The hippocampus and the prefrontal cortex are interconnected brain regions, playing central roles in higher brain functions, including learning and memory, planning complex cognitive behavior, and moderating social behavior. The axons in these regions continue to be myelinated into adulthood in humans, which coincides with maturation of personality and decision-making. Myelin consists of dense layers of lipid membranes wrapping around the axons to provide electrical insulation and trophic support and can profoundly affect neural circuit computation. Recent studies have revealed that long-lasting changes of myelination can be induced in these brain regions by experience, such as social isolation, stress, and alcohol abuse, as well as by neurological and psychiatric abnormalities. However, the mechanism and function of these changes remain poorly understood. Myelin regulation represents a new form of neural plasticity. Some progress has been made to provide new mechanistic insights into activity-independent and activity-dependent regulations of myelination in different experimental systems. More extensive investigations are needed in this important but underexplored research field, in order to shed light on how higher brain functions and myelination interplay in the hippocampus and prefrontal cortex. To support rapid encoding of new information and consolidation and organization of memory networks, the brain relies on two important structures, the hippocampus and the prefrontal cortex (PFC). The hippocampus belongs to the limbic system and is a paired structure with mirror-image halves in the left and right sides of the brain. The hippocampus forms and organizes memories, allowing for efficient consolidation of objects, locations, behaviors, and temporal organization at specific events and retrieval of this information at later dates. Hippocampal neurons carry out these functions by communicating with regions of the cerebral cortex. One important region of the cerebral cortex involved in this process is the PFC. The PFC is the anterior part of the cerebral cortex in the frontal lobe. It is responsible for regulating social and cognitive behavior, planning, and decision-making. Neural communications between the PFC and the limbic system lead to behaviors modulated by emotions and motivations. Specific interactions between the medial PFC (mPFC) and the hippocampus orchestrate efficient encoding and retrieval of information to assist in environment-specific actions . While iA receptor agonist, muscimol, rats that were previously trained to employ spatial-contextual rules to guide object selections had decreased task performance [Proper communications between the hippocampus and PFC are essential for memory and cognition. The pathway from the hippocampus to the mPFC supports memory consolidation, likely through strong synchronization of their neuronal activities –6. Conveformance . Inactivformance . Abnormaformance , 10. Theformance . Moreoveformance . Communiformance .Myelinated axons allow rapid and reliable propagation of action potentials over long distances in the nervous system. Demyelination of the axons that connect two separate brain regions can disrupt the communications between them. Myelin alterations in the hippocampus and the PFC were commonly reported in the above-mentioned disorders –16. It iMyelin is composed of compacted lipid membranes that wrap around the axons of many neurons, providing electrical insulation and trophic support. Myelin allows action potentials to propagate along an axon in a saltatory fashion with higher speed and less energy consumption. Whereas Schwann cells are myelinating glia in the peripheral nervous system (PNS), myelin in the central nervous system (CNS) is formed from oligodendrocyte progenitor cells (OPCs) that differentiate into oligodendrocytes (OLs) and form myelin sheaths surrounding axons. Bundles of myelinated axons give rise to the appearance of the white matter. The mechanism and function of myelin in the white matter have been extensively studied. However, many axons in the gray matter that contains neuronal cell bodies and dendrites are also myelinated. A recent study showed that a large fraction of neocortical myelin ensheathes axons of local inhibitory neurons . Gray maMyelination is important in establishing connectivity in the growing brain by facilitating rapid and synchronized information transfer across the nervous system, which is essential to higher-order cognitive functions. Once thought of as solely a passive insulator, myelin alteration is now known to be actively involved in the function and development of the CNS (see review ). DisrupMyelination is not merely a transient event at the perinatal stage. In fact, remodeling of myelin continues throughout adulthood and includes different modes, such as remodeling of existing myelin and new myelination of partially myelinated or unmyelinated axons. Quantification of OPCs and OLs in regions of the adult mouse brain shows that some OPCs are still dividing, differentiating into OLs, and generating myelin –22. In aThe hippocampus and the PFC are two brain regions that display significant myelin plasticity in response to experience and environmental cues. Using magnetic resonance imaging (MRI), the Hofstetter group showed that short-term learning can cause significant alterations of the white matter in the fornix of the hippocampus . HoweverMyelination can be regulated in different ways to impact the computation of neural circuits. Different steps of proliferation and differentiation of OPCs and OLs can be regulated to alter the amount of myelin generated, which will be discussed in more detail later. These steps could be altered due to signals from the cells' microenvironment or signals from individual axons. Interestingly, even the pattern of myelin segments along a single axon may be manipulated to alter axonal functions. A recent study revealed distinct profiles of myelin distribution along individual axons of pyramidal neurons in the neocortex . These rThe hippocampus, in coordination with other brain regions, plays an important role in the consolidation of information from short-term memory to long-term memory, as well as in spatial learning and navigation. In humans, the hippocampus is located subcortically in the medial temporal lobe. The hippocampus receives inputs from various cortical and subcortical structures via the perforant pathway from the entorhinal cortex. Information flow in the hippocampus is mainly unidirectional and involves three synaptic connections. Most axons in the perforant pathway project to the granular layer in the dentate gyrus (1st synaptic connection). The dentate granule cell axons (mossy fiber) pass the information to the dendrites of CA3 pyramidal cells (2nd synaptic connection). The mossy fibers are the only axonal tracts exclusively containing unmyelinated axons. From there, CA3 axons  leave the deep part of the cell body and loop up to the apical dendrites extending to CA1. Axons from CA1 then project back to the entorhinal cortex (3rd synaptic connection) completing the trisynaptic neural circuit. Additional output axons go to other cortical areas including the PFC. There are also interneurons within the hippocampal neural circuits. Myelin can form along the axons projecting into, out of, or within the hippocampus.Myelination in the limbic system, including the hippocampus and amygdala, is quite complex and has not been extensively investigated. In humans, hippocampal myelination begins during fetal development and continues into postnatal development . ExpressDisruption of this progressive myelination is evident in a variety of disorders. It was reported that 53–79% postmortem MS brains showed demyelination in the hippocampus , 33. To Moreover, demyelination in the hippocampus was observed in patients with Alzheimer's disease, temporal lobe epilepsy, or psychotic disorders , 37–39. Abnormal conditions are also associated with increased myelin in the hippocampus. A recent study focusing specifically on the hippocampus indicated that veterans with PTSD had significantly increased hippocampal myelin compared to trauma-exposed controls . It appeThe PFC is among the last brain regions to mature in humans . It is hSocial experience has significant and long-lasting effects on myelination in the PFC during early development. Researchers found that the white matter in the mPFC changed in children raised in neglectful institutions among Romanian orphanages and that the changes were irreversible following foster care placement , 45. In Environmental alterations during a critical period of myelin maturation can lead to long-lasting cognitive and behavioral deficits. Similar to myelination in adolescence, the ongoing myelination during adulthood can be influenced by environment or experiences, exemplifying its role in brain plasticity, but appears to be reversible following the event . Eight wPFC myelination can also be damaged by heavy alcohol consumption and may be involved in the behavioral and cognitive impairments associated with alcoholism. In a rat model, adolescent binge drinking reduced myelin density in the mPFC and disrupted T-maze working memory in adulthood . This fiWhereas social interactions seem to affect PFC and hippocampal myelin in a similar manner, with isolation resulting in decreased myelination in both regions, other experiences may cause different effects. This was observed in response to stress, a condition studied for its association with many neurological and mental disorders . Mice exThe opposite effects of social isolation and stress on myelination in the PFC and the hippocampus could contribute to the behavioral and cognitive differences between diseases such as Alzheimer's disease and PTSD. While both diseases involve neural disconnections between the PFC and hippocampus, recent studies showed that increased myelin in the hippocampus and decreased white matter in the PFC observed in PTSD may lead to stronger connections between the hippocampus and the amygdala, causing heightened fear responses that cannot be modulated by the PFC –55.Experience-dependent regulation of myelination in the hippocampus and the PFC deserves further investigation into the underlying mechanisms, due to physiological significance under both normal and abnormal conditions. Some progress has been made in understanding the potential mechanisms underlying intrinsic and extrinsic regulation of myelination using different experimental systems. These findings may shed light on experience-dependent regulation of myelination in the two key regions involved in higher brain functions.Myelin formation in the CNS contains multiple highly regulated steps including proliferation of OPCs and differentiation of OLs. During development, OPCs are generated from the neural stem cells in different regions at different times. These OPCs then proliferate and migrate throughout the CNS, and upon reaching their destination, they differentiate into OLs and myelinate axons. So far, both extrinsic and intrinsic mechanisms have been implicated in the regulation of these steps .The microenvironment of OPCs and OLs, including locally secreted factors, can influence their development, independent of neuronal activity. This may in part explain the varying degree of myelin plasticity between regions in the CNS. Using organotypic slice cultures from the forebrain and cerebellum of early postnatal mice, the Hill group compared basal and platelet-derived growth factor- (PDGF-) induced proliferation of neural/glial antigen 2- (NG2-) positive OPCs in different brain regions . They foRecent studies have refined our view of axon-OL interactions during myelination. It was previously thought that axonal activity is required for OL differentiation and myelination. However, the Rosenberg group showed that packing constraints provided by artificial beads were sufficient to induce OL differentiation . SurprisNeuronal activity can regulate the early steps of myelin formation, including OPC proliferation and differentiation, to impact overall myelination . SeveralTwo recent studies showed that activity-dependent regulation of OPCs takes place in motor learning. The first showed that optogenetic stimulation of premotor cortex neurons in awake and behaving mice led to OPC proliferation and increased oligodendrogenesis and myelination, within the deep layers of the premotor cortex and subcortical white matter . This efActivity-dependent myelination also occurs in sensory inputs. Etxeberria et al. found that manipulation of sensory experience through visual stimuli was able to modulate the myelin in the optic nerve in what seems to be an activity-dependent manner . In thisActivity-dependent modulation of OPCs has been implicated in stress-dependent regulation of myelin in the hippocampus and PFC. In stress-promoted oligodendrogenesis in the hippocampus of adult rats, the results were recapitulated when treating the rats with the stress hormone cortisone . The corA receptor antagonist, they found that increased synaptic activity led to a roughly 40% increase in myelination [2+ transients in developing myelin processes regulate sheath elongation, also using zebrafish as the in vivo model [Neuronal activity can regulate myelin formation at the levels of OL differentiation and myelination . A recenlination . Therefolination . Recent vo model , 73.Activity-dependent regulation of myelination was implicated in the studies showing that social isolation led to myelin disruption in the mPFC , 48. Redin vitro and in vivo experimental systems deserve major efforts in future investigations. Perhaps, it is more important to determine whether there is a unified mechanism underlying activity-dependent regulation of myelination throughout all brain regions. Additionally, the exact physiological and pathological roles of myelin alterations must be better understood. For instance, future research should reveal how abnormal myelination is involved in the pathogenic process in various neurological and psychological disorders and conditions, such as Alzheimer's disease, Parkinson's disease, alcohol abuse, and PTSD. Knowing the specific sites of interruption can guide research in targeted therapies for myelin disruption. The findings of such research will contribute to the development of novel strategies for treating these devastating disorders and conditions.Regulation of myelination likely plays a key role in experience-induced long-term alteration of higher brain functions. In particular, myelin regulation in the hippocampus and the PFC may have long-lasting effects on memory, cognition, decision-making, and social behaviors. Importantly, myelination of these two regions involving both the gray and white matter takes decades to fully mature, and myelin plasticity may occur throughout an individual's lifetime. Although some progress has been made, our understanding of activity-independent and activity-dependent regulations of myelination remains very limited in many brain regions, including the hippocampus and the PFC. Moreover, compared to white matter myelination, we currently still know little about gray matter myelination. While synaptic plasticity in the gray matter is an established form of neural plasticity, myelin alteration may be a novel form and remains to be fully understood. However, to further complicate the issue, myelin regulation appears region-dependent. Therefore, to elucidate specific molecular mechanisms governing the regulation of myelin formation in the hippocampus and the PFC, both


The current scenario regarding the widespread Zika virus (ZIKV) has resulted in numerous diagnostic studies, specifically in South America and in locations where there is frequent entry of travelers returning from ZIKV-affected areas, including pregnant women with or without clinical symptoms of ZIKV infection. The World Health Organization, WHO, announced that millions of cases of ZIKV are likely to occur in the USA in the near future. This situation has created an alarming public health emergency of international concern requiring the detection of this life-threatening viral candidate due to increased cases of newborn microcephaly associated with ZIKV infection. Hence, this review reports possible methods and strategies for the fast and reliable detection of ZIKV with particular emphasis on current updates, knowledge, and new hypotheses that might be helpful for medical professionals in poor and developing countries that urgently need to address this problem. In particular, we emphasize liposome-based biosensors. Although these biosensors are currently among the less popular tools for human disease detection, they have become useful tools for the screening and detection of pathogenic bacteria, fungi, and viruses because of their versatile advantageous features compared to other sensing devices. This review summarizes the currently available methods employed for the rapid detection of ZIKV and suggests an innovative approach involving the application of a liposome-based hypothesis for the development of new strategies for ZIKV detection and their use as effective biomedicinal tools. Flaviviridae, genus Flavivirus, and is similar to Dengue virus (DENV), yellow fever virus, Japanese encephalitis virus, and West Nile virus , the causative agent of the infectious disease Zika fever, is a positive-sense RNA virus that belongs to the family le virus . ZIKV wareported . Now, ZIreported .In the north-eastern states of Brazil, the public health authorities recently confirmed autochthonous transmission of ZIKV with the first known reported case of ZIKV infection in mainland South America , followeAedes aegypti and Aedes albopictus. Infections have now dramatically increased in highly populated areas of South, Central, and North America due to the increased frequency of the international travel from Zika-infected areas (The virion of ZIKV consists of an approximately 11 kb positive-sense RNA with a single capsid and two membrane-associated envelope proteins (M and E) . Recent ed areas . ConsideZIKV, an emerging flavivirus, shares common clinical symptoms with DENV and chikungunya virus (CHIKV). The outbreaks caused by these viruses present a large number of diagnostic challenges. The clinical manifestations of ZIKV involve similar clinical symptoms to DENV and CHIKV, which include fever, exanthema, conjunctivitis, retro-orbital headache, and arthralgia . The diaThe symptoms of ZIKV infection usually tend to be mild, and the initial symptoms can escape notice, reducing the opportunity to collect a sample. Although the viremic period has not been completely defined, viral RNA has been detected in serum after the onset of symptoms up to day 10. In addition, RNA particles of ZIKV have been detected in urine over an extended period in the acute phase, leading to the possibility of considering an alternative sample type. Evidence suggests that serum samples should be taken during the first 5 days after the onset of symptoms supported in some more detailed studies . SymptomFigures 1 and 2). However, there is still a need to search for and improve upon more sensitive and reliable detection methods for the challenging virus candidate ZIKV for daily diagnoses. Developed and applied methods for the detection of ZIKV are listed in Table 1.Diagnosis of ZIKV in the laboratory is usually based on the serum analysis employing viral RNA or antibody-based detection assays . However50) in plaque assays - or real-time PCR-based detection methods. In propagated cells, the detection of a virus is confirmed by its cytopathic effect in cell culture, and positive results are confirmed using tissue culture with an infectious dose 50  antibodies typically develop within a few days after the onset of illness and can generally be detected up to three months . In addiin vitro qualitative detection of ZIKV-specific IgM antibodies in human sera. In addition, testing of ZIKV has been applied based on CDC clinical and epidemiological criteria for ZIKV which include clinical signs and symptoms associated with ZIKV infection and/or history of residence in or travel to a geographic region with active ZIKV transmission at the time of travel or other epidemiologic criteria that may indicate ZIKV testing (n = 11), during the ZIKV virus outbreak in Yap , the Centers for Disease Control and Prevention (CDC) requested that a letter be issued authorizing the emergency use of the Zika IgM antibody capture enzyme-linked immunosorbent assay (Zika MAC-ELISA) for the presumptive detection of ZIKV-specific IgM in human sera or cerebrospinal fluid . The Zik testing . As repok in Yap . When MAk in Yap . SubsequAlong with ZIKV and DENV, yellow fever is another acute viral infection transmitted through mosquito bites. It is strongly believed that the current emergence and re-emergence of yellow fever and other arboviruses is partly attributed to the increased migration of people from disease-endemic regions and the expanding establishment of the vector. The use of flavivirus antigens in the development of MAbs and diagnostic tests has not been well documented . The appZika fever is a zoonotic infection caused by ZIKV, which shares the limelight with other well-known members of the flavivirus family, such as DENV, yellow fever virus, West Nile virus, and Japanese encephalitis virus . ConsequOne approach that could be useful for the detection of DENV involves concentrating virus particles using ultracentrifugation and polyethylene glycol-mediated precipitation. Although these methods have been used successfully for variety of viruses, ultracentrifugation shows numerous practical limitations, such as the great amount of time required, which may increase the false-positive rate when applied for PCR analysis . RegardiA number of magnetic nanoparticles, such as iron, nickel, or cobalt, have been successfully used for biomedical and environmental applications due to their highly/specific surface area and the ease of the magnetic collection of target materials adsorbed by the magnetic nanoparticles . HoweverSalmonella antibodies, could be achieved , detection of virus antigen (by ELISA), detection of anti-DENV antibody , and detection of virus nucleic acid . The hemagglutination inhibition is the most widely accepted serological technique in developing countries; however, ELISA has become the technique that is most often applied for the serological diagnosis of DENV infection in DENV epidemic regions due to its stability, simple handling procedure, and no need of any complicated equipments.The characterization and detection of viruses is a labor-intensive and time-consuming process. Upon the emergence of new viral pathogens with a high frequency and catastrophic outbreaks, there is always a need for improved detection and identification methods to control the proliferation of these pandemic viral candidates. Currently, at laboratory scale, only PCR-based molecular techniques provide accurate detection of a variety of viruses based on trial-and-error methods using a cell culture-based procedure. PCR-based methods require thermal cycling instruments and transformation of DENV/ZIKV genomic RNA to DNA . ZaytsevAlthough these techniques are readily available, they are expensive and present engineering challenges regarding miniaturization and field utilization. In addition, PCR products, which consist of double-stranded DNA, must be denatured before being subjected to a probe hybridization-based detection method . In contin vitro and in vivo, providing the potential for drug delivery and imaging in tumors. in vitro and in vivo  according to manufacturer’s recommendations. Extracted RNA was used for further real-time PCR detection system using two real-time primers/probe amplification sets specific for ZIKV  on a nitrocellulose membrane strip, which is exposed to the target antigen, consisting of a virus particle in a solution containing immunoliposome. Liposomes are encapsulated in sulforhodamine B and tagged with anti-ZIKV antibody specific for the binding of the specific ZIKV particle. In the presence of the ZIKV particle, the immunoliposome and ZIKV particle complex migrates along the test strip via capillary action and subsequently binds to the capture antibody zone of the membrane, producing a purple band. However, some of the immunoliposomes do not bind the ZIKV particles at the test line and continue to migrate and bind to the control line of membrane, resulting in the development of a purple band, showing a positive result for the presence of ZIKV particles . In the absence of ZIKV particles in test samples, the immunoliposomes are not able to bind to the specific antigen (ZIKV) and they therefore migrate and bind at control line of the test membrane, leading to the development of a purple line in the control line only, confirming a negative result for ZIKV particle detection . In addition, there is another simple liposome-based detection strategy utilizing a liposome immunoassay, in which detection is measured via the lysis of liposome particles . Furthermore, there might be another strategy for developing a combined assay involving immunoliposomes and immunomagnetic particles for the sensitive detection of ZIKV particles as shown in Figure 5. The assay procedure can be divided into the following three steps: immunomagnetic concentration and separation of target ZIKV; reaction of the immunoliposome particles with virus particles attached to immunomagnetic nanoparticles; and fluorescence signal generation, as the principle of the developed assay discussed in our earlier research    may alsoAlthough few antibody-based ZIKV detection kits are available, we have presented a potentially easy method for the development of pathogen detection kits based on laboratory-produced antibodies and liposomes, which could provide a cheaper alternative for pathogen detection compared with expensive commercial pathogen detection kits. In the near future, studies should attempt to confirm the practical applications of liposome-based virus detection assays in various food samples contaminated with foodborne viruses, including ZIKV.Regarding laboratory safety, ZIKV is classified as a biological safety level 2 pathogenic agent. These pathogens must be handled according to the biosafety guidelines of microbiological and biomedical laboratories, and risk assessment should be performed for each laboratory for any specific procedure used in the laboratory. Because of the major concern regarding congenital microcephaly and ZIKV infection, precautions should be taken by pregnant women while working in the laboratory, and regular ZIKV testing should be maintained in the laboratory. The CDC recommends that each laboratory should perform risk assessment when implementing any new viral methodology in the laboratory as a safety precaution .The widespread ZIKV epidemic in the Americas and Asia has led to the urgent need to develop rapid, sensitive, and specific assays for virus detection with regular monitoring of viral infection. Rapid detection of the virus in field-collected specimens can accelerate the application of appropriate mosquito control measures that could prevent transmission and disease among human populations. Early diagnosis of ZIKV infection, supportive care, symptomatic treatment, and referral of children with microcephaly to specialized care are all necessary measures to improve the neuro-development of affected children. The hypothesis and strategies that we have presented herein provide a relevant platform, emphasizing the importance of liposome-based detection methods in ZIKV diagnosis for improving global health. In overall view, the best advantage of these hypothesized assays is easy handling, no requirement of any sophisticated instruments, rapid detection efficacy, and cost effectiveness than other molecular approaches. On the other side, major limiting factor of these hypothesized assays especially for the detection of viral infections including ZIKV, DENV, and others is their antigen-antibody-based detection ability. Identification of major antigenic and protective epitopes of the target virus particles importantly needed to understand the antibody response while developing these detection strategies. In brief, virus particles can easily go for mutation, and antigenic variations by which an infectious virus alters its surface proteins called antigenic structure eventually result in the differentiation of virus strains. These antigenic variations make difficulty in the process of specific antibody production, thus, may affect in the developmental process of these diagnostic assays. In conclusion, the present review summarizes and updates the methods available for the detection of ZIKV in human clinical samples. New insights and interpretations should be obtained by studying the mechanisms of several similar detection strategies that are being developed. Innovative approaches based on liposome particles should be of interest for the detection of ZIKV, particularly in relation to previously developed liposome-based strategies, which may provide new insights for future research and strategies for the development of fast and sensitive assays for ZIKV infections.MK and SS conceived and designed the review theme. S-YH and SHC helped in writing and reviewing the paper.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.


Cancer is a genetic disease characterized by unregulated growth and dissemination of malignantly transformed neoplastic cells. The process of cancer development goes through several stages of biochemical and genetic alterations in a target cell. Several dietary alkaloids have been found to inhibit the molecular events and signaling pathways associated with various stages of cancer development and therefore are useful in cancer chemoprevention. Cancer chemoprevention has long been recognized as an important prophylactic strategy to reduce the burden of cancer on health care system. Cancer chemoprevention assumes the use of one or more pharmacologically active agents to block, suppress, prevent, or reverse the development of invasive cancer. Piperine is an active alkaloid with an excellent spectrum of therapeutic activities such as anti-oxidant, anti-inflammatory, immunomodulatory, anti-asthmatic, anti-convulsant, anti-mutagenic, antimycobacterial, anti-amoebic, and anti-cancer activities. In this article, we made an attempt to sum up the current knowledge on piperine that supports the chemopreventive potential of this dietary phytochemical. Many mechanisms have been purported to understand the chemopreventive action of piperine. Piperine has been reported to inhibit the proliferation and survival of many types of cancer cells through its influence on activation of apoptotic signaling and inhibition of cell cycle progression. Piperine is known to affect cancer cells in variety of other ways such as influencing the redox homeostasis, inhibiting cancer stem cell (CSC) self-renewal and modulation of ER stress and autophagy. Piperine can modify activity of many enzymes and transcription factors to inhibit invasion, metastasis, and angiogenesis. Piperine is a potent inhibitor of p-glycoprotein (P-gp) and has a significant effect on the drug metabolizing enzyme (DME) system. Because of its inhibitory influence on P-gp activity, piperine can reverse multidrug resistance (MDR) in cancer cells and acts as bioavailability enhancer for many chemotherapeutic agents. In this article, we emphasize the potential of piperine as a promising cancer chemopreventive agent and the knowledge we collected in this review can be applied in the strategic design of future researches particularly human intervention trials with piperine. Cancer is a deadly disease affecting human health in today's world and causes a huge economic and human loss throughout the world  can initiate tumor growth in animal models and transform normal cells into mass of neoplastic cells  and Piper longum L. (long pepper) species of Piperaceae family , free radicals, and ultimate reactive forms produced from metabolic activation of procarcinogens are known to assume a critical role in cancer development , cyclins, and CDK inhibitors (CKIs). Cancer development is often associated with loss of cell cycle regulation  are known to exist in several forms of human cancers and have profound implications for cancer chemoprevention. Cancer stem cells undergo continuous self-renewal and differentiation, giving rise to a heterogeneous mass of cancer cells  is the most dangerous type of human breast cancer  system  in cancer is a severe problem that limits the use of chemotherapeutics in successful treatment of cancer  has long been used in cancer therapy -R causes DNA damage (mutations) and induces excessive generation of reactive oxygen species (ROS) which leads to cancer initiation and promotion. Piperine is a potential photochemopreventive agent. Piperine attenuates the (UV)-R induced DNA damage in human HaCaT keratinocytes through its influence on the NF-κB and Bax/Bcl-2 pathways (Verma et al., There are a large number of alkaloids that can prevent the development of cancer. Many natural alkaloids have been screened, identified, and developed successfully into FDA-approved anticancer drugs. Chemoprevention, using phytochemicals from fruits, vegetables, and spices, is an important prophylactic strategy against cancer development. Piperine has recently garnered much attention for its chemopreventive properties. Piperine possesses potential chemopreventive properties which may be due to induction cell cycle arrest, increased cell apoptosis, disruption of redox homeostasis, attenuation of CSC self-renewal, inhibition of angiogenesis, modulation of ER stress, and autophagy, influence on the Wnt/β-catenin and inhibition of PI-3K/Akt signaling pathways. Notably, the hydrophobic nature and poor aqueous solubility of piperine limits the clinical use of this natural molecule. The information collected by us in this review has revealed that piperine can target different types of cancer cells specifically and manifest specific mechanisms of action in accordance with the type of cancer it acts on. However, the exact mechanism involved in the chemopreventive effects of piperine against the cancer development is not fully understood. Therefore, the precise mechanism of action of piperine must be validated before final recommendations on the clinical use of this natural molecule can be made. The hope is that piperine could be administered with minimum risk to human subjects and that it would produce a significant chemopreventive effect.RR conceived the idea and wrote the manuscript, MB edited the manuscript and helped to improve the quality of this review paper.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.


Adverse reactions to commonly prescribed medications and to substances of abuse may result in severe toxicity associated with increased morbidity and mortality. According to the Center for Disease Control, in 2013, at least 2113 human fatalities attributed to poisonings occurred in the United States of America. In this article, we review the data regarding the impact of systemic sodium bicarbonate administration in the management of certain poisonings including sodium channel blocker toxicities, salicylate overdose, and ingestion of some toxic alcohols and in various pharmacological toxicities. Based on the available literature and empiric experience, the administration of sodium bicarbonate appears to be beneficial in the management of a patient with the above-mentioned toxidromes. However, most of the available evidence originates from case reports, case series, and expert consensus recommendations. The potential mechanisms of sodium bicarbonate include high sodium load and the development of metabolic alkalosis with resultant decreased tissue penetration of the toxic substance with subsequent increased urinary excretion. While receiving sodium bicarbonate, patients must be monitored for the development of associated side effects including electrolyte abnormalities, the progression of metabolic alkalosis, volume overload, worsening respiratory status, and/or worsening metabolic acidosis. Patients with oliguric/anuric renal failure and advanced decompensated heart failure should not receive sodium bicarbonate. In the USA, at least 34% of the population regularly takes at least one prescription medication . In the The goal of this article is to review the data and evidence on the use of sodium bicarbonate in the management of some pharmacological overdoses. We will first briefly review the mechanisms of metabolic acidosis related biochemical derangements since some of the overdoses are associated with metabolic acidosis. Second, we will discuss the mechanism of action, potential side effects, and typical dosing of sodium bicarbonate. Third, we will review the literature on the role of sodium bicarbonate in the management of sodium channel blocker toxicities. Fourth, the data on the role of sodium bicarbonate in the management of salicylate poisoning will be provided. Finally, we will discuss the place of sodium bicarbonate in the management of toxic alcohol ingestions.The management of the toxicities mentioned above is complicated, requiring additional measures than sodium bicarbonate alone. Additional information on other aspects of management can be obtained elsewhere and is not the goal of this article.2) is a major byproduct of energy metabolism in living organisms and a conjugate acid. Carbonic anhydrase enzyme facilitates the chemical interaction between CO2 and water producing carbonic acid (H2CO3). Carbonic acid in turn dissociates into bicarbonate (HCO3−) and hydrogen ion (H+) with the latter being removed via kidneys. HCO3− can also bind extra H+ producing carbonic acid. Indeed, all the reactions are reversible and can go in any direction.Bicarbonate is an essential chemical regulating the acid-base balance acting as a buffer . Carbon 3) is one of the few pharmacological agents aiming to mimic the endogenous effects of HCO3−. Sodium bicarbonate is widely used in many clinical situations including cardiac arrest [Sodium bicarbonate NaHCO is one oc arrest  and prevc arrest  and in pc arrest , despiteThe potential benefits of exogenous intravenous sodium bicarbonate include the correction of metabolic acidosis with its associated detrimental effects. However, the role of sodium bicarbonate in the management of acute acidosis remains controversial and may even be associated with potential side effects and complications such as volume overload, metabolic alkalosis, hypercapnia, hypokalemia, hypernatremia and hyperosmolality, and ionized hypocalcemia , 7.When administered, sodium bicarbonate dissociates into a molecule of sodium and bicarbonate. The molecule of bicarbonate in turn binds hydrogen converting into carbonic acid with its subsequent dissociation into carbon dioxide and water.2 penetrates cellular membranes easily, and through this ability may exacerbate intracellular acidosis. Furthermore, by correcting the systemic acidosis, sodium bicarbonate administration may reduce respiratory drive leading to accumulation of CO2 in the central nervous system and associated adverse neurological sequelae [Carbon dioxide under normal conditions (intact lung perfusion and ventilation) is exhaled, maintaining delicate acid-base equilibrium. Under extreme conditions such as shock states and impaired ventilation, carbon dioxide may accumulate, leading to worsening acidosis , 9. CO2 sequelae . Serum psequelae , which msequelae . Serum ssequelae . Lactic sequelae , 14, andsequelae . Decreassequelae , 17. LasNevertheless, these adverse effects of sodium bicarbonate such as an increase in systemic pH and high sodium load may be useful in the management of certain pharmacological toxicities and overdoses. Below we will review the utility and likely mechanisms of sodium bicarbonate in the management of certain pharmacological toxicities: sodium channel blockers, salicylates, methanol and ethylene glycol poisonings, and, finally, miscellaneous pharmacological toxicities.Sodium channels are essential ion channels responsible for transcellular sodium influx, primarily in cardiac and neurological tissue . PharmacTricyclic antidepressants (TCAs) are among the oldest antidepressant medications that may also be used in the management of mood disorders, generalized anxiety disorder, panic disorder, and neuropathic pain . DespiteThe scientific data on the use of sodium bicarbonate in the management of TCA toxicity is predominantly originated from animal studies, case reports, and case series , 33. SodBased on clinical experience and available literature, the majority of patients tend to respond via improvement in hemodynamic and ECG parameters. 12-lead ECG of sodium channel blocker toxicity before and after administration of sodium bicarbonate is presented in Figures It may be necessary to continue sodium bicarbonate after bolus doses in the form of IV infusion by diluting 2-3 ampules in 1 liter of dextrose 5% solution that is nearly isotonic to plasma to decrease the risk of potential rebound deterioration, while, on IV sodium bicarbonate, patients should be monitored for evidence of fluid overload, respiratory status with advanced airway management when indicated, electrolyte abnormalities , and metabolic alkalosis . It is important to keep in mind that because of its anticholinergic properties, the absorption of the TCA may be delayed ; these patients should be closely monitored, and, in cases of reemerging symptoms, sodium bicarbonate and other therapies must be timely administered. Patients treated with sodium bicarbonate should be monitored in the intensive care setting with continuous monitoring and reassessment. Frequency of laboratory testing and electrocardiographic monitoring should be individualized. