective delivery of the therapy, both genetic material and other neurotrophic factors, and stem cell to the target tissue have been a formidable task. Worldwide researches with numerous samples are expected.From the long-term perspective, delaying the occurrence and progression of RP and establishing an efficient and practical prevention and control system is the focus of the future RP research in the world. TCM may be able to play an important role in this. Possible future research direction of integrating TCM with western medicine may include (a) TCM treatment of RP by regulating stem cells and (b) TCM treatment of RP by regulating microglia.In addition, for complicated life phenomenon, both metabonomics and pharmacometabonomics take an organic conception of the human body, which conforms to the way of thinking of traditional Chinese medicine (TCM). The application of metabonomics and pharmacometabonomics in the TCM treatment in RP can deepen the evaluation of the therapeutic effects of TCM in RP through the study of intrinsic quality of TCM syndrome and the treatment by differentiation of syndrome. The research about integration of TCM with modern biological science and technology in RP may provide a new space for the development of therapy against RP, and these treatments would fill an enormous therapeutic gap that we have right now.


Circadian clocks exhibit stochastic noise due to the low copy numbers of clock genes and the consequent cell-to-cell variation: this intrinsic noise plays a major role in circadian clocks by inducing more robust oscillatory behavior. Another source of noise is the environment, which causes variation in temperature and light intensity: this extrinsic noise is part of the requirement for the structural complexity of clock networks. Advances in experimental techniques now permit single-cell measurements and the development of single-cell models. Here we present some modeling studies showing the importance of considering both types of noise in understanding how plants adapt to regular and irregular light variations. Stochastic models have proven useful for understanding the effect of regular variations. By contrast, the impact of irregular variations and the interaction of different noise sources are less well studied.Rhythmic behavior is essential for plants; for example, daily (circadian) rhythms control photosynthesis and seasonal rhythms regulate their life cycle. The core of the  Such os) cycles .Arabidopsis thaliana . An alternative approach adopts linear time invariant (LTI) models  models . These mllations , and to llations . Howeverling see .Ordinary differential equation models provide a good representation of the dynamical behavior of a population of cells, or a whole organism, but represent the dynamics of a single-cell less accurately. This is due to the underlying assumption that discrete variables representing molecule copy numbers can be approximated by continuous ones representing concentrations when the number of molecules is large. This assumption is generally valid in a cell population but not in single-cells, particularly in gene regulatory networks where genes can be present in low copy numbers.The discrete stochastic modeling paradigm differs from the ODE approach in two main ways: firstly, model variables represent discrete molecule numbers rather than continuous concentrations, and secondly, the time evolution of the model is obtained by taking into account the probability of each reaction to occur, computed assuming the mass action law or other kinetics . Stochastic models are generally simulated using a stochastic simulation algorithm SSA; . The timUntil recently, experimental techniques were focused on measuring large populations of cells, meaning that single-cell computational results did not have an experimental counterpart. Recent advances in experimental techniques and high-resolution imaging have allowed for measurements of smaller cell populations. Indeed, even single-cell measurements are becoming feasible , generatintrinsic noise, has been observed in circadian clock networks of animal, plant, and fungal species, and has been shown to increase the robustness of oscillations in the concentrations of network components . However, without entrainment, the oscillations are not synchronized across different cells, causing the mean behavior of the system to dampen. This result suggests that when copy numbers of clock components are low, stochasticity promotes oscillations, and helps cells to keep time autonomously.An additional and useful model organism in this context is the alga med CCA1 . Ostreocof yeast , as wellof yeast . Many ofnditions . Both annditions  and a stnditions  have beenditions . By contOstreococcus  is characterized by strong intercellular coupling, yielding a timing mechanism that is robust to environmental noise, whilst weaker coupling is observed in the peripheral clocks, enabling them to respond flexibly to signals from the SCN and other systems . The obvious need for sunlight in photosynthesis directly links environmental conditions to cellular metabolism and survival; it is therefore of great importance to plants to accurately trace the timing of dusk and dawn throughout the seasons. This timekeeping allows anticipation of predictable daily changes, and proper alignment of cellular metabolism to the most efficient phase of the day. Weather is intrinsically unpredictable, however, and therefore clocks have to be buffered against fluctuations in light level and temperature. Models have been increasingly used to understand the molecular mechanisms by which clocks buffer circadian-regulated processes against variations in these environmental time cues  used for most laboratory experiments was isolated at the surface of the Thau lagoon in France , such as humidity changes, and heat and cold stress. Moreover, most circadian models developed to date have focused on the central oscillator network. The introduction of post-translational modifications and the interaction of the clock network with signal transduction and metabolic pathways are also important (Another interesting line of work would be the integration of other sources of variability (mportant .Arabidopsis circadian clock could be developed. These could help to establish, for instance, whether coupling contributes to the organ specific properties of the Arabidopsis clock (Possibly the most exciting future direction is the development of single-cell mathematical models. Recent advances in experimental techniques now permit single-cell measurements, making it possible to develop, and individually parameterize, models at this scale. Single-cell work has already been carried out in cyanobacteria , and oncis clock . Single-All authors contributed equally to this work, read and approved the final manuscript.The Associate Editor Dr Naomi Nakayama declares that, despite being affiliated to the same institution as author Dr Gerben van Ooijen, the review process was handled objectively. 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.


