Post-traumatic inflammation is formed by molecular and cellular complex mechanisms whose final goal seems to be injured tissue regeneration.In the skin -an exterior organ of the body- mechanical or thermal injury induces the expression of different inflammatory phenotypes that resemble similar phenotypes expressed during embryo development. Particularly, molecular and cellular mechanisms involved in gastrulation return. This is a developmental phase that delineates the three embryonic germ layers: ectoderm, endoderm and mesoderm. Consequently, in the post-natal wounded skin, primitive functions related with the embryonic mesoderm, i.e. amniotic and yolk sac-derived, are expressed. Neurogenesis and hematogenesis stand out among the primitive function mechanisms involved.Interestingly, in these phases of the inflammatory response, whose molecular and cellular mechanisms are considered as traces of the early phases of the embryonic development, the mast cell, a cell that is supposedly inflammatory, plays a key role.The correlation that can be established between the embryonic and the inflammatory events suggests that the results obtained from the research regarding both great fields of knowledge must be interchangeable to obtain the maximum advantage. Inflammation is considered the fundamental scientific principle underlying the practice of surgery . AlthougWhen acute tissue damage is produced by a mechanical or thermal harmful stimulus, both types of energy are etiologically involved, either in tissue injury production, usually a wound , or in tThe most relevant mechanisms culminating in cell necrosis correspond to mitochondrial dysfunction and ATP depletion; loss of intracellular ion homeostasis, with osmotic swelling and oxidative stress; activation of degradative hydrolases, and degradation of cytoskeletal proteins with disruption of cytoskeletal integrity . SurprisThe skin is protecting the organism against physical, chemical and microbial impacts of the environment ,12. It rThe inflammatory response expressed by this organ after a wound can have exogenous and endogenous inducers . Noxious"per se" plays in cutaneous wound repair is most likely very limited. Thus, it is accepted that inflammation is only another component of the repair process. Thus, the common description of wound repair evolution includes three classic types: Inflammation, new tissue formation and remodeling [Today, the role that inflammation modeling -19. Howemodeling  and evenmodeling .Nowadays, we need integrative pathophysiology to integrate all the new knowledge to understand the inflammatory response because the distance between new molecular knowledge and every day patient care is increasing. Now we need to understand cell biology and genetics of inflammation better to identify gene and metabolic targets in order to modulate aspects of the inflammatory response . We haveThe inflammatory response that is induced in the injured tissue could be described as a succession of three overlapped phases, during which the phenotypes of metabolic progressive complexity related to the use of oxygen are expressed. Each one of these phases emphasizes the trophic role of the mechanisms developed in the damaged tissue. Hence, nutrition by diffusion predominates the first phase; trophism is mediated by inflammatory cells in the second phase; and finally blood circulation and oxidative metabolism play the most significant nutritive roles in the third phase .Since these trophic mechanisms are of increasing complexity, progressing from anoxia to total specialization in the use of oxygen to obtain usable energy, it could be speculated that they represent the successive reappearance of the stages that took place during the evolution of life without oxygen on Earth from ancient times. In this sense, the inflammatory response not only could recapitulate phylogeny, but also ontogeny, through the successive expression of phenotypes that have a trophic meaning for the injured tissue ,3,10 Fi.The successive inflammatory phenotypes are expressed mainly in the interstitial space. Therefore, the interstitial space always seems to be the battlefield for inflammation, whether it is due to trauma ,3, infecIn the first or immediate phase of the inflammatory response, interstitial hydroelectrolytic alterations stand out. This phase has been referred to as the nervous phase, because the sensory  and motor alterations  respond to the injury. Particularly, the vasomotor response -with vasoconstriction and vasodilation- is responsible of the ischemia-reperfusion phenomenon, with the subsequent excessive production of reactive oxygen and nitrogen species (ROS/RNS) that causes oxidative and nitrosative stress in the injured tissue. In this phase, during the progression of the interstitial edema, the space between epithelial cells and capillaries increases, and the lymphatic circulation is simultaneously activated (circulatory switch) ,10.In the following intermediate or immune phase of the inflammatory response, the tissues which have undergone ischemia-reperfusion suffer an immunological activation. In addition, they are infiltrated by inflammatory blood-born cells, particularly leukocytes. In order to infiltrate the interstitial space, bacteria takes advantage of the chemotactic call, which activates and induces the recruitment of blood cells. In the tissue which suffers oxidative and nitrosative stress, symbiosis of the leukocytes and bacteria for extracellular digestion by enzyme release, i.e. fermentation, and by intracellular digestion, i.e. phagocytosis, produces enzymatic stress. Furthermore, macrophages and dendritic cells take advantage of the lymphatic circulation activation, and migrate through it until reaching the lymph nodes, where they activate lymphocytes ,3.During the third phase of the inflammatory response, angiogenesis permits numerous substances, including hormones, to be transported by the blood circulation. For this reason, it has been considered that the predominance of angiogenesis during the last phase of the inflammatory response would allow for calling it the endocrine phase. Although the final objective of the angiogenic phenotype is to form new mature vessels for oxygen, substrates and blood cells, other functions could be carried out before the new mature vessels are formed. Thus, angiogenesis could have antioxidant and antienzymatic properties, favoring the resolution of the inflammation as well as wound repair by epithelial regeneration and scarring. Therefore, in this phase the new formed tissue is structured, specialized and matures by remodeling ,3,10 Fi.The three overlapped trophic phases of the post-traumatic inflammatory response could also be named, by their corresponding length, as acute, subacute and chronic, respectively. The acute phase is characterized by the quick molecular infiltration of the interstitial space that would for favoring the establishment of a trophic axis based in the interstitial fluid flow. In the following or subacute phase, the cellular infiltration of the interstitial space predominates. In this phase, the invasion of the interstitium by blood cells would create another trophic axis based on a hypothetical enzymatic digestive ability that is assumed by the leukocytes in the injured tissue. Finally, it could be interpreted that through the confluence in the interstitial space of both trophic axes, molecular and cellular, the appropriate metabolic conditions would be generated so that tissue repair takes place during the last so-called chronic phase of the inflammatory response.The inflammatory response could recapitulate ontogeny through the expression of the two hypothetical trophic axes, molecular and cellular, in the interstitial space of the injured tissue.We have previously proposed the hypothesis that inflammation would represent the debut during post-natal life of ancestral biochemical mechanisms that were used for normal embryonic development. The re-expression of these old mechanisms, with a prenatal solvent path, are perhaps inappropriate and hard to recognize since they are anachronistic during post-natal life and because they are established in a different environmental medium ,26.The early mammalian embryo already has the ability to manage fluids in the interstitial space. In the human blastocyst, the inner cell mass or embryoblast, differentiates into two layers, the hypoblast and epiblast. The epiblast is the source of all three germ layers and develops within a small cavity named amniotic cavity . At the Body fluid is distributed among three major fluid spaces: Intracellular fluid, interstitial fluid and plasma. Nevertheless, the fluid distribution in each of these compartments is dramatically different in the fetus compared to the adult. Particularly, the amniotic fluid that surrounds the fetus may be considered an extension of the extracellular space of the fetus . Thus, tThe yolk sac is the final destination of migrating visceral endoderm cells, that in turn are derivatives of the hypoblast Figure . The yolde novo formation of embryonic blood cells to support embryonic and fetal growth prior to the establishment of the adult hematopoietic system. The very first blood cells to appear in the embryonic circulation arise in the extraembryonic yolk sac [Mammalian development requires the rapid yolk sac . Particuyolk sac . As the yolk sac . The yolyolk sac  , fibroblast growth factor-2 (FGF-2), transforming growth factors (TGFs), angiopoietins, platelet-derived growth factor (PDGF), and thrombospondin-1 and angiostatin. "Non classic" endogenous stimulators of angiogenesis include erythropoietin, angiotensin II, endothelins, adrenomedullin, adipokines , neuropeptide-Y, vasoactive intestinal peptide (VIP) and substance P ,74. TheyAs granulation tissue forms in the healing wound, the vascular cells, intermingle with the provisional matrix, which is composed mainly of fibrin, fibronectin and vibronectin . Then, tRemodeling begins two to three weeks after injury and lasts for a year or more. A framework of collagen and elastin fibers replaces the granulation tissue and produces progressive tissue sclerosis ,76. FinaThe inflammatory mechanisms also develop a fundamental role in the production of post-traumatic pain.Inflammatory pain is associated with sensitization of the nociceptive system. Central sensitization represents an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy. It also reduces inhibition and is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to inflammation . To induPeripheral inflammation induces a phenotypic switch in primary sensory neurons that comprises a change in their neurochemical character and properties due to alterations in transcription and translation . HoweverAn immediate component of the stress response to pain is the efferent nervous