Healthcare costs have exploded in the past 30 years and they are a major concern for governments worldwide. Care management of musculoskeletal disorders and advanced imaging account for a large part of this socioeconomic burden.Musculoskeletal ultrasound is now performed primarily by nonradiologists. Both musculoskeletal ultrasound and MRI total utilization rates continue to increase. Despite the existence of evidence-based diagnostic recommendations and the potential cost-savings of using musculoskeletal ultrasound instead of MRI in certain clinical situations, ensuring appropriate use of imaging among health professionals remains difficult for various reasons.In the context of healthcare budgets restraints, use of imaging must be shown scientifically, to improve patient outcomes and be cost-effective. Current evidence recommends musculoskeletal ultrasound as the primary imaging modality in the investigation of rotator cuff disease. Policies aiming at ensuring the application of imaging guidelines among physicians are needed. In all countries, there is pressure on budgets dedicated to healthcare and social resources that has been steadily increasing in the past 30 years, notably because of the aging of the population . MusculoAnother contributing factor in the escalating cost of healthcare is the use of advanced imaging . The diaThis review summarizes the recent literature related to the economics of MSK imaging, with an emphasis on ultrasound, and the impact on diagnosis, care management, and improved health of MSK disorders.The search strategy used combined words and expressions for these three conceptual groups: (1) economics, (2) musculoskeletal system, and (3) imaging. We used words and expressions from controlled vocabulary  and free text searching in order to identify studies in CINAHL (from 1937 onwards), EMB Review (from 1991 onwards), EMBASE (from 1974 onwards), MEDLINE (from 1946 onwards), PubMed, and the grey literature . We provided a detailed report of the search strategy translation used in each database. The results from multiple searches were merged using the reference management software EndNote (version X7.4) and duplicate records were removed. The search yielded 3031 results. The first author scanned the titles of all retrieved publications and when necessary, also read the abstracts. Forty-seven papers published over the past 20 years were deemed relevant to the topic of this review article and were read in preparation on the present paper. In addition to the electronic search strategy, searching the reference lists of the retained papers identified other relevant publications.Musculoskeletal disorders are extremely common across all ages in industrialized and developing countries. These conditions are among the leading causes of pain and physical disability. They represent a diverse group of pathologies including inflammatory diseases such as rheumatoid arthritis (RA) and other arthriitdes; degenerative and microtraumatic diseases such as osteoarthritis and tendon disorders; conditions related to traumatic, sports, and occupational injuries; and other common disorders such as back pain. Some of these conditions are recurrent; others are acute and of short duration but many are chronic with increasing severity over time. Furthermore, the prevalence of many of these disorders increases with age.It is difficult to capture the real impact of MSK disorders on individual well-being and societal healthcare costs and resources as statistics, which have been traditionally used to measure the societal burden of disease, are biased towards diseases with high mortality and underestimate the onus of MSK conditions . MSK conSince the first description of the technique of ultrasound examination of the normal rotator cuff by Middleton et al.  in 1984,More recently, the advent of compact, portable, and more affordable ultrasound machines has democratized the utilization of MSK ultrasound beyond the traditional confines of imaging departments. Rapidly, the use of MSK ultrasound as a diagnostic and intervention-guiding technique has gained acceptance in the fields of rheumatology, orthopedic surgery, physiatry, and podiatry , 16. Thehttp://www.aium.org), the European Society of Musculoskeletal Radiology (ESSR) (http://www.essr.org), and the European League Against Rheumatism (EULAR) (http://www.eular.org). Besides the important commitment that this self-training requires, according to a Canadian study, nonradiologists may also face other challenges of time restraints related to clinical workflow, costs associated with equipment acquisition, and the ability to receive remuneration for MSK ultrasound examinations [When incorporating MSK ultrasound into their practice, to ensure high standards of patient care, radiologists and nonradiologists alike must address several issues , 21. Firinations .MSK ultrasound should be performed using standard scanning techniques and protocols with image documentation and a written report for quality assurance. The question of certification and accreditation should also be addressed, as training alone does not guarantee competency. In that regard, the American College of Rheumatology has been proactive in defining the role of MSK ultrasound in the rheumatologist’s scope of practice and establishing the pathways of certification , whereasIn an effort to appraise the changes in practice generated by the increase in the number and diversity of MSK ultrasound providers, Sharpe et al.  looked aAnother question that arises concerning MSK ultrasound utilization is: who should perform imaging? Most imaging done by nonradiologists is self-referred, whereas radiologists in their capacity as consultants are generally not in a position to self-refer and may advise appropriate, cost-effective imaging. A study showed that Medicare reimbursement to nonradiologists for noninvasive diagnostic imaging grew more rapidly between 1998 and 2006 than for radiologists and that in 2008, nonradiologists received 4 % more Medicare payments than radiologists for these studies . KennedyThis demonstration of the tremendous increase in MSK ultrasound utilization over a period of 10 years raises the interrogation of appropriateness of utilization. In other words, are these imaging studies justified because they improve health outcomes of patients? Is the performance of these imaging studies driven by a concern for cost-effective care management? Do evidence-based diagnostic guidelines exist and do MSK ultrasound providers follow them?In 2013, the Society of Radiologists in Ultrasound published a consensus conference statement on the recommendations for imaging of patients suspected of having rotator cuff disease . Based oThese studies illustrate the difficulty in ensuring appropriate use of imaging among health professionals , 32. AnoIn 2009, a large American insurance company declared nonoperative spinal and MSK ultrasound experimental with the consequence of denying reimbursement to the radiologists and nonradiologists who perform MSK ultrasound . This poEconomic evaluation studies assess both costs and outcomes of health care interventions. These evaluations may take the form of cost-minimization, cost-effectiveness, cost-utility and cost-benefit analyses. In 2012, Ifedayo et al.  publisheIn our literature search, we found a very small number of economic evaluation studies on the subject of MSK ultrasound. One meta-analysis examined the role of MRI for the assessment of soft-tissue and articular disorders of the shoulder and elbow compared to ultrasound, MR arthrography, and CT arthrography . The autBesides the importance of practice standards, certification, and accreditation to ensure that MSK ultrasound is ethically and adequately performed in the best interest of patient care, health technology assessment in the form of cost-effectiveness, and cost-utility analysis using model or trial-based data is mandatory in the context of healthcare budgets restraints. Use of imaging must be shown to improve patient outcomes and be cost-effective. Current evidence recommends musculoskeletal ultrasound as the primary imaging modality in the investigation of rotator cuff disease because of its high diagnostic accuracy and its cost-effectiveness when compared to MRI, but studies show that physicians do not follow these recommendations. Incentives, computerized tools and policies aiming at ensuring the application of imaging guidelines among physicians are mandatory. Self-referral should also be controlled as this practice has been shown to encourage inappropriate use of imaging.