Pneumomediastinum, and subcutaneous emphysema usually result from spontaneous alveolar wall rupture and, far less commonly, from disruption of the upper airways or gastrointestinal tract. Subcutaneous neck emphysema, pneumomediastinum, and retropneumoperitoneum caused by nontraumatic perforations of the colon have been infrequently reported. The main symptoms of spontaneous subcutaneous emphysema are swelling and crepitus over the involved site; further clinical findings in case of subcutaneous cervical and mediastinal emphysema can be neck and chest pain and dyspnea. Radiological imaging plays an important role to achieve the correct diagnosis and extension of the disease. We present a quite rare case of spontaneous subcutaneous cervical emphysema, pneumomediastinum, and pneumoretroperitoneum due to perforation of an occult sigmoid diverticulum. Abdomen ultrasound, chest X-rays, and computer tomography (CT) were performed to evaluate the free gas extension and to identify potential sources of extravasating gas. Radiological diagnosis was confirmed by the subsequent surgical exploration. Subcutaneous cervical and mediastinal emphysema usually can occur as a result of surgery or trauma. Their spontaneous onset in absence of previous disorders or provocating factors is very rare.Potential sources of extravasating gas are the respiratory tract , the gastrointestinal tract (perforation), and infective causes (necrotising fasciitis) .Pneumomediastinum and subcutaneous emphysema are very rare; reported signs of colonic perforation most often are associated with diverticulitis, toxic megacolon, and colonoscopy .The continuum of fascial planes connecting cervical soft tissues with the mediastinum and retroperitoneum allows this dissection .Clinical appearance depends on the degree and the extension of emphysema, and typical findings of spontaneous subcutaneous emphysema are swelling and crepitus over the involved site.Imaging studies are helpful to confirm the diagnosis on doubtful cases, exclude local associated complications, determine the extension, and monitor the evolution.Most commonly the diagnosis of subcutaneous emphysema and pneumomediastinum is made by chest X-ray, except in case of small gas collections that can be identified only by chest CT scan.We describe a rare case of spontaneous subcutaneous emphysema, extending from the soft tissues of the abdominal wall to the neck, pneumomediastinum, and pneumoretroperitoneum resulting from an unknown sigmoid diverticulum perforation.A 57-year-old man was referred to our institution with a few days' history of severe left iliac fossa pain and pyrexia. The patient medical history included chronic diverticular disease.At clinical examination he was pasty, sweaty, tachycardic and tachypneic, and in pain and he had a temperature of 38°C. The abdomen was slightly distended, vaguely tender on palpation over the lower region, without signs of peritoneal irritation, but he became febrile and confused. Peristalsis remained active and bowel function was normal.His initial blood tests showed polycythemia and rise up transaminases.The patient was transferred to our radiology department for ultrasonography exams, basic X-ray studies, and CT scanning.We performed an abdomen ultrasonography that excluded subdiaphragmatic parenchymal tissue alterations.Chest X-ray showed no sign of pneumothorax or pneumomediastinum.A CT scan of the abdomen  showed iGas was finally visualized within the scrotal sac, indicative of pneumoscrotum.CT scan revealed also mesenteric and mural thickening of the sigmoid colon, multiple sigmoid diverticula, peritoneal fat stranding, and evidence of inflammatory changes.Considering patient's history and clinical and radiological features, the main diagnostic hypothesis was a diverticular perforation.A few hours later the clinical evaluation showed subcutaneous emphysema and crepitus developed in correspondence to neck's soft tissue, to sternoclavicular joints, and to maxillary muscles bilaterally so a second chest radiograph was performed.The radiograms  showed sDue to the clinical and radiological worsening, the patient underwent a new computed tomographic evaluation.The whole body CT scan  revealedFree gas was also noted in correspondence of the dorsal and pectoral soft tissues.This condition was suggestive of some communication between the chest and the retroperitoneum. Based on the CT scan, no other possible cause of the extraperitoneal gas except a diverticular perforation was found.After the tomography, an urgent exploratory laparotomy was undertaken, under the suspicion of sigmoid diverticulitis rupture. During the operation, a perforation over the posterior wall of the sigmoid colon was found. Segmental resection of the sigmoid colon and end-colostomy (Hartmann's procedure) were performed.Histologically, severe inflammatory changes with a mixed population of leucocytes, edema, and fresh haemorrhage at the edges of the rupture site were observed, with no sign of malignancy. The patient's subcutaneous emphysema and pneumomediastinum disappeared few days after the operation. One month later, the patient was still alive.Pneumomediastinum and subcutaneous emphysema are uncommon clinical entities that occur when gas leaks from the lungs or any of the luminal organs, such as the bronchial tube, larynx, trachea, esophagus, and very rarely, the colon, with subsequent dissection into the mediastinum .They can occur in trauma: subcutaneous emphysema has been observed in