The effective treatment of wounds remains a major global health challenge. Failure to heal or elongation of the wound healing process results in increased financial and social stress being placed on health institutions, care-givers, patients, and their families. The occurrence of various forms of wounds such as chronic and acute wounds, pressure ulcers, venous stasis ulcers, and diabetic ulcers has increased over the years in most countries, especially developed countries where life expectancy has been increasing over time and is accompanied by geriatric diseases. Acute and chronic, nonhealing wounds impose heavy financial and quality of life burdens on patients . ChronicMedicinal plants have been used in the management of various diseases since ancient time. It is estimated that about 70 to 80% of the world's population depends on medicines of plant origin for treatment of diseases. The use of medicinal plants in the management of acute and chronic wounds is common in most traditional medicine practices in the world. Based on this, many plants in the tropical and subtropical regions of the world have been screened for their wound healing activity. Yet there are still many medicinal plants that need to be screened in the search for newer, efficacious, and cost effective wound healing agents. This special issue provides the platform for bringing to the limelight recent efforts in this regards.This issue contains eight articles which focus on studies on the current trends for managing wounds and associated complications, newer natural products including animal products, and/or isolated compounds possessing wound healing activity. Aspilia africana (Asteraceae), a plant used in African traditional medicine to treat wounds. The authors reported that in vitro and in vivo investigations provided evidence of the wound healing properties of the plant's derived extracts and phytochemicals, including alkaloids, saponins, tannins, flavonoids, phenols, terpenoids, β-caryophyllene, germacrene D, α-pinene, carene, phytol, and linolenic acid. These phytoconstituents were linked with strong anti-inflammatory, antimicrobial, and antioxidant activity, all essential for wound healing. Specific activities of the extracts of A. africana and its constituents beneficial to wound healing were reported to include inhibitory effects on bleeding, enhancement of wound contraction, increases in the levels of basic fibroblast growth factor (BFGF) and platelet derived growth factor, and stimulation of haematological parameters like white and red blood cells.R. Komakech et al. presented a review on the wound healing potential of in vitro analysis were used to determine the antioxidant activity of listed extracts and compounds, warranting the use of alternative testing methods, including in vivo assays, for confirmation of observed effects. They also clamoured for identification of compounds responsible for the antioxidant activities and evaluation of wound healing properties of isolated compounds in applicable cases.M. Gulumian et al. reported on African herbal remedies with antioxidant activity as potential resource base for wound treatment in a form of a review article. This is based on the premises that excess free radicals have been linked with wound chronicity and antioxidant therapy facilitates wound healing. The review highlighted tests that have been used to assess antioxidant activities of African medicinal plant extracts; compounds isolated from African medicinal plant extracts with confirmed antioxidant activities; and crude extracts of African medicinal plants with confirmed antioxidant activities. The authors reported that either single assays or Ouratea fieldingiana (Ochnaceae) and investigated their possible antifungal, antioxidant, and anticholinesterase activities. The plant is popularly used in Brazilian folk medicine for wound healing and treatment of inflammation and infectious diseases. Amentoflavone and kaempferol 3-O-rutinoside were isolated, respectively, from the ethanol seeds and leaves extracts of the plant. The extracts and compounds were shown to possess antifungal activity against several Candida strains via inhibition of ergosterol biosynthesis, antioxidant, and anticholinesterase activities.J. E. T. do Nascimento identified and isolated the main chemical compounds present in extracts ofK. Xu et al. in a review article on plant-derived products for treatment of vascular intima hyperplasia (IH) described the different originating cells involved in vascular IH and highlighted the effect of different natural products on inhibiting abnormal cellular functions, such as vascular smooth muscle cells (VSMC) proliferation and migration. The review article covered diverse cells involved in vascular IH; antiproliferation, migration, and cellular functions of abnormal VSMCS as a target to decrease intimal hyperplasia; typical signal pathways involved in the growth and physiology of VSMCs in IH disease; different natural compounds being used for preventing neointimal formation; and selective inhibition of VSMCs versus vascular endothelial cells (VECs).In another review article, L. Tan et al. evaluated the clinical effective rate, safety, and financial cost of traditional Chinese medicine injections (TCMIs) in treating diabetic foot and ulcer wound healing. The findings from the study suggest that TCMIs are beneficial to patients with diabetic foot ulcers, increasing the clinical effective rate of conventional therapies, and eliciting better performance in safety and financial burden. The authors however suggested more rigorous designed randomized control trials (RCTs) with large sample size to provide more high-quality evidence to support the benefits of TCMIs in the treatment of various types of wounds. Centella asiatica (Apiaceae) extract in cream for the prevention of scar development of the split-thickness skin graft (STSG) donor site. A prospective randomized, controlled, double-blind trial was conducted on the Centella cream for scar improvement. The amelioration of hypertrophic scar by the extract cream was attributed to better pigmentation, improvement of objective measurements, and longer follow-up times.K. Jenwitheesuk et al. evaluated the efficacy ofM. Çalışır et al. investigated the effect of humic acid on the healing of excisional wounds in the palate of rats as a follow-up to previous demonstration of enhancement of cutaneous wound healing and antibacterial properties. The findings from the study showed that humic acid treatment enhanced the rate of wound closure and recovery. This provides a basis for the use of humic acid as an alternative in the treatment of oral wounds.In the last publication in this special issue, J. Kim et al. in a research article investigated the effect of tracheloside, a plant lignin, on keratinocyte proliferation using scratch wound healing and cell proliferation assays and western blot analysis based on the fact that cell migration and proliferation are important for proper wound healing after skin injury. In the study, it was demonstrated that tracheloside positively affects the proliferation of HaCaT keratinocyte cell line through the regulation of ERK1/2 phosphorylation. The authors concluded that tracheloside is a potential therapeutic candidate for promotion of wound healing.The high quality articles constitute authors located at affiliations and institutions from nine different countries and parts of the world. This special issue has extended the frontiers of knowledge in exploring the therapeutic application of natural products and/or isolated compounds in wound healing which accounts for significant morbidity and mortality worldwide. It has also provided the desired basis for future research in complementing and/or replacing existing therapeutic agents used in the treatment of wounds.


The connections linking neurons within and between cerebral cortical areas form a multiscale network for communication. We review recent work relating essential features of cortico-cortical connections, such as their existence and laminar origins and terminations, to fundamental structural parameters of cortical areas, such as their distance, similarity in cytoarchitecture, defined by lamination or neuronal density, and other macroscopic and microscopic structural features. These analyses demonstrate the presence of an architectonic type principle. Across species and cortices, the essential features of cortico-cortical connections vary consistently and strongly with the cytoarchitectonic similarity of cortical areas. By contrast, in multivariate analyses such relations were not found consistently for distance, similarity of cortical thickness, or cellular morphology. Gradients of laminar cortical differentiation, as reflected in overall neuronal density, also correspond to regional variations of cellular features, forming a spatially ordered natural axis of concerted architectonic and connectional changes across the cortical sheet. The robustness of findings across mammalian brains allows cross-species predictions of the existence and laminar patterns of projections, including estimates for the human brain that are not yet available experimentally. The architectonic type principle integrates cortical connectivity and architecture across scales, with implications for computational explorations of cortical physiology and developmental mechanisms. The mammalian cortex possesses multiple dimensions of organization, for instance, the connectional and the cytoarchitectonic dimension. Are there principles that link the different dimensions? Here we review an architectonic type principle that links cytoarchitectonic aspects of the cerebral cortex, such as neuron density or morphology across the cortical layers, to large-scale interregional cortical connection patterns. The reviewed findings highlight the existence of a natural axis of spatially ordered, concerted changes of multiple architectonic, connectional, and functional features stretching from less to more differentiated cortical areas. This framework comprises species-general, but also species-specific, principles of the organization of the mammalian, and particularly the primate, cerebral cortex and highlights potential developmental underpinnings as well as functional ramifications of such principles. The wiring of the cerebral cortex appears highly structured, but its precise organization is overwhelmingly difficult to discern. In particular, the large number of neural elements and the vast number of intricate interactions among them obscure potential regularities. A similar level of complexity exists in other aspects of brain organization, such as the diversity and distribution of different cell types  for cortico-cortical connections of the macaque monkey brain  was found to be inversely correlated to the area’s type or neuronal density, with less dense (low-type) areas having more connections than dense (high-type) areas .“The thinkers however to whom we are referring attempt to state the nature of the soul only: with regard to the nature of the body which is to receive the soul they determine nothing in particular. And thus, although every body seems to possess a distinctive form and character, they act as if it were possible for any soul to cloth itself in any body…” (


Preterm birth poses a global challenge with a continuously increasing disease burden during the last decades. Advances in understanding the etiopathogenesis did not lead to a reduction of prematurely born infants so far. A balanced development of the host microbiome in early life is key for the maturation of the immune system and many other physiological functions. With the tremendous progress in new diagnostic possibilities, the contribution of microbiota changes to preterm birth and the acute and long-term sequelae of prematurity have come into the research focus. This review summarizes the latest advances in the understanding of microbiomes in the amniotic cavity and the female lower genital tract and how changes in microbiota structures contribute to preterm delivery. The exhibition of these highly vulnerable infants to the hostile environment in the neonatal intensive care unit necessarily entails the rapid colonization with a nonbalanced microbiome in a situation where the organism is still very prone and at an early stage of development. The global research efforts to decipher pathologic changes will pave the way to new pre- and postnatal therapeutic concepts. Microbiomes comprise commensal, symbiotic, and pathogenic bacteria, fungi, and viruses, which form an ecological entity and interact with themselves and with their particular host. For a long time, it has been assumed that microbiota colonization is restricted to body surfaces like skin and the gastrointestinal tract. However, it became clear in the recent years that microorganisms reside in nearly every human tissue including the mammary glands, the ovaries, the uterus, and the placenta. Thus the human body is colonized by trillions of microbial inhabitants. They constitute a diverse and individually varying ecological community which in addition changes with age . In line Escherichia coli [The amniotic cavity has long been viewed as a sterile environment where the fetus is protected from the harmful external influences and threats. First reports emerged with the beginning of the new millennium, which questioned this hypothesis and described an intrauterine and placental microbial environment –4. With hia coli . As its hia coli . Lactobacillus strains without any negative impact on pregnancy outcomes. During pregnancy, microbial richness and diversity are reduced along with an increased bacterial load. At the same time, the prevalence of potential pathogens like microbial species of ureaplasma and mycoplasma is reduced. The taxonomic composition of the microbial community of the vagina remains stable during pregnancy with an increase of the microbial diversity before birth of the healthy infant at term. These data lead to the conclusion that the composition of the vaginal microbiota is tightly regulated during pregnancy and that the switch to the nonpregnant situation precedes and maybe even triggers birth [The vaginal microbiome resembles that of the cervix and is physiologically dominated by Lactobacillales, but Clostridiales, Bacteroidales, and Actinomycetales are also regularly detected. Bacterial community differences and shifts are almost exclusively detected between differentrs birth –13.Microbial diversity and orchestrated structural changes during early life are key features for a healthy microbiome. Ethnicity and regional differences have a key impact on the vaginal microbiota. It remains to be determined whether changes in the vaginal microbiome observed in Hispanic and black women account for the increased rate of preterm delivery in these ethnic groups –16. Bacteroides species, which display a delayed colonization pattern after caesarian section. Although microbiomes are principally able to adapt to that of the term infant within several weeks, the intrauterine and postnatal miscolonization poses a major threat to the health of the preterm infant [The fetus swallows huge amounts of amniotic fluid. This explains why its gut gets colonized with the intrauterine microflora already before birth. After birth, the infant gets rapidly colonized by maternal vaginal, gut, and skin microbiota. In the term infant, the mode of delivery either by vaginal birth or by caesarian section determines microbial diversity and whether the gut is primarily colonized by the maternal vaginal and fecal or the skin microbiota. These data are a first scientific indication that early events have a long-term health impact on microbiota structures –20. In cm infant –23. The  Streptococcus, E. coli, Gardnerella spp., Prevotella, Gonorrhea, Treponema, Chlamydia, Ureaplasma, and Mycoplasma as well as yeasts like Candida [The reasons for preterm labor comprise a multitude of different causes including maternal psychosocial distress, hormonal changes, uterine overdistension, cervical disease, vascular and maternal disorders, and breakdown of the maternal-fetal tolerance . Among t Candida , 36–38.  Chlamydia trachomatis infection, which predisposes for preterm birth, differ completely from that of healthy women with respect to microbial diversity. They display a change in microbial taxa away from Lactobacillus species to anaerobes [ Lactobacillus species that dominated cervical microbiota have a lower risk of invasion of the amniotic cavity and chorioamnionitis after premature rupture of membranes, the prevalence of Gardnerella and Sneathia increases the probability [In fact, the microbiome gets dominated by abundance of bacteria from the urogenital tract, the gut, and the oral cavity . This shnaerobes , 45. Whibability . Streptococcus, Porphyromonas, Filifactor, Campylobacter, and Fusobacterium represent species which were repetitively connected with preterm labor. The scientific data point out that gut microbiota constitute the third source for bacterial translocation and can cause amniotic infection and chorioamnionitis. Reduction in microbial diversity and changes in gut microbiota occur during pregnancy with a dominance of Proteobacteria and Acinetobacteria away from Bifidobacterium, Streptococcus, Clostridiales, and Bacteroides, which predisposes for preterm delivery and disease [ Enterobacter, Enterococcus, Photorhabdus, and Tannerella, which are known for their inflammatory, and potentially preterm birth inducing, properties [Microbiota from the oral cavity can equally induce chorioamnionitis, when they are translocated via the bloodstream or by sexual practices. Members of the genera disease –51. The operties , 52, 53.operties .Inflammatory diseases represent the biggest threat to the preterm infant and affect all organs, including the immature lung, cardiovascular system, immune system, brain, eye, and gastrointestinal tract, with acute and persistent consequences for the patient's health. Infection accounts for or aggravates acute respiratory distress, leakage, and arterial hypotension after birth. Simultaneously, all organs are at high risk for secondary complications including NEC, nosocomial infection, cerebral damage, retinopathy of prematurity, and endocrinological nonbalance. Infection promotes the establishment of BPD and somatic and developmental disorders .Antibiotic therapy is aimed at combating life-threatening pre- or postnatal infections with pathogenic microbiota, but they cannot reduce or prevent the concomitant inflammatory organ damage. So far, most pathomechanistic insights are available for the inflammatory damage to the immature lung and efficient therapeutic interventions are restricted to a very limited number of drugs. The reason for the so far unsuccessful establishment of effective therapeutic interventions is based on the complexity of the involved pathomechanisms. The complex interplay between different central pathways and persistent cell phenotype distortion after a one-time injury poses further obstacles that need to be bypassed to reach therapeutic efficiency –59. The  in utero and after birth was neglected until recently [ Lactobacillus species in the airways of infants with severe BPD was recapitulated in the murine animal model with major impact on the regulation of central lung signaling pathways [Bronchopulmonary dysplasia (BPD) is the chronic lung disease of the preterm infant leading to life-long limitations in lung function . On a parecently –63. Thisrecently . Reducedpathways –68. The In contrast to BPD, the important contribution of bacteria to the pathogenesis of necrotizing enterocolitis, which constitutes one of the most devastating morbidities of prematurity, is well established. NEC is considered to be a multifactorial disease. The inflammatory response of the gut to microorganisms is a central hypothesis of necrotizing enterocolitis pathogenesis , 70. The Bacteroides. In the preterm infant the presence of a large number of different genera including Anaerococcus, Aquabacterium, Bacillus, Bifidobacterium, Corynebacterium, Micrococcus, Oceanobacillus, Propionibacterium, Pseudomonas, Rothia, Sarcina, Sneathia, and Streptococcus has been described. As a general phenomenon, the gut microbiome of the preterm infant is dominated by Proteobacteria even when breast milk provision is assured and the appearance of Clostridium and Vellonella species is retarded [Postnatally, the gut gets colonized by Gram-positive and Gram-negative bacteria mostly with a facultative or strictly anaerobic metabolism. In the term infant the gut is dominated by Bifidobacteriales andretarded , 75–78. retarded . In this Escherichia coli and Candida albicans and hospital acquired microbial structures including Klebsiella, Enterobacter, and Acinetobacter species and Candida species other than Candida albicans [ Staphylococcus aureus, Escherichia coli, Shigella spp., Citrobacter spp., and Klebsiella spp. before the onset of clinical symptoms of necrotizing enterocolitis [A strong dominance of Gram-negative bacteria and a decrease in anaerobic bacteria are described before onset of clinical symptoms of necrotizing enterocolitis, but whether altered microbial structures predispose for necrotizing enterocolitis or are a consequence of gastrointestinal or immunologic immaturity remains an open question. The discrepancies in microbiome structures between the feces and samples obtained from the oral cavity or stomach and the impact of microbial dysbiosis of the upper gastrointestinal tract are awaiting further clarification. Presence of Gram-negative bacteria and staphylococci allows the conclusion of their acquisition from the NICU environment . Microbialbicans . Taken tocolitis , 82–85. Staphylococcus, Enterococcus, and several Enterobacteriaceae, while Bifidobacteria are infrequently detected. Reduction in microbial diversity with predominance of Staphylococci is again another feature predisposing for late-onset infection [Nosocomial infections pose a special risk to the premature infant. Due to the immaturity and immunologic incompetence of the immune system, the preterm infant is particularly vulnerable to nosocomial infections in the hostile environment of the neonatal intensive care unit , 86–90. nfection . Not surnfection , 101–103Taken together, the gut microbiome of the preterm infant is highly impacted by endogenous and environmental factors and maternal and postnatal therapeutic interventions which accounts for the high susceptibility for nosocomial infection . Bifidobacteria in the gut microbiome is associated with improved scores for mental development at 24 months [ Vice versa, it remains to be determined how impaired brain function impacts physiologic microbiota structures.Brain development and function undergo fundamental steps in the last trimester and in the first year of life. The physiologic steps of brain folding and the developmental steps of the brain connectome far outreach the increase in brain volume and highly impact functionality. Their functional importance can be derived from preterm infants with severe limitations in brain functions, which display tremendous alterations in these critical steps , 105. Mo4 months . Convinc4 months –117. The4 months –120. Thi4 months . Future 4 months . Vice ve Bifidobacteria and Lactobacillus species but also presence of species of the genera Staphylococcus, Streptococcus, Propionibacterium, Bacteroides, Rothia, Enterococcusi, and Pseudomonas [ Blautia, Clostridium, Collinsella and Veillonella species were detected in breast milk together with Coprococcus, Faecalibacterium, and Roseburia species, which were simultaneously isolated from the mothers' breast milk and stool. This allows the conclusion that additionally to the skin-gut axis a maternal gut-breast microbiome axis exists and that the infants' gut microbiome is shaped by the maternal gut microbiome [ Bifidobacterium to Enterococcus species. It is impacted by perinatal maternal antibiotic therapy with a decrease in Lactobacillus, Bifidobacterium, Staphylococcus, and Eubacterium species [ Bacteroides [Breast milk is the optimal nutrition of the preterm infant with respect to acute and long-term health, somatic growth, and psychomotor development. It is well established from studies in healthy newborn that the infant's microbiome is crucially promoted and shaped by the microbiota, anti-inflammatory and antioxidative properties, growth factors, hormonally active substances, and cytokines provided by breast milk feeding. Overall, physiologic gut microbiota establishment and enrichment are facilitated by breast milk . The matudomonas , 123–129crobiome , 131. Gu species . Formulateroides , 126. Interoides , 74. Lacteroides . In contteroides .The available data convincingly support the hypothesis that the pre- and postnatal microbiome contributes to premature delivery and to the acute sequelae in the preterm infant. Despite the tremendous scientific progress, we have just scratched the surface to understand the consequences of aberrant microbiota and their dynamic changes to disease initiation and progression. The current data convincingly highlight their impact on nosocomial infection and NEC, which constitute not only a tremendous disease burden to the preterm infant but more importantly entail life-long consequences and considerable lethality. Nonetheless, for most of the acute complications and short-term sequelae including pulmonary and cerebral problems a clear cause-relationship is still missing. It remains to be determined whether pathogenic microbiota also account for the distortion of long-term somatic and psychomotor development in preterm infants which did not suffer from severe acute complications like infection or cerebral hemorrhage. Therefore, comprehensive and long-term oriented research efforts are urgently needed to cover these important and clinically highly relevant aspects. A comprehensive and mechanistic understanding of the connection between microbial dysbiosis and disease initiation and progression will help to develop new therapeutic concepts aiming to control and restore physiologic microbial structures. Further important topics of research are to gain detailed knowledge on microbial structures and how to avoid of sample contamination and to enable the comparability of studies with respect to techniques and sample preparation . It remaThe successful implementation of postnatal probiotic therapy and further clinical guidelines raises hopes to reduce the maternal and fetal disease burden in the near future and to come to a targeted or even personalized medicine. Next steps can be derived from the observational studies and should include (1) the design of point-of-care techniques to determine microbial structures onsite and in real time to immediately identify the mother and infant at risk, (2) evaluation of the benefits of personalized medicine strategies of vaginal fluid or feces transplantation to the fetus and newborn, (3) the development of new strategies to detect bacterial infection with high prediction accuracy to avoid unnecessary and prolonged antibiotic therapy and subsequent microbial dysbiosis, and (4) to test more potent alternatives to current classical probiotics including mixtures of different bacterial strains and bacterial metabolites. Each of these areas poses tremendous challenges and opportunities to finally reduce the rates of prematurity and of the associated morbidities. Opening and reaching these new frontiers in perinatal science offer the opportunity to come closer to efficient prevention of preterm birth, which poses an ever greater global burden and challenge.


Cerebrovascular diseases pose a serious threat to human survival and quality of life and represent a major cause of human death and disability. Recently, the incidence of cerebrovascular diseases has increased yearly. Rapid and accurate diagnosis and evaluation of cerebrovascular diseases are of great importance to reduce the incidence, morbidity and mortality of cerebrovascular diseases. With the rapid development of medical ultrasound, the clinical relationship between ultrasound imaging technology and the diagnosis and treatment of cerebrovascular diseases has become increasingly close. Ultrasound techniques such as transcranial acoustic angiography, doppler energy imaging, three-dimensional craniocerebral imaging and ultrasound thrombolysis are novel and valuable techniques in the study of cerebrovascular diseases. In this review, we introduce some of the new ultrasound techniques from both published studies and ongoing trials that have been confirmed to be convenient and effective methods. However, additional evidence from future studies will be required before some of these techniques can be widely applied or recommended as alternatives. As our understanding of the pathogenesis of carotid atherosclerosis and stroke increases, the importance and necessity of carotid ultrasonography have become increasingly apparent in clinical practice. Carotid ultrasonography allows for the real-time dynamic monitoring of the vascular lumen and tunica intima, visual display of the hemodynamic changes in the carotid artery and accurate measurement of the degree of carotid artery stenosis   , 2 . InUltrasound techniques employed to examine and evaluate carotid artery lesions include the conventional B-mode ultrasound, color Doppler ultrasound, spectral Doppler ultrasound, vascular enhancement technology (VET), carotid plaque contrast agent enhancement, intravascular ultrasound (IVUS) and echo-tracking techniques.In clinical practice, high-frequency ultrasound is highly useful for examination of the carotid artery. Conventional two-dimensional   D DoppleWith the continuous development of ultrasound imaging technology and the increasing accumulation of clinical diagnostic experience   , carotiRapid and accurate diagnosis and evaluation of cerebrovascular diseases are important to reduce the incidence, morbidity and mortality of these conditions   , 25 . TTCD has been widely used in clinical practice. Due to its advantages, such as its non-invasiveness and facile operation, TCD has become increasingly important in the clinical diagnosis of ischemic cerebrovascular diseases in recent years   - 30 . HColor and power Doppler TCD were developed based on TCD. Although they exhibit certain improvements and enhancements over TCD, the phenomenon of “high energy overflow”, which is attributed to the thinness of the intracranial vasculature and conventional angle-dependence of ultrasound examinations, still greatly influences the diagnosis of cerebrovascular diseases   - 34 .Holscher et al. explored a novel ultrasound technique called tUSA   , which Stroke is closely related to intracranial arterial stenosis and occlusion   . 3D ultWith the rapid development of medical ultrasound, ultrasound imaging technology has become increasingly incorporated in clinical practice for the treatment of cerebrovascular diseases   - 40 . TUltrasound thrombolysis includes IVUS thrombolysis and ultrasound-assisted extracorporeal thrombolysis. In recent years, researchers have conducted many in vivo experiments, in vitro experiments and clinical trials on ultrasound thrombolysis   , 50 . TDespite the obvious advantages of ultrasound thrombolysis, the data available on its safety are limited   . FurtheCEUS is a non-invasive, fast, efficient, reproducible and apparently very sensitive imaging modality   - 57 . CCurrently, ultrasound technology is developing rapidly and is becoming involved in an increasing number of fields. The application of ultrasound has expanded from traditional diagnosis to treatment and has achieved remarkable results. As the number of patients with brain diseases has increased, cranial sonography techniques have advanced from simple morphological imaging to complex functional recovery and treatment. We believe that ultrasound technology has great potential and will be a promising method for the diagnosis and treatment of cerebrovascular diseases in the future.


The practice of diagnosis is fundamentally designed to orient treatment. In the case of early diagnosis for schizophrenia spectrum disorders (SSP) risk, the empirical base for such a practice is still young, and many clinical questions arise in the everyday clinical application of risk algorithms and ensuing therapeutic options. One of the key questions that we will focus on is the following: in cases of SSP where symptoms are successfully treated, why does residual social functioning impairment remain the most serious obstacle to remission and reinsertion in society? We will present the evidence suggesting that the roots of residual social functioning impairment may, in many cases, come from thwarted or arrested development in the specialization of social cognition during adolescence and early adulthood. We will review the evidence suggesting that both during the premorbid phase and clinical high-risk phase, attenuated psychotic symptoms may impede the maturation of key social cognitive processes, particularly the suite of reflective thinking processes coming under the term of mentalization. From this evidence base, we will adapt the staging model of SSP progression in function of our mentalization-informed model, tailored to provide a coherent framework of care addressing the key clinical needs at every stage of psychosis progression. In its short history, the topic of early diagnosis for clinical high-risk states to develop psychosis (CHR-P) has stirred both hope and controversy. Early diagnosis aiming to shorten the duration of untreated psychosis (DUP) proved valuable to improve outcome along the clinical course of schizophrenia spectrum disorders (SSP) . PoweredIn the past quarter of a century, research on the risk of developing schizophrenia spectrum and other SSPs [Diagnostic and Statistical Manual of Mental Disorders DSM-5)] has dramatically transformed our clinical and scientific approach to what Eugene Bleuler referred to as the « schizophrenias »  for individuals meeting the established criteria for CHR-P states a clear and structured perspective on the studies performed over the past 10 years , also poInterestingly, however, the available meta-analyses examining early treatment during CHR-P find no treatment superiority effects when comparing psychological vs neuroleptic medication, nor any superiority effect within the different psychological treatments under study , 25, 30.In many different domains of mental health treatment, a discrepancy can be observed between, on the one hand, an individual’s symptomatic improvement with treatment, and on the other hand, the same individual’s stability or worsening of adaptive functioning. In SSP, the functional outcome or global functioning beyond symptom severity represents the sum of several different but correlated domains, such as cognitive, role and social functioning. Further, several studies suggest that impairments in social functioning create the most disability in SSP. Conversely, the “symptom-disability gap” observed over the course of treatment is often portrayed in the treatment of SSP . This gaIn SSP, the issue of intact impairment of social functioning regardless of treatment also seems to apply to treatment for earlier stages of the disease, notably treatment for youth at CHR. In a recent meta-analysis of early interventions for youths at CHR for psychosis, Devoe et al. specifically examine the effect of preventive treatment on social functioning . The metmentalization, that is, the suite of social cognitive imaginative activity enabling the interpretation of behaviour in terms of intentional mental states  was reduced when participants demonstrated strong mentalizing skills , hintingIndeed among the therapeutic models adapted to focus on the early impairments in social cognition, Mentalization-Based Therapy (MBT) constitutes an integrative intervention first developed to address psychotherapeutic treatment for Borderline Personality Disorder (BPD), and more recently successfully adapted to psychological treatment for the most severe psychopathologies in adolescents and adults , 68. TheBroadly speaking, the clinical staging model is a trans-diagnostic heuristic approach aimed at understanding the neurobiological and environmental processes underpinning the onset and course of a disorder. Clinical staging, through integrating stage and timing with evolution of clinical phenotype, also allows interventions to be tested from a preventive standpoint in reducing the risk of progression and persistence of illness. The idea of a clinical staging approach for psychosis as a progressively intensive intervention model aimed at prevent/delay the transition to psychosis in CHR-P subjects has been firstly developed by McGorry and colleagues more than 10 years ago . This moIn accordance and as a consequence of the hypothesis that we formulated in the previous section, we propose a revised staging model, which is more focused on treating the progressive delay/impairment in social cognition  alongside the monitoring of potentially progressing psychotic (and others) symptoms. As showed in In We further attempt to integrate notions of primary and indicated selective prevention within the MBT-informed care plan. Referring again to Moving along in Overall, the mentalization-based approach to clinical staging of psychosis provides a coherent theoretical and clinical framework. This framework affords two key advantages: it provides a clinical intervention that is suited for both the psychotic related symptoms, but also the other psychiatric comorbidity issue that ultimately influence the severity of clinical outcome. Second, it provides a framework for training professionals that is applicable to a range of professionals who are susceptible to intervene at different stages of the progression of psychosis, from educators to general practitioners, as well as case managers, psychiatric nurses, psychologists and psychiatrists. The MBT model is based on the past 20 years of empirical research in child, adolescent and adult clinical interventions , 90. WitConsequently, the usefulness of MBT in these early stages should be tested empirically with pilot randomized single-blind superiority trials comparing the efficacy of the MBT model with TAU in CHR-P adolescent population on several targets. Indeed, such trials should test firstly the 1) acceptability and attrition rate of the MBT model. Secondly, the efficacy of MBT in improving 2) mentalization abilities and 3) social functioning in CHR-P patients indipendently to transition to psychosis should confirmed. Thirdly, the efficacy of MBT in reducing 3) severity of psychotic symptoms and 4) transition to psychosis rates should be investigated. As a fourth step, the presence of biological substrates of the effect of MBT such as stress hormones and brain function (f-MRI) should be investigated in order to confirm the validity and the specificity of the MBT model.In providing a mentalization-informed framework for the staging of CHR-P and transition to psychosis, we attempt to target a key problem in the treatment of SSP, namely, the symptom-disability gap in outcomes of treatment where individuals still suffer from poor social functioning. We argue that the roots of residual social functioning impairment may, in many cases, come from thwarted or arrested development in the specialization of social cognition during adolescence and early adulthood. Our approach is also pragmatic, and sensitive to the cases of “non-conversion” to psychosis, for which important clinical care is still needed. Much of the clinical practice in developmental psychopathology is performed under conditions of uncertainty as to the symptomatic evolution and clinical outcome of individuals seeking help. Further clinical research that integrate the principles of good practice in the respect of empirical evidence will further sculpt the tools and methods of early diagnosis and intervention, to provide the most adapted care plan sustaining the development of the individual while attempting to divert the negative impact of psychosis progression on the interpersonal and social functioning domains, which today represent the key obstacles to therapeutic success with psychosis.All three authors contributed to writing the manuscript.M.D. from the Swiss National Science Foundation (100019_159440).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.


Magnolia species. Studies of these phytochemicals using human HNSCC cell lines from different sub-sites have demonstrated significant protective effects against HNSCC in both in vitro and in vivo models. Treatment of human HNSCC cell lines with GSPs, (−)-epigallocatechin-3-gallate (EGCG), a polyphenolic component of green tea or honokiol reduced cell viability and induced apoptosis. These effects have been associated with inhibitory effects of the phytochemicals on the epidermal growth factor receptor (EGFR), and cell cycle regulatory proteins, as well as other major tumor-associated pathways. Similarly, the cell migration capacity of HNSCC cell lines was inhibited. Thus, GSPs, honokiol and EGCG appear to be promising bioactive phytochemicals for the management of head and neck cancer.Despite the development of more advanced medical therapies, cancer management remains a problem. Head and neck squamous cell carcinoma (HNSCC) is a particularly challenging malignancy and requires more effective treatment strategies and a reduction in the debilitating morbidities associated with the therapies. Phytochemicals have long been used in ancient systems of medicine, and non-toxic phytochemicals are being considered as new options for the effective management of cancer. Here, we discuss the growth inhibitory and anti-cell migratory actions of proanthocyanidins from grape seeds (GSPs), polyphenols in green tea and honokiol, derived from the  Head and neck squamous cell carcinoma (HNSCC) is diagnosed in >40,000 individuals in the United States each year and it is responsible for approximately 20,000 deaths annually ,2. Over Natural products obtained from plants, herbs and shrubs have been used for thousands of years in traditional systems of medicine, such as the Chinese, the Unani the Indian Ayurvedic systems of medicine. Bioactive components from members of the plant kingdom that are non-toxic at effective doses offer both promising new options for the development of effective chemotherapeutic or adjuvant therapy for conventional cytotoxic therapies and the development of chemopreventive approaches. Thus, considerable attention is being paid to analysis of the effects on HNSCC growth and cell invasion of those phytochemicals that have low toxicity. This article provides information on selected phytochemicals that have shown promising chemopreventive or chemotherapeutic effects on the growth of HNSCC cells and their migration.Two of the phytochemicals described in this review (grape seed proanthocyanidins and (−)-epigallocatechin-3-gallate) are polyphenols. Polyphenols are one of the largest and most ubiquitous groups of phytochemicals. They are subdivided according to their molecular structure, including the number of aromatic phenol rings and the structural elements that link these rings. The polyphenols, which includes phenolic acids, stilbenes, lignans and flavonoids, are ubiquitous in the human diet, with flavonoids and phenolic acids being the most common. The richest dietary sources of polyphenols are fresh fruits and vegetables (including legumes), green tea and red wine. In recent years, there has been a growing awareness of the possibility that a lower incidence of cancer in some populations may be associated with the consumption of certain nutrients and especially a diet rich in polyphenols.Systematic studies of the potential health benefits of naturally occurring polyphenols have included investigations of their protection against oxidative stress, inflammation, diabetes, cardiovascular disease, asthma, and aging, as well as their anti-cancer properties. The combination of their wide range of potential chemopreventive characteristics, their efficacy and their lower associated toxicity as compared to conventional therapeutic drugs has drawn particular interest. The intention of this article is to outline the anti-HNSCC effects of some promising phytochemicals, including polyphenols that have shown encouraging protective effects against the growth and metastasis of HNSCC based on in vitro studies and/or preclinical animal models. The phytochemicals reviewed are: (i) grape seed proanthocyanidins; (ii) honokiol; and (iii) (−)-epigallocatechin-3-gallate (EGCG), a major component of green tea polyphenols. The molecular structures of these agents are shown in Proanthocyanidins are widely distributed in fruits, vegetables, seeds, nuts, and bark and are found in some flowers. They are a class of phenolics that take the form of oligomers or polymers of polyhydroxy flavan-3-ol units, such as (+)-catechin and (−)-epicatechin monomers . Grapes Numerous studies have documented the anti-cancer activity of GSPs in various preclinical models ,29,30,31Inhibition of cell cycle progression in cancer cells has been identified as an effective strategy for the control of cancer growth ,34. In vThe induction of apoptosis is a tightly regulated and complex process. Induction of apoptosis of tumor cells can involve the upregulation of pro-apoptotic proteins and/or downregulation of anti-apoptotic proteins. Proteins in the Bcl-2 family can play a pivotal role in determination of the fate of the cells as they can either promote cell survival or promote apoptotic cell death depending on circumstance ,37. TreaAs described in the Introduction to this article, EGFR is overexpressed in most cases of HNSCC and its inhibition is considered as a promising therapeutic approach in head and neck cancer. The stimulation of EGFR in HNSCC results in cell proliferation, a reduction in apoptosis and increased tumor cell metastasis, and is associated with poor clinical outcome in this malignancy ,12,13. TThe in vitro cell culture models described above are a good system for preliminary screening of the effects of chemotherapeutic agents; however, testing in preclinical models is necessary to move the field forward. The outcomes of treatment must be verified in vivo using animal models prior to potential consideration of their application in humans. Thus, tumor xenograft models were used to further determine the anti-carcinogenic effects of GSPs. The GSPs were administered in the diet of the animals as this approach has proven effective in other types of cancers ,30,31,38The migration capacity or metastatic potential of HNSCC cells is a significant contributing factor to the high mortality rate of this malignancy as well as the difficulties associated with its treatment. As advances in surgical and medical therapies for HNSCC have resulted in only a modest improvement in the mortality rate ,4,5,6, eE-cadherin and certain cytokeratins, concomitant with the acquisition of mesenchymal phenotypes or biomarkers, e.g., vimentin, N-cadherin and fibronection. Treatment of OSC19 cells with GSPs resulted in not only the downregulation of mesenchymal biomarkers but also reactivation of epithelial biomarkers. This suggests that GSPs have the ability to reverse the EMT process in HNSCC cells and this reversal may be considered as one of the possible mechanisms through which GSPs inhibit the migratory potential of HNSCC cells. Notably, NF-κB, which has been identified as a target of HNSCC cells, as described above, has been identified as an important regulator of the EMT in cancer cells [The epithelial-mesenchymal transition (EMT) in cancer cells plays a major role in determining the metastatic potential of epithelial tumors. EMT can render tumor cells migratory and invasive through its effects on all involved stages, including invasion, intravasation and extravasation ,44. The er cells ,41,42.These data suggest that inhibition of the migratory potential of HNSCC cells by GSPs involves the: (i) inhibitory effect of GSPs on EGFR overexpression; (ii) inhibitory effect of GSPs on the activation of the ERK1/2 proteins and inactivation of NF-κB; and (iii) reversal of the EMT, as summarized in 18H18O2) is a biphenolic plant product that is isolated from the bark and leaves of plants of the Magnolia spp. Honokiol has been demonstrated to have anti-carcinogenic, anti-inflammatory, anti-oxidative, and anti-angiogenic effects as well as inhibitory effects on the malignant transformation of skin papillomas to carcinomas [Honokiol  are a popular beverage worldwide because of their characteristic aroma, flavor and health benefits [.Infusions of the leaves of the tea plant -containing drinking water for 6 months. At the termination of the experiment, liver specific enzymes/contents, such as aspartate aminotransferase and alkaline phosphatase were determined in the serum samples of mice using standard procedures. It was observed that there was no significant difference in the levels of these enzymes in the serum samples of GTPs-fed and non-GTPs-fed group of mice, suggesting the non-toxic effect of GTPs on liver after its long-term treatment . In contrast, Church et al. [w/w). Nanosuspensions were prepared by using bovine serum albumin and polyvinylpyrrolidone as stabilisers in a solvent precipitation-ultrasonication method. Honokiol nanosuspensions improved the oral bioavailability of honokiol in in vivo studies in rats. Intraperitoneal administration of honokiol nanosuspensions was found better than oral administration in terms of biodistribution of honokiol.The bioavailability and toxicity of therapeutic phytochemicals is an important issue in all investigations. It has been recognized that polymeric proanthocyanidins are not absorbed as such in the gut . Howeverh et al.  has repoh et al.  have devHNSCC is a challenging clinical problem and it has been recognized that there is a need to develop alternative options for the management of this malignancy and, especially, for prevention of the invasiveness of these tumors. Plant products and phytochemicals, which have been used for thousands of years, may provide novel leads. If, any phytochemical is non-toxic or less toxic than currently available therapeutic strategies and has adequate anti-cancer properties, they should be considered candidates for assessment of their therapeutic efficacy against HNSCC in humans. The current literature analysis summarizes the evidence demonstrating the effects of three promising phytochemicals, GSPs, honokiol and GTPs, in HNSCC. Notably, these phytochemicals, and in particular GSPs and GTPs, are already used routinely as a part of the human diet or as dietary supplements. As described in this communication, GSPs, GTPs/EGCG and honokiol inhibit the growth and cell migration abilities of HNSCC cells. Notably, they all target multiple molecular targets in a manner that is consistent with their anti-carcinogenic effects, as summarized in


Trypanosoma brucei, which causes human disease. The molecular details of VSG switching in T. brucei have been extensively studied over the last three decades, revealing in increasing detail the machinery and mechanisms by which VSG expression is controlled and altered. However, several key components of the models of T. brucei antigenic variation that have emerged have been challenged through recent discoveries. These discoveries include new appreciation of the importance of gene mosaics in generating huge levels of new VSG variants, the contributions of parasite development and body compartmentation in the host to the infection dynamics and, finally, potential differences in the strategies of antigenic variation and host infection used by the crucial livestock trypanosomes T. congolense and T. vivax. This review will discuss all these observations, which raise questions regarding how secure the existing models of trypanosome antigenic variation are. In addition, we will discuss the importance of continued mathematical modelling to understand the purpose of this widespread immune survival process.Many pathogens evade host immunity by periodically changing the proteins they express on their surface — a phenomenon termed antigenic variation. An extreme form of antigenic variation, based around switching the composition of a variant surface glycoprotein (VSG) coat, is exhibited by the African trypanosome  Neisseria, Borrelia, Anaplasma, Giardia, Plasmodium, Babesia and African trypanosomes  and the emergence of differentiation and tissue compartmentalisation having an influence on the infection dynamics, it is clear that we must continue to evaluate our mechanistic understanding of antigenic variation with mathematical modelling (Trypanosoma species. Finally, though antigenic variation is a strategy to maintain chronic infections, it is very likely that it is also needed to allow pathogens to counter the emergence of herd immunity and thereby infect pre-infected hosts. Innovative modelling of VSG switching is needed to make testable predictions regarding how antigenic variation operates at the cellular, within-host and between-host scales [Experimental analysis of antigenic variation is critical, but frequently focuses on aspects of mechanism and biology that are amenable to genetic perturbation. Given the huge size of the odelling , Q.5. Ont scales , and ultUnderstanding of the roles and mechanisms of mosaic VSG switching is incomplete.How infection dynamics and antigenic variation are shaped by density-dependent differentiation needs to be determined.The roles and impact of tissue compartmentalisation needs to be evaluated.Comparison must be made of antigenic variation in human and livestock trypanosomes.Continued modelling remains central to understanding antigenic variation.


Furthermore, progesterone has been reported to be implicated in critical developmental events, such as cell differentiation and neural circuits formation. This view is supported by the increase in progesterone synthesis observed during pregnancy in both the placenta and the fetal brain. In the present review, we will focus on progesterone actions during CNS development.Although progesterone is a steroid hormone mainly associated with female reproductive functions, such as uterine receptivity and maintenance of pregnancy, accumulating data have shown its physiological actions to extend to several non-reproductive functions in the central nervous system (CNS) both in males and females. In fact, progesterone is  Progesterone  is a sex steroid hormone classically associated with female reproductive functions, including sexual behavior, uterus preparation for embryo implantation and maintenance of pregnancy . Althougde novo from cholesterol as they express the enzymes responsible for its synthesis and metabolism  from the blood plasma, where it is transported as low-density lipoprotein (LDL) cholesterol and is internalized by receptor-mediated endocytosis in vesicles. These are then fused to lysosomes to allow the release of the free cholesterol form present in the cytoplasm  and starde novo by steroidogenic cells through the condensation of two molecules of acetyl-CoA, forming acetoacetyl-CoA which is successively converted into 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Thereafter, the HMG-CoA reductase enzyme converts HMG-CoA to mevalonate, which is used to produce the two cholesterol precursors, i.e., squalene and lanosterol, by the squalene synthase and lanosterol synthase enzymes, respectively  . This caThe progesterone synthesis presents a conserved pathway in the vertebrate species, which begins with the transport of accumulated cholesterol from the outer to the inner mitochondrial membranes by transporter proteins, such as the 18 kDa translocator protein (TSPO) and the steroidogenic acute regulatory protein (StAR) . ThereafGiven its lipophilic structure, the progesterone produced from steroidogenic tissues, including the gonads and the adrenal glands, can cross the blood–brain barrier to reach the CNS. Importantly, the enzymes necessary for the synthesis and metabolism of progesterone are also expressed in neuronal and glial lineages in the adult CNS, in a region and cell-dependent manner . HoweverProgesterone’s potential actions throughout development are supported by the high concentrations of the hormone during mammalian pregnancy in both the maternal and fetal circulation . For exade novo synthesis of progesterone within the developing CNS  in mice and at E10.5 in rats . This exSimilarly, 3β-HSD expression was detected in the CNS during prenatal and early postnatal development in several vertebrates, and particularly, in the mammal species. Interestingly, while 3β-HSD expression and activity were found to significantly increase throughout the brain right before birth and during the first postnatal days in rodents and sheep, without a marked sexual dimorphism, the cerebellum exhibits the highest production of progesterone within the CNS during neonatal life in rats . In thisWith regards to the enzymes involved in progesterone metabolism, the expression and activity of both the 5α-reductase and 3α-HSD were detected in the female and male fetal brain of guinea pig and sheep from the second half of the pregnancy and in late pregnancy in rodents. This leads to high concentrations of allopregnanolone in different brain regions in all the mentioned species during prenatal and the first postnatal days . MoreoveProgesterone is essential for the maintenance of pregnancy and its circulating levels in pregnant women increase between sixfold and eightfold when compared with non-pregnant subjects due to placental secretion . ExistinProgesterone regulates several reproductive and non-reproductive functions in vertebrates. Specifically, its action in its target cells is promoted by two central pathways, namely the classical and non-classical ones. The classical signaling pathway  involves progesterone crossing the plasma membrane due to its lipophilic structure and binding to its intracellular receptor (PR). This leads to the activation of the transcription factor, which dimerizes and translocates to the nucleus. There, it binds to specific DNA sequences  that are mainly located in the gene promoter regions, thus regulating their expression  Camacho.Although two PR isoforms  are encoded in the same gene, they have different transcription start sites, resulting in the PR-A being the N-terminal truncated form of the complete PR-B isoform . Both is2+-dependent protein kinase C (PKC), PI3K/Akt and ERK/MAPK pathway can be found  signaling pathway involves several molecular processes related to rapid cellular responses, ranging from minutes to a few hours after progesterone exposure. Examples include the PR ligand-independent activation by membrane-associated kinases, the activation of G protein-coupled membrane progesterone receptors , the stimulation of the progesterone receptor membrane components (PGRMC1/2) to enhance the activity of mPRs, and the modulation of the gamma-aminobutyric acid type A (GABA-A) receptors after the conversion into allopregnanolone  Follesa. In addibe found   as a model of demyelination. Progesterone treatment significantly enhanced myelination of axons (seen by MBP immunostaining) when compared to the non-treated cerebellar cultures and the PR knockout mice-derived cerebellar cultures  in the subcortical white matter of the offspring. Moreover, the blockage of progesterone and other steroid hormones flow from the maternal placenta to the fetus at mid-pregnancy decreases MBP expression in their fetal brain. In these experiments, PR expression is upregulated due to a reduction in progesterone levels, an effect which was found to be higher in females . Observacultures . The impcultures .Finally, progesterone was described to stimulate both OPC proliferation and oligodendrocyte differentiation in the adult CNS of rats, especially after demyelinating damage . This isNeurons and glial cells form complex functional networks implicated in several functions carried out by the CNS. Although the arrangement of these networks, usually referred to as neural circuits, varies according to the related function of each CNS region , the proin vivo when male newborn rats are treated with exogenous progesterone, as observed by electron microscopy  pathway of mice and rats, which projects from the midbrain ventral tegmental area (VTA) to the prefrontal cortex. In both species, PR expression is high during the first postnatal week and then declines in both genders. Administration of mifepristone during this postnatal period decreases both the tyrosine hydroxylase expression in the VTA and the dopaminergic innervation of the prelimbic prefrontal cortex , impairing cognitive behaviors later in adulthood . These dGiven the significant differences in PR expression in several brain regions between male and female vertebrates at critical stages of neurodevelopment progesterone was proposed to be involved in brain sexual differentiation.Differences in prenatal and postnatal PR expression between male and female rats are observed in sex dimorphic brain regions, such as the medial preoptic nucleus (MPN) of the preoptic area, the arcuate nucleus, and the paraventricular nucleus (PVN) of the hypothalamus. While the PR expression in these regions is detectable at the mRNA and protein levels in males from E18, it is only observed in females from P10 , 2007. SThe observed differences in PR expression indicate the existence of a period during neurodevelopment  in whichknockout male mice exhibit an impaired adult male sexual behavior  reported that mifepristone treatment at birth blocks the masculinization effect of testosterone in the total volume of the MPN, which is larger in males than in females . Consistbehavior . Interesbehavior , suggestbehavior  on sexuaGlutamate and GABA are the most abundant neurotransmitters in the CNS. Specifically, while glutamate is the major excitatory neurotransmitter, GABA is the main inhibitory one. Given that the CNS functionality relies on a crucial balance of neural excitation and inhibition , progestDuring neurodevelopment, fetal CNS progesterone and allopregnanolone levels was mainly found to increase at late stages of pregnancy in sheep . This fiWith regards to allopregnanolone, it is relevant to mention its effects as an anxiolytic and antidepressant drug for postpartum women and rodents , which ain vitro and in vivo studies. For example, progesterone has a significant role in the neurological recovery following brain and spinal cord traumatic or hypoxic-ischemic injury by reducing the oxidative damage, preserving mitochondrial functions and attenuating cell death  female and male rats, progesterone treatment was demonstrated to reduce neuronal cell death caused by oxygen/glucose deprivation. These protective effects were attenuated when the slice cultures were co-treated with mifepristone and finasteride, indicating that either progesterone itself or its metabolites exert neuroprotective effects during development . InteresTumorigenic processes are often observed from the developmental biology perspective, given that they frequently recapitulate molecular and cellular events carried out by stem cells that shape the organism during development. Cancer is considered as an abnormal reactivation of a developmental program, in which the tumor, and all its intracellular heterogeneity, can be visualized as a developing organ .in vitro demonstrated that progesterone present at the physiological levels (10 nM) increases the content of many proteins, including SRC-1/3, p-Akt, and p-Src  were reported to reduce GMB tumor growth in a xenograft mouse model by increasing apoptosis and inhibiting cell proliferation, which was accompanied by an improvement in the survival rate . These rProgesterone actions extend beyond the regulation of brain functions associated with reproduction. In fact, its physiological actions extend to several non-reproductive functions in the CNS of both male and female mammals from early prenatal life, by regulating the fundamental molecular and cellular processes underlying its proper development.Understanding the precise role of progesterone and other steroid hormones is relevant to the overall comprehension of the nervous system development and its subsequent normal functioning during life. Important clinical advances were made, including the implementation of progesterone treatment in pre-clinical phase 2 trials to assess its efficacy as a neuroprotector in patients with traumatic brain injury and the recent success in pre-clinical phase 3 trials to treat depression in postpartum women by using the analogous compounds of allopregnanolone .The study of sex steroid hormone actions during the development of the nervous system in the prenatal and early postnatal life is yet to be widely explored. Therefore, this field implies promising research that will provide us with a better understanding of the molecular and cellular processes underlying the mechanisms that shape this system. In fact, the knowledge of the mechanisms of action of sex hormones, including progesterone, is essential to fully understand the critical processes that occur in neurodevelopment . Once the precise involvement of sex hormones in neurodevelopment is known, this knowledge could be translated to attempting to reverse specific pathologies related to the cited processes during postnatal life. Understanding the mechanisms of progesterone and its metabolites, the types of cellular receptors that are activated, the signaling pathways involved, the regulated genes, and the cytokines secreted by the effects of these steroids in the nervous tissue, could be advantageous in clinical therapies to: (1) reduce premature infants’ CNS susceptibility to injury, which could in turn allow the normal behavioral and cognitive development of the infant; (2) optimize the therapeutic strategies that are already in use to alleviate the depression and anxiety symptoms seen in postpartum women; and (3) attenuate the damage in demyelinating lesions or diseases. Finally, the understanding of progesterone actions in brain tumors development may also be useful to elaborate more effective clinical approaches aimed at stopping the progression of such neoplasms in patients.Both authors have contributed equally to the elaboration of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The authors describe the case of a young woman who developed a clinical pictures resembling a septic shock-related multiple organ dysfunction syndrome a couple of months after having been diagnosed suffering from a hemophagocytic lymphohistiocytosis associated with an infectious mononucleosis. Despite the aggressive treatment, which included antibiotics, vasopressors, IV immunoglobulins, and the use of an extracorporeal device aimed to remove mediators released both during sepsis and the cytokine storm determined by the hemophagocytic lymphohistiocytosis, the patient died. At the autopsy, an extremely uncommon aggressive lymphoma of Epstein-Barr virus-positive T-lymphocytes with systemic involvement was discovered. Although most patients with infectious mononucleosis (IM) recover without major clinical sequelae, a number of harmful complications can occur, including hepatitis, splenic rupture, and hematological abnormalities ; among tIndependently of the underlying triggering cause(s) the differential diagnosis of secondary HLH is difficult and relies mainly on a high index of suspicion and a number of hematological and biochemical criteria basically derived from those used in the pediatric form which is mostly caused by genetic abnormalities , making Here we describe the case of a patient who developed a rapidly evolving MODS a couple of months after the occurrence of an IM complicated by HLH. Staph. aureus (MRSA) was isolated from the blood cultures and a septic shock-related MODS possibly in association with a cytokine storm caused by the HLH were hypothesized; the patient was intubated and mechanically ventilated and treated with IV vasopressors at incremental doses, IV vancomycin, meropenem, and caspofungin; the PICC was removed and replaced with a central venous catheter; as the patient remained unresponsive to the treatment, a Coupled Plasma Filtration and Adsorption treatment  that aimed at removing the inflammatory mediators was added to the RTT along with the IV administration of IgM and IgA-enriched IvIg . Despite this increasingly aggressive approach, the MODS further worsened and the patient died 18 hours after the ICU admission.A 24-year-old woman was admitted to the Department of Infectious Disease with fever  which was attributed to a relapse of a IM-HLH occurring about two months prior to the current hospitalization. At that time, the diagnosis of IM was confirmed by the presence of EBV DNA in the bloodstream and the diagnosis of HLH was suspected on the basis of the clinical findings such as persisting fever, the enlargement of the liver and the spleen as well as of blood abnormalities including pancytopenia, abnormally elevated values of ferritin (> 15.000 mcg/ml), triglycerides 789 mg/dl), and liver enzymes ; a bone marrow biopsy confirmed the presence of hemophagocytosis and viral RNA in many cells by means of in situ hybridization (EBER) [89 mg/dl,At the autopsy, the liver and the spleen appeared enlarged, weighting 3110 g and 1230 g, respectively. Microscopically, the spleen showed lymphocyte depletion and the scattered necrosis of Malpighi's follicles  combinedDifferent pathologic conditions, including macrophage activation syndrome (MAS), adult onset Still's disease (AOSD), catastrophic antiphospholipid syndrome (cAPS), and septic shock share a similar clinical presentation characterized by fever, arterial hypotension, and multisystem involvement due to the action of a number of inflammatory mediators . This ovThe autoptical findings demonstrated that the septic shock occurred concomitantly with an aggressive lymphoma with multiorgan involvement; actually, it is likely that long-term treatment with immunosuppressant agents, albeit indicated for the treatment of the HLH, may have determined the evolution of the underlying chronic active EBV infection towards the aggressive T-cell lymphoma with systemic involvement. This is an extremely uncommon finding, as the tropism of EBV for B-lymphocyte has been associated with B-cells cancers, including Burkitt, Hodgkin, and diffuse large cell lymphomas , 15; conThe occurrence of EBV infection-associated HLH and the prevention of its relapse consists in the prolonged administration of immunosuppressant agents possibly associated with bone-marrow transplantation. Similar to other conditions associated with the decrease of the immune capabilities, this treatment exposes the patients to infectious complications, including viral reactivation and overwhelming bacterial infections. The occurrence of aggressive hematologic cancers is uncommon but must be kept into consideration in patients with HLH admitted with conditions resembling septic shock.


Colorectal cancer is one of the most common cancers in the world, and it is one of the leading causes of cancer-related death. Despite recent progress in the development of screening programs and in the management of patients with colorectal cancer, there are still many gaps to fill, ranging from the prevention and early diagnosis to the determination of prognosis factors and treatment of metastatic disease, to establish a personalized approach. The genetic profile approach has been increasingly used in the decision-making process, especially in the choice of targeted therapies and in the prediction of drug response, but there are still few validated biomarkers of colorectal cancer for clinical practice. The discovery of non-invasive, sensitive, and specific biomarkers is an urgent need, and translational proteomics play a key role in this process, as they enable better comprehension of colorectal carcinogenesis, identification of potential markers, and subsequent validation. This review provides an overview of recent advances in the search for colorectal cancer biomarkers through proteomics studies according to biomarker function and clinical application. Colorectal cancer (CRC) is the third most commonly diagnosed cancer among adults and is the third leading cause of cancer-related death in the United States . Most coThe current gold standard screening strategy is through a colonoscopy. The guidelines recommend that individuals aged 45 years and older with an average risk of CRC undergo regular screening . HoweverTherefore, alternative cost-effective, non-invasive, easily measurable, and accurate screening procedures are urgently required for CRC screening. Thus, the clinical applications of biomarkers in CRC are not only needed for the early detection of the disease but are also essential for prognostic stratification, surveillance, and therapy selection  12–14).–14.12–14Recent progress in genomics, transcriptomics, proteomics, and metabolomics has expanded the number of candidate biomarkers and led to better comprehension of the progression of colorectal cancer as well as the identification of molecular signatures –22.Dysplastic and neoplastic tissues regulate the expression of proteins and generate protein profiles that may be associated with the progression of these lesions in many different and interacting signaling pathways . ProteomThis review aims to provide an overview of recent advances in mass spectrometry-based proteomics in the search for protein biomarkers of CRC with the potential for clinical application according to biomarker functions: diagnostic, predictive, or prognostic.A diagnostic biomarker can be defined as a biological characteristic that detects or suggests the presence of a disease or condition of interest or identifies an individual with a subtype of the disease .It is well-established that colorectal cancer screening strategies that lead to the identification and removal of adenomatous polyps and other premalignant lesions result in a decrease in CRC mortality . ColonosSome studies report the non-attendance rate of colonoscopies to be 10–20% after a positive fecal occult blood test , 30. TheNon-invasive methods such as fecal immunochemical tests, gFOBT, and stool DNA tests can be used for regular screening, but positive results should be followed up with timely colonoscopy . The curMany proteomic approaches have been used in the search for potential diagnostic biomarkers. Ghazanfar et al.  performeFormalin-fixed paraffin-embedded (FFPE) tissues can also be used in proteomics approaches, allowing access to archival samples, allowing usage of larger cohorts and more robust analyses, and optimizing the follow-up data of patients' clinical conditions. Quesada-Calvo et al.  analyzedBlood-based biomarkers are potentially the best matrices for early diagnosis and surveillance of colorectal cancer because the specimens can be obtained easily by a non-invasive method with minimal cost and risk , 39. IvaYu et al.  used magFan et al.  also conDespite the expansion of MS-based proteomics research and the large number of diagnostic biomarker candidates  present a dense Th1 lymphocytic infiltration and a cytokine-rich microenvironment that is related to the highly upregulated expression of multiple immune checkpoint proteins . UnfortuTherefore, a complete understanding of the response of the immune system to MSI-H is crucial to optimizing the immunotherapy approach. Some studies have demonstrated promising prognostic biomarkers, such as the expression of heat shock protein 110 and protein ß2-microglobulin, to stratify patients with MSI-H CRC according to prognosis , 59.In this scenario, the application of mass spectrometry-based immune-proteomic methods is a powerful tool in the search for overexpressed immunogenic proteins that could be new targets of immunotherapeutic development. Yang et al.  used masThe current treatment of locally advanced rectal cancer (stages II and III) is neoadjuvant chemoradiation followed by surgery . The maiThe predictive protein biomarkers face the same problem of slow translation to clinical application as the diagnostic biomarkers. A prognostic biomarker can be defined as a biological characteristic that gives information about the patient's overall cancer outcome, independent of therapy . The curThe main prognostic biomarker used in clinical practice is carcinoembryonic antigen (CEA), a high-molecular-weight glycoprotein expressed in embryonic tissue and colorectal malignancies. This antigen was discovered in 1965, but it remains the most widely used blood-based biomarker for CRC. Elevated levels are associated with cancer progression and can indicate recurrence after surgery. However, high CEA levels are not specific to CRC and can also be found in other malignancies and inflammatory conditions, such as inflammatory bowel disease, liver disease, and pancreatitis , 68.Recently, other parameters have been used to determine the prognosis. The effect of microsatellite instability (MSI) and BRAF mutation on survival in colorectal carcinoma was elucidated, and these genetic markers already have clinical applications . DespiteThe presence of metastases represents the main unfavorable prognostic factor in patients with colorectal cancer. The estimated 5-year survival for stage IV patients is ~8% . The majRecently, Kirana et al.  performeZhu et al.  used anoThe collagen proteins seem to be promising candidates as biomarkers in the metastatic scenario of colorectal cancer. A recent MS-based proteomic approach compared colorectal liver metastasis tissues with healthy adjacent liver tissues, demonstrating the upregulation of 19 of 22 collagen-α chains in colorectal liver metastasis tissue. Posterior validation with immunohistochemistry showed significant upregulation of collagen type XII in the metastatic context .Some studies have also demonstrated the possibility of detecting colorectal liver metastases through the identification of collagen peptides in urine , 76. UriThe determination of nodal status in CRC is another point that requires new candidate prognostic biomarkers. Lymph node involvement results in poor prognosis, reducing the 5-year survival rate from 70 to 80% in patients with node-negative disease to 30%−60% in those with node-positive disease . The curNon-invasive methods to predict the nodal status could improve the management of patients with colorectal cancer, guiding the indication of chemotherapy or the extension of the surgery. Mori et al. , in a reIn another study by the same group, iTRAQ was used in a comparative proteomics approach, demonstrating that a high level of ezrin protein was an independent predictor of lymph node metastasis in colorectal cancer . The ezrOne of the most concerning points in the postoperative follow-up of CRC is recurrence detection. After surgery with curative intent, 30–40% of the patients present locoregional recurrence or distant metastasis . RegardiThe expression of maspin was also described as a marker for early recurrence in stage IV colorectal cancer. Snoeren et al.  analyzedDespite the cited potential prognostic biomarkers , carcinoThe approach to patients with colorectal cancer has been dramatically updated recently thanks to a better understanding of the process of carcinogenesis and advances in the field of genetics. The determination of KRAS, BRAF, and MSI status has become an indispensable step in therapeutic planning, especially in patients with metastatic disease. Furthermore, the emergence of immunotherapy and the increasing use of liquid biopsies have extended the possibilities in the decision-making process toward personalized medicine. However, even with these advances, there is a lack of biomarkers that can guide the early diagnosis or the targeted treatment, prognosis, and surveillance of patients with colorectal cancer. Despite the improvements in MS technologies and the large number of proteomics-based studies to find biomarkers, this approach is not mainstream, especially regarding the management of colorectal cancer patients. This difficulty in translating protein markers into clinical practice is probably due to the small sample sizes of studies and to the heterogeneity in the processes of sample obtainment, preparation, and storage. These factors, coupled with complexities of data analysis and interpretation of proteomic approaches, result in poor reproducibility of the studies. However, the greatest limitation is related to the absence of validation of the possible biomarkers in large cohorts, comparing the data with the current methods of diagnosis, prediction, and prognosis. In this scenario, translational proteomics remains a powerful and promising tool for the discovery of biomarkers that can lead to important changes in the management of patients with colorectal cancer. Probably, the key to personalized medicine in colorectal cancer relies on studies that can integrate genomic, transcriptomic, and proteomic data, from a multiomics point of view, in the search for a biomarker panel that combines strong clinical data and accurate molecular findings.BA has contributed to the drafting, writing, conceptualizing, and final revision of the manuscript. GB and IC have contributed to the writing, organizing of data and tables, and reference revision. MM has contributed to early drafting, writing, and reference surveys. PO has contributed to the conceptualizing of the manuscript. AM has contributed to the conceptualizing, writing, final revision, and supervision of the manuscript. All authors approved the review final form.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.