Aging is the phenotype resulting from accumulation of genetic, cellular, and molecular damages. Many factors have been identified as either the cause or consequence of age-related decline in functions and repair mechanisms. The hypothalamus is the source and a target of many of these factors and hormones responsible for the overall homeostasis in the body. With advanced age, the sensitivity of the hypothalamus to various feedback signals begins to decline. In recent years, several aging-related genes have been identified and their signaling pathways elucidated. These gene products include mTOR, IKK-β/NF-κB complex, and HIF-1α, an important cellular survival signal. All of these activators/modulators of the aging process have also been identified in the hypothalamus and shown to play crucial roles in nutrient sensing, metabolic regulation, energy balance, reproductive function, and stress adaptation. This illustrates the central role of the hypothalamus in aging. Inside the mitochondria, succinate is one of the most prominent intermediates of the Krebs cycle. Succinate oxidation in mitochondria provides the most powerful energy output per unit time. Extra-mitochondrial succinate triggers a host of succinate receptor (SUCN1 or GPR91)-mediated signaling pathways in many peripheral tissues including the hypothalamus. One of the actions of succinate is to stabilize the hypoxia and cellular stress conditions by inducing the transcriptional regulator HIF-1α. Through these actions, it is hypothesized that succinate has the potential to restore the gradual but significant loss in functions associated with cellular senescence and systemic aging. Aging is an irreversible phenomenon in all species that is characterized by a progressive decline in all physiological functions –3. With in vitro  and organelles  are more crucial than others in the aging process by virtue of the dominant role they play in the body , 20–22. The purposes of this review are to (1) highlight the commanding role of the hypothalamus in organismal aging; (2) reassess the prominent role of the mitochondrion and the emerging role of one of its metabolites, succinate, in cellular aging; and (3) evaluate our current understanding of key genes and signaling pathways involved in the aging process. A better understanding of these important components of senescence has the potential benefit of guiding the development of effective therapeutic interventions in enhancing the quality of life of the aging population.The hypothalamus is a collection of distinct neurosecretory cells located at the base of the brain. These neurosecretory cells receive a multitude of external and internal signals from virtually all organs in the form of hypothalamus-end-organ axes. They interpret, integrate, and respond to these messages accordingly and maintain homeostasis in the body. The vital processes under control of the hypothalamus include regulation of body temperature, nutrient intake and energy balance, sleep and wake cycle, sexual behavior, reproductive cyclicity, water and electrolyte balance, stress adaptation, nursing, growth, and circadian or ultradian cycles , 7, 25. Historically, one of the earliest ideas suggesting that the aging process stems from a progressive loss of hypothalamic sensitivity and homeostatic imbalance came from studies conducted in aging rodents that are corroborated with clinical conditions in humans . In a se3H-estradiol uptake with advancing age  neurons are located showed marked decreases in cing age . Adminis of GnRH  restoresertrophy .When the adaptive homeostat  and the energy homeostat  were studied using their respective feedback regulators , thresholds of the hypothalamic sensitivity were raised toward these agents in both aging rodents and humans , 40, II Dilman and Anisimov reasoned that before menopause, the hypothalamus constantly adjusts to inputs from internal and external sources with accuracy and precision. However, with aging, the sensitivity of the hypothalamus to feedback regulators begins to decline. This results in a progressive loss of homeostasis and eventually, disruption of appropriate hormone production and an inability of the hypothalamus to appropriately regulate its target tissues. In order to maintain the same level of responsiveness, stronger feedback signals or increased sensitivity of the hypothalamus are required. This disruption of homeostasis and the age-dependent loss of responsivity are manifested with syndromes such as menopause, andropause, adrenopause, somatopause, and many other metabolic disturbances. Dilman’s hypothesis about the primary role of the hypothalamus in aging has been described in an exhaustive review of the age-related changes in the structure and function of the hypothalamus .Better understanding of the mechanism of end-organ resistance in chronic stimulation.Discovery of key longevity genes and their regulatory pathways.Determination of the role of succinate in systemic and hypothalamic metabolic adaptation.In retrospect, this neuroendocrine theory of aging is in no way in conflict with or excludes other paradigms of aging, but instead, accentuates the importance of the interconnection of many hallmarks of aging , 19. A mAlthough the neuroendocrine theory of aging is supported by experimental evidence, the exact cellular and molecular mechanisms were not known when it was first proposed. Advances in our understanding of the consequence of over-stimulation or chronic, low-grade activation of various neuroendocrine cells allow us to revisit and better interpret this theory. From a large body of research conducted since the 1980s on down-regulation and desensitization of various endocrine organs [see below], we begin to understand the underlying cellular and molecular mechanisms by which neuronal and endocrine cells terminate the action of their stimulatory signal. The accumulation of both types of over-stimulation during a life-time results in a progressive elevation of the threshold of sensitivity of the target cell toward their cognate activator. This eventually leads to the end-organ refractoriness. This phenomenon has been demonstrated in virtually all endocrine glands, including targets of insulin , 45, catThe cellular and molecular mechanisms for down regulation and desensitization largely depend on the cell type. The β-adrenoceptor desensitization/down-regulation is the most extensively studied , 47 and the mammalian target of rapamycin) nutrient response pathways; and (3) the target gene modulator, IKK-β/NF-κB . The two intracellular signaling pathways, TOR and NF-κB, previously thought to be independent, are in fact, closely linked, and both are strongly influenced by dietary status and ROS  down regulate mTOR activity in the hypothalamus. This eventually leads to the loss of sensitivity of various hypothalamic nuclei and their ability to regulate their respective homeostatic loops -generating role in energy metabolism, succinate, and to a lesser extent, fumarate, are involved in sensing and regulating the metabolic activity during cellular stress, including during hypoxia and exercise. This allows most organisms to coordinate and adapt to transient or prolonged oxygen-deficit conditions. When oxygen is abundant, the Krebs cycle generates ATP and NADH which are used for virtually all cellular activities. When oxygen is insufficient, the Krebs cycle runs in reverse resulting in an accumulation of succinate in the mitochondrial matrix . This haC. elegans  and menopausal symptom relief. Intriguing questions are raised about the potential benefit of using succinate in alleviating age-associated metabolic disturbances. In a series of studies, succinate is shown to facilitate the formation of glutamate, which increases the turnover of adenylate and glutamine and induces nitric oxide synthesis in the brain. This results in stimulation of the vascular tone, blood flow, antioxidant activity, and improvement of age-related degenerative changes .Another succinate target in the hypothalamus is the hypothalamus-POMC axis involved in nutrient sensing as well as other functions including the regulation of sexual behavior, lactation, the reproductive cycle, and possibly central neural control . This stA pulsatile GnRH secretion pattern is essential for follicle-stimulating hormone (FSH)/LH release by the pituitary gland and the integrity of positive and negative feedback loops involving estrogens . An addeFrom recent groundbreaking discoveries of mTOR and NF-κB pathways in the aging hypothalamus, one of the casualties of an overactive NF-κB is the suppression of GnRH gene expression, and a reduction in GnRH synthesis and secretion . Since GAging is a multi-faceted decline of body functions. Many hypotheses have been proposed to explain the cause of aging. They include permanent damage of the genetic material, hormonal imbalance, and environmental/lifestyle insults, such as excessive caloric intake, free radical or oxidative stress, and inflammation.The hypothalamus is the master regulator of homeostasis in vertebrates and is the source and target of continual regulatory adjustments throughout one’s lifetime. The neuroendocrine theory of aging proposed by Dilman over 40 years ago postulates the functional decline of the hypothalamus is due to a decrease in its sensitivity toward feedback control.Succinate is not only an important intermediary metabolite in the energy generating Krebs cycle, but also has diverse extra-mitochondrial roles, acting in both cell and non-cell autonomous manner in peripheral tissues. The concept of succinate as a signaling molecule is confirmed by the identification of the succinate receptor, elucidation of its signal transduction pathways, and recognition of its diverse action in many tissues.Recently, mTOR has been identified as a proximal molecular switch in the onset and progression of systemic aging. Over-stimulation of hypothalamic mTOR as a result of chronic exposure to nutrients and activation of the pro-inflammatory NF-κB that inhibits expression of the GnRH gene are responsible for the loss of sensitivity of the hypothalamus. Activation of HIF-1α which activates POMC gene expression appears to reverse the decline of hypothalamic function.Succinate stimulates the expression of the HIF-1α gene, stabilizes the HIF-1α protein, and mitigates the functional decline in both the stress adaptation/energy-balancing pathway and the GnRH loop. This helps to moderate age-related processes that lead to weight gain, menopausal symptoms, and other degenerative diseases. Since the succinate receptor is widely distributed throughout the body, succinate may play a central role in reversing the gradual but significant dysregulation of the hypothalamus as well as peripheral cellular senescence.The authors have made the following declarations about their contributions: conceived and designed studies cited in this manuscript: EM and MU. Drafting and revising the manuscript: EM, MU, and TC. Final approval of the work: EM, MU, and TC.Eugene Ilich Maevsky, Mikhail Lvovich Uchitel, and Thomas T. Chen serve as scientific advisers to Lunada Biomedical.


Conventional angiography is still considered the gold standard for the study ofthe anatomy and of vascular diseases of the abdomen. However, the advent ofmultidetector computed tomography and techniques of digital image reconstructionhas provided an alternative means of performing angiography, without the risksinherent to invasive angiographic examinations. Therefore, within the field ofradiology, there is an ever-increasing demand for deeper knowledge of theanatomy of the regional vasculature and its variations. Variations in the renalvascular system are relatively prevalent in the venous and arterial vessels. Forvarious conditions in which surgical planning is crucial to the success of theprocedure, knowledge of this topic is important. The aim of this study was tofamiliarize the general radiologist with variations in the renal vascularsystem. To that end, we prepared a pictorial essay comprising multidetectorcomputed tomography images obtained in a series of cases. We show patternsrepresentative of the most common anatomical variations in the arterial bloodsupply to the kidneys, calling attention to the nomenclature, as well as to theclinical and surgical implications of such variations. It is the job of the radiologistto identify and describe the anatomical patterns of venous and arterial vasculature,particularly when the tests in question are done in preparation for complex kidneysurgeries.Variations in the patterns of blood supply and ramification of the abdominal vesselsare common in the vascular bed of the genitourinary system, and knowledge of thesevariations is almost as important as is that of the so-called "normal" pattern. Upuntil the middle of the last century, the vascular anatomy of the abdomen was atopic of discussion restricted to surgeons and anatomists. With the advent and rapiddevelopment of imaging tests, radiologists have become indispensible in thediagnostic process and therapy planning for many vascular conditions,3. However, computed tomography angiography (CTA) studies carryfewer risks and are more accurate than digital angiography studies, with theadvantage of evaluating not only the vascular lumina but also the vessel walls andother viscera, and is now used more frequently in various scenarios: kidneytransplant, Takayasu's disease, and ureteropelvic junction (UPJ) stenosis due tocompression of the inferior polar artery. In addition, CTA has the advantages ofallowing a better evaluation of the renal collecting system-to identifyhydronephrosis-and of the kidneys themselves-to identify tumors, parenchymalatrophy, and congenital disorders, such as horseshoe kidney and duplication of therenal pelvis.Digital angiography continues to be the gold standard for comparison with any othertype of tests for morphological analysis of renal arterial anatomy. Therefore, although MIP and VRhave similar resolution and contrast, some authors, such as Urban et al., ascribe a certain advantage to VR,particularly in the visualization of tortuous vessels when it is necessary todetermine which are closer or farther from the observer .Digital image processing and manipulation in diagnostic workstations equipped withprograms and monitors dedicated to this purpose are indispensible for CTA studies.Such studies allow two-dimensional (2D) and three-dimensional (3D) multiplereconstructions to be performed on the basis of raw data extracted from the originalaxial plane images. The multiplanar reconstruction (MPR), maximum intensityprojection (MIP) and volume rendering (VR) methods are widely used and merit a briefexplanation. The MPR method provides 2D sectional images in all axial, coronal, andsagittal planes, which can be perpendicular to the axial plane, but variations onoblique or even curved planes are particularly useful in the study of tortuousstructures such as vessels. The MIP method selects the higher-density voxels incontiguous axial, coronal, or sagittal sectional images, summing and projecting themin a single image, generally in 3D. After intravenous injection of contrast, whenvascular luminal density increases significantly, MIP highlights veins and arteriesagainst the other less dense intra-abdominal structures. Combining consecutivesections allows long tortuous vascular segments, which usually enter and exit froman isolated conventional section plane, to be shown in a single image. This effectgives the MIP image the visual sensation of three dimensions. A limitation of thistechnique is in fact the excess of structures that are added to the image as theslab encompasses more sections, which may visually confuse the examiner. The VRmethod attributes opacity values ranging from 0% (transparent) to 100% (opaque)between various sections in any plane, in an artificial line of sight projection. Bycombining these values with luminous effects, the VR 3D image generated reproducesthe perspective of depth in a more reliable way than does MIP® , at a concentration of 769 mg/mL. The injection wasapplied with an injector pump  with a flowrate of 5 mL/s, and the dosage was approximately 1.5 mL/kg . Only the post-contrast arterial phase was used for the sample cases. Theaxial sections (1 mm thick) were acquired at a pitch of 0.8, a reconstructionthickness of 2 mm, and a standard 250 mm field-of-view. During the arterial phase,image acquisition was started with a 6-s delay, after the threshold of 100Hounsfield units had been reached at the region of interest within the abdominalaorta. The acquisition parameters used for the arterial phase in the abdominalprotocol were similar to those used for CTA tests and showed sufficient spatial andtemporal resolution to characterize the arterial vessels studied in this paper. Theimages were processed in a Philips Extended Brilliance workstation using a viewerprogram. Finally, we used the MPR (2D), MIP and VR (3D) methods to acquire images inthe axial, coronal, and sagittal planes.The objective of this pictorial essay was to familiarize radiologists with thevariations found in the renal vascular system, emphasizing prevalence, the mostadequate appropriate terms and the clinical and surgical implications involved. Tothat end, we searched our teaching files, selecting sample cases in whichmultidetector computed tomography (MDCT) studies had produced scans that illustratedthe most common anatomical patterns. The studies were carried out with a Brilliance64-channel scanner . All patients were adultsand were given intravenous iodinated contrast Ultravist,6.The vascularization of the embryonic kidney  originates from a group of lateral branches of the abdominal aorta.During the upward migration of the kidney to the lumbar region, many arterialbranches regress and a main (or hilar) artery supplies blood to the renalparenchyma. Despite sequential regression of those structures, the caudal arteries,located between the tenth thoracic segment and the third lumbar segment, can persistin the fully formed kidney, evolving into the superior and inferior polararteries.In the so-called "normal" pattern, the kidneys are supplied by a single main renalartery, which originates from the abdominal aorta at the L1-L2 level. The main renalartery is also referred to as the hilar artery, because it splits into two, three,or four branches near the hilum ,providi,9, should be avoided, because theyminimize the importance of these vessels and do not have objective morphologicalmeaning,7. Despite the diversity and even disagreement amongthe various terms suggested, the nomenclature adopted by Sampaio et al. is, in our opinion, the one thatcomes closest to the aforementioned precepts and was therefore chosen to classifythe findings described in this paper. The arterial patterns of the kidneys  are listed and described below, referenced to the correspondingexamples in the figures.Given the diverse patterns of renal arterial blood supply, a standardizednomenclature should be adopted, avoiding dubious terms and contemplatingdesignations that carry an objective anatomical sense and are self-sufficient intransmitting an idea of the morphology to which they refer. Uniform usage of theseterms among professionals in various fields is fundamental to facilitatingcommunication, avoiding errors, and allowing statistical data from various studiesto be synthesized. The terms "extra", "aberrant", and "supernumerary", which havebeen used by some authorsHilar artery . In the case of two or more hilar arteries, the one with thelargest caliber will be referred to as the main artery.urcation  and6 - , because the authors employed a nomenclature closest tothat employed by Sampaio et al..The lack of uniformity in the nomenclature employed in many papers published on thissubject hinders and many times precludes data unification or cross-studycomparisons.The prevalence statistics for the morphological patterns mentioned above wererestricted to the study by Palmieri et al.,3,5. Theanatomical information provided can affect the chosen surgical technique.When planning surgical procedures such as partial nephrectomy, pyeloplasty for UPJstenosis, and kidney transplantation, imaging studies are indispensible diagnostictools-12. Whenplanning partial nephrectomies, previous knowledge of the vascular anatomy isindispensible. Reducing warm ischemia time is one of the technical measures that canimprove the functional results of partial nephrectomy-16. Themain technique applied is segmental arterial clamping, which potentially improvesrenal function in the immediate postoperative phase, in comparison with clamping ofthe main artery. Thedevelopment of high-definition 3D models of renal vasculature based on imagingstudies allows greater precision in the application of the segmental arterialclamping technique.Recent studies have shown that partial nephrectomy for tumors produces an oncologicalresult equivalent to that of radical nephrectomy, with a lower rate of progressionto chronic kidney disease and cardiovascular events,19. Prior knowledge of the presenceof these vessels can influence the surgical approach because they can makeendoscopic procedures more difficult and reduce the success rate of conventionaltreatment-22. Therefore, MDCT offersadvantages over methods such as ultrasound and intravenous urography in theevaluation of UPJ stenosis, particularly when applied in order to identify polararteries.Polar or extrahilar renal arteries are involved in 29-65% of cases of UPJstenosis increases theincidence of vascular thrombosis, warm ischemia time, blood loss, and the difficultyof carrying out anastomosis, as well as the possibility of urinary fistulas andurethral lesions,23. However, the rate of graft rejection in thefirst year and five-year survival rate do not seem to be affected by the presence ofarterial anatomical variations. As well as mentioning variations in quantity and bifurcationmeasurements, it is important that the radiology report makes reference to two otheraspects: a) the orthogonal diameter of the renal arteries and its variations (.In live-donor kidney transplantation, prior identification of a single renal arteryis a favorable factor and lowers the incidence of complications. The presence ofvariationsriations , given triations , because. In CTA, it is recommended that the examiner operate theworkstation directly. In practice, the dynamic use of reconstruction resourcesconfers greater security and agility in comparison with the isolated use offilms.Axial images are still the basis of diagnosis. However, MPR, MIP, and VR provideimportant additional informationWhen interpreting and elaborating the test report, it is recommended that theradiologist follow a basic script. The identification of arterial calcifications ispossible in the pre-contrast phase. During the arterial phase, both renal arteriesshould be followed, from emergence to the renal sinus, in order to identify earlybifurcation and extrahilar branches, after which the kidneys should be checked forthe presence of polar arteries. Especially in the case of kidney transplantation, itis important to mention the orthogonal diameter of the hilar arteries and occasionalvariations, as well as the length of the arteries from their origin to the firstbifurcation. makes it apracticable alternative to digital angiography in many situations. Considering theimportance of this anatomy in the treatment planning for various clinical andsurgical urological conditions, the radiologist should be prepared to identify anddescribe findings using standardized terminology that is in accordance with theconsensus in the literature.Variations in the arterial vasculature of the kidney are highly prevalent. The lowrisk and excellent accuracy of MDCT in the evaluation of the arterial anatomy of thekidney


There has been a proliferation of cognitive training studies investigating the efficacy of various cognitive training paradigms as well as strategies for improving cognitive control in the elderly. While some have found support for the transfer of training, the majority of training studies show modest to no transfer effects. When transfer effects have been observed, the mechanisms contributing to enhanced functioning have been difficult to dissociate. In this review, we provide a theoretical rationale for the study of mindfulness in older adults as a particular type of training program designed to improve cognitive control by capitalizing on older adults’ acquired behavioral orientation toward higher socioemotional goals. Given the synergistic relationship between emotional and cognitive control processes, the paradoxical divergence in older adults’ functional trajectory in these respective domains, and the harmonious interplay of cognitive and emotional control embedded in the practice of mindfulness, we propose mindfulness training as an opportunistic approach to cultivating cognitive benefits in older adults. The study of mindfulness within aging, we argue, capitalizes on a fundamental finding of the socioemotional aging literature, namely the preferential change in motivational goals of older adults from ones involving future-oriented wants and desires to present-focused emotion regulation and gratification. A central focus of the field of cognitive aging involves securing the quality of life of older adults. This requires, first, an examination and understanding of age-related changes in the fundamental processes of controlled regulatory behavior and secondly, the design and development of intervention programs to reduce such age-related decline in the controlled processes. The centerpiece of this controlled regulatory processing may be theoretically differentiated into the complementary processes of emotional control and cognitive control, which, interestingly show divergent functional trajectories with age. While cognitive control operations have been known to show a steady decline with increasing age  in representing and storing such contextual information  programs (Lutz et al., Contextualizing the limited efficacy of current training paradigms in improving cognitive control in the elderly within the framework of the shifting socioemotional motivations associated with older adults’ capacity for enhanced emotional processing, we hypothesize that a training program that simultaneously targets cognitive and emotional control and their neurobiological substrates would be more likely to successfully improve the overall quality of life in older adults. Mindfulness, as will be shown in this section, strengthens the neural circuitry associated with emotional and cognitive control. In addition, it has been shown to enhance the integrity of a critical resting-state system, the default-mode network, which underlies the functionality of these two inter-related networks. From this standpoint, the study of mindfulness appears to be uniquely capable of modifying not only the neuroarchitecture associated with controlled regulatory processing, but also the elementary infrastructure on which the brain’s baseline functioning is contingent Figure .Emotion regulation, refers to the change in the subjective experience of emotion, including the temporal context in which it is experienced as well as the intensity and behavioral expression of that emotion Gross, . This inMindfulness, involving an attitudinal orientation of curiosity, openness, and acceptance, has been linked to emotional intelligence in its shared focus on perceptual clarity to one’s emotional state (Salovey and Mayer, While there is unequivocal evidence for the role of mindfulness in enhancing overall emotional well-being and its associated facets, an interesting perspective, debating the involvement of bottom-up versus top-down neural control systems, has emerged in the neuroscientific study of mindfulness and emotional regulation (Chiesa et al., Indeed, an examination of the association between mindfulness and the neural correlates of emotion regulation provides evidence for the recruitment of separate, yet inter-related processes of bottom-up and top-down emotional control in experts of mindfulness, relative to the short-term practitioners of mindfulness. Taylor et al.  examinedComplementary MRI research involving short-term mindfulness training programs (Allen et al., Similarly, short-term mindfulness-based studies also provide evidence for such engagement of the prefrontal cortices during affective regulation following limited training in principles and practices of mindfulness. In a recent study, Allen et al.  examinedThese studies collectively support a theoretical model of mindfulness and emotional regulation that offers the possibility of increased top-down regulation of the prefrontal cortices on the sub-cortical structures supporting emotional reactivity to increase emotional regulation in the early stages of mindfulness training. It seems likely that even though mindfulness training appears to be theoretically divergent from training that involves explicit cognitive appraisal, short-term training in this approach may in fact be associated with the engagement of systems supporting conscious cognitive regulation of affective experiences. With increased exercise of mindfulness skills and consistent engagement in consciously controlled emotion regulation, the practice of open monitoring, likely becomes habitual and pervasive. This shift, thereby enables an engagement of the neural circuitry supporting interoceptive awareness and somatosensory representation. For future research, it would be interesting to examine if a qualitative shift in the practice of mindfulness in novice participants is accompanied by a shift in reliance on the top-down regions to ones supporting sensory awareness.At the crux of the construct of mindfulness lies its promotion of single-minded goal maintenance in the face of external or internal interference. The study of cognitive control, thus as an outcome variable has garnered critical interest in mindfulness-related research (Jha et al., One of the widely used tasks in the mindfulness literature is the ANT, and as noted earlier, this task helps differentiate between three inter-related components or subsystems of attention: alerting, orienting, and executive control. The training of mindfulness skills has been found to enhance the executive control component of attention (Tang et al., In addition to the malleability of the executive control component, research also provides support for the enhanced functioning of the alerting sub-system in expert meditators, relative to novices. The long-term cultivation of mindfulness, thus enhances the capacity to maintain a constant state of alertness, resulting in increased moment-to-moment awareness and thereby increasing the capacity for sustained attention (Lutz et al., Interestingly, mapping the emotional regulation literature, there appears to be some consistent differences surfacing between the techniques of expert practitioners, relative to individuals having undergone brief mindfulness-related programs. In the first direct test of these differences, Jha et al.  comparedMirroring these behavioral findings, Brewer et al.  found a Corroborating this involvement of the default-mode network regions, specifically the mPFC, as well as the PCC during mind-wandering, Brewer et al.  found suWhile still preliminary and needing replication, these studies suggest that brief mindfulness training programs that cultivate both focused attention and open monitoring allow the development of enhanced cognitive control operations. This is thought to take place primarily through the engagement of the top-down cognitive control system, with the frontal and parietal cortices being critically involved in the selection of task-relevant attributes and suppression of task-irrelevant attributes Figure . Long-teThe above-reviewed literature provides support for the potential of mindfulness training in improving controlled regulatory processing. By virtue of enhancing one-minded concentration and sustained attention, mindfulness training gradually cultivates the development of attentional skills that promote goal maintenance, while reducing distractions not just from external, competing stimuli, but also from the internal disruptions and wanderings of the mind (Mrazek et al., This area of research has further been strengthened by the growing contributions of neuroimaging studies aiming to examine the contributions of cortical and sub-cortical regions in cognitive and emotional control. The involvement of the lPFC in both emotional and cognitive control suggests the possibility of neural overlap in these two inter-dependent processes. This, in turn, has the potential to predict functional overlap, which is associated with broad transfer effects (Lustig et al., Another critical theme that emerges from the above reviewed literature is the presence of qualitative differences in neural engagement in long-term practitioners of mindfulness, relative to short-term practitioners of the techniques. Transliterating these findings to the study of mindfulness, it is critical for future studies to systematically examine the amount of time spent by participants engaging in the formal practice of mindfulness during the 8 week period. Short-term training studies that have investigated the association between time spent in formal practice and psychological and neural benefits evince support for the critical variance explained by engaging in such formal practices of concentrative attention and open monitoring (Allen et al., Interestingly, in our own research, we have found evidence for an association between higher levels of dispositional mindfulness and connectivity of the default-mode network in older adults (Prakash et al., Finally, keeping in perspective the growing interest in intervention studies that “train the brain”, it is critical to examine the efficacy of mindfulness training, relative to an active control group, that reduces participant bias and accounts for the amount of time spent by participants engaging in activities related to the program. While these threats to internal validity of a randomized controlled trial have been well-known for a while (Campbell and Stanley, The unique capacity for flexible, consciously-controlled, dynamic behavior distinguishes the human species from all others, providing us with the seeds of adaptability and creativity and granting us a communicable sense of free will and a degree of control over the environment. In the current work, we present a comprehensive review of how cognitive and emotional control change, behaviorally and neurally, as a function of age and examine how a mindfulness-based model may have the potential to counteract such nuanced age-related alterations in controlled regulatory processing. It is hoped that the comprehensive review provided in this paper may be somehow used to guide future investigations of emotion-cognition processes in the elderly. By developing more refined methods of examining age-related changes in cognitive, affective, and neural functioning, we move closer towards understanding the complex metamorphosis of the aging brain and our powerful role in relationship to it.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.


Inflammatory incompetence is characteristic of acute pediatric protein-energy malnutrition, but its underlying mechanisms remain obscure. Perhaps substantially because the research front lacks the driving force of a scholarly unifying hypothesis, it is adrift and research activity is declining. A body of animal-based research points to a unifying paradigm, the Tolerance Model, with some potential to offer coherence and a mechanistic impetus to the field. However, reasonable skepticism prevails regarding the relevance of animal models of acute pediatric malnutrition; consequently, the fundamental contributions of the animal-based component of this research front are largely overlooked. Design-related modifications to improve the relevance of animal modeling in this research front include, most notably, prioritizing essential features of pediatric malnutrition pathology rather than dietary minutiae specific to infants and children, selecting windows of experimental animal development that correspond to targeted stages of pediatric immunological ontogeny, and controlling for ontogeny-related confounders. In addition, important opportunities are presented by newer tools including the immunologically humanized mouse and outbred stocks exhibiting a magnitude of genetic heterogeneity comparable to that of human populations. Sound animal modeling is within our grasp to stimulate and support a mechanistic research front relevant to the immunological problems that accompany acute pediatric malnutrition. Moreover, this toll of mortality undoubtedly is exceeded numerically by an additional burden of infection-related morbidity. Immune depression is widely accepted as an important link between acute forms of malnutrition and susceptibility to infection )It would be shortsighted to dismiss the potential of the low-protein stunting model as a laboratory tool with which to probe immunological plasticity, but focusing on a detail of dietary composition rather than on details of a pathophysiology has produced a type of animal model bearing no clear relationship to any human pathology. By contrast with stunting models, appropriately crafted protocols that produce a negative nitrogen balance in rodents, albeit by means of dietary nitrogen levels uncharacteristic of human consumption patterns, nevertheless reproduce the diagnostic features of kwashiorkor in weanlings  and proEndocrinological considerations lead to the same conclusion regarding low-protein weanling rodent models, a point discussed elsewhere  in relatThis is a significant and controversial matter that extends far beyond the research front under consideration here. For example a prestigious international journal centered on basic nutritional science has recently adopted the policy that “Studies involving animal models of human nutrition and health or disease will only be considered for publication if the amount of a nutrient or combination of nutrients used could reasonably be expected to be achieved in the human population” . ClarityThe limited genetic diversity of animals used in modeling acute malnutrition, when compared to the diversity within and among human populations, is a longstanding and important concern. In particular, inbred strains of mice have been widely used for immunological studies because of the powerful array of available reagents. Panels of inbred strains can be used for the purpose of testing against a broader genetic background , althougOutbred strains offer the advantage of heterozygosity in which each animal is genetically unique, and examples of the use of outbred animals in modeling acute pediatric malnutrition are numerous. That said, the genetic diversity of standard outbred strains of mice does not model a fully outbred population and, hence, is limited relative to that of most human populations ,35. The It is important to acknowledge that many features of the immunopathology of acute pediatric malnutrition have been reproduced against diverse inbred and outbred genetic backgrounds and have been duplicated, also, across species. However, advancement beyond a largely descriptive phase toward a meaningful pursuit of mechanisms deserves a modeling strategy designed to account for the unknown scope and impact of a magnitude of genetic diversity comparable to that typical of human populations.Two basic dietary strategies predominate in animal modeling of acute protein and energy deficits, viz. restricted intake of a complete diet and ad libitum consumption of an imbalanced diet containing a low level of nitrogen relative to calories . Complete diets for rodents are sufficiently nitrogen-rich that, apart from the occasional strategy of acute withdrawal of all nutrients except water, a regimen sometimes imposed on adult animals e.g., ,39) but  but 39])Regardless of the basic type of model, effort is usually made to ensure that dietary levels of micronutrients at least meet the species-specific standards of a complete diet. In this respect, the diet formulations usually used in studies of experimental malnutrition differ from the micronutrient-poor diets associated with malnutrition in childhood , althougin vivo [Muroid rodents have been the most widely used experimental animals in studies pertaining to malnutrition and anti-infectious defences. This undoubtedly reflects the arsenal of reagents that has been available, and growing, for decades to probe the immunological defences of these species, particularly the mouse. Despite substantive broad similarities between the immune defences of humans and muroid rodents, however, there are a great many differences in points of detail as outlined elsewhere in relation to the laboratory mouse ,51. Thesin vivo ,53. This(a) Secretory IgA is released into the intestinal mucus of humans mainly by transport across the intestinal epithelium, whereas the liver of humans plays a negligible role in this function . Diverse(b) Invasive procedures are required to access macrophages in sufficient numbers for research purposes. For this reason most information pertaining to malnutrition and the mononuclear phagocyte system, with the exception of the blood monocyte, derives from studies of experimental animals, . In turnFive stages of mammalian immunological ontogeny are commonly recognized . A consein vivo in weanlings of both strains at the same chronological age following subjection to a standardized protocol of acute protein deficit. The response was profoundly depressed in the weanlings of the less ontogenetically advanced CBA/J strain [The importance of immunological ontogeny when attempting to model the immunopathology of pediatric malnutrition can be illustrated by means of a small cluster of reports involving two inbred mouse strains ,43,64,65J strain ,64, but J strain ,65.The decisive importance of immunological windows continues to escape notice in animal modeling of the immunopathology of pediatric malnutrition. For example, the potential of the suckling rat model has been outlined recently in convincing detail for the purpose of studies pertaining to the influences of pediatric nutrition on immunological development and competence , yet theWeanling models of acute malnutrition present the risk that diet-related influences may be confounded by ontogeny. Consequently a zero-time control has been used occasionally when modeling acute pediatric malnutrition-associated immune depression  Comparison with an age-matched control group emphasized the small sizes of both the splenic IgG-containing cellular compartment and the intestinal IgA-containing cellular compartment of acutely malnourished weanling mice . Many co+ subset [(b) Among the most striking immunological features of acute pediatric malnutrition is the small size and denuded architecture of T cell compartments in secondary lymphoid organs ,69. This+ subset . In turn+ subset ,72.(c) Acutely malnourished weanling mice exhibit some immunological characteristics that resemble neonatal forms of competence. For example, a type 2 cytokine polarization is reported on the part of both the effector/memory T cell compartment  and the To date, animal modeling of acute pediatric protein and energy deficits clearly leaves much to be desired, and skepticism regarding its real value is understandable. Nevertheless, attention to a modest shortlist of critical design features, notably prioritizing characteristics of human pathology rather than dietary minutiae specific to humans, recognizing the decisive importance of immunological ontogeny, and use of a zero-time control, has permitted some animal-based research to yield insights unavailable from clinical or epidemiological investigations. Arguably some uniquely animal-derived contributions can be characterized as sufficiently far-reaching and fundamental that, considered together, they provide a foundation for a unifying hypothesis to probe the mechanistic underpinning of malnutrition-associated immunopathology. The following commentary, elements of which can be found elsewhere ,6,13,69,i.e., not system-wide) decline in synthesis of inflammatory cytokines is reported in a rodent model of acute nitrogen deficiency [Malnutrition-induced depression in immune defences and infectious disease resistance is often portrayed as consequent to a disintegration of metabolic control, most notably a non-selective and systemic decline in protein synthesis ,13,69. Hficiency . Furtherficiency ,68,76,77ficiency ,49, an oin vivo, even during advanced stages of experimental malnutrition pathology. Importantly, the studies span three endocrine hormones  and four hematopoietic cytokines , seven independent research groups and eight distinct rodent models of acute malnutrition. None of the experimental systems used in these investigations could be characterized as sophisticated, but the weight and diversity of evidence is undeniable. An overriding implication is that rapid enhancement of infectious disease resistance can be achieved even without prior stabilization of severely malnourished patients. This realization could be seen as sufficient to justify application of research resources toward an understanding of the mechanisms underlying malnutrition-associated inflammatory immune depression.Intervention studies involving metabolically diverse forms of acute, experimental malnutrition reveal that infectious disease resistance and components of both innate and adaptive inflammatory immune competence can be sustained, or even restored, independently of ongoing weight loss and in the face of profound lymphoid involution ,39,42,78The animal-based findings cited herein demonstrate manipulation of immune competence independently of nutritional status even in the advanced stages of catabolic malnutrition, and provide proof-of-concept that immune regulation by way of soluble mediators continues uninterrupted in the face of acute forms of pediatric malnutrition. At this stage, the real value of this body of information is in its incompatibility with the classic and prevalent point of view that malnutrition-associated depression in immune competence reflects a chaotic attrition of inflammatory capacities. Collectively, the findings have given rise to an alternative unifying hypothesis dubbed the Tolerance Model ,41,77.The Tolerance Model is an animal-based challenge to the classic attritional paradigm and centers on the proposition that acute malnutrition elicits a regulated immunological revision toward a non-inflammatory form of competence that, even in pediatric stages of life, is sustained into advanced stages of wasting disease. The proposed immunomodulation is presented in the model as an attempt to adapt to the catabolic pathology of acute malnutrition, and a presumptive benefit is reduction in the risk of inflammatory autoimmune pathologies albeit at the cost of susceptibility to opportunistic infection. The model is far from static and can accommodate new information pertaining to immune regulation as it comes available. For example, the impact of short-term caloric withdrawal on B cell development appears to be mediated in significant measure through the central nervous system , an intrAs to hints of mechanism, one model of acute weanling malnutrition has been used in studies pointing to the dendritic cell as the primary limiting factor in the depressed adaptive cell-mediated immune competence that consistently accompanies acute pre-pubescent malnutrition ,72. AnotDespite obvious inadequacies, animal modeling has already challenged understanding of malnutrition-associated immunopathology in a fundamental way. In so doing, animal-based studies have provided some justification, together with specific possibilities, for pursuing mechanistic studies. Substantively improved modeling sophistication will be needed to proceed further, but one might hope to see research strategies that incorporate the design precautions outlined here in studies utilizing the immunological humanizing technology ,53 and aTwenty-five years ago, while summarizing an international conference under the sponsorship of the World Health Organization, the late Nevin Scrimshaw pointed out “There is still a large gap between what can be demonstrated by experimental single nutrient deficiencies in inbred strains of laboratory animals and evidence of relevance to the phenomenon of increased infection among malnourished human populations. It is still uncertain whether some experimental observations of this kind have any relevance at all to public health nutrition.” . This in


The activation of G-Protein Coupled Receptors (GPCRs) by their respective ligands initiates a cascade of multiple signaling processes within the cell, regulating growth, metabolism and other essential cellular functions. Dysregulation and aberrant expression of these GPCRs and their subsequent signaling cascades are associated with many different types of pathologies, including cancer. The main life threatening complication in patients diagnosed with cancer is the dissemination of cells from the primary tumor to distant vital organs within the body, metastasis. Communication between the primary tumor, immune system, and the site of future metastasis are some of the key events in the early stages of metastasis. It has been postulated that the communication is mediated by nanovesicles that, under non-pathological conditions, are released by normal cells to relay signals to other cells in the body. These nanovesicles are called exosomes, and are utilized by the tumor cell to influence changes within the recipient cell, such as bone marrow progenitor cells, and cells within the site of future metastatic growth, in order to prepare the site for colonization. Tumor cells have been shown to release an increased number of exosomes when compared to their normal cell counterpart. Exosome production and release are regulated by proteins involved in localization, degradation and size of the multivesicular body, whose function may be altered within cancer cells, resulting in the release of an increased number of these vesicles. This review investigates the possibility of GPCR signaling cascades acting as the upstream activator of proteins involved in exosome production and release, linking a commonly targeted trans-membrane protein class with cellular communication utilized by tumor cells in early stages of metastasis. Increasing evidence links the aberrant protein expression of G-protein coupled