hanged persons and reported in the literature.In these cases, the mechanism of closing of the upper airways by compression of the larynx or pharynx and pressure of the tongue against the palate with an increase of intrathoracal pressure was assumed to be the main pathogenesis .Another rare cause has been described in a case of sudden infant death syndrome with intravascular gas due to intraosseous medication application .In this case gas embolism may passively occur when a puncture is made in a vessel with a pressure lower than the atmospheric one. The gas can enter the vessel when the needle is disconnected from the syringe to change medication or by accident .Emesis may also cause esophageal rupture, which may lead to pneumomediastinum and subcutaneous emphysema .Instead spontaneous pneumomediastinum commonly occurs when an increased intra-alveolar pressure  leads to the rupture of the marginal pulmonary alveoli. The air ascends along the bronchi to the mediastinum and the subcutaneous space of the neck, causing cervicofacial subcutaneous emphysema in 70–90% of cases .In the literature there are only a few cases of subcutaneous emphysema of gastrointestinal origin reported –9, that Other causes include Borehaave's syndrome, perforated peptic ulcers, traumatic perforation, appendicitis, and diverticulitis .The anatomical site of perforation largely determines the route of escape of the gas to the subcutaneous position. In addition, the direction of gas diffusion usually follows the least resistance, loose areolar fascial structures .In our case the perforation was located in the posterior wall of the sigmoid colon, so the escaped gas penetrated first into the retroperitoneal space and then may continue diffusing superiorly through the paravertebral retroperitoneal tissues and diaphragmatic hiatus into the mediastinum and finally into the neck and facial areas.Diagnosis is made most commonly by chest X-ray, which reveals subcutaneous emphysema and pneumomediastinum. Small pneumomediastinum not seen on chest X-ray will be seen on chest CT.Although, as mentioned above, subcutaneous neck emphysema, pneumomediastinum, and retropneumoperitoneum are rarely caused by nontraumatic perforations of the colon, this possibility should be considered when no obvious case can be found for the origin of free gas at these sites.In this case, abdomen CT scan plays an important role in identifying an occult perforation and whole body CT allows us to evaluate the extension of escaped gas to different body districts.In fact, in cases of suspected soft tissues emphysema, for a fast management of the patient, we recommend performing a CT, that is, the most preferable diagnostic tool for the detection of air in soft tissues .Finally radiological imaging plays also an important role in allowing a proper therapeutic planning and followup.We conclude that performing CT is very useful in making a secure diagnosis of pneumomediastinum and soft tissue emphysema because it allows us to define a precise extension of gas to different body districts.Patients can be scanned very quickly and easily and other information supplied by CT is also necessary to achieve the final diagnosis and ruling out other causes of pneumomediastinum and soft tissues emphysema.Radiological evidence of pneumomediastinum and soft tissues emphysema may lead to early diagnosis and surgical management with a better outcome.


Liver diseases are now increasing, especially the chronic ones. The therapy of liver diseases is often challengeable because conditions of the liver are complicated in both structure and function. Different pathological liver conditions are associated with reactive oxygen species, viruses, toxins, inflammation and infection, and others. The resultant liver fibrosis and liver cirrhosis are a problem that every year thousands of people suffer from and many doctors are puzzled by. Liver cirrhosis, a potential cause of liver cancer, has long been considered irreversible or extremely difficult to reverse.There has been a good deal of interest in complementary and alternative therapies for the treatment of various liver diseases. Patients generally appreciate the treatment of liver diseases with natural agents because of their diverse effects and mild side effects. One natural agent commonly has multiple therapeutic effects including antioxidant, anti-inflammatory, antiviral, and antitoxic properties. The selection of a plant or plants as a medicine needs sufficient data and definite proof of the efficacy in liver diseases. ex vivo, in vivo, and clinical studies. A number of natural agents are deeply investigated and analyzed for the treatment of liver diseases on the basis of evidence in the aspects of cell signal pathways and other molecular mechanisms and clinical practice.This special issue provides original research, review, and meta-analysis about the recent information on complementary and alternative therapies for liver diseases involvingReaders of this journal are expected to find in this special issue recent developments not only in treatment but also in prevention of liver diseases by complementary and alternative methods. The readers might be interested in studies on Fuzheng-Huayu Formula against liver fibrosis and cirrhosis by developing healthy liver cells to replace the damaged ones. The cure of a cirrhotic liver is no longer like getting blood out of a stone.Yong-Song GuanYong-Song GuanQing HeQing HeMohammad Ahmad Al-ShatouriMohammad Ahmad Al-Shatouri