response, which is mediated by the somatic motor and autonomic nervous system . The somWith respect to the autonomic nervous system, both the sympathetic and parasympathetic nervous systems, participate in the acute inflammatory response . CatechoIn addition, the inflammatory reflex of Tracery is a pathway in which the autonomic system detects the presence of inflammatory stimuli and modulates inflammation. Particularly, afferent signals are transmitted to the brain, via the vagus nerve, which activates a reflex response that culminates in efferent vagus nerve signaling termed the "cholinergic anti-inflammatory pathway" .functio laesa, favors vascular blood and lymphatic stasis and interstitial edema [Also, by anterograde inflammatory signals, neural cells contribute to local tissue responses. Noxious stimuli cause nerves to release neuropeptides in the injured tissue, i.e. substance P and Calcitonin gen related peptide (CGRP). When released into injured tissues, neuropeptides contribute to the pro-inflammatory responses against injury. The evidence that neuropeptides contribute to inflammation includes changes in endothelial cell shape, leading to capillary leak, smooth muscle cell relaxation leading to vasodilatation, mast cell degranulation leading to histamine, serotonine, proteolytic enzymes and growth factor release, induction of inflammatory cell chemotaxis, increase expression of adhesion molecule and increase cytokine and growth factor production -90. Expeal edema .Complex Regional Pain Syndrome type I is formerly identified as "reflex sympathetic dystrophy". This syndrome is the new term for "causalgia" that always coexists with documented nerve injury . ComplexFetal wounds heal by regenerating normal epidermis and dermis with restoration of the extracellular matrix architecture, strength and function ,95. AlsoThe spectrum of scarring includes normal scars, hypertrophic scars and keloids . HypertrRecently, the role of mast cells in wound repair and the remodeling process have been attracting attention. Mast cell proteases may provoke matrix degradation; histamine stimulates fibroblast migration and thus may contribute to wound healing regulation . ParticuAlthough after the traumatism, vascular and neuronal inflammation are the main clinical manifestations, it must not be forgotten that the principal cells that constitute the skin organ, or parenchyma, are the keratinocytes, and the fibroblasts, whose primary function is to establish, maintain and modify the connective skin stroma  Figure .In the human body the fibroblasts form a heterogeneous collection of mesenchymal cells -105 and Fibroblasts are mesodermal-derived cells and perhaps this embryonic origin could justify their great postnatal plasticity. The mesodermal cells of the embryo participate in the extraembryonary structures, including the corion, the amnios and the yolk sac . Also, iIf the post-traumatic tissue repair is based on the re-expression of metabolic, histologic and functional conditions that made the first stages of embryo development possible, then the fibroblast would play a fundamental role in this repair process. In fact, this cell is recognized as a mesoderm or embryonic trace and perhaps the most qualified cell for re-expressing this original phenotype  Figure .Local fibroblasts residing in the skin are considered the most prominent source of myofibroblasts ,109. HowThe reason why the myofibroblast is attractive to a broad scientific and clinical audience is due to the large panel of cells that can develop this phenotype upon activation. It appears that myofibroblasts can be recruited from whatever local cell type and it is suitable for rapidly repairing injured tissue . FibroblSeveral days after injury a subset of wound fibroblast can differentiate into myofibroblast which are responsible for repopulating the wounded area in parallel to angiogenesis, thus forming the granulation tissue ,21,99. AGastrulation is the first major shape change of the developing embryo and cell-directed mechanical forces have a critical role . ContracGranulation tissue is then repopulated with fibroblasts to produce a more densely collagenous extracellular matrix which is more akin to the matrix found in interstitial stroma . RecentlTissue remodeling requires the removal of granulation tissue and maturation of collagen is oxygen dependent. Indeed increasing wound oxygenation results in increased collagen deposition and tensile strength . HoweverThe synthesis and deposition of extracellular matrix largely occurs in response to mechanical signals mediated via cell receptors ,116, cytThe notochord is an embryonic structure that could be a candidate for comparison with this phase of tissue remodeling. This anatomical structure of the embryo dominates early morphogenesis as a source of molecular signals i.e. growth factors, and later as a mechanical structure .Degradation and remodeling of the extracellular matrix by proteases, particularly matrix metalloproteases (MMPS) is a key feature of re-epithelialization and tissue remodeling . InteresThe phenotypic changes suffered by the keratinocytes during re-epithelialization suggest a partial epithelial-mesenchymal transition Figure . FollowiA cut in the skin produces a current that can be detected. This "injury" potential represented the short circuiting of a transepithelial potential that generated electrical field vectors as current flowed from areas of high resistivity, namely, with intact tight junctions, to the cut, where resistivity is low. Thus, the short circuiting of transepithelial potentials can be sensed over 1-2 mm from the wound and will persist until repair and re-epithelialization is complete ,125.One to two days after injury, the migration of keratinocytes from the epidermis at the wound edge and from injured appendages is produced ,21. EpitThe keratinocytes that are behind the leading edge in larger wounds proliferate and mature and finally restore the barrier function of the epithelium ,21,49. TIt has long been known that chronic wounds are at risk for neoplastic progression. Chronic inflammation is a major risk for various types of cancer . The risThere is now broad evidence that tumor cells depend on metabolic alterations for their continued growth and survival, and that these changes make cancer cells peculiarly addicted to the rapacious uptake of glucose and glutamine ,130. ThiIn the current review we have proposed that the inflammatory response employed by the adult for wound repair could resemble the early phases of embryogenic development. This hypothesis is based on the comparison of the successive phases of the inflammatory response, particularly in the mechanisms that regulate the earliest steps, in amniote gastrulation Figures  and 4.gaste", meaning stomach or gut, that transforms the rather unstructural early embryo into a gastrula with several specific characteristics: The three primary germ layers are formed; the basic body plan is established, including the construction of the rudimentary body axes; and the cells assume new positions, allowing them to interact with cells that were initially not close to them [Gastrulation is a developmental phase that delineates the three embryogenic germ layers: Ectoderm, endoderm and mesoderm. Haeckel coined the term gastrulation derived from the Greek word " to them .In essence, gastrulation could be represented as the creation of an interstitial space that is successively infiltrated by molecules and cells, in a similar fashion as the inflammatory interstitium of the traumatized tissue. Therefore, during gastrulation, the extraembryonary mesodermis internalizes and occupies the space located between the amnion and the yolk sac. The primitive streak is a subpopulation of the epiblast in the organizing center for amniote gastrulation . Once thThe vast arrangement of the mesenchyme around and between the developing amniotic and yolk sac cavities suggests an important role of the mesenchyma in orchestrating embryo development. Mesenchymal stem cells are a versatile group of cells derived from mesodermal progenitors and can be found in several fetal and adult tissues . The amnvitellum) [The extraembryonic visceral yolk sac in mammals is composed of two layers and the visceral endoderm, which is active in endocytosis/digestion and has large lysosomes and the underlying mesoderm layer . In the itellum) . Particuitellum) ,146. Theitellum) . Interstitellum) .The molecular and cellular contribution made by both embryo structures -the amnion and yolk sac- to the interstitial space located between them, that is the mesoderm, are essential for organogenesis. However, both in the amnion as in the yolk sac structures, the extraembryonic mesenchyma plays an important role Figure . It coulIt could be accepted that these primitive functions are internalized during gastrulation to create the mesoderm. Thus, this germ layer would integrate the amnion- and yolk sac-related functions and would strengthen its functional ability compared to the extraembryonic mesenchyma Figure . TherefoIn the adult organism, many pathways that play an essential role during embryo development are inactivated later in life although some of them may be transiently expressed during adult repair . This hyAs in the gastrulation process, it is possible that the primitive functions of the extraembryonic mesenchyma, whose re-expression is induced by the wound, would be internalized by the adult body. But, this mechanism would produce a serious loss of its health. So, if embryonic developmental pathways, representative of its primitive life, would re-emerge in the adult organism, they would take the place of post-natal specialized functions, impeding or hindering its actual life.Nonetheless, according to the proposed hypothesis, the failure of adult skin regeneration after a wound suggests the need of researching those factors and mechanisms that must be upregulated and those that must be reduced or even avoided to efficiently reproduce the early embryonic conditions for development. Understanding the process that gives rise to early embryonic development may lead to advances in wound therapies. Perhaps, the mechanisms of scarless wound healing in the fetus are related to this supposed ability to maintain the memory of their origin while undergoing reprogramming events that could allow them to re-enter the embryonic programs of tissue formation to obtain the regeneration after injury ,154.Mast cells are ubiquitous in the interstitial spaces of the body and normally reside in the connective tissue close to blood vessel nerves and epithelia . CurrentParticularly, mast cells could orchestrate the inflammatory response inducing the expression of embryonic programs of tissue formation. Mast cells are derivatives of hematopoietic progenitor cells that migrate into virtually