This review provides a broad look on the recent investigations on the synthesis, characterization and physico-chemical properties of noble metal nanoparticles, mainly gold and silver nanoparticles, stabilized with ligands of different chemical nature. A comprehensive review of the available literature in this field may be far too large and only some selected representative examples will be reported here, together with some recent achievements from our group, that will be discussed in more detail. Many efforts in finding synthetic routes have been performed so far to achieve metal nanoparticles with well-defined size, morphology and stability in different environments, to match the large variety of applications that can be foreseen for these materials. In particular, the synthesis and stabilization of gold and silver nanoparticles together with their properties in different emerging fields of nanomedicine, optics and sensors are reviewed and briefly commented. Noble metal nanoparticles, whose average size falls in the range from some nanometers to micrometers, are considered, due their unusual optical properties, their size-dependent electrochemistry and their chemical stability , one of In particular, in recent years, the use of gold nanoparticles (AuNPs) in biomedicine garnered considerable attention for the potential to facilitate both the diagnosis and the treatment of cancer through their peculiar chemical and physical characteristics. One of the main properties that allows these particles to be employed in different biomedical applications is the scattering and absorption of light at resonant wavelengths. This phenomenon is known as due to the excitation of plasmon oscillations . The resonant wavelength depends on the size, shape and geometry of the nanostructures, thus providing important information and making them the model system of choice in a wide range of biomedical applications. For example, the study of interactions of gold nanoparticles with biomolecules and cells provides new tools for the diagnosis and treatment of cancer (theranostic) and drug delivery ,10, in pGold nanoparticles can be stabilized by many different ligands, whose chemical nature is generally chosen on the basis of the specific technological applications that are foreseen. Among the others, the most common method to synthesize AuNPs, is the liquid phase , becauseSince then, many other approaches have been proposed, performed in specific organic solvents or in the presence of different types of surfactants and other reducing agents. One of the most popular is the so-called two phases route of Shiffrin-Brust  a methodMore recently, many other groups have explored different methods in order to control size distribution. Among them, Natau et al.  proposedThe functionalization of AuNPs can be achieved in situ during the synthesis or through ligand-exchange reactions . DependiIn the last few years, a great number of ligands have been used for the stabilization of gold . Among them, we mention alcohols , phosphiHowever, one of the most convenient approaches that allows an accurate control on composition, shape and narrow size distribution consists of particle functionalization with thiols . Indeed,3+, Au+) since the available thiol concentration is less than the amount needed for the nanoparticle capping, while for ratios S/Au > 1/4, size is determined by the competition between passivation and growth of the nanoparticle (surface coverage).The size control together with the size distribution is a rather delicate process, being driven by the reactivity and passivation rate of the nanoparticles . For exaThe reaction mechanisms of the redox reaction have been recently studied in depth by different groups ,28,29 an2 to the benzene layer of Au(III) after phase transfer with tetraoctylammonium bromide (TOAB). Gaulet et al. [2 reduced Au(III) to Au(I) with no formation of a Te–Au bond [2]), soluble gold thiolate ([TOA][AuSRX] and [TOA][Au(SR)2]) are the precursors of the Shriffin-Brust reaction and that their relative contents depend on the concentration of reactants −, while for a positively charged Ag+ ion, such interaction becomes impossible. Nonetheless, the reduction process was widely applied in the preparation of organo-sols of metallic silver ) which was in situ deacylated to give the −SH derivative covalently bound to Ag. The structure of these nanoparticles was defined by high-resolution transmission electron microscopy (HR-TEM), selected area electron diffraction (SAED), synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS) and finally energy-dispersive X-ray diffraction (EDXD) analysis  [Antimicrobial activity against the model microbes es [DHC] . It is interesting to mention another bioinspired application. Wound healing can be enhanced by electrospun nanofibers that contain antibacterial silver nanoparticles. The nanofibers are made by a mussel-inspired copolymer, poly(dopamine methacrylamide-co-methyl methacrylate) (MADO), that uniformly attaches the AgNP at its surface, through the catecholic moiety of dopamine methacrylamide in polymeric backbone.2 containing atmosphere, like ambient air.In vitro and in vivo tests assessed the bioavailability and antimicrobial activity of MADO-AgNPs . Althoug2 (Ag/SiO2) and containing 50 wt % Ag were made by flame spray pyrolysis (FSP) of appropriate solutions of silver acetate and hexamethyldisiloxane. Nanosilver slowly dissolves and releases Ag+ ions in solution over a much longer period than the initial dissolution of any Ag2O layer on nanosilver, thus increasing the antibacterial efficacy, while enhancing the risk to environment by CO2 absorption in water suspension [AgNPs (size 7–30 nm) immobilized or supported on nanostructured SiOspension .This review gives an overview of the most recent achievements on gold and silver nanoparticles, which exhibit a variety of properties and applications depending on the kind of ligands that are their capping agents. The breakthroughs and perspectives range from biotechnology, nanomedicine, sensors and catalysis. It is well known that prerequisite for every possible application is the proper surface functionalization of the nanoparticles, which determines their interaction with the environment. The functionalization affects the size, shape, solubility, stability and assembly of both AuNPs and AgNPs. Therefore, the careful and proper choice of the nanoparticles ligands is the leading feature for the achievement of the desired application. Hydrophobic ligands are also suitable for biomedical purposes, often in combination with hydrophilic ones, especially in the case of AuNPs, giving nanoparticles that fulfil promising theranostic properties. AgNPs stabilized with hydrophobic ligands are also widely investigated for being effective growth inhibitors against various microorganisms and then to be used in medicine as well. Catalysis is also well addressed among the perspectives for silver nanoparticles use.Hydrophilic ligands for both Au and Ag nanostructures are preferred in case of therapeutic requests, because their water solubility allows the cells viability and circulation in blood vessels, in order to successfully reach target organs. Moreover, these ligands can be further functionalized with biomolecules such as drugs or antibodies, in order to match with the needs of fighting tumors or cancer.Finally, the applications of AuNPs and AgNPs in sensors have been only occasionally mentioned here because the choice of ligands is less crucial for the nanoparticle performance. However, these topics are also important features that need our attention.


The Editorial on the Research TopicTumor Hypoxia: Impact in Tumorigenesis, Diagnosis, Prognosis, and TherapeuticsHorsman and Vaupel. The stroma and tumor parenchyma coexist in a network of nutrients, growth factors, metabolites, acids, interstitial pressure, and other physiological agents . The temporal and spatial dynamics of those complex interactions, considered “abnormal and adverse” relative to conditions of normal tissues (Horsman and Vaupel), affect individual cancer cells, contribute to the natural selection of distinct clones, and establish aggressive tumors.A key to advance the rational design of better tools for cancer detection, prognosis, and therapeutics is to increase our knowledge of the tumor microenvironment. This concept is supported by a continuously growing volume of literature reviewed by Horsman and Vaupel). The abnormal and chaotic vasculature of growing solid tumors cannot provide proper delivery of oxygen to all tumor cells. Not only observed in solid tumors, but also in aggressive non-solid tumors as indicated by the Mazurier group , irregular oxygen supply is a crucial component of tumorigenesis. A yet unexplored field related to the involvement of the hypoxia pathway in tumorigenesis is its association with heritable cancer syndromes. Thus, the inactivating germline changes in tumor-suppressor genes belonging to DNA repair pathways are associated with an increased risk of carcinogenesis. Henegan and Gomez propose the hypoxia pathway can be linked to heritable cancer syndromes. Further exploration of this hypothesis may provide emergent concepts relevant for personalized stratification and treatment of tumors associated with germline mutations of genes associated with the hypoxia pathway.Among the multiple components of the tumor microenvironment with strong effects on tumor aggressiveness, tumor-associated hypoxia is a particularly relevant one . Aberrant in cancer, the ubiquitination cycle of HIFα is associated with disease progression and poor prognosis (Schober and Berra).Oxygen levels affect the cells largely by regulating activity of the transcription factor hypoxia-inducible factor (HIF). Regulation of HIFα subunits is complex. As noted by Mazure highlights the involvement of the voltage-dependent anion channel in cancer under the context of hypoxia. This channel, present in mitochondria, under hypoxia acts as a survival factor by promoting survival pathways in tumor cells and increased resistance to therapy agents (Mazure). These and other signaling molecules define a core for the response of cancer cells to varying oxygen conditions. Components of these networks adapt to low oxygen, play a critical role in tumor development, and offer a yet unexplored therapeutic potential.Other intracellular signaling mechanisms such as stress or redox response mechanisms constitute the hypoxia-activated gene expression program in tumors. For instance, the review from van Kuijk et al. provide the first comprehensive meta-analysis of the association between CAIX expression and treatment outcome in tumors. Patients having tumors with high CAIX expression have higher risk of locoregional failure and disease progression . The results of this study suggest that measuring CAIX expression can improve disease management, which in turn may decrease overtreatment and clinical relapse.Recently, tumor-associated hypoxia molecules have been identified as markers of poor prognosis. One example is carbonic anhydrase IX (CAIX), an enzyme involved in maintaining the cellular pH balance. Most of the studies, limited by low numbers of patients, were inconclusive. Espinoza et al. in their original research article, HURP expression in prostate tumors was associated with the increased expression of HIF-1α, vascular endothelial growth factor, and heat-shock protein 60, as well as increasing tumor grade. The data reinforce the relevance of hypoxia-related molecules as predictors of tumor aggressiveness, and propose a basis to further advance our understanding of the mechanistic role of hypoxia responsive molecules in therapy resistance.Due to the adaptation mechanisms of cancer cells to low oxygen, hypoxic tumors have reduced sensitivity to cytotoxic therapeutic agents. Hepatoma upregulated protein (HURP), a hypoxia-related molecule , conferrMcDonald et al.). Since pH regulation is particularly relevant for cancer stem cells in hostile microenvironments, inhibition of pH regulatory enzymes, such as CAIX and monocarboxylate transporters, may result in a reduced response to hypoxia . Remarkably hypoxia promotes various mechanisms of immunoevasion . A hypothesis that will need clinical validation can be proposed: use of checkpoint inhibitors to restore antitumor immunity in combination with inhibitors of pH regulation, in the context of hypoxia, may effectively target aggressive tumors.On the establishment of novel approaches targeting hypoxia-related targets, the Dedhar group proposes exploiting pH regulation in the hypoxic niche .Equally relevant for therapeutical development is the application of novel models to study the adaptation of cancer cells to low oxygen. Chronic myeloid leukemia and hepatoblastoma are suggested by On the success of any experimental drug targeting tumor hypoxia, the continued adaptability of tumors to their microenvironmental stresses must be considered. Tumor cells are endowed with a very high plasticity and capacity to adapt. It is our challenge to find populations and conditions of the tumor microenvironment germane for target success. Interdisciplinary work will be the key for achievement of these goals. Benefits include; increased understanding of the involvement of hypoxia in tumorigenesis, development of better biomarker development, and more effective therapeutics.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Azadirachta indica) active ingredients which exhibit agro-medicinal properties conferring insecticidal as well as immunomodulatory and anti-cancer properties. The most prominent constituent of neem is azadirachtin, which has been established as a pivotal insecticidal ingredient. It acts as an antifeedant, repellent, and repugnant agent and induces sterility in insects by preventing oviposition and interrupting sperm production in males. This review discusses, key neem pesticidal components, their active functional ingredients along with recent strategies on employing nanocarriers, to provide controlled release of the active ingredients and to improve their stability and sustainability.Over the years, extensive use of commercially available synthetic pesticides against phytophagous insects has led to their bioaccumulation in the environment causing increased resistance and reduction in soil biodiversity. Further, 90% of the applied pesticides enter the various environmental resources as a result of run-off, exposing the farmers as well as consumers of the agricultural produce to severe health issues. Therefore, growing attention has been given toward the development of alternate environmentally friendly pesticides/insecticides that would aid an efficient pest management system and also prevent chronic exposures leading to diseases. One such strategy is, the use of neem plant's (Binomial name:  Pesticides are chemical substances used in agricultural practices to aid the production and yield by repelling, preventing, and destroying pests  belonging to the Meliaceae family has emerged as a highly potent bio-pesticide , with a significant increase in the development time of the surviving adults. However, neither of the formulations caused any significant effect on the fecundity of the insects and the mortality rate was not immediate. Further, a non-target effect of neem treatments on the larval survival and development time of H. axyridis was observed, which requires further investigation  in 50 pathways. 920 and 9984 unique genes were found to be up and down regulated significantly. Such detailed gene profiling to assess the azadirachtin internalization with M. alternatus, can promote the development of efficient azadirachtin derived herbal pesticides . Molting hormones from prothoracic glands are responsible for controlling the formation of new cuticle, and play a central role in ecdysis. The formation of juvenile stages during each molt is controlled by the juvenile hormone from the corpora allata Nisbet, . DisruptTwo main active ingredients; Nimbolide B and Nimbic acid B also demonstrate herbicidal activity of neem. Their allelopathic and phytotoxic activity was observed in a study where they inhibited the growth of lettuce, crabgrass, alfalfa, jungle rice, and barnyard grass. The allelopathic activity increased with an increase in the concentration of active compounds, but the intensity varied with different species of weed , National Health and Medical Research Council (NHMRC) and Indian Council of Agricultural Research (ICAR) Ph.D. fellowship ID-29-1/2009-EQR/Edn (Pt.III), for financial support.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.


Oxidative stress is the result of the imbalance between reactive oxygen species (ROS) formation and enzymatic and nonenzymatic antioxidants. Biomarkers of oxidative stress are relevant in the evaluation of the disease status and of the health-enhancing effects of antioxidants. We aim to discuss the major methodological bias of methods used for the evaluation of oxidative stress in humans. There is a lack of consensus concerning the validation, standardization, and reproducibility of methods for the measurement of the following: (1) ROS in leukocytes and platelets by flow cytometry, (2) markers based on ROS-induced modifications of lipids, DNA, and proteins, (3) enzymatic players of redox status, and (4) total antioxidant capacity of human body fluids. It has been suggested that the bias of each method could be overcome by using indexes of oxidative stress that include more than one marker. However, the choice of the markers considered in the global index should be dictated by the aim of the study and its design, as well as by the clinical relevance in the selected subjects. In conclusion, the clinical significance of biomarkers of oxidative stress in humans must come from a critical analysis of the markers that should give an overall index of redox status in particular conditions. The redox equilibrium is important in preserving the correct functionality of cellular vital functions . Oxidati2•−) is mainly generated at the level of the mitochondrial electron transport chain and can be converted to hydrogen peroxide (H2O2) by SOD or undergo spontaneous dismutation . In particular, in the context of metabolic syndrome and chronic inflammation, the oxidized LDL (oxLDL) activate leukocytes and/or platelets to produce ROS and RNS . S. S129]. While measures of oxidative stress in spinal cord  and tissLipid oxidation end product determination is a widely used marker of oxidative stress.• and ROO•, which catalyze a hydrogen-atom subtraction at the unsaturated bonds generating a carbon radical that can further react with oxygen producing a lipid peroxyl radical. The chain reaction proceeds with lipid peroxyl radical acting as chain-carrying radicals and the formation of lipid hydroperoxydes. In the presence of transition metals, lipid hydroperoxides may generate lipid alkoxyl and ROO• as well as HO•, which can further sustain the chain oxidation reaction to produce short-chain oxidation products, including a variety of different aldehydes, alkanes, and alkenes. Malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE) represent the most investigated end product of lipid oxidation . F. F129]. The nonenzymatic antioxidant capacity (NEAC), also named total antioxidant capacity (TAC), is defined as the moles of oxidants neutralized by one liter of body fluids , 394–396581/591 as lipophilic fluorescence probe. The MeO-AMVN-C11-BODIPY581/591-based total antioxidant performance (TAP) assay was reported to be sensitive to plasma antioxidants localized in both the lipophilic and hydrophilic compartments [• reacts with the target compound resulting in changes of fluorescence or absorbance of probe , which is AAPH's lipophilic equivalent. Aldini et al.  monitoreartments . In all of probe .• via Fenton reaction [•+ or 2,2-diphenyl-1-picrylhydrazyl (DPPH), the target compound extracts an electron from the antioxidant and changes color , lag phase, or Stern-Volmer-like relation are used in order to measure the competition reaction and the standard antioxidant Trolox is used as reference . NEAC vareaction . In othees color . In theses color . The lates color . Similares color . Althouges color . Differeeglected , 406. Theglected , 422.Despite a correspondence between the effect on F2-IsoPs (the golden standard of oxidative stress) and NEAC has been reported in 67% (14/21) of the interventions with foods and in 77% (10/13) of the interventions with galenics  of humanIn order to avoid the UA interference, methods for UA independent NEAC have been proposed in both plasma and urine –430. In Although UA-independent NEAC could be a good approach also for salivary NEAC, it has been observed that salivary NEAC was affected by emotional and psychological factors . The latIn fact, sample type, collection, processing, and methodological limitation must be taken into account when measuring NEAC. Despite the fact that the use of a refrigerated microcentrifuge to rapidly prepare plasma could avoid any thermal stress and instability of antioxidants in biological samples , recent On the other hand, although NEAC of saliva or urine has led to increasing interest, due to simple and noninvasive collections, many factors could give spurious results. In particular, blood contamination, periodontal diseases, bacterial counts and flow rate must be evaluated in order to avoid misinterpretation of the results of salivary NEAC and normalize for dilution , 436. AlFrom the mentioned above limitations and potential confounding, it appears that a clear association between increase in NEAC and health benefit is difficult to evaluate , 406. ThA clinically useful biomarker, besides being correctly measured, must be diagnostic, have prognostic value, and correlate with the disease degree. It must also be reasonably stable, present in an easily accessible specimen, and its measurement should be cost-effective.In order to evaluate the redox status in particular conditions , ex vivo free-radical production and oxidative stress in body fluids are measured. These methods are used also in human intervention studies to associate the levels of ingested antioxidants (by foods or supplements) with improvement of the body antioxidant status. Despite the fact that it has been suggested that nutraceuticals are capable of improving health, significant methodological bias must be taken into account in the interpretation of data from the measurement of reactive species in leukocytes and platelets by flow cytometry, from the evaluation of markers based on ROS-induced modifications, from the assay of the enzymatic players of redox status, and from the measurement of the total antioxidant capacity of human body fluids.It has been suggested that the bias of each method could be overcome by the evaluation of oxidative stress by using more than one criterion , 404. InThe OXY-SCORE  was compThese scores are related to CVD, age, gender, and smoking habit –442. TheMore recently, a multiple factor analysis (MFA) that allows for simultaneous analysis of multiple parameters, classified according to their physiological meaning in athletes following strenuous endurance exercise, was applied . This inOn the other hand, in some diseases, the choice of the markers that must be considered in the global index should dictate the clinical relevance in the subjects selected. Condezo-Hoyos et al.  measuredIn conclusion, the clinical significance of biomarkers of oxidative stress in humans must come from a critical analysis of the markers that should be dictated by the study aim and design and should give overall an index of redox status in particular conditions.


Since the initial discovery of septin family GTPases, the understanding of their molecular organization and cellular roles keeps being refined. Septins have been involved in many physiological processes and the misregulation of specific septin gene expression has been implicated in diverse human pathologies, including neurological disorders and cancer. In this minireview, we focus on the importance of the subunit composition and subcellular localization of septins relevant to tumor initiation, progression, and metastasis. We especially underline the importance of septin polymer composition and of their association with the plasma membrane, actin, or microtubules in cell functions involved in cancer and in resistance to cancer therapies. Through their scaffolding role, their function in membrane compartmentalization or through their protective function against protein degradation, septins also emerge as critical organizers of membrane-associated proteins and of signaling pathways implicated in cancer-associated angiogenesis, apoptosis, polarity, migration, proliferation, and in metastasis. Also, the question as to which of the free monomers, hetero-oligomers, or filaments is the functional form of mammalian septins is raised and the control over their spatial and temporal localization is discussed. The increasing amount of crosstalks identified between septins and cellular signaling mediators reinforces the exciting possibility that septins could be new targets in anti-cancer therapies or in therapeutic strategies to limit drug resistance. In humans, 13 septin proteins have been identified, which can be clustered into four groups according to their gene structure homology , which involves the formation of cell protrusions and changes in the way cells interact with the extracellular matrix (ECM). Depletion of SEPT9 in various metastatic cancer cells allows the reversion of EMT and reduces cell spreading, migration and invasion , which do not only act during mitosis but also interfere with MT dynamics during the interphase. MT-associated septins by modulating the MT environment may therefore modulate MT-based activities. Several septins have been proposed to participate in cancer cell resistance to MTA. Low SEPT10 expression level would promote paclitaxel resistance  in breast cancer (Gonzalez et al., Although, septin roles in cancer have been largely documented, the understanding of how the spatial and temporal dynamics of septin subcellular localization is regulated remains to be fully addressed. As described above, some clues are emerging, as the incorporation of specific SEPT9 isoforms into oligomers was found to orient the final destination of septin filaments inside the cell. Other septins are also involved, as the SEPT5-containing complexes are enriched in the lamellipodia of squamous cell carcinoma DJM-1 cells, while complexes recovered along MTs exclude this septin (Mizutani et al., Drosophila embryos (Mavrakis et al., Besides filament composition, much remains to be learned about the potential roles of septin monomers vs. oligomers and vs. filaments. Indeed, while SEPT2, 7, and 11 are required at the early stages of cytokinesis, only the SEPT9 deletion impairs the final separation of daughter cells (Estey et al., Regarding cancer therapy or cell adaptation and resistance to chemotherapies, the direct targeting of septins could have many side effects. Nevertheless, septins have been proposed as molecular targets in solid tumors, where they are required for cytokinesis completion as opposed to hematopoietic cells (Menon et al., CP, LK, and AB designed and wrote the manuscript.This work was supported by INSERM and by Univ. Paris-Sud.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.


Microglial cells are thought to colonize the human cerebrum between the 4th and 24th gestational weeks. Rodent studies have demonstrated that these cells originate from yolk sac progenitors though it is not clear whether this directly pertains to human development. Our understanding of microglial cell dynamics in the developing human brain comes mostly from postmortem studies demonstrating that the beginning of microglial colonization precedes the appearance of the vasculature, the blood–brain barrier, astrogliogenesis, oligodendrogenesis, neurogenesis, migration, and myelination of the various brain areas. Furthermore, migrating microglial populations cluster by morphology and express differential markers within the developing brain and according to developmental age. With the advent of novel technologies such as RNA-sequencing in fresh human tissue, we are beginning to identify the molecular features of the adult microglial signature. However, this is may not extend to the much more dynamic and rapidly changing antenatal microglial population and this is further complicated by the scarcity of tissue resources. In this brief review, we first describe the various historic schools of thought that had debated the origin of microglial cells while examining the evidence supporting the various theories. We then proceed to examine the evidence we have accumulated on microglial dynamics in the developing human brain, present evidence from rodent studies on the functional role of microglia during development and finally identify limitations for the used approaches in human studies and highlight under investigated questions. Microglia are resident macrophages of the mammalian central nervous system (CNS) with a plethora of functions including innate immunity and neuroprotection , 2, synaIn 1899, Franz Nissl, a German neuropathologist, reported on the presence of rod-shaped cells in human brain cases of syphilitic paralysis, a severe neuropsychiatric condition characterized by eventual dramatic cerebral atrophy . This waIn vitro evidence of rodent neuroepithelial or astroglial cultures generating microglia supported this theory  progenitors appear prior to embryonic day 8 in the YS and generate the entire microglial adult population independently of any bone-marrow derived contribution -dependent manner before they acquire their identity as microglial cells upon invading the brain rudiment (+) and monocyte-associated markers (UCHM1+) with no detectable HLA-DR antigen, and the minority expressed class II (HLA-DR and -DP) and no RFD markers, alluding to the possibility of distinct signatures in these populations prior to BM development . In the cerebellum, its molecular and granular layers are apparent by the 12th gw . RamifieOverall, microglial cells enter the developing brain very early preceding neurogenesis, neuronal migration, and gliogenesis in the regional neuroepithelia , 91. As The early colonization of the developing brain by microglia antecedes neurogenesis, neuronal migration, and many other cellular processes  or histochemical markers (RCA-1) that do not offer the possibility to distinguish between microglial cells and macrophages. This is likely to be a challenge for the field as development is highly dynamic, and we do not have specific markers to distinguish between cell lineages. New methods are needed to help identify a possible developmental microglial signature in the like of RNA-sequencing and single cell sorting methods from embryonic/fetal human tissue. To the author’s knowledge, only one study has emerged on this topic (Postmortem studies on human tissue are invaluable for investigating the antigenic features and morphology of microglial cells across various developmental ages. The identified studies in this review give us a qualitative insight into microglial dynamics during development. However, there are multiple caveats. First, though the total number of cases investigated in each study varied between is topic . At presis topic , 10. QuaFinally, microglia feature as part of the pathophysiological signature of various neurodevelopmental disorders such as schizophrenia , intelleIn the past decade, the field of study of microglia has rapidly expanded, and although rodent studies provide the opportunity to investigate how these cells populate the brain, develop, and proliferate, studies on the developing human brain are needed, particularly as the human and rodent adult brains have different microglial signatures and regional distributions. It remains unclear how these differences contribute to function and further studies correlating anatomy with function are needed.DAM and DG-N conceived the structure and content of the manuscript. DAM wrote the manuscript and prepared the figures. DAM and DG-N drafted 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.


Acute Myeloid Leukemia (AML) in pediatric patients is a serious disease, although, for the subgroup of patients who receive proper treatment, a long-term survival rate above 50% is typical. The cycles of chemo- and radiotherapy used to treat AML can impair dental development.Herein, we describe the oral condition of a 25-year-old male patient treated for AML with chemo- and radiotherapy from 5 to 7 years of age; his AML has remained in remission for the past 18 years. He had lost only one permanent tooth, but the remaining teeth demonstrated serious deformations and radicular hypoplasia. Two teeth required immediate extraction and subsequent replacement by implant-supported crowns. We found that the decayed, missing, filled teeth (DMFT) index was not representative of the real oral condition. Here, we report the full case and provide a brief review of the literature.Antitumor treatment of pediatric leukemia can induce total impairment of dental development and function. These adverse effects may become clinically evident many years after the resolution of cancer, and can be significantly detrimental to the patient’s quality of life. Erythroblast reduction leads to strain, anemia, pallor and tiredness; granulocyte reduction allows persistent infection and fever and platelet reduction produces petechiae, ecchymosis and spontaneous bleeding. Leukemic cells can invade the spleen, lymph nodes, central nervous system, and the gingiva, and sometimes induce bone pain and arthralgia .The leukemias are the most frequent form of pediatric cancer, representing 27% of the malignant pathologies in the USA. Acute leukemia takes on two different forms: Acute Lymphoblastic Leukemia (ALL), which represents 21% of malignant tumors, and Acute Myeloid Leukemia (AML), which represents 5% . The incvia chemo- and radiotherapy [Acute leukemia is treated otherapy . The prootherapy -8. Thoseotherapy , 9-11.Oral signs of leukemia appear precociously in two-thirds of all patients. Although not specific, signs that should alert physicians include the simultaneous presence of different lesions, the absence of pathogenic noxae, and the timing of and size at onset . The mosThe effects of chemo and radiotherapy on the orofacial area depend on the age of the patient at the beginning of treatment and the chronic irradiation dose . Dental 2In February 2016, a male patient, 25 years of age, came to the Dental Service of the Department of Clinical Surgical, Diagnostic and Pediatric Sciences of University of Pavia, reporting dental mobility and pain in the superior second premolar on the right side.After a complete anamnesis, the first clinical examination showed moderate-to-severe dental mobility in all teeth except for the maxillary and mandibular first molars.1).At this point, a panoramic radiograph was acquired . Reduced lacrimal secretion; Minor restrictive dysventilation syndrome secondary to the GVHD. Hyperplastic thyroid nodules caused by the treatment received.Because of the risk from the thyroid nodules, the patient underwent a total thyroidectomy in May 2009, and is currently on levothyroxine for the subclinical hypothyroidism and Testoviron® for the treatment of hypogonadotropic hypogonadism.Clinically, the dental crowns presented with normal dimensions and calcification. Upon our examination, though, all his present teeth showed anomalies in radicular shape, such that the roots were decapitated and seriously hypoplastic. We did not know if the current radicular conformation was present at the end of his anti-neoplastic therapy, or if it changed into the current conformation afterward. The second superior premolar on the left side self-exfoliated without clinical intervention.The patient presented with a Decayed Missing Filled Teeth (DMFT) index of 39.29%. When including the number of dental elements affected by aberrations, and not only DMF scores, the percentage increased to 100%. The two lateral incisors were missing because of agenesis, as opposed to extraction.The two premolars on the superior right side were extracted; however, it is likely that in a short time, the patient will require further dental treatment related to dental damage by the previous anti-neoplastic therapy.2), two screw-type implants , Italy) with an etched and sandblasted surface were placed via a conventional submerged surgical technique [3). Stitches were removed after 14 days and during healing, no adverse event occurred.Three months after dental extraction . The patient followed a strict protocol of oral hygiene [6). No sign of peri-implant soft tissue inflammation was present. Written informed consent to use the patient’s data was obtained. Patient’s data were reported anonymously.Three months after placement of the implants, a second surgery was conducted and routine prosthetic procedures were performed to finally fix the crowns for rehabilitation . He also underwent a conditioning regimen of busulphan, cyclophosphamide, and melphalan, three alkylating agents potentially capable of killing dormant preleukemic stem cells . The oriAll of the patient’s teeth presented with radicular shape anomalies, demonstrating decapitation and severe hypoplasticity. As mentioned above, we do not know if the radicular conformation observed at our examination remained unchanged since the time his teeth developed, or if it changed following a radicular reabsorption occurring after the complete formation of roots. The inferior incisors and first molars were the teeth that presented with the least radicular shape alterations; the roots had developed for over half of their regular length. Notably, those are the first permanent teeth to erupt, so it is likely that their roots were almost completely formed at the moment of the pathogenic insult. The canines and central superior incisors showed roots shorter than half their usual length. All of his premolars presented with only a hint of the roots, and the second molars demonstrated no radicular portion, and they were retained. The wisdom teeth were not visible. The severity of the dental-facial anomalies caused by anti-neoplastic treatment is linked to the age of the patient at the start of the treatment and to the administration of cranial radiotherapy .The literature reports that children treated before the age of 5, presented with the most serious dental anomalies, because underdeveloped teeth have a higher risk of developing deformities compared to the already developed ones. Chemotherapy without cranial irradiation causes less dental aberrations. The effects of radiotherapy on dental development are well documented: doses of 2000-4000 cGy induce dental or radicular hypoplasia, radicular reabsorption, microdontia, or abnormal radicular morphology. Radiotherapy administered before morphodifferentiation and calcification can prematurely halt tooth germ development. In the later development phases, dental aberrations and developmental terminations have been reported [i.e. before radiotherapy. In this situation, the DMFT index does not seem to be informative, since it is related to clinical and not radiographic aspects; this leads to an underestimation of the severity of the dental situation. We feel that the long-term side effects of anti-neoplastic treatment on dental health should be taken into consideration by the Italian legislature for the evaluation of handicap status.Even though in this case the patient was treated for AML after the age of 5, the long-term side effects of the chemo and/or radiotherapy caused anomalies in all his permanent teeth that, although they are still mostly present in the oral cavity, showed such compromising anomalies as to demand extraction and the precocious loss of teeth. Due to the development stage of incisors, probably the inhibition of dental growth occurred around the age of six years, Dental long-term effects of anti-neoplastic therapy in childhood are poorly reported . FrequenImplant therapy is a good treatment option  in healtWe treated a 25-years old male patient treated with chemo- and radiotherapy for AML 18 years prior to his dental examination in our clinic, during the development of his permanent teeth. The repeated anti-neoplastic therapies cured the AML, but induced long-term adverse effects that caused complete impairment of the development of his permanent teeth, and the premature loss of several of them.Those issues, because of their gravity and the early manifestation, greatly compromised the patient’s quality of life.Not applicable.Not applicable.Written informed consent to use the patient’s data was obtained. Patient’s data were reported anonymously.


Individuals who did not consume fresh fruits and vegetables daily had more than double the risk of HNC compared to those with daily intake of vegetables and fruits . The results of the current study supported an inverse association between the consumption of fresh vegetables and fruits and HNC risk. In addition to cessation of cigarette smoking and betel quid chewing and reduction of alcohol drinking, a public health campaign for preventing the occurrence of HNC should promote a healthy diet that contains plenty of fresh vegetables and fruits.Most studies reporting an inverse association between the consumption of vegetables and fruits and head and neck cancer (HNC) risk were conducted in Western populations and only a few included East Asians. The current case-control study investigated the association between diet and HNC risk using data of 838 HNC cases and 998 controls from a case-control study of HNC conducted in Taiwan. Each participant was asked about their consumption of fresh vegetables, pickled vegetables, fresh fruits, citrus fruits, meat, processed meat, fish, egg, and dairy products. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with each food category, adjusted for sex, age, education, and use of alcohol, betel quid and cigarette. An inverse association was observed between HNC risk and daily intake of fresh vegetables (OR = 0.44, 95% CI: 0.20-0.95,  HNC is Most studies published to date on the role of diet in HNC risk focused on Western populations and only a few originated from East Asian countries. Compared with a Western diet, the Asian diet tends to contain more vegetables and fruits and less meat. Although Taiwan has experienced westernization of lifestyle in recent decades, according to the 1993-1996 and 2005-2008 Nutrition and Heath Surveys in Taiwan (NAHSIT), Taiwanese people increased their consumption of vegetables and fruits, soy products, fish, whole grain, nuts and seeds, while decreasing the consumption of red meat, carbohydrates, and sodium-containing foods, and the intake of dairy products has remained low . Given tThe aim of the current study was to investigate the association between diet and HNC using data from an ongoing hospital-based case-control study of HNC in Taiwan. In addition, we examined whether the relationship between diet and HNC risk might differ according to the use of alcohol, betel quid, and cigarette.p > 0.05) in mean age and distribution of sex (Table p < 0.0001), with 65% of the controls having completed at least a high school education vs. 43% of the cases. More HNC cases were users of alcohol, betel quid, or cigarette compared to the controls (p < 0.0001).HNC cases and controls were not significantly different , whereas those who only had daily intake of fresh fruits did not have a significant increase in HNC risk  (Table p-heterogeneity > 0.05) by the use of alcohol, betel quid, or cigarette  and fruits  was associated with a reduced HNC risk [Consistent with results from published studies , the curHNC risk . AnotherHNC risk . Our resOur results showed that the highest HNC risk occurred among individuals who had neither daily intake of vegetables nor daily intake of fruits. For those who had only daily intake of vegetables but no daily intake of fruits, their risk of HNC was lower than those who had neither daily intake of vegetables nor daily intake of fruits , but was higher than those who had both daily intake of fruits and vegetables . This suggests that daily intake of fruits and daily intake of vegetables are both necessary to achieve the maximum benefit to reduce the risk of HNC.Our analyses showed that the inverse association between consumption of fresh fruits and vegetables and HNC risk was not significantly different by the use of alcohol, betel quid, or cigarette. The pooled analysis by Chuang et al. also reported that the reduced risk of HNC associated with consumption of vegetables and fruits was not affected by the status of tobacco use or the intensity of alcohol consumption . In a caIn our analysis, we found a significant association between consumption of egg and pharyngeal cancer. Due to the smaller number in the analysis stratified by HNC subsite, we could not rule out chance for this result. The inverse association between HNC and egg has been reported by other studies. Butler et al. reported a reduced HNC risk associated with egg consumption, particularly among non-smokers . Chen etProcessed meat, which is classified by the International Agency for Research on Cancer as “carcinogenic to humans” , has beeThis study has several limitations. First, the study participants were asked to recall their dietary habits in the year prior to the diagnosis of HNC or before the interview date (for controls). This might have introduced reverse-causality if the development of HNC had forced HNC patients to change their dietary habits. However, this short time-frame for recalling dietary habits had the advantage of reducing recall errors. Second, recall bias could be an issue in a case-control study because case subjects are often likely to ruminate more heavily on their past exposures that might cause their disease. As a result, recall bias could have biased our results away from the null and overestimated the association between diet (particularly consumption of vegetables and fruits) and HNC. However, because of public health campaigns, Taiwanese are more aware of the association between HNC and use of alcohol, betel quid, and cigarette, and less aware of the role of diet in the development of HNC. Therefore, recall bias in the association between diet and HNC is less likely in our study. Another limitation is that we asked about diet in broad categories instead of using a food frequency questionnaire with individual food items. The diet questions that we asked are a component of a comprehensive questionnaire that also surveys other exposure factors. To keep the interview at a reasonable length to minimize disruption to patients’ hospital visits, we could only ask a limited number of questions on diet. Finally, information bias is another limitation because the dietary questionnaire we used was not validated. Consequently, the risk estimates generated by our study might be imprecise and might only reflect a general trend for the association between diet and HNC risk.The major strength of the current study is that it provides important data for the role of diet in the risk of HNC in an East Asian population. The majority of the studies published to date on the association between diet and HNC were conducted in Western populations. Given the difference in dietary patterns, it is important to investigate the relationship between diet and HNC in different ethnic populations. Our results provide additional evidence to suggest that consumption of vegetables and fruits is beneficial in reducing HNC risk not only for Western populations but also for Taiwanese. Another strength of the current study is that we collected detailed data on the use of alcohol, betel quid, and cigarette, which are the three major risk factors of HNC. With this information, we were able to show that even after adjusting for alcohol, betel quid, and cigarette, consumption of fresh vegetables and fruits was still significantly associated with a reduced HNC risk. In addition, we were able to show that the inverse association between intake of fresh vegetables and fruits and HNC did not differ according to the status of alcohol, betel quid, or cigarette use. This suggests that consumption of vegetables and fruits might be beneficial in reducing HNC risk even for users of alcohol, betel quid, and cigarette.In conclusion, the results of the current study supported an inverse association between consumption of fresh vegetables and fruits and HNC risk. In addition to cessation of cigarette smoking and betel quid chewing and reduction of alcohol drinking, a public health campaign for preventing the occurrence of HNC should also promote a healthy diet that contains plenty of fresh vegetables and fruits.The current study received an approval from the institutional review boards of the National Health Research Institutes and the National Cheng Kung University Hospital. Signed informed consent was obtained from each study participant.The current analysis included data from an ongoing HNC case-control study that started subject recruitment on September 1, 2010 in the Department of Otolaryngology and the Department of Stomatology at the National Cheng Kung University Hospital. Eligible cases included individuals who were diagnosed with pathologically confirmed squamous cell carcinoma of the head and neck, including cancers of the oral cavity, oropharynx, hypopharynx, and larynx , had no history of any cancer diagnosis, were aged 20 years or older, and were able to provide informed consent. To compare the experience of risk factor exposure, controls frequency-matched to cases on sex- and age (±5 years) were recruited. Eligible controls were those who received surgery for non-cancerous conditions that are not associated with the use of alcohol, betel quid and cigarette, had no history of cancer diagnosis, and were aged 20 years or older.A trained interviewer interviewed each study participant using a standardized questionnaire to collect information on dietary habits in the past year before the diagnosis of HNC for the case subjects or before the interview date for the control subjects. Each subject was asked about the frequency of consumption  for four plant-based food categories  and five animal-based food categories . Data on potential confounders, including consumption of alcohol, betel quid, and cigarette, were also collected.To compare the distributions of demographic characteristics  and lifestyle factors  between cases and controls, T-tests (for continuous variables) and chi-squared tests  were performed.The association between each food category and HNC risk was evaluated by an OR and 95% CI calculated using unconditional logistic regression, adjusted for sex, age, educational level, alcohol drinking (frequency), betel quid chewing (pack-years), and cigarette smoking (pack-years). The pack-year of cigarette smoking = (number of cigarettes smoked per day/20) x total number of year of cigarette smoking. The pack-year of betel quid chewing = (number of betel quids chewed per day/20) x total number of year of betel quid chewing.Additional analyses were performed with consumption of fresh vegetables and fruits, which were the food categories that showed a significant inverse association with HNC risk in our analysis. We examined the joint effect of fresh vegetables and fruits by examining the risk of HNC associated with different combinations of fresh vegetable and fruit consumption . Further analyses were conducted to examine the association between consumption of fresh fruits and vegetables stratified by the use of alcohol, betel quid, or cigarette to determine whether the relationship between consumption of fresh fruits and vegetables and HNC risk might differ according to the use of alcohol, betel quid, and cigarette. Heterogeneity between strata of alcohol, betel quid, or cigarette use was evaluated with log-likelihood ratio test comparing the unconditional logistic regression model with the product term  to the model without the product term.


In 2015, the Global Commission for the Certification of Polio Eradication certified theeradication of type 2 wild poliovirus, 1 of 3 wild poliovirus serotypes causing paralyticpolio since the beginning of recorded history. This milestone was one of the key criteriaprompting the Global Polio Eradication Initiative to begin withdrawal of oral poliovaccines (OPV), beginning with the type 2 component (OPV2), through a globallysynchronized initiative in April and May 2016 that called for all OPV using countries andterritories to simultaneously switch from use of trivalent OPV  to bivalent OPV , thuswithdrawing OPV2. Before the switch, immunization programs globally had been usingapproximately 2 billion tOPV doses per year to immunize hundreds of millions of children.Thus, the globally synchronized withdrawal of tOPV was an unprecedented achievement inimmunization and was part of a crucial strategy for containment of polioviruses.Successful implementation of the switch called for intense global coordination during2015–2016 on an unprecedented scale among global public health technical agencies anddonors, vaccine manufacturers, regulatory agencies, World Health Organization (WHO) andUnited Nations Children’s Fund (UNICEF) regional offices, and national governments.Priority activities included cessation of tOPV production and shipment, nationalinventories of tOPV, detailed forecasting of tOPV needs, bOPV licensing, scaling up ofbOPV production and procurement, developing national operational switch plans, securingfunding, establishing oversight and implementation committees and teams, traininglogisticians and health workers, fostering advocacy and communications, establishingmonitoring and validation structures, and implementing waste management strategies. TheWHO received confirmation that, by mid May 2016, all 155 countries and territories thathad used OPV in 2015 had successfully withdrawn OPV2 by ceasing use of tOPV in theirnational immunization programs. This article provides an overview of the global effortsand challenges in successfully implementing this unprecedented global initiative,including (1) coordination and tracking of key global planning milestones, (2) guidancefacilitating development of country specific plans, (3) challenges for planning andimplementing the switch at the global level, and (4) best practices and lessons learned inmeeting aggressive switch timelines. Lessons from this monumental public healthachievement by countries and partners will likely be drawn upon when bOPV is withdrawnafter polio eradication but also could be relevant for other global health initiativeswith similarly complex mandates and accelerated timelines. Since the World Health Assembly (WHA) resolved to eradicate polio in 1988, polio cases havedeclined dramatically, from >350 000 cases annually to 37 cases in 2016 . Di. Di34]. Some of the early challenges with developing a work plan, defining roles, and agreeing onthe basics of the global strategy were related to the inherent complexities of the task . Nevertheless, following the first SWG meeting,which occurred in Geneva during February 2015, the working group gained momentum, and theplans for progressing became more clear and consolidated. Moreover, as GPEI progressedtoward fulfilling the readiness criteria for the switch, the need to initiate switchplanning and better define activities became more pressing . Having While the switch was ultimately fully accomplished, many of the initial challenges couldhave potentially jeopardized successful implementation of the switch and, hence, increasedthe risk for cVDPV2 outbreaks. Specifically, the slow start in initiating the SWG led toinefficiencies and confused messaging that could have been avoided had the necessary humanresources been committed at the global level earlier. Nevertheless, the SWG played acritical role in defining milestones, establishing a clear policy and overarchingoperational objectives and setting firm timelines necessary to achieve the switch.In all, a globally synchronized switch with 12 months of planning seemed an insurmountabletask for some partners. However, in identifying the smaller individual components and tasksof the switch, the SWG recognized that the switch was no different from other immunizationactivities, including planning, inventory and stock management, regulatory approval,establishment of technical advisory and management groups, training, communications andadvocacy, monitoring and validation, and waste management . Also, tWorking from the adage that countries are more alike than different, the SWG focused ondeveloping guidance for core activities that would be relevant and necessary to meet theultimate goal and that countries could adapt as needed. The SWG developed a comprehensivework plan with priority activities that warranted action at global, regional, and countrylevels. Partner agreement on these core activities, including assigning roles andresponsibilities, was crucial for clarifying global roles and for advancing regional- andcountry-level planning with regard to the switch. The SWG realized that the work plan neededto be simple and standardized to the greatest extent possible, identifying core activitieswithin each of the key components of the switch, including decision making, managementstructure, stock management, training, communications, monitoring, disposal, and validation.Keeping the documents simple and standardized allowed regions and countries to advance thedevelopment of their own switch plans that were tailored to meet country-specific needs.This template motivated global, regional, and country partners to identify key activitiesspecific to them, enabling each partner to conceive their individual roles andresponsibilities.As the switch neared, detailed guidance on logistic protocols, budget templates, monitoringand validation frameworks, and health worker training modules were drafted and disseminatedfor regional and country adaptation and use, if needed . In thisAn important milestone for the SWG was the recognition that certain activities anddeliberations could occur in parallel to ongoing communication with countries and globalpartners. For example, guidance on country monitoring and validation of the switch outcomeswas a complicated and debated topic in the SWG because of the inherent complexities ofdeveloping normative guidance for validating the switch in the 155 countries and territoriesthat used OPV in 2015 . As suchA consistent principle among members of the SWG and countries was that of adaptability. Theswitch was an evolving activity that was defined gradually as the various activities wereaccomplished by partners and countries worldwide. For example, practical guidance onappropriate disposal of tOPV emerged as a pressing country need. This was a complex topic onwhich preexisting normative guidance and subject matter expertise was lacking . ComprehAnother enabling factor of the switch’s success was the field-testing of switch activities,guidance, and tools in a diverse range of settings worldwide, which provided some key earlylessons . These wTo raise global awareness and confidence on the feasibility of the switch, technicalguidance and communication materials on the switch were rapidly disseminated through variousofficial and unofficial channels. Working groups of the IMG routinely updated details on theswitch on the WHO website. . PartnerIn May 2015, the SWG coordinated a global switch training workshop for consultants andregional office focal points from all of the WHO and UNICEF regions. This workshop wasinstrumental for vetting the initial global switch guidance and was a unique opportunity toraise switch awareness on detailed activities necessary for implementation, to seek input onmaterials developed to date, and to provide a platform for voicing country and region needs.The workshop attendees became switch ambassadors and later provided invaluable guidance tocountries through direct support in country planning and implementation or through otheractivities . Thematerials vetted and revised at this workshop, including the agenda, were modified andreplicated throughout the world in numerous regional workshops, webinars, and dry runs andprovided the foundation for developing country switch plans. These workshops, webinars, anddry runs were the backbone of the global planning and implementation of the synchronizedswitch.Early engagement with the regional offices by the SWG was critical to the success of theswitch. Developing a core set of guidance and tools reflecting the switch strategy beforeengaging the regions and countries provided a useful frame of reference and a platform forconcrete discussions. Engagement with regional offices provided the necessary input forcustomization of the guidance and identified approaches to field-testing the materialsrapidly during the dry run. Initial consultations through global workshops and callsincluded all regional offices simultaneously, which provided transfer and exchange of usefulideas across and within the regions. For example, the South-East Asia Regional Officedeveloped a tracking tool for monitoring country-specific switch progress, and the RegionalOffice for the Americas developed monitoring and validation tools that were then adapted forother regions of the world. Later, each of the regions adopted globally available materialsor developed its own materials that catered to the needs of countries in its region. The SWGmaintained close communication and collaboration with the regional offices, and it monitoredregional progress through frequent conference calls, emails, and consultations, providingadditional guidance and support as needed. Overall, ownership of the switch by the regionaloffices—by monitoring progress, providing country support, and identifying issues warrantingglobal attention—was critical to the success of the globally synchronized switch.Global health initiatives are known to have an emergent quality, but the switch also had acompressed timeline. The initial approach to global switch planning did not meet therequirements of the task. As switch planning progressed and the switch window approached,the strengths of the IMG percolated throughout the partnership to help address the earlyshortcomings of the switch planning .Overall


ONJ prevention, early diagnosis and management are presented. The critical question of the performance of dental extraction, during BTA therapy, as indicated with the recent studies, is supported. The importance of the collaboration between dental and oncology professionals and the patients is highlighted and can be achieved through appropriate education. The ecancer modules are valuable tools for successful e-learning in medical oncology education, including ONJ.The definition, pathobiology and risk factors of ONJ in cancer patients who receive BTAs are discussed in the recent ecancer module for osteonecrosis of the jaw ( Bone Targeting Agents (BTAs), such as bisphosphonates and denosumab, can reduce the risk of skeletal-related adverse events and are widely used to protect the skeleton in patients with osteoporosis or bone metastases from various types of cancer , 2. OsteSince the first reports of ONJ, in 2003, an increasing number of research data has been published and dedicated researchers continuously produce new knowledge. Osteonecrosis is classically an area of painful exposed necrotic bone on the mandible or maxilla. Today, we know that ONJ may also present as non-exposed bone . Cases oWe also increasingly realize that the collaboration between dental and oncology professionals and patients is the key factor in the prevention and management of ONJ related to the bone targeted medications. Research and daily clinical practice have shown, beyond any doubt, that “education” can improve this multidisciplinary, successful collaboration.The ecancer online learning ONJ module offers a unique tool for oncology training and education, always at a real time setting. Basic Knowledge on the mechanism of action of the bisphosphonates and denosumab, the updated clinical presentation of ONJ and the most recently described early diagnostic clinical criteria, the prevention, risk factors and effective management of ONJ are presented, through a successful multidisciplinary collaboration. Ecancer educational module on ONJ offers the appropriate knowledge to achieve ONJ prevention, early diagnosis and successful management, allowing for a successful BTAs protection of the bones in osteoporosis and in the cancer setting.Ecancer online educational module for ONJ was based on a program which evaluated the potential of online communities in knowledge measuring [easuring . To our Bone targeting agents, administered in osteoporosis or cancer with bone metastases, protect the skeleton and reduce skeletal-related adverse events, maintaining quality of life. BTAs have been associated with ONJ, a rare, but dose-limiting bone complication.The ecancer online educational module offers information to clinicians prescribing these drugs. Their collaboration with dental professionals can contribute to improved and efficient prevention, early diagnosis and successful management of ONJ.Ourania Nicolatou-Galitis has received consultant fees from AMGEN.Ourania Nicolatou-Galitis wrote the article and Dr Cesar Migliorati edited it.


Limestone is widely used in the construction industry to produce Portland limestone cement (PLC) concrete. Systematic evaluations of hydration kinetics, compressive strength development, and carbonation resistance are crucial for the rational use of limestone. This study presents a hydration-based model for evaluating the influences of limestone on the strength and carbonation of concrete. First, the hydration model analyzes the dilution effect and the nucleation effect of limestone during the hydration of cement. The degree of cement hydration is calculated by considering concrete mixing proportions, binder properties, and curing conditions. Second, by using the gel–space ratio, the compressive strength of PLC concrete is evaluated. The interactions among water-to-binder ratio, limestone replacement ratio, and strength development are highlighted. Third, the carbonate material contents and porosity are calculated from the hydration model and are used as input parameters for the carbonation model. By considering concrete microstructures and environmental conditions, the carbon dioxide diffusivity and carbonation depth of PLC concrete are evaluated. The proposed model has been determined to be valid for concrete with various water-to-binder ratios, limestone contents, and curing periods. With increasing water-to-binder ratios or decreasing cure periods, the carbonation depth of concrete increases. When the curing period increases from one day to three days, the concrete carbonation depth decreases by approximately 25%. While the curing period increases from three days to 28 days, the concrete carbonation depth decreases by approximately 25%–30%. This is because the rate of cement hydration at early ages (before three days) is much quicker than that at late ages (28 days). Hence, early age curing is effective for reducing the carbonation depth of concrete.The experimental results for the carbonation of PLC concrete from references ,7 were uParrot  investigThe carbonation resistance of PLC concrete depends on a trade-off between some competing effects. First, the limestone replacement increases the degree of cement hydration. This factor increases the carbonation resistance of PLC concrete. Second, limestone replacement reduces the cement content in concrete. This factor decreases the carbonation resistance of PLC concrete. The increasing and deceasing factors contribute to the carbonation resistance of concrete with different weights. The carbonation resistance of PLC concrete relates to increasing and deceasing factors.2 diffusivity on local relative humidity requires additional examination. Second, the change in carbonation depth may also be related to the changes in the pore solution and the composition of the cement hydrates with limestone present (and reacting) in the cement paste. This point was not considered.In this study, the effects of carbonatable material contents, porosity, and environmental conditions on concrete carbonation are considered. However, the carbonation model also shows some limitations. First, the drying of concrete during carbonation tests was not considered . The depThis study presents a systematic study on hydration, strength development, and carbonation of PLC concrete. The conclusions of this study are summarized as follows:First, a kinetic hydration model is proposed for cement-limestone blends. The dilution effect and physical effect from limestone powder replacements are taken in account. The dilution effect is considered by the effective W/C ratio. The physical effect is considered by the limestone nucleation effect indicator. The input parameters of the hydration model are concrete mixing proportions, compound compositions, Blaine surface area of cement and limestone, and concrete curing temperatures. The values of the reaction coefficients of the hydration model can be determined using the input parameters. Furthermore, the time-dependent degree of hydration can be calculated.Second, the compressive strength of PLC concrete is evaluated using the gel–space ratio. Limestone replacement can increase the degree of cement hydration. For concrete with low water-to-binder ratios, the improvements related to the degree of cement hydration are more obvious. At late ages, for concrete with higher water-to-binder ratios, limestone replacements impair compressive strength, while, for concrete with lower water-to-binder ratios, strength reduction due to limestone replacements is marginal. Regarding compressive strength, the use of limestone in concrete with low water-to-binder ratios is a more rational option.2 diffusivity and carbonation depth of PLC concrete are evaluated by considering concrete material properties and environmental conditions. With increasing water-to-binder ratios and limestone content or reductions in curing period, the carbonation depth of concrete increases. The carbonation resistance of PLC concrete is related to both increasing factors (limestone replacements can increase the reaction degree of cement) and deceasing factors (limestone replacements decrease cement contents in mixing proportions).Third, the calculation results from the hydration model, such as carbonatable material contents and porosity of concrete, are used as input parameters for the carbonation model. CO


Editorial on the Research TopicInflammation in the CNS: Advancing the Field Using Intravital ImagingInflammation of the central nervous system (CNS) contributes to a diverse array of life-threatening and debilitating conditions. These include autoimmune conditions such as multiple sclerosis (MS), progressive degenerative conditions [Alzheimer’s disease (AD)], sterile inflammation as occurs in stroke/cerebral ischaemia, and inflammation stemming from parasitic, fungal, viral, and bacterial infections. Whilst recent developments have led to improved outcomes in some of these conditions, most notably MS , there rin vivo imaging has been a critical tool for understanding the mechanisms of inflammation throughout the body, including in the brain  images. These advances have proved pivotal in understanding animal models of CNS inflammation such as EAE. Moreover, the combination of ongoing technical developments in imaging technologies, reporter mice, and novel fluorophores for detection of cellular signalling, in parallel with improved animal models of CNS disease, has meant that the understanding of inflammatory processes in this unique organ is better than ever before.Whilst application of intravital imaging to the CNS has been technically challenging, several issues have been systematically addressed over the years to facilitate generation of high-quality four dimensional , and ageing and amyloid-related pathology . These studies use markers to differentiate between myeloid cells and astrocytes. Importantly, the authors illustrate the capacity of contemporary imaging approaches to move beyond simply describing cell behaviour into understanding intracellular biochemistry and signalling of specific cell types in inflamed tissues, focussing on NAD(P)H oxidase (Nox) activity and Ca2+ signalling. In a separate article focussing on the remission phase of EAE, Radbruch et al. show that Nox activity remains elevated specifically in microglia. In contrast, under conditions of amyloid deposition, Nox activity is predominantly elevated in astrocytes .Radbruch et al. present two studies applying advanced Shi and Mody describe the use of confocal intravital microscopy to investigate the dynamic interactions undergone by Cryptococcus neoformans in the CNS microvasculature, and the unusual nature of the neutrophil response to this infection.Fungal pathogens are an important cause of CNS pathology, particularly in immunocompromised individuals, although the mechanisms of fungal invasion of the brain are poorly understood. Sonar and Lal provide an overview of the role of TNFSF receptor–ligand interactions in driving the pathogenesis of neuroinflammation and autoimmune disease in the CNS.Finally, Frontiers Research Topic will provide researchers with a useful resource for understanding how imaging can be used to investigate the dynamics of CNS inflammation in its various forms.In summary, we anticipate that the collection of articles in this SP: inviting contributions, handling and tracking submissions, setting timeline for research topic, acting as associate editor for selected manuscripts, inviting reviewers, coordinating with co-editors, and drafting and critically revising editorial. MH: inviting contributions, handling and tracking submissions, acting as associate editor for selected manuscripts, inviting reviewers, and drafting and critically revising editorial. WW: handling and tracking submissions, acting as associate editor for selected manuscripts, inviting reviewers, and drafting and critically revising editorial.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.


Localized prostate cancer (LPCa) is an heterogeneous disease extending from individuals who harbor indolent cancer, that are highly unlikely to develop metastases, to individuals with more aggressive disease, that have higher risk of metastatic burden. This would translates into different oncologic outcomes and have implications for disease management. Once the diagnosis of LPCa is established, remains challenging to identify those patients who may benefit from delayed or immediate treatment. Several options exist, from active surveillance (AS) to the whole-gland treatments . HoweverBased on the recently findings of the PROTECT trial , we beliWith the introduction of PSA screening in the early 1990s, a sharp increase of earlier stage PCa at diagnosis was observed. However, the release of the United States Preventive Services Task Force statements against PSA-based screening combined with the discordant findings provided by ERSPC  and PLCOTo date is widely accepted that PSA has a suboptimal performance as a biomarker due to its low specificity. For this reason, several biomarkers were developed and will be developed to better identify LPCa patients at increasing risk of harboring clinically significant PCa at biopsy, who might benefit from early treatment. For example, the Prostate Health Index text (PHI), combining total, free and [-2]proPSA, was demonstrated to outperform its individual components in predicting clinically significant PCa, also in biopsy naïve setting , reducinOur ability to identify clinical significant PCa has dramatically improved during the last decades with the advances in imaging techniques. Multiparametric Magnetic Resonance Imaging (mpMRI) was demonstrated to have high accuracy in detecting clinically significant PCa (range: 44-87%) . MoreoveAccording to the most updated urological international guidelines , AS is rThe increase of low-risk and focal PCa afterwards the introduction of PSA screening combined with the well-known side effects related to whole-gland treatments, has led to the development and spreading of more conservative approaches, namely focal therapy (FT). FT is a treatment of specific focus (targeted ablation) or limited defined region (quadrant ablation or hemiablation) , aiming Despite the well-known side effects and the consequently impact on quality of life, whole-gland therapies still have a dominant role in the management of LPCa patients  and reprIn conclusion, our ability to identify and stratify clinically significant PCa has dramatically improved and it is likely to improve even further. First, because of the development of new biomarkers and genetic testing. Second, because mpMRI have definitely changed PCa pathway in the last few-years. Third, and most importantly, because the combination of these tools will positively lead to an accurate selection of LPCa patients who will undergo immediate treatment. The latter combined with the improvement of FT, the availability of long-term oncological data on FT, and the increasing surgical expertise with minimally invasive approach will lead to an increase of LPCa that will be safely treated in the future with more personalized approach starting from the assumption of the inter-patient and intra-glandular heterogeneity.


The Editorial on the Research TopicFocus on Systemic Lupus ErythematosusSystemic lupus erythematosus (SLE) is a serious systemic autoimmune disease. In the absence of specific targeted therapies, the majority of patients suffer inadequate disease control: a 20-year-old diagnosed with SLE has up to a 10% chance of death before turning 40. SLE has long been considered the archetypical autoimmune disease, involving innate and adaptive mechanisms of inflammation and the generation of autoantibodies. A combination of genetic predisposition and environmental triggers leads to activation of the innate immune system. This results in the release of inflammatory mediators, including cytokines, which activate both innate and adaptive immune responses. Autoantibodies bind nucleic acids or cellular debris to form immune complexes, which further activate innate immune cells through Fc and toll-like receptors. This positive feedback loop eventually leads to systemic inflammation and tissue damage, which feeds back to further potentiate immune responses.The apparent simplicity of this model belies the complexity seen by the physician. SLE presents with a broad range of symptoms and manifestations; some patients might develop renal disease, others central nervous system complications and immune correlates with one “type” of SLE might not be same as for others. This makes diagnosis and treatment challenging. Current therapies are largely centered on non-specific immunosuppressants, including corticosteroids, which can have profound long-term side effects. The development of biological therapies for SLE has proven problematic, not least the fact that different cytokines and cells might play different roles at different stages, in the many different manifestations. Key to developing new treatments for SLE will be unraveling the complex interplay between the many arms of the immune system, from the underlying inflammation, to the specific roles of the many cell types involved. Moreover, the ability to stratify patients in a way that tells us what shape their disease will likely take would help us to embrace, rather than grapple with, the heterogeneous nature of SLE, perhaps allowing us to develop different drugs for different subsets of patients.Focus on Systemic Lupus Erythematosus brings together reviews from some of the world’s leading experts on SLE and the immunology that underlies SLE pathogenesis. Mahajan et al. present the arguments for cell death and deficiencies in dead cell clearance by phagocytes as a central pathway in the pathogenesis of SLE. This review highlights findings that suggest phagocytes from patients with SLE may have a defect in their ability to engulf and clear apoptotic cells, leading to the exposure of autoantigens and a break in B cell tolerance, resulting in the development of autoimmunity and SLE.This Rother and van der Vlag. In particular, they focus on aberrant T cell receptor (TCR) signaling and roles of Th17 and regulatory T cells (Tregs) in the development of SLE. Defects in the TCRζ chain, Syk kinase, and calcium signaling molecules, which have been associated with SLE, lead to the proliferation of autoreactive T cells, including Th17 cells. Concurrent with this is a reduction in numbers of Tregs and impairment of their function, leading to inappropriate and poorly controlled inflammation.The role of T cell signaling and different T cell subsets is the focus of the review by Lang et al. focus specifically on macrophage migration inhibitory factor (MIF) and its roles in SLE pathogenesis. MIF was first identified in the 1960s, yet still remains surprisingly enigmatic. There are numerous ways in which MIF might be linked with SLE, and this is borne out both in mouse models and clinical studies. Moreover, polymorphisms that lead to increased MIF secretion have been linked with SLE in interesting ways, potentially conferring protection against development of SLE, but leading to more severe disease after onset. The potential of targeting MIF therapeutically is also discussed.Cytokines play a complex and critical role in the pathoetiology of SLE. Huang et al. review the most recent developments in this exciting area of SLE research.Plasmacytoid dendritic cells (pDCs) have recently been demonstrated to play an important role in the development of autoantibodies and SLE pathogenesis. These cells are potent producers of type I interferons (IFN-I), a family of cytokines that has been intricately linked with SLE. The role of pDCs in SLE and other diseases has been difficult to establish due to their rarity, difficulty to identify, and rapid but transient release of IFN-I. Woods et al. discuss, many mouse models of lupus are characterized by the spontaneous formation of GC, induced through a number of different mechanisms, both innate and adaptive. The review also highlights the role of B cell-activating factor (BAFF), defects in dead cell clearance in GC, and the potential for targeting GCs therapeutically in SLE.Germinal centers (GCs) are key sites of B cell clonal expansion and affinity maturation. Also present in GC are follicular dendritic cells, which capture and retain antigen, T follicular helper cells, and T follicular regulatory cells. As Yung and Chan focus on the contribution of anti-double stranded DNA (dsDNA) antibodies to the pathology of lupus nephritis. Deposition of anti-dsDNA antibody-containing immune complexes in the kidney is an initiating factor in lupus nephritis. However, as this review discusses, direct and indirect binding of anti-dsDNA antibodies to cross-reactive antigens in the kidney also plays a major role. The downstream effects of this, including proliferation, apoptosis, inflammation, and fibrogenesis, are highlighted. In addition, recent data are discussed suggesting that mycophenolic acid (MPA), the active ingredient of the drug mycophenolate mofetil, has specific inhibitory effects on anti-dsDNA-induced processes, independent of its known immunosuppressive actions.Kidney injury in SLE (lupus nephritis) is a major cause of both morbidity and mortality, affecting over half of all SLE sufferers over the course of the disease. Gottschalk et al. provide an important overview of the current state of play with regard to SLE therapies and where they may lead in the future. Individual biological targets, especially cytokines, are discussed. In particular, the potential of targeting IL-6, an important inflammatory mediator in SLE, is highlighted, as well as the idea of targeting multiple pathways with combination treatments.Finally, Both authors wrote and edited this editorial.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.


TM is used to build a planned resection model, based on a previous intracranial EEG evaluation. Intraoperative MRI is then used to ensure a complete resection of the planned model. As stereoEEG becomes more common in the presurgical evaluation of epilepsy, these tools will become increasingly important to facilitate targeted cortical resections.Surgical resection in non-lesional, extratemporal epilepsy, informed by stereoEEG recordings, is challenging. There are no clear borders of resection, and the surgeon is often operating in deep areas of the brain that are difficult to access. We present a technical note where 3D multimodality image integration in EpiNav Surgical treatment of nonlesional extratemporal epilepsy is challenging. There is no single diagnostic test for the epileptogenic zone, and patients typically undergo detailed presurgical evaluation comprising of video-EEG telemetry, structural and functional MR imaging and neuropsychometric assessment. Most patients require further advanced imaging such as interictal-ictal single photon emission computed tomography (SPECT) and fluorodeoxyglucose positron emission tomography (FDG-PET), and intracranial electroencephalography (IC-EEG) to further define the site of seizure onset.TM  is software used for image integration, advanced visualisation and epilepsy surgery planning.TM is used to support the strategic decision making, planning of SEEG and visualisation of implanted depth electrodes. Following recording of seizure activity, advanced segmentation tools are used to highlight electrode contacts of interest, that indicate interictal and early ictal epileptic activity and then to build a planned resection model. This model accounts for the gyral anatomy, blood vessels and the preferred surgical approach, incorporates the electrode contacts implicated in seizure activity and excludes eloquent areas of brain where language and motor function were mapped extra-operatively. This tool facilitates the translation of the neurophysiological data into a 3D surgical plan that can be imported into neuronavigation systems and used for guidance in the operating theatre. Following resection, the patient undergoes intraoperative MRI, and a rigid body coregistration is undertaken to confirm that the resection plan has been followed and that the salient points of interest have been resected.EpiNavGT is a 30-year old right-handed male, with a 13-year history of medically refractory hyperkinetic seizures with no lateralising signs. His nocturnal seizures occur 2–3 times per week, have no aura and consist of him waking with violent movements of all limbs. His daytime seizures occur 2–3 times per month, and consist of an aura of abnormal feelings in the chest and abdomen followed by violent movements of the limbs and loss of consciousness. Scalp ictal EEG localised to the left frontocentral region. Repeated structural imaging was normal, and FDG-PET showed hypometabolism in the left anteromesial frontal and anterolateral temporal lobes. Magnetoencephalography showed dipole clusters in the left orbitofrontal and left temporal pole. Verbal fluency functional MRI demonstrated left hemisphere language dominance. Neuropyschometry testing showed poor verbal memory, nominal skills and executive skills, consistent with dominant frontal dysfunction. GT underwent an intracranial SEEG study, with electrodes targeting the left orbitofrontal area, inferior and mesial frontal areas, the insula, the cingulate gyrus, the temporal pole, the amygdala and the supplementary motor area . RecordiTM , and coregistered to the neuronavigation scan undertaken at the beginning of the operation in the interventional MR suite. The resection model and landmarks provided guidance for the neurosurgeon during the resection procedure. At the end of the operation, the extent of the proposed resection was confirmed with an intraoperative MRI that was coregistered to the previous MRI with the models overlaid (Image integration, segmentation and 3D visualisation was performed in EpiNavTM . The coroverlaid .TM, tailoring them to the needs of visualization of electrode contacts and to epilepsy surgery. We will also incorporate tractographic representations of important transiting white matter pathways, such as the uncinate fasciculus, inferior fronto-occipital fasciculus and arcuate fasciculus, to further aid planning and improve the safety of surgery in these deep cortical areas.We report the combined use of 3D multimodality imaging and intraoperative MRI to guide the surgical management of nonlesional and extratemporal epilepsy. The generation of a planned resection area clarifies the surgical strategy between the surgeon and neurophysiologist and the use of intraoperative MRI gives the surgeon confidence that the proposed resection is complete. These tools are increasingly needed as more challenging nonlesional, extratemporal surgery takes place, informed by SEEG recordings.


These associations between pathologies that presumably have different etiologies suggest shared pathological mechanisms. Gut microbiota is a mediating factor between the environmental pressures  and host physiology, and its alteration could partly explain the cross-link between those pathologies. Westernized dietary patterns are known to be a major cause of the obesity epidemic, which also promotes a dysbiotic drift in the gut microbiota; this, in turn, seems to contribute to obesity-related complications. Experimental studies in animal models and, to a lesser extent, in humans suggest that the obesity-associated microbiota may contribute to the endocrine, neurochemical and inflammatory alterations underlying obesity and its comorbidities. These include dysregulation of the HPA-axis with overproduction of glucocorticoids, alterations in levels of neuroactive metabolites  and activation of a pro-inflammatory milieu that can cause neuro-inflammation. This review updates current knowledge about the role and mode of action of the gut microbiota in the cross-link between energy metabolism, mood and cognitive function.Obesity continues to be one of the major public health problems due to its high prevalence and co-morbidities. Common co-morbidities not only include cardiometabolic disorders but also mood and cognitive disorders. Obese subjects often show deficits in memory, learning and executive functions compared to normal weight subjects. Epidemiological studies also indicate that obesity is associated with a higher risk of developing depression and anxiety, and  The microorganisms inhabiting the mammalian's intestinal tract (collectively termed microbiota) include bacteria, viruses, protozoa, archaea, and fungi, with bacteria representing a majority  are associated not only with diseases affecting the intestine like inflammatory bowel disease (IBD) but also with extra-intestinal organs and systems. These include, but are not restricted to metabolic diseases , autoimmune arthritis, and psychiatric disorders -γ, tumor necrosis factor (TNF)-α and interleukin (IL)-6 secretion following mitogen stimulation of whole blood immune cells. They also observed a marked increase in plasma concentrations of tryptophan and kynurenic acid, as well as a reduction in 5-HIAA concentration in the frontal cortex and a decrease in DOPAC in the amygdaloid cortex in the Bifidobacterium-treated rats when compared to controls. These results indicate that gut microbiota modulation could produce changes in immune, neuroendocrine and monoaminergic activity.The gut-brain axis is formed by the central nervous system (CNS), the enteric innervation that includes extrinsic fibers of the autonomous nervous system (ANS) and intrinsic neurons of the enteric nervous system (ENS), the HPA-axis and the intestinal microbiota. The extrinsic innervations of the GI tract connect the gut with the brain through vagal and spinal fibers, while the brain sends efferent sympathetic and parasympathetic fibers to the GI tract  is regulated by the integrated action of both CNS and the ENS. While the CNS controls gut functions through the extrinsic innervations of the ANS, the ENS may act autonomously and independently of the brain. The extrinsic innervations consist of vagal (first order cell bodies in nodose and jugular ganglia) and spinal  afferents which project centrally to the brainstem or spinal cord for transmitting sensory information from the gut to the CNS  is essential to promote epithelial cell proliferation and regulate innate immunity , all of which are regulated by the brain and strongly influence the gut microbiota  into the cerebrospinal fluid , which regulates the stress response to cold temperatures, produces a stomach lumen secretion of serotonin, possibly mediated by vagal activation of gastric ECs , on their cell surface, whose binding activates their pathogenic features and the use of adrenergic antagonists blocked this activation  and decreased pro-inflammatory cytokines regulating tryptophan metabolism and the neurotransmitters in the CNS in a rat model of depression induced by maternal separation  and amygdala there was a decrease in GABA Aα2 mRNA, but an increase in the hippocampus. This was accompanied by attenuation of stress, anxiety and depressive-like behaviors in healthy animals. Results of the same study confirmed that communication between the microbiota and the brain occurred partly via the vagus nerve, which provided information from the lumen to the CNS. This was evident when vagotomized animals failed to show neurochemical and behavioral effects. Thus, the vagus nerve was identified as a constitutive modulator of the communication pathway between the gut microbiota and the brain. Other authors have also shown that components of the microbiota are able to produce molecules that act as local neurotransmitters in the ENS, for example GABA, 5-HT, acetylcholine, melatonin or histamine . Leaky gut is a loss of intestinal barrier integrity making it less able to protect the internal environment. This loss of integrity allows bacteria, toxins and other molecules to arrive to the bloodstream. In recent studies it has been demonstrated that gut compositional changes and inflammation related with leaky gut may contribute to the pathophysiology of several diseases like depression, chronic fatigue syndrome, obesity, Type-2 diabetes or IBS  and increased intestinal permeability  and some differences in the attention test performance, suggesting an association between elevated BMI and lower cognitive performance, independently of age. Several studies with obese children showed alterations in attention and attentional shifting compared to normal children  improved cognitive reactivity to sad mood in normal individuals  mice displayed higher levels of anxiety.Animal studies have investigated the effects of stress and Western diets leading to obesity on mood, and investigated the possible interactions and mediating mechanism. Santos et al.  demonstrLactobacillus helveticus restored the Firmicutes/Bacteroidetes ratio altered in HFD-fed mice and reduced anxiety-like behaviors. Abildgaard et al.  to the offspring, corrected the oxytocin levels and social deficits in MHFD progeny, suggesting that probiotics may relieve abnormalities associated with neurodevelopmental disorders. Other studies have suggested that obesity-related inflammatory processes, originating either from the adipose tissue or gut microbiota, affect the brain, leading to substantial changes in different neuro circuitry, neuroendocrine activity (impaired feedback response to cortisol), neurotransmitter metabolism and activity , and neurogenesis (impaired in the hippocampus)  in epidemiological and experimental studies point to shared contributing factors and pathophysiological mechanisms. These associations could be related to dietary-induced alterations in the intestinal microbiota that, in turn, may contribute to (neuro) inflammation and dysregulation of the neuroendocrine system associated with obesity comorbid with mental impairments. This hypothesis has been confirmed to some extent in experimental models, which have investigated the effectiveness of some probiotics or compounds altering the gut microbiota, in both attenuating obesity and associated mental disorders. These studies, however, do not help us discern whether interventions affecting the gut ecosystem play a primary or secondary role in alleviating obesity-associated mental impairments. Fecal transplants have, however, provided more direct evidence for the role of dysbiotic microbiota in neurobehavioral alterations, since the colonization of lean mice with the HFD-induced microbiota of obese mice led to the neurologic complications of obesity. Although we still lack a full understanding of the mechanisms by which microbiota may influence the gut-brain axis and, thereby, brain function and behavior, studies have shed light on numerous factors, including: regulation of the gut barrier, inflammation and signaling through TLR that recognize bacterial motifs and mediate in the communication with ENS, regulation of enteroendocrine secretions and the HPA stress response, and production and regulation of host neurotransmitter levels and their receptors. However, further translational and functional studies are needed to progress in the identification of molecular targets/pathways that could be favorable modulated by microbiota-based interventions to help reduce obesity associated complications.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.