receptors with numerous pathologies, including cancer. Exosomes are membrane-bound nanovesicles that have been implicated as an important component in preparing distal organs for tumor cell metastasis. This review intends to explore and speculate about G-protein coupled receptors and their links to cancer, exosomes, and the involvement in cancer metastasis.Guanine nucleotide binding-protein coupled receptors (GPCRs) make up the largest family of proteins found within the mammalian genome , and this conformational change results in the exchange of GDP with guanine triphosphate (GTP) of the associated G-protein within the intracellular domain of the GPCR. This phosphate exchange alters the affinity of the G-protein with the GPCR and results in the dissociation of that G-protein  which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers: inositol triphosphate (IP3), which are released into the cytoplasm, and diacylgycerol (DAG), which remains associated with the plasma membrane. Discharged IP3 initiates the activation of protein kinase C (PKC), which is involved in phosphorylation of various proteins to participate in numerous cellular functions. The hydrolysis to the second messenger IP3 results in the mobilization of calcium from the endoplasmic reticulum, and the subsequent activation of various calcium dependent kinases , when ectopically expressed in melanocytes, was sufficient to induce in vitro melanocytic transformation and spontaneous malignant melanoma development in vivo in a transgenic mouse model, TG-3  functions on the newly formed endosome to initiate the internal budding of the multivesicular bodies (MVB) membrane to form smaller intraluminal vesicles within the MVB, these vesicles are exosomes. Ceramide, a sphingolipid, was found to trigger budding of exosome vesicles into the multivesicular body , a transmembrane protein present on recipient cells  are potential biomarkers for cancer; however, depending on the stage of cancer, there can be as few as 1-10 CTCs per mL of blood. Exosomes, however, are found in abundance within the blood, typically, 1 × 10in vitro, redirecting from oxidative phosphorylation to a glycolysis and glutamine-dependent reductive carboxylation  that influence the physiology of the recipient cells. The engulfment of MIF-containing exosomes promotes the release of transforming growth factor beta (TGFβ) by Kupffer cells, which then initiates the production of fibronectin by the hepatic stellate cells  glycoprotein, within the premetastatic site, which may protect the cancer cells from apoptosis  by fibroblasts, which acts as a bridge that binds to TN-C as well as fibronectin and collagen , matrix metalloproteinase 3 (MMP-3), and MMP-10. Huang et al., showed that knocking down these proteins reduces the vascular permeability and decreases the infiltration of myeloid cells and inhibits spontaneous lung metastasis in an + myeloid cell recruitment, which led to interactions with the collagen and production of MMP-2, breaking down collagen into peptides that act as chemoattractants for bone marrow derived cells (BMDCs) and circulating tumor cells  express VLA-4, which allows them to adhere to the newly synthesized fibronectin to initiate the cellular clustering  myeloid cells to the lung. Furthermore, Hiratsuka et al., found these chemoattractants were involved in the ability of the tumor cells to migrate, using pseudopodia for invasion. When the protein expression of these inflammatory chemoattractants was abolished, migration of both tumor cells and Mac1+ myeloid cells was prevented  and The Bristol-Myers Squibb Graduate Research Fellowship in Toxicology.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The state-of-the-art immunosuppression drugs do not ensure indefinite transplant survival, and most transplants are continuously lost to chronic rejection even years posttransplantation. This form of rejection is responsible for long-term failure of transplanted organs. The mechanisms involved in development of chronic rejection are not well-understood. One of the main features of chronic rejection is progressive luminal narrowing of graft vessels, which results in compromised blood flow, ischemia, cell death, and finally graft failure. All the existing immunosuppressive regimens are targeting acute rejection, and at present there is no available therapy for prevention of chronic rejection. Chronic rejection involves two major, but interrelated responses: The first is the host immune response against the transplant mediated primarily by alloreactive T and B cells, and the second is injury and repair of the graft (vasculopathy of graft vessels). Here we focus on recent advances in understanding the cellular and molecular aspects of chronic transplant vasculopathy and function of macrophages, topics pivotal for development of novel antichronic rejection therapies. There are three major types of allograft rejection: Hyperacute, acute, and chronic rejection. HyperacuChronic rejection develops within months to years after transplantation and is the major cause of long-term graft loss. The main feature of chronic rejection is accelerated arteriosclerosis or progressive luminal narrowing of graft vessels (vasculopathy or graft vascular disease (GVD)) often accompanied by graft tissue  fibrosis. These, in turn, result in ischemia, cell death, and graft failure. All the existing immunosuppressive regimens are highly focused on prevention of acute rejection, and at present there are no available antichronic rejection therapies. Thus, understanding the cellular and molecular events contributing to chronic rejection of transplanted organs is pivotal for development of novel antichronic rejection therapies.One of the most distinctive features of chronic rejection of heart, kidney, liver, and lung allografts is the progressive occlusion or intimal hyperplasia of the blood vessels, which compromises blood flow and results in ischemia and eventual failure of the graft.Normal blood vessel is built of several distinct layers .1] The  The 1] TAlthough the narrowing of vessel lumen can be caused by one of the three major types of vascular remodeling: Thickening of the intima (through the recruitment of extraneous smooth muscle cells and some leukocytes), constrictive remodeling , and vasoThere are two major hypotheses concerning the initiation of vascular remodeling and inflammatory response. Traditional concept called the “inside-out” response assumes that the inflammatory response to various types of injuries (including immune injury during chronic rejection) is initiated at the endothelial layer of the intima, that is, at the luminal (inside) surface of the vessel . Accordiet al., –24 et aligration.,20,23 an vessels.,25 Inter vessels.,27 and p vessels.,28 In vi vessels., it stilAlthough very little is known about the route and mechanisms, operating in the migration of SMCs into the intima during chronic rejection per se, a plethora of information on the SMC movement in various model systems may apply to the SMC movement during vessel wall remodeling in chronic rejection. It is well-established that the cell migration starts when cell surface receptors are stimulated, which, in turn, initiates a cascade of cytoskeleton remodeling events such as actin polymerization, repositioning of the microtubule organizing center (MTOC), changing the adhesiveness to the substratum, and eventually the emergence of the actin-rich leading and trailing edge (uropod) of the motile cell .18,29,3,329,30 NIt is well-established that after migration to the intima SMCs undergo extensive proliferation. Although the signaling pathways responsible for SMCs proliferation during alloimmune response are not fully understood, it seems that platelet-derived growth factor (PDGF) is one of the regulators involved.,41 RecenOver the years, several therapeutically important drugs have been identified that prevent vessel wall thickening by either inhibiting SMC migration or inhibiting cell cycle-progression, and thus decreasing SMC proliferation or both. For example, sabiporide, a new Na/H exchanger inhibitor, rapamyciMacrophages are one of the most plastic and mysterious cell types of immune response and allograft injury. Macrophages are professional phagocytes and antigen-presenting cells , which dMacrophages present within the transplanted organs derive from two main sources: 1. Donor-derived macrophages, which are present in the organ during transplantation, and 2. recipient-derived macrophages; which enter the graft after transplantation. Within first few weeks posttransplantation donor-derived macrophages proliferate, and subsequently, in non-rejecting graft, their number gradually declines. Studies on kidney transplant models showed that during acute rejection there are massive accumulation of recipient-derived macrophages and their proliferation within the allograft and thus amplify rejection response. AlthoughMacrophage functions such as cell polarity, motility, interactions with extracellular matrix, phagocytosis, and antigen presentation; are all actin cytoskeleton-dependent, and as such they are regulated by small GTPase RhoA/ROCK and Rac1 pathways , 6 and 7Chronic allograft rejection is a major hurdle to transplant success in the clinic and overcoming this hurdle is critical to advance transplant medicine. One of the most striking features of chronic rejection is the concentric neointima formation affecting virtually all blood vessels in the transplanted organs. The mechanisms behind this distinct pathology remain incompletely defined and multiple mechanisms, pathways, and cell types have been implicated in this process. Further understanding of the fundamental mechanisms related to cell motility, migration, and polarization as well as tissue repair and remodeling may lead to the development of new therapies to treat or prevent chronic allograft rejection.


Temperate montane grasslands and their unique biotas are declining worldwide as they are increasingly being invaded by forests. The origin and persistence of these landscapes have been the focus of such controversy that in many areas their conservation is in doubt. In the USA some biologists have largely dismissed the grass balds of the Southern Appalachians as human artifacts or anomalous and transitory elements of regional geography, worthy of only limited preservation efforts. On the basis of information from biogeography, community ecology, regional history and palaeontology and from consideration of two other montane grassland ecosystems—East Carpathian poloninas and Oregon Coast Range grass balds—we hypothesize that these landscapes are more widespread than was formerly recognized; they are, in many cases, natural and ancient and largely owe their origin and persistence to past climatic extremes and the activities of large mammalian herbivores. Introduction 467Southern Appalachian balds 467Hypothesis 468The case for the climate–herbivore hypothesis 468Historical eastern USA grasslands 468Palaeobotanical and palynological evidence 469Questionable Native American influence 469European settlement history 469Rare, relictual and endemic plant community 469Extant grass bald fauna 469Current dependence on mowing and grazing management 469Pleistocene megaherbivores and the ecological role of extant keystone herbivores 470The loss of the megafauna 471Criticisms of the grazing hypothesis 471Additional candidate ecosystems 471East Carpathian poloninas 471Oregon Coast Range balds 473Current status and further tests of the climate–herbivore hypothesis 473Conclusions 474Acknowledgements 474References 474Temperate montane grasslands and their associated rare, endemic and relict biota are declining worldwide Zald, . Mountaii) each is a montane, gramminoid community located below present-day climatic treeline. (ii) Each hosts a diverse herbaceous community marked by light-dependent (i.e. shade-intolerant) species, suggesting a long, shade-free history. (iii) All are located at northern latitudes, but south of maximal Pleistocene ice coverage, which likely repeatedly limited the elevational range of forest vegetation. (iv) Each is within the well-established range of a diverse Pleistocene mammalian megafauna, which grazed and browsed these regions, until reduced in diversity and body size at the time of the Holocene extinctions. (v) All experienced modern grazing by domestic animals, with loss of grassland area to woody invasion after grazing ceased.The three candidate ecosystems discussed herein share several common features:  Mark, . Grass bPicea rubens), Fraser fir (Abies fraseri), beech (Fagus grandifolia), and yellow birch , and in some cases, stands of red oak (Quercus rubra), chestnut oak (Q. montana), buckeye (Aesculus flava) and a few smaller tree species. Along with the rocky outcrops imbedded within them, the balds are famous for their biotic diversity, scenic beauty and their frequent mention in the accounts of early explorers , we advance the idea that grassy areas have persisted on the upper elevations of some of the Appalachians from at least the late Pleistocene. These open landscapes were initially created by the severe climatic conditions associated with glacial advances, which displaced woody vegetation from peaks and ridges  and other hardwoods along with groups of mountain ash (Sorbus sp.), green alder (Alnus viridis) and Rhododendron species; in more central areas are islands of ericaceous shrubs. Such subcommunities are now known from other temperate, montane grasslands, suggesting similar histories and conditions.In addition to supporting rare plants, the balds are associated with a number of distinctive woody species and subcommunities. At the bald periphery are ecotones of invading conifers, beech , mastodon (Mammut americanum), horse (Equus sp.), muskox , bison , moose , elk (Cervus elaphus), caribou (Rangifer tarandus), stag moose , fugitive deer (Sangamona fugitiva), tapir (Tapirus veroensis), peccaries , and ground sloth . Such animals possessed a high degree of climatic tolerance, high mobility, immense strength, and diverse dietary preferences—characteristics which would have permitted them radically to modify high-elevation habitats, especially grassland–forest mosaics. The impact of these animals would not have been limited to feeding activities alone, but would also have included physical damage from trampling, thrashing, rubbing and trail-making. Nor would their influence be limited to warm conditions; they may have been present whenever plant foods were not snow covered and paths to the peaks unblocked.Although the influence of recent livestock grazing has started to receive greater attention, the impact of large herbivores from the past has largely gone unrecognized. Prior to 13000 y BP, a diverse fauna occupied the southern Appalachians  were covered by continuous, climax forest until modified by anthropogenic influences. On the basis of a re-evaluation of palynological interpretations, the autecology of certain dominant tree species, an analysis of the behaviour and impact of large herbivores and seed dispersers, and studies of existing old growth areas, he flatly rejected this hypothesis in favour of the following alternative hypothesis:… that the natural vegetation is a mosaic of grasslands, scrub, trees and groves in which large plant-eating mammals play an essential role in the process of the regeneration of trees and have a determining effect on the succession of species of trees. Vera, , p. 378.Thus, one can envision the critical presence of large herbivores on natural grasslands in post-glacial Europe, as we have done for the eastern USA.et al., Such a novel analysis has prompted much debate , mountain ash (Sorbus aucuparia), and ericaceous shrubs, and are being invaded primarily by conifer and hardwood forests. The vertebrate and arthropod faunas include many rare and relict species, and, on the basis of descriptions and the illustrations of Winnicki & Zemanek (In 2005, we learned of the existence of the  Halada, . The pol Zemanek , some ap Zemanek , publica Zemanek  and the  Zemanek  that havet al. (The geological record, landscape history, and botanical data support the idea that these open grasslands are an ancient part of the vegetation of these mountains and were initially the result of climatic extremes. Using the 1980 data of Ralska-Jasiewiezowa on the late Pleistocene and Holocene pollen record, Winnicki & Zemanek  documentet al.  date thiWhat, then, can be said about the potential former impacts of ancient herbivores? In this case, we actually have a special source of data on the mammals that could have occupied the poloninas in the late Pleistocene and Holocene. In addition to fossil data and descriptions from the literature (Sutcliffe, et al. (Zald  describeet al. , have siWe have proposed this hypothesis to explain the origin and persistence of grass balds in three temperate regions, along with the existence of their special biotas. The hypothesis is largely based on historical data, the comparative method, modern inventories and analyses, and the recognition that these grasslands persist today only where there is an adequate herbivore presence, active intervention by people in the form of cutting and mowing, or perhaps, in a few cases, frequent fires. None of the other explanations reviewed previously (White & Sutter, Our hypothesis might further be supported or falsified by several types of information. Identification of additional candidate mountain grasslands with the same climatic and grazing histories could strengthen the hypothesis. On the other hand, the location and study of temperate montane grasslands with diverse, shade-intolerant floras, which are both stable and persistent, in the absence of a long history of large herbivores, episodic fire, or human intervention would require a reassessment of our hypothesis. Experimental approaches, through controlled studies of mountain grasslands exposed to various combinations of grazers and browsers could further support our hypothesis, or result in a re-evaluation of the mechanisms responsible for bald formation and maintenance.Additionally, new historical or palaeontological data may come to light. In the 1540s, the Spanish explorer Hernando de Soto led an expedition into the Southern Appalachians from North Carolina, and in the 1560s one of his officers, Juan Pardo, traveled over the mountains as far as Saltville, Virginia Beck, . AlthougIn addition, new discoveries of fossil pollen, fungal spores, phytoliths and charcoal in soils and sediments could reveal different processes and time sequences for bald formation and history than those we propose here.A group of north-temperate montane grasslands, often known as balds or poloninas, which support highly diverse, light-dependent plant communities along with an array of resident and seasonal animal populations is disappearing worldwide as a result of woody plant invasion. Long-standing debate about the origins and maintenance of these grasslands—whether they are natural ecosystems or human artifacts—has confounded conservation initiatives that would preserve these landscapes and their special biotas.Historical records indicate that some North American balds pre-date European settlement. Their high species richness of shade-intolerant, rare, relictual and endemic plants is best explained by a long evolutionary history of open conditions.Three such ecosystems—southern Appalachian grass balds, East Carpathian poloninas, and the Oregon Coast Range balds—are candidates for a new, unified hypothesis for origins and maintenance, involving climate and the activities of mammalian herbivores. Each of these grasslands occupies peaks well south of the maximal advance of Pleistocene ice sheets, and each is well within the known range of diverse, abundant mammalian mega- and meso-herbivores.Our hypothesis posits that these grasslands owe their origin to forest suppression during maximal glacial advances, which replaced forest or woodland with open grasslands and alpine tundra. During subsequent periods, mammalian grazers and browsers, perhaps along with occasional fire, suppressed woody plant invasion, maintaining the full-sun conditions needed for the evolution of shade-intolerant plant communities, and thereby preserving the balds as long-term landscape features. The grazing hypothesis fills a gap in our understanding of the long-term persistence and dynamics of a globally significant reservoir of biodiversity.Our hypothesis further posits that the end-Pleistocene megaherbivore extinctions resulted in significant woody invasion of many grasslands, although remaining herbivores such as deer, elk and bison continued to keep some areas open, albeit much reduced in areal extent. Continued reduction in native herbivore diversity and density throughout the Holocene restricted these grasslands to a few scattered peaks. Subsequently, some of these grass balds were maintained by the activities of European pastoralists, whose domestic animals acted as ecological surrogates for the extirpated native grazers.We emphasize that the patterns of past and current impacts of climate and herbivores on grass balds of the Appalachians appear to be paralleled by trends in the grasslands of the East Carpathian mountains and the Oregon Coast Range, where similar conditions have promoted and preserved similar biotas and communities.If this climate–herbivore hypothesis is plausible, then it may be time to rethink bald conservation in terms of preserving a natural community degraded by the absence of the ancient disturbance regime of herbivory. Only restoration of the balds will protect their rare biotas, vistas and historical places. It is also likely that, because of recent changes to these landscapes and their possible resistance to returning to their original state (Suding, Gross & Houseman,