all vascularized tissues, where they complete their maturation. Upon activation their "plasticity" allows them greater flexibility and diversity in term of responsiveness to meet the requirements of the inflammatory response in which these cells are involved . In thisMesenchymal post-traumatic dedifferentiation induced by activated mast cells could favor the expression of extraembryonic mesenchymal associated functions. In this way, embryonary mesenchymal functional axes are again expressed in the injured tissue, favoring in turn neurogenesis, hematopoiesis and angiogenesis. But mast cells also could simultaneously activate the mechanisms associated with gastrulation and this would mean the internalization of the above mentioned mesenchymal functional axes. In this developmental process, generation of the mesoderm from the ectoderm, that is the epiblast, by epithelial to mesenchymal transition , is assoMast cells could also participate in the worsening of the inflammatory response when a noxious factor is associated . Mast ceUnder conditions of long-lasting inflammation, wound healing is associated with excessive interposition of fibrotic tissue. Prolonged inflammation in wounds contributes to the development of fibroproliferative scars, in other words, keloids and hypertrophic scar, both with erithematous and increased mast cell density ,102. IntGrowth factors pivotal for repair in mammalians are PDGF/VEGF. In general, fibroblasts could respond in a pathological fashion to PDGF/VEGF promoting fibrotic tissue scarring . InflammIf we hypothesize that during wound healing a process similar to the embryonic gastrulation with internalization of the primitive extraembryonic functions is developed, we could deliberate about the original nature of these functions and their corresponding mediators. Therefore, it could turn to the mast cell functions and mediators because of its ubiquity during all the phases of the inflammatory response . Mast ceLikewise, the venoms of some species of coelenterates, octopus, spiders, scorpion, cone snails, centipedes, insects, amphibians and snakes contain serotonin . It is tExamination of the effects of venoms on monoaminergic systems points out the great diversity of venom effects and also the cases of evolutionary convergence. For example, the venoms of scorpions, spiders and jellyfish cause a catecholamine storm in the victim ,176-178.Phylum Cnidaria, i.e. hydroids, anemones, corals and jellyfish, are tentacles with stinging cells, i.e. nematocytes or cnidocytes, which contain a nematocyst discharge mechanism. The nematocyst neurotoxins can paralyze and often kill the small prey, which are their food [A common feature of the eir food ,179. BotIt is possible that during the evolution, these invertebrate armaments -defensive and offensive- were internalized into in the mesenchyma. If so, an evolutive advantage was associated with the risk of self-poisoning when the body suffered an injury that caused the cells to be stuffed with toxic products, i.e. the mast cells. Even psychological stress  because Mast cells exhibit phenotypical and functional heterogeneity in different anatomical sites . Two typThe ability of the tissues to involute or dedifferentiate could represent a return to early stages of development. Therefore, it could form an effective defense mechanism to escape death after injury since it could make retracing a well-known route possible, i.e. the initial phases of embryonic development during the evolution of the inflammatory response. Particularly, the up-regulation of signaling pathways during gastrulation, in which the internalization of extraembryonary functions would be made, could help explain the meaning of the diverse and complex mechanisms expressed by the mature organism in response to skin injury.If so, even the embryonary mechanisms to generate pigment cells could be responsible of the post-inflammatory hyperpigmentation with higher concentrations of melanocytes ,184. NowThis amazing property of the cells to conserve a memory of their origin undergoing reprogramming events could allow them, post-injury, to re-enter the embryonic programs of tissue formation and obtain regeneration . GeneralInterestingly enough, quiescent and active adult stem cells coexist in several tissues that have the ability to renew and regenerate, like bone marrow, intestinal epithelium and hair follicles, all of them placed in the vicinity of a mesenchymal cell . This stIn summary, the post-traumatic inflammatory response could be considered a reaction of the body in which the mesenchymal cell plays a leading role during which the early events of embryonic development and particularly gastrulation are recreated. The mesenchymal cell due to its strategic and privileged location in the interstitial space, is able to induce the successive phases of inflammation. Therefore, the mesenchymal cell uses the mast cell, to induce the expression of neurovascular inflammatory axes that have an extensive corporal projection and whose activity converges in the wounded skin.The correlation that can be established between the embryonic and inflammatory post-traumatic events suggests that the results obtained from the research about both great fields of knowledge must be interchangeable to obtain the maximum advantage in the daily care of patients' wounds.AP1: Activator protein 1; ATP: Adenosin-triphosphate; BDNF: Brain-derived neurotrophic factor; CGRP: Calcitonin gen-related peptide; CTMC: Connective tissue mast cell; FGF-2: Fibroblast growth factor-2; GM-CSF: Granulocyte-macrophage colony stimulating factor; GTP-ASE: Guanidine triphosphatase; HB-EGF: Heparin-binding epidermal growth factor; HDL: High-density lipoproteins; HGF: Hepatocyte growth factor; MMC: Mucosal mast cell; MMPS: matrix metalloproteases; NGF: Nerve growth factor; PDGF: Platelet-derived growth factor; RICE: Rest, Ice, Compression and Elevation; RNS: Reactive nitrogen species; ROS: Reactive oxygen species; STAT3: Transcription factor signal transducer and activator of transcription 3; TGF: Transforming growth factor; VEGF: Endothelial growth factor; VIP: Vasoactive intestinal peptide; VLDL: Very low-density lipoproteins; WNT/PCP: Wnt/planar cell polarity pathway.The authors declare that they have no competing interests.All the authors conceived, discussed, wrote and approved the manuscript.


Gorlin-Goltz syndrome is a rare hereditary disease. Pathogenesis of the syndrome is attributed to abnormalities in the long arm of chromosome 9 (q22.3-q31) and loss or mutations of human patched gene (PTCH1 gene). Multiple basal cell carcinomas (BCCs), odontogenic keratocysts, skeletal abnormalities, hyperkeratosis of palms and soles, intracranial ectopic calcifications of the falx cerebri and facial dysmorphism are considered the main clinical features. Diagnosis is based upon established major and minor clinical and radiological criteria and ideally confirmed by DNA analysis. Because of the different systems affected, a multidisciplinary approach team of various experts is required for a successful management.We report the case of a 19 year-old female who was involved in a car accident and found to present imaging findings of Gorlin-Goltz syndrome during a routine whole body computed tomography (CT) scan in order to exclude traumatic injuries.Radiologic findings of the syndrome are easily identifiable on CT scans and may prompt to early verification of the disease, which is very important for regular follow-up and better survival rates from the co-existent diseases. Gorlin-Goltz syndrome also known as Nevoid Basal Cell Carcinoma Syndrome (NBCCS), was first reported in 1894  in 1960,PTCH1 gene have been identified in patients with NBCCS  were detected.By definition the radiologists could play an important role in the diagnosis of this rare entity, because several major and minor criteria are detected only after a radiological exam, however the syndrome is not well known among them.Therefore high suspicion is mandatory concerning detection of odontogenic keratocysts or calcifications of falx cerebri and tentorium, especially at young patients since the syndrome is mostly known among dentists. These easily detectable abnormalities in CT scans, can prompt further chromosomal diagnostic work-up to confirm the diagnosis.Several imaging modalities can be used for the detection and investigation of Gorlin-Goltz syndrome. Skull radiography shows calcifications of the falx cerebri, tentorium cerebelli and diaphragma sellae, while skeletal X-ray reveals bifid, hypoplastic, fused, partially missing, or splayed ribs in 38-60% of patients with the 3rd, 4th and 5th ribs most commonly affected. Other imaging findings of the syndrome are malformations at the occipitovertebral junction, cervical or upper thoracic vertebral fusion and small, pseudocystic, lytic bone lesions known as "flame-shaped lucencies" on radiographs of the hands (30%) and feet (17%) of affected individuals.Odontogenic keratocysts, which are relatively common in Gorlin-Goltz syndrome, are diagnosed with dental panoramic radiography. Keratocysts may show a uni- or multilocular pattern and the cystic spaces may have a smooth or scalloped border . CardiacEarly recognition of the disease, a detailed family history and a thorough evaluation of signs and symptoms are the cornerstones for an appropriate management. Because of the different systems affected and the diversity in clinical picture, once diagnosis is established, a multidisciplinary approach team of various specialists is required for a successful treatment. A dermatologist should maintain ongoing surveillance and treatment of BCCs, thus planned visits are recommended to identify and treat lesions when they are as small as possible . SurgicaOur case highlights the importance of the awareness of this rare syndrome especially in young people without any skin lesions. We have seen that it is useful to keep in mind the existence of the syndrome and recognize the presence of some major criteria  as these are easily recognizable in CT scan of the head and neck thus establishing the diagnosis, even as an incidental finding offering the opportunity for frequent follow-ups and therefore increasing the chances for better overall survival rates.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.NSM is the referring doctor for patient's follow-up and co-ordinates other sub-specialities for that reason. He also focused on the clinical relevance of this rare entity. CK, PZ, SK and PK analyzed and interpreted the radiologic findings, as well as they found all the relevant information regarding this relatively rare entity. CK, SK, PZ, PK were also major contributors in writing the manuscript, focused on the radiologic findings, while NSM focused on the clinical relevance. All authors read and approved the final manuscript.


Using birth addresses, we examined the geographical variation in risk for all types of childhood cancers in the UK, on a scale corresponding to the 10-km squares of the National Grid. The effects of socioeconomic and environmental factors, including natural background radiation, were investigated and their relative importance assessed using Poisson regression. Data came from a national collection of all fatal cancers between 1953 and 1980 in children aged 0-15 years and consisted of 9363 children of known place of birth from 12 complete annual cohorts born in the period 1953-64. For solid cancers, as well as for leukaemias and lymphomas, there was marked variation of cumulative mortality according to place of birth. High mortalities were associated with areas characterized as having high social class, higher incomes and good housing conditions, but also with high population densities (births per hectare). Each of these contrasting social indicators operated independently of the other, indicating complex determining mechanisms. Mortalities increased with increased radon exposure, and the relationship operated independently of the socioeconomic factors. At this scale of analysis, we found no increased mortality in industrialized areas. A population-mixing infective hypothesis, which postulates high rates of leukaemia when highly exposed urban populations are introduced to isolated rural areas, was supported by observations of high mortalities in 'growth areas' and New Towns, but was not readily reconcilable with the high rates seen in the high-density areas. If these correlations do indeed represent an infective mechanism, then the outcomes are not limited to malignancies of the immune system alone.


The modal DNA values of 1465 tumours, together with other factors of possible prognostic importance, were related to the survival of the patients, using regression models . For most tumour sites except the testis, the distributions of modal DNA values were bimodal, with peaks at the diploid level and in the triploid-tetraploid range. For all tumour sites except the cervix uteri, patients in the low (near-diploid) range showed better survival; the reverse was true for squamous-cell carcinoma of the cervix uteri. Other variables showed the following effects: for all sites except the testis, younger patients showed a better survival; for the cervix and corpus uteri, breast and ovary, increasing clinical stage was associated with poorer survival. Where evaluated, histological grade appeared to be associated with survival rate, the less well differentiated tumours having a worse prognosis, except for the breast, where the reverse correlation was noted. For carcinoma of the bladder, females and a poorer survival rate than males.


Not surprisingly, dysregulation of microRNA expression has been linked to the pathogenesis of a variety of diseases, among which cancer, cardiovascular disorders, and neurodegeneration have proven fertile grounds for investigation.The recent explosion of research on the role of noncoding RNAs (ncRNA) in the control of gene expression has revealed multifaceted implications concerning the regulation of numerous mammalian systems, ranging from determination of cell fate during development to maintenance of terminally differentiated states. Among the various types of ncRNA, microRNAs are probably the best known group; their functional impact in signaling pathways controls normal processes regulating apoptosis, cell cycle traverse, differentiation, cytoskeletal organization, C. elegans, with the latest miRbase 10.1 version stating that 73 out of 139 worm miRNAs have sequence relationship to known human miRNAs. Understanding how they control the signaling networks that modulate aging in the worm should provide major insights into the aging process of mammalian species, including man. Notwithstanding the essential role of microRNA in cancer etiology, the biggest impact of microRNA regulation of post-transcriptional control of gene expression may be that associated with neurodegeneration. The paper by Maes, et al. reviews the basic knowledge of how microRNAs control neuronal cell fate during development, and includes recent evidence that changes in expression levels of this noncoding RNA species are vital to the pathogenesis of a wide variety of disorders associated with the central nervous system, as well as being systemically manifested in peripheral blood mononuclear cells. Of all the complex hormonal control mechanisms of the mammalian aging process, estrogen is perhaps the most significant single factor, since many of the disorders seen in the female aging population are attributed to the functional decline associated with menopause. In this context, the paper by Klinge describes aberrant patterns of microRNA expression in assorted estrogen-related cancers, the most notorious being breast cancer; the role of estrogen-regulated changes in expression of microRNAs and their downstream target genes in the aging process are discussed. Beyond the recognition of microRNAs as a vital molecular species for repression of gene expression at the post-transcriptional level, increasing reports indicate that their transcriptional regulation is equally important, and follows the well-established mechanisms of promoter-dependent regulation with coordinated genomic organization in terms of transcriptional start sites, cis elements, activation by transcriptional factors, etc. Along this line, Liang,  et al. reviews the genomic structures and organization of microRNA genes, and how changes such as oxidative stress during aging can affect the transcriptional regulation of microRNA expression. Among all the transcriptional factors affecting microRNA expression, p53 may be the best known, since its multiple functions are implicated in cancer, senescence, and apoptosis. In the paper by Takwi and Li, the p53-directed pathway is reviewed in detail, specifically how it activates microRNAs which affect genes involved in various components of this noted signaling network. In conclusion, this issue provides, for the first time, a collection of papers describing the importance of microRNAs in controlling the aging process, and their possible roles in the etiology of age-dependent diseases. We hope this compendium will stimulate further research in this area, a fertile ground for study of the post-transcriptional control of gene expression during the aging process.This issue focuses on a discussion of microRNA’s post-transcriptional control of the aging process. The paper by Ibáñez-Ventoso and Driscoll provides a comprehensive review of the potential impact of microRNA expression on health span, based upon the well-known aging model,


Effective malaria control requires information on both the geographical distribution of malaria risk and the effectiveness of malaria interventions. The current standard for estimating malaria infection and impact indicators are household cluster surveys, but their complexity and expense preclude frequent and decentralized monitoring. This paper reviews the historical experience and current rationale for the use of schools and school children as a complementary, inexpensive framework for planning, monitoring and evaluating malaria control in Africa. Consideration is given to (i) the selection of schools; (ii) diagnosis of infection in schools; (iii) the representativeness of schools as a proxy of the communities they serve; and (iv) the increasing need to evaluate interventions delivered through schools. Finally, areas requiring further investigation are highlighted. Plasmodium falciparum parasite rate (PfPR): the proportion of surveyed persons harbouring parasites in their peripheral blood. The PfPR among children aged 2-10 years provides an indirect quantitative measure of transmission intensity across a range of malaria endemicities [PfPR had important roles during the first phase of the Global Malaria Elimination Programme (GMEP) and was subsequently used to monitor progress and verify interruption of transmission [PfPR can provide important information for national malaria control programmes by targeting interventions according to endemicity, thus cost-effectively targeting resources for malaria control [The burden of malaria in some areas of sub-Saharan Africa (SSA) has started to decline over recent years: analyses of hospital admission data provide evidence of declining morbidity and mortality in Kenya ,2, The Gmicities ,10. Histsmission . Moreove control ,13.PfPR among these age groups is not optimal as pregnant women sequester infections [Currently, the most robust sampling framework for national malaria surveys are household cluster surveys, including: Demographic and Health Surveys , the Mulfections  and infefections ,19. Morefections , lack difections , and arefections ,23 and efections ,25. ThisConducting school malaria surveys is not a new approach in malariology. School surveys were a common feature of early approaches to malaria reconnaissance and control ,27 Figu. During Malaria in Tanzania by Clyde [Plasmodium species was mainly based on school surveys conducted in different ecological settings across the country [School surveys were also an important component of early, particularly colonial, malaria reconnaissance and monitoring in Africa. In his survey of malaria in Southern Rhodesia, Alves reports results of school surveys conducted between 1937 and 1948 , while iby Clyde  many of  country . In Keny country ,35. Seem country .The practical advantages of sampling children at school are clear: identification and selection of individuals is simplified, compliance is high, and costs are reduced, since only a fraction of the population is examined. In addition, ministries of education are increasingly developing or upgrading national school databases using geographical information systems (GIS). This allows incorporation of information on schools location and enrolment into a single database, and the use of geo-statistical methods to model risks between schools and across unsampled schools.PfPR among children aged 2-10 years and geographical reconnaissance of malaria was recommended in all areas prior to a control programme launching into an attack phase of the GMEP [PfPR rises during early childhood and the age at which maximum PfPR is attained [PfPR consistency has a convex relationship with age, with PfPR rapidly rising in among young children, attaining a maximum within the 5-10 year old age class, and declines among adolescents and young adults, thereafter maintaining a relatively stable low value throughout adulthood  , which hPlasmodium sp. in circulating peripheral blood is microscopy. This method is, however, only as reliable as the quality of the blood slide preparation and equipment, skills of the microscopist and quality control [P. falciparum-specific histadine-rich protein (HRP) or species-specific isotypes of lactate dehydrogenase [P. falciparum when compared to expert microscopy even at relatively low parasite densities [Pf-HRP can persist for two weeks after parasite clearance. Although Pf-HRP-based tests are more likely to generate false positives, which has implications on their use for case-management [The most common and widely used technique to detect  control ,49. An arogenase . When stensities . The tesnagement , these tnagement ,30. In anagement -56. ThesP. falciparum transmission intensity [An important determinant of the representativeness of schools of the communities they serve is the level and equity of school enrollment. Current commitment of national governments and donors to achieving universal primary school participation , means tntensity .PfPR data collected through school surveys may depend on size of the catchment area of schools. If, for example, a school's catchment area is large, it may include villages with varying malaria ecologies; if the catchment area is small, then the derived PfPR is likely to be more representative of the immediate community. Little is known about the size and structure of school catchment areas in Africa, and this merits further investigation. It is known, however, that there is only a minor influence of household distance to schools on enrollment [Finally, the representativeness of rollment .There is increasing recognition that universal mosquito net coverage is one of the most effective malaria prevention tools, such that LLINs should be distributed freely or should be highly subsidized and used by all community members, including school children . In addiThe routine surveillance of malaria infection is uncommon in any national malaria strategy in Africa and it is notable that countries in southern Africa have identified elimination as an achievable immediate target without any mapped reconnaissance of malaria risk. It is argued that surveys of school attending children provide a rapid, cheap and sustainable platform to assemble information on malaria risk among communities, and that in time, children attending school will increasingly become the focus of intervention as the epidemiology of malaria risk changes. This is not a new approach but its significance has re-emerged during a renewed international interest in malaria control and elimination. The use of schools as sentinels does however require further validation and optimization. Notable areas of investigation that require attention include studies on the representativeness of schools and how this varies in relation to levels of school enrolment as well as malaria endemicity; the potential sampling and diagnostic biases introduced when transmission intensity declines and all new infections become clinical events resulting in absenteeism; and the validity of children's reporting on intervention, especially mosquito net, use among household members. However, it is likely that as pupil enrollment continues to expand schools will increasingly provide a representative sample of community events. Furthermore, the technical capacity to conduct school malaria surveys already exists in most SSA countries, and engaging the health and education sectors in malaria control promotes inter-sectoral collaboration at national levels.The authors declare that they have no competing interests.SB and RWS conceived the idea for the paper, and SB developed the initial draft paper. JK and AMN contributed to the survey design issues, and CWG contributed to the issues surrounding the representativeness of schools. All authors read and approved the final manuscript.


NuMA is a protein that has been previously shown to play a role in focusing microtubules at the mitotic spindle poles. However, most previous work relies on experimental methods that might cause dominant side effects on spindle formation, such as microinjection of antibodies, overexpression of mutant protein, or immunodepletion of NuMA-containing protein complexes.To circumvent these technical problems, we performed siRNA experiments in which we depleted the majority of NuMA in human cultured cells. Depleted mitotic cells show a prolonged duration of prometaphase, with spindle pole defects and with unattached, unaligned chromosomes.Our data confirm that NuMA is important for spindle pole formation, and for cohesion of centrosome-derived microtubules with the bulk of spindle microtubules. Our findings of NuMA-dependent defects in chromosome alignment suggest that NuMA is involved in stabilizing kinetochore fibres. NuMA, the protein of the 'Nucleus and Mitotic Apparatus', is a structural protein in vertebrates of approximately 230 kDa. It localizes to the nucleus during interphase, and accumulates at the spindle poles during mitosis . NuMA haSeveral reports have taken advantage of silencing NuMA expression with siRNA ,24-28. ITo determine whether the formation of spindle microtubules was inhibited in depleted cells, we performed assays of microtubule re-growth after cold treatment Fig. . After 6In conclusion, our depletion experiments suggest that NuMA is necessary for proper spindle formation in prometaphase, and that NuMA-dependent defects manifest in less efficient formation of kinetochore fibres. Improperly formed kinetochore fibres may in turn be responsible for defects in chromosome alignment and tension at kinetochores. Because we observed that even cells that were only partly depleted of NuMA (45% remaining at the mitotic poles) showed defects in chromosome alignment, we favour a model in which reduced levels of NuMA lead to prolongation of prometaphase due to an active spindle assembly checkpoint, until bipolar attachment and tension at kinetochores is finally achieved. We believe that the fraction of NuMA that localizes to the cell cortex in regular cells, as described by ,4, playsIn our RNA silencing experiments we detected smaller amounts of severely malformed spindles as compared to spindle formation assays after NuMA depletion in Xenopus egg extracts . DrasticThe authors declare that they have no competing interests.LH and NG participated in the conception of the work, performed microscopy and biochemical experiments, and contributed to the drafting of the manuscript. MW contributed to the design of the study, drafting of the manuscript, and provided logistic help. AM contributed to conception of the work, performed microscopy experiments, and drafted the manuscript. All authors read and approved the final manuscript.


Proteins perform many of their biological roles through protein–protein, protein–DNA or protein–ligand interfaces. The identification of the amino acids comprisingthese interfaces often enhances our understanding of the biological function ofthe proteins. Many methods for the detection of functional interfaces have been developed,and large-scale analyses have provided assessments of their accuracy. Amongthem are those that consider the size of the protein interface, its amino acid compositionand its physicochemical and geometrical properties. Other methods to thiseffect use statistical potential functions of pairwise interactions, and evolutionaryinformation. The rationale of the evolutionary approach is that functional and structuralconstraints impose selective pressure; hence, biologically important interfacesoften evolve at a slower pace than do other external regions of the protein. Recently,an algorithm, Rate4Site, and a web-server, ConSurf (http://consurf.tau.ac.il/), forthe identification of functional interfaces based on the evolutionary relations amonghomologous proteins as reflected in phylogenetic trees, were developed in our laboratory.The explicit use of the tree topology and branch lengths makes the methodremarkably accurate and sensitive. Here we demonstrate its potency in the identificationof the functional interfaces of a hypothetical protein, the structure of which wasdetermined as part of the international structural genomics effort. Finally, we proposeto combine complementary procedures, in order to enhance the overall performanceof methods for the identification of functional interfaces in proteins.


Portal hypertension is a clinical syndrome that manifests as ascites, portosystemic encephalopathy and variceal hemorrhage, and these alterations often lead to death.Splanchnic and/or systemic responses to portal hypertension could have pathophysiological mechanisms similar to those involved in the post-traumatic inflammatory response.The splanchnic and systemic impairments produced throughout the evolution of experimental prehepatic portal hypertension could be considered to have an inflammatory origin. In portal vein ligated rats, portal hypertensive enteropathy, hepatic steatosis and portal hypertensive encephalopathy show phenotypes during their development that can be considered inflammatory, such as: ischemia-reperfusion (vasodilatory response), infiltration by inflammatory cells (mast cells) and bacteria  and lastly, angiogenesis. Similar inflammatory phenotypes, worsened by chronic liver disease (with anti-oxidant and anti-enzymatic ability reduction) characterize the evolution of portal hypertension and its complications  in humans.Low-grade inflammation, related to prehepatic portal hypertension, switches to high-grade inflammation with the development of severe and life-threatening complications when associated with chronic liver disease. Portal hypertension is a clinical syndrome defined by a pathological elevation of blood pressure in the portal system -3. It maNowadays, a fundamental objective of both experimental and clinical research is the knowledge of the molecular mechanisms underlying this complex syndrome. However, the integration of these pathophysiological mechanisms in trying to understand their possible meaning is also of great interest.Knowing the final meaning of the alterations associated with portal hypertension could help to understand the meaning of the mechanisms involved in its production and maintenance. Therefore, it would be justified to speculate about the hypothetical purpose of the splanchnic and systemic responses to portal hypertension  since thWe have, therefore, proposed an inflammatory etiopathogenic hypothesis of the complications of portal hypertension . If so, As science grows more complex it is also converging on a set of unifying principles that link apparently disparate diseases through common biological pathways and therapeutic approaches . Thus reMechanical energy represents an old stimulus that causes, by cell mechanotransduction, responses considered both physiological and pathological . SpecifiMechanical energy is obviously involved in the etiopathology of mechanical traumatisms and can produce either local or generalized acute inflammation -15.The successive pathophysiological mechanisms that develop in the interstitial space of tissues when they undergo acute post-traumatic inflammation are considered increasingly complex trophic functional systems for using oxygen -15. AlthThe nervous or immediate functional system presents ischemia-reperfusion and edema, which favor nutrition by diffusion through injured tissue. This trophic mechanism has a low energy requirement that does not require oxygen (ischemia) or in which the oxygen is not correctly used, with the subsequent development of reactive oxygen and nitrogen species (ROS/RNS) (reperfusion). The intense activation of the hypothalamic-pituitary-adrenal axis and the adrenomedullary system with glucocorticoids secretion, the release of epinephrine into the circulation and the activation of the renin-angiotensin-aldosterone system, makes the selective accumulation of these substances in the interstitial space of the tissues and organs that suffer ischemia-reperfusion possible because their endothelial permeability is increased ,14. DistThe immune or intermediate functional system activates the coagulation-fibrinolisis system and produces infiltration of the injured tissue by inflammatory cells, especially by leukocytes and bacteria. Also, the immune cell residents in the interstitial space of the affected tissues and organs are activated. Hence, symbiosis of the inflammatory cells and bacteria for extracellular digestion by enzyme release (fermentation) and intracellular digestion by phagocytosis, could be associated with a hypothetical trophic capacity -14. ImprDuring the evolution of the nervous and immune phase of the inflammatory response, the body loses its more specialized functions and structures. In this progressive deconstruction, depletion of the hydrocarbonate, lipid and protein stores occurs , as wellHowever, consumption of the substrate deposits and the dysfunction or failure of the specialized epithelia of the body could also represent an accelerated process of epithelial dedifferentiation ,14,32. TThus, the endocrine functional system facilitates the arrival of oxygen transported by red blood cells and capillaries. It is considered that angiogenesis characterizes this last phase of the inflammatory response, so nutrition mediated by the blood capillaries is established. The ability to use oxygen in the oxidative metabolism is recovered when patients recover their capillary function. This type of metabolism is characterized by a large production of ATP (coupled reaction) which is used to drive multiple specialized cellular processes with limited heat generation and which would determine the onset of healing. In the convalescent phase, the dedifferentiated epithelia specialize again, the energy stores that supplied the substrate necessary for this demanding type of metabolism are replete, and complete performance is reached, thus making active life possible -14,18  up to an oxidative metabolism (oxidative phosphorylation) with a correct use of oxygen (coupled reaction) that produce usable energy. If so, it is also tempting to speculate on whether the body reproduces the successive stages from which life passes from its origin without oxygen  until itThe sequence in the expression of progressively more elaborated and complex nutritional systems could hypothetically be considered the essence of the inflammation, regardless of what is etiology  or localization may be. Hence, the incidence of harmful influences during their evolution could involve regression to the most primitive trophic stages, in which nutrition by diffusion (nervous system) takes place ,14. ThusPortal hypertension (PH) is characterized by an increase in portal vein pressure as a result of the obstruction to portal flow ,36. DepeIntrahepatic portal hypertension is most often caused by chronic liver disease, with the majority of preventable cases attributed to excessive alcohol consumption, viral hepatitis, or non alcoholic fatty liver disease . TherefoPrehepatic portal hypertension is most often caused by a cavernoma of the portal vein. This cavernoma is related to acute portal-vein thrombosis and it is developed concomitantly with splenomegaly, portosystemic shunts and the reversal of flow in the unaffected intrahepatic portal veins . It is aPost-hepatic portal hypertension, as the intrahepatic type, is also associated with hepatocellular dysfunction . TherefoPartial portal vein ligation in various animals, but particularly in the rat, has been widely used for portal hypertension studies -45.The surgical technique most frequently used in the rat was described by Chojkier and Groszmann in 1981 . In brie4), the resistance (R) to the flow of a vessel depends of the length (L) on the radius (r), and the coefficient of viscosity of the blood (μ). In brief, three partial ligations were performed in the superior, medial and inferior portion of the portal vein, respectively and maintained in position by the previous fixation of the ligatures to a sylastic guide. The stenoses were calibrated by a simultaneous ligation (3-0 silk) around the portal vein and a 20-G needle. The abdominal incision was closed on two layers [If it is taken into account that the intensity of the portal hypertension is determined by the resistance to the inflow produced by the constriction of the portal vein conditioning its posterior evolution, this experimental model of prehepatic portal hypertension could be improved by increasing the initial resistance to the blood flow. With this objective in mind, we have modified the surgical technique by increasing the length of the stenosed portal tract with three equidistant stenosing ligations since, according to the Poiseuille equation  rat ,49. In tPortal pressure can be measured by a direct or indirect method. In the first case, it is done by cannulation of the mesenteric vein through the ileocecal vein or a small ileal vein with a PE-50 catheter placing its tip in the distal part of the superior mesenteric vein . The indIt has been considered that at two weeks of evolution portal hypertension is a consequence of a pathological increase in the portal venous inflow ("forward" hypothesis) and resistance ("backward" hypothesis) ,49 Figu. The inc2), endothelium-derived hyperpolarizing factor, endocannabinoids, adrenomedullin and hydrogen sulfide (H2S) [Hyperdynamic circulation in short-term PVL rats has been principally attributed to two mechanisms: Increased circulating vasodilators and decreased response to vasoconstrictors ,55, likede (H2S) . In turnde (H2S) . FurtherIn this evolutive phase of prehepatic portal hypertension in the rat, mainly two types of portosystemic collateral circulation are established: splenorenal and paraesophageal . The devIt is considered that portal vein stenosis does not produce liver damage . HoweverIt has been suggested that the rat model of gradual portal vein stenosis is much more homogenous than human portal vein obstruction, because it has a narrow range of portal hypertension, degree of portosystemic shunts and hepatic atrophy . HoweverAll of the variations presented by the animals after PVL, aside from invalidating the experimental model and thus disappointing the investigator, probably add complexity and even more importantly, pose problems that are tempting challenges for the investigator. It is also possible that the knowledge of the etiopathogenic mechanisms involved in the evolutive variability of this experimental model will make it easier to understand the evolutive characteristics of human portal hypertension .The different mechanisms that contribute to the development of prehepatic portal hypertension in the rat make it possible to attribute different evolutive phases to this disease ,49. The One of the reasons that this prehepatic portal hypertension experimental model presents great evolutive variability could be based on its inflammatory nature. If so, it would be the individual variability of the inflammatory response intensity, inherent to portal hypertension, which would condition the different evolution in the animals. In this way, the pathogenic mechanisms proposed for the post-traumatic inflammatory response as phylogeny unifiers, and therefore for the category of generics , could aPortal hypertension is essentially a type of vascular pathology resulting from the chronic action of mechanical energy on splanchnic venous circulation. This kind of energy can stimulate the endothelium which, owing to its strategic position, plays an exceedingly important role in regulating the vascular system by integrating diverse mechanical and biochemical signals and by responding to them through the release of vasoactive substances, cytokines, growth factors and hormones -11. MechSeveral of the early as well as the late morphological and functional disorders presented by the splanchnic organs in experimental prehepatic portal hypertension make it possible to suspect that inflammatory type mechanisms participate in their etiopathogeny ,6,18,62.The evolution of portal hypertension as an inflammatory response would be comprised of three phenotypes with a trophic meaning, as previously proposed for the post-traumatic inflammatory response -14. In tEnteropathy and encephalopathy are between the most important splanchnic and systemic manifestations derived from experimental portal hypertension. In both anatomical sites, gastrointestinal tract and liver, inflammatory pathophysiological mechanisms come together to produce complications characteristic of the PVL rats .The gastrointestinal tract immediately and directly suffers the sudden increase in venous pressure produced by the PVL. In an early evolutive period, portal venous hyperpressure is highest ,49 when Ischemia/reperfusion injury is an important mechanism of mucosal injury in acute and chronic intestinal ischemic disorders . HypoxiaTwo days after PVL in the rat, portal hyperpressure is associated with intraperitoneal free exudates, peripancreatic edema, hypoproteinemia and hypoalbuminemia. The inflammatory nature of these alterations can be hypothesized, since the oral administration of budesonide prevents these early exudative changes . The acuAnd so we have shown that prophylaxis with Ketotifen, an anti-inflammatory drug that stabilizes mast cells , reduces2 and LTC4 [The intestinal effects of portal hypertension are not only harmful, since in this case the sudden obstruction of the portal venous flow would possibly cause death, which normally does not occur ,62. So, and LTC4 . The migand LTC4 ,73.In a later evolutive phase (4 days) portal hypertension is associated with features of hyperdynamic circulation. In the first 24 hours after the operation, hypoxia in the mucosa may stimulate the upregulation of e-NOS in the intestinal microcirculation with NO hyperproduction. This increase in eNOS expression occurs through VEGF upregulation and subsequent AKT/proteinkinase B activation in highly vascularized areas of the mucosa, and might initiate the cascade of events leading to hyperdynamic splanchnic circulation in prehepatic portal hypertension ,75. Ther4, CBDL or TAA, the event of bacterial translocation is also produced.In prehepatic portal hypertension in the rat, bacterial translocation is an early event. Two days after the PVL, it has been demonstrated that a significant greater portion of rats had positive mesenteric lymph node cultures  Figure  and coinA microscopic splanchnic alteration that is usually present in stenosed portal vein ligated rats is dilation and tortuosity of the branches of the upper mesenteric vein. We have called this alteration "mesenteric venous vasculopathy" . In earlSince 1985, when McCormack et al.  describePortal hypertensive rats at six weeks of evolution show increased mast cell infiltration in the duodenum, jejunum, ileum and superior mesenteric lymph node complex ,86. MastThe activation of the mast cells in the mesenteric lymph nodes in rats with portal hypertension, would not only collaborate in the production of mesenteric adenitis, but also would constitute a source of mediators for the inflammatory response between the intestine and systemic blood circulation . The lymThe ability of the mast cells for the synthesis and selective or dedifferentiated release of different mediator molecules of the inflammatory response would explain their participation in multiple and different pathological processes, as well as in the different evolutive phases of prehepatic portal hypertension. With respect to the splanchnic inflammatory response induced by portal hypertension, the mast cells could participate in the initial or acute phases, producing vasodilation, increased endothelial and epithelial permeability, edema, increased lymphatic flow and mesenteric adenitis, as in the more advanced, late or chronic phases. In the last phases, the chemotactic factors derived from the mast cells stimulate the proliferation of fibroblasts and the synthesis of collagen. Meanwhile, histamine and heparine promote the formation of new blood vessels. Both fibrogenesis and angiogenesis are responsible for fibromuscular and vascular proliferation in the intestinal wall, respectively .In portal hypertensive rats six weeks after the operation, the increase in diameter and number of blood vessels in the submucosa has already been shown in the duodenum, which at the same time is correlated with the infiltration by the mast cells . TherefoSplanchnic hyperemia, increased splanchnic vascularization and the development of portal-systemic collateral circulation in portal hypertensive rats are partly a VEGF-dependent angiogenic processes ,91. ThisThere are multiple factors involved in the development and enlargement of portosystemic collaterals, which regulate the collateral flow . At two The structural changes that are produced in the long-term in prehepatic portal hypertension in the rat could be similar to those described in other chronic inflammatory processes. These morphological alterations would not only be vascular, both macro- and microscopic, but also the rest of the intestinal structures would participate in greater or lesser intensity . In partOne of the reasons why the prehepatic portal hypertension experimental model in the rat is far from having a uniform evolution, is because it presents a wide variability in hepatic weight ,81.The wide variation of hepatic weight presented by the portal vein ligated rats in both early as well as late evolutive phases suggests that the liver could be one of the factors that determine the evolutive heterogeneity of this experimental model . If the A histological study of the liver, performed in order to verify if the existence of a liver pathology could justify this wide spectrum of liver weight, has demonstrated that hepatocytic fatty infiltration exists in portal prehepatic hypertensive rats . It has Hepatic steatosis alone is thought to be the most common form of nonalcoholic fatty liver disease (NAFLD) and is considered "benign", but not quiescent. In this way, the NAFLD spectrum is wide and ranges from simple fat accumulation in hepatocytes (fatty liver), without biochemical or histological evidence of inflammation or fibrosis, to fat accumulation plus necroinflammatory activity with or without fibrosis (steatohepatitis) to the development of advanced liver fibrosis or cirrhosis (cirrhotic stage) ,100. How2 -) induces peroxynitrite (ONOO-) formation, which in turn inhibits various mitochondrial respiratory chain complexes [The mechanisms by which portal hypertension could induce liver steatosis are not fully understood. In prehepatic portal hypertensive rats at 6 weeks of evolution, the increase of TNF-α, IL1β and NO in the liver is associated with megamitochondria . The redomplexes .Possible factors involved in fat accumulation in the hepatocytes also include components of the neuroendocrine response to portal hypertensive stress, among others. Specifically, corticosterone and glucagon, which increase in this experimental model, promote lipolysis in fat tissue and a plasma increase of free fatty acids. Therefore, both hormones could produce an excess "input" of fatty acids to the liver . InsulinPrehepatic portal hypertension in the rats, both in the short- (1 month) and in the long-term (1 year) produce hepatic accumulation of triglycerides and cholesterol . In the Furthermore, the mechanisms that have been proposed in order to explain the pathogeny of the fatty liver disease also correspond with those expressed for the inflammatory response -15. The From an embryological point of view, the liver can be thought of as a substitute of the yolk sac. In all vertebrates, the liver develops in close association with the yolk sac ,115; in It has been proposed that the failure to upregulate fatty acid oxidation systems and the ensuing burning of energy in the liver may play a role in the modulation of hepatic steatosis . The livExtra-splanchnic alterations are circumstantial in prehepatic portal hypertension and constitute the clearest argument in favor of its systemic nature.Prehepatic portal hypertension in humans is associated with neuropsychological and brain magnetic resonance changes consistent with minimal hepatic encephalopathy . Since iThe partial portal vein ligated rat model could be appropriate for the experimental study of the minimal hepatic encephalopathy related to prehepatic portal hypertension because portal-systemic shunting is developed. Hence, it should be considered that an associated hepatic pathology exists .The important role that inflammation has on the modulation of the molecular pathogenesis of hepatic encephalopathy has recently been highlighted ,124. InfAt one month of evolution, prehepatic portal hypertensive rats present increased SDF-1 alpha levels in the hippocampus and cerebellum associated with increased TNF-α and CXCR4 levels in the hippocampus and decreased RANTES levels in the striatum . The incChemokines have a dual role as neurodegenerative or neuroprotective molecules in the central nervous system. In experimental portal hypertensive encephalopathy, chemokines can contribute to creating an immune phase in the hippocampus and cerebellum that does not necessarily involve just harmful phenomena, but rather exerts a beneficial remodeling effect. The objective would be to adapt cerebral areas to the new metabolic state created by portal hypertension . At the It is now generally accepted that mast cells are present in the normal brain in many mammalian species, including humans and rodents. Since these cells, when activated, could translocate from the splanchnic area to the central nervous system  we have Other alterations that have been described in this experimental model could also be related to the establishment of a low grade cerebral inflammatory response. These include, for example, an altered blood-brain barrier permeability , neuro-eCardiovascular and metabolic derangements in prehepatic portal hypertensive rats are related to pathologic changes in regulatory mechanisms in the central nervous system. Central deregulation, i.e. brain stem cardiovascular nuclei, contributes to blunted cardiovascular responsiveness in prehepatic portal hypertension . Also thTwo pulmonary vascular disorders can occur in liver disease and/or portal hypertension: the hepatopulmonary syndrome, which is characterized by intrapulmonary vascular dilations, and portopulmonary hypertension, in which pulmonary vascular resistance is elevated . The exaIt is accepted that partial portal vein ligation in the rat does not result in the development of hepatopulmonary syndrome . HoweverThe hepatopulmonary syndrome is a consequence of abnormal angiogenesis of the pulmonary microcirculation induced by portal hypertension . TherefoSodium retention along with peripheral vasodilation are features of prehepatic portal hypertension. However, in portal vein ligated rats, sodium retention occurs only when a factor that produces decompensation is involved, for example, a liver function-dependent factor .The existence of peripheral vasodilation is an important predisposing factor for developing prerenal failure in rats with prehepatic portal hypertension. A factor that causes extreme underfilling of the arterial circulation and therefore renal hypoperfusion in this experimental model would favor the production of acute renal failure (preischemic state) . If so, In rats with prehepatic portal hypertension, the sum of the splanchnic  and extra-spanchnic (systemic) alterations allows for proposing a hypothetical portal hypertensive syndrome. During the evolution of this syndrome, the hemodynamic changes that play the leading roles in the early evolutive phases are replaced later by the metabolic alterations.Hyperdynamic splanchnic and systemic circulation are early hemodynamic alterations in this experimental model, and are associated with the development of portosystemic collateral circulation -50. HypeBoth objectives of hyperdynamic circulation could be considered the result of an ischemia-revascularization phenomenon, but a "masked" one since it essentially would produce oxidative and nitrosative stress related to the relative tissue hypoxia, and consequently hydration or swelling ,14. SincThis systemic inflammatory response progresses through the induction by oxidative stress to an acute response phase. Since in these initial phases of prehepatic portal hypertension, there is no significant degree of hepatic or intestinal failure, both organs are capable of carrying out an acute phase response that offers the suitable mediators for continuing the inflammatory response already underway and for regulating the enzymatic tissue stress associated with this phase ,148. TheThe chronicity of such inflammatory response is perhaps the fundamental factor so that more metabolic alterations progressively develop. And as a result, the body adapts to the new situation or state created by portal hypertension. Thus, in rats with prehepatic portal hypertension, tissue remodeling processes are established in the long-term by angiogenesis and fibrogenesis . One of Furthermore, the inflammatory response participates in all stages of prehepatic portal hypertension in the rat, not only during the initiation and first weeks of evolution, but also in the long-term stages. In this hypothetical situation, steatosis and dyslipidemia are thought to represent a common underlying factor of this syndrome, which features a chronic low-grade inflammatory state.This chronic inflammatory state in the rat with portal hypertension could have splanchnic origin. In early evolutive stages, an increase in Fractalkine is produced in the mesenteric lymph nodes, associated with increased intestinal CX3CL1 . FractalFKN could play a crucial role in the initiation and progression of inflammation in portal hypertensive rats. And so, the intestinal increase of CX3CL1, the unique receptor for FKN, is likely to be implicated in stimulating angiogenesis. FKN stimulates angiogenesis by activating the Raf-1/MEK/ERK and PI3K/Akt/eNOS/NO signal pathways via the G protein-coupled receptor CX3CR1 . By thisLiver disease could be the most frequent factor for decompensating portal hypertension. Particularly, chronic liver disease and cirrhosis aggravate the portal hypertensive syndrome exceedingly.4) [The most studied models of cirrhosis in the rat are those achieved by extrahepatic cholestasis ,158,159,4) ,160 or b4) ,161. Hep4) .Hepatic dysfunction related to fibrosis or cirrhosis in the rat would aggravate the grade of systemic inflammation characteristic of prehepatic portal hypertension and as a result would increase the incidence of complications. Consequently, the vascular dysfunction or hyperdynamic circulation with increased mesenteric blood flow would get worse ,164 and The disturbance of splanchnic blood flow may contribute to an impairment of the intestinal barrier function and thus bacterial translocation is produced  with incA decreased anti-oxidant capacity of the liver plays an important role in the pathogenesis of liver fibrosis or cirrhosis and portal hypertension -172. ThaIt is possible that another organ, like the endothelium, associated with the progressive reduction of the anti-oxidant capacity of the liver in the evolution of cirrhosis, tries to make up for the deficit. In this case, the objective of angiogenic systemic hyperactivity could be to reduce oxidative and enzymatic stress associated with inflammation .Mammals, along with other aerobic organisms, have evolved an array of mechanisms to protect themselves from the potential harmful effects of reactive oxygen species . OxidantMultiple enzymes expressed in vascular cells are involved, not only in the production but also in the elimination or scavenge of reactive oxygen species, including superoxide dismutases, catalase, thioredoxin reductase, glutathion, peroxidase, NAD(P)H oxidase, xanthine oxidase, myeloperoxidase and endothelial oxide synthase . Anti-oxIn the cirrhotic stage, the impaired modulation of vascular growth with deregulation of vascular remodeling is a pathophysiological mechanism that not only participates in the production of splanchnic alterations  but also in different systemic alterations  ,180,181.Angiogenesis associated with inflammation when the anti-oxidant capacity of the cirrhotic liver fails could also reflect the establishment of a substitute anti-oxidant mechanism, which would explain its excessive response and the extensive diffusion. The anti-oxidant, anti-enzymatic and anti-inflammatory properties of endothelium  allow foThe study of experimental prehepatic portal hypertension and its decompensation when associated with "hepatic failure" offers results that could be extrapolated with caution to the evolution of patients with chronic liver disease related to cirrhosis ,39. At t• Ischemia-revascularization phenotype, which has hemodynamic alterations and oxidative and nitrosative stress• Leukocytic phenotype with predominant enzymatic stress and acute phase inflammatory response.• Angiogenic phenotype, that evolves early, and whose objective is tissue remodelingSplanchnic venous stasis related to increased intrahepatic resistance could be the initiating factor of this phenotype. This would be the origin of reflex responses within the brain-splanchnic axis, mediated by the autonomic nervous system, the renin-angiotensin-aldosterone system and the hypothalamic-pituitary-adrenal axis ,41. The The hyperdynamic circulatory syndrome that is produced in chronic liver diseases has recently been called "Progressive Vasodilatory Syndrome" because vasodilation is the factor that brings about all the vascular changes and finally leads to the multi-organ involvement observed as a consequence of this hemodynamic change ,184.The mechanisms promoting vasodilation in the Progressive Vasodilatory Syndrome are complex ,184. HowIn polytraumatized patients, prolonged and severe hypotension are also the cause of vasodilatory shock  with relDuring the evolution of chronic hepatic disease, the factors that produce its decompensation and aggravate hypoxia ,190,191 The alterations associated with this phenotype have driven experts in chronic hepatic disease to support the inflammatory nature of this disease -195.The immune response underlying the expression of the leukocytic phenotype could also have a gastrointestinal origin. The gastrointestinal tract mucosa contains the largest reservoir of macrophages in the body. As effector cells, intestinal macrophages, together with mast cells ,87 are p1-anti-trypsin and α1-anti-chymotrypsin) and anti-bacterian (opsonization and trapping of micro-organisms and their products) properties [At the same time, a compensating response is produced through the induction of a systemic acute and chronic phase reaction, where the liver and intestine mainly participate -202. In operties .If this defense capacity of the Systemic Acute and Chronic Phase Reaction is overtaken, the intestine, as in the critically ill surgical patient, becomes an "undrained abscess" ,205 and Angiogenesis is defined as the growth of new vessels from preexisting ones . AlthougIn the initial phases of the inflammatory response, the new endothelial cells formed could have a function associated with anti-inflammatory effects. That is, with anti-oxidative and anti-enzymatic stress properties, favoring the resolution as well as the progression of the inflammation .Angiogenesis is essential for embryogenesis, tissue growth and tumorigenesis. Also, it is been found to be central to the progression of various chronic inflammatory conditions including chronic hepatic disease ,182,209.In chronic hepatic disease, endothelial proliferation could be associated with anti-inflammatory effects. In this hypothetical situation, endothelial growth would represent an ancient mechanism that the body uses to protect cellular structures against oxidative and enzymatic stress . This coAngiogenesis is critically dependent on the VEGF action, but VEGF also plays a critical role in macrophage recruitment and infiltration. Also, in concert with angiopoietin 1, VEGF may act to help maintain vascular integrity in adipose tissue in a paracrine manner . TherefoThis precarious balance between oxidative/enzymatic stress and anti-oxidant/anti-enzymatic abilities that could characterize chronic liver disease, is difficulty decompensated. Mainly the liver, due to its important anti-oxidant/anti-enzymatic capacity when suffering functional damage from fibrosis or cirrhosis, would aggravate the complications characteristic of portal hypertension and consequently, would increase morbidity and mortality .Factors that are secreted mainly from the liver counteract obesity and related insulin resistance, acting as endocrine signals in the peripheral tissues to regulate metabolic homeostasis . On the Angiogenesis participates actively in the remodeling process that cirrhotic patients suffer, in which macrocirculatory  and microcirculatory changes are produced in all tissues and organs of the body. Increasing the catabolism of glycogen, adipose fat and muscle proteins, the redistribution of materials for remodeling is achieved. In this organic restructuring, there could be more autophagic activity . AutophaThese three phenotypes, ischemia-revascularization, leukocytic and angiogenic, could represent the pathological functions that are predominantly expressed during the evolution of chronic liver disease. If the three phenotypes are compared to the three pathological systemic functions suggested to make up the systemic inflammatory response -15, it cHepatic fibrogenesis is the common result of injury to the liver. This process is progressive and leads to hepatic dysfunction. In particular, the incapacity of the liver to provide the body anti-oxidant factors when the organism returns to the metabolic stages characterized by a deficient use of oxygen (ischemia-revascularization phenotype) would prevent the progression of the inflammatory response and therefore would favor the persistence of the metabolic regression with progressive worsening of the mentioned complications .Since the phenotypes of chronic liver disease, like the phases described for post-traumatic inflammation -15 go fr2S) and glutathione [4, a prebiotic metabolite, and its relation to the ancient use of the electron acceptor N to reduce this gas to NH3 [The persistence in the expression of old metabolic states, linked to the deficient use of oxygen, could be associated with the accumulation of metabolites that in ancient evolutive states favored life. Today, some of these metabolic mechanisms are still used by fishes, amphibians and reptiles to survive the extremes of oxygen availability . And so,tathione  and the tathione ; the hyps to NH3 ; or the s to NH3 .The progressive specialization in the use of oxygen can be considered one of the pathways for understanding the successive metabolic stages that play leading roles in life on earth from its anaerobic origin through today. The hypothesis that atmospheric oxygen concentrations affected the timing of the evolution of cellular compartmentalization by constraining the size of domains necessary for communications across membranes has been suggested . This poIn summary, the pathology considered to be the expression of ancestral biochemical functional systems could support the information needed for better understanding how life evolved on earth, mainly involving five elements: hydrogen, carbon, nitrogen, sulfur and oxygen ,228.All the authors conceived, discussed, wrote and approved the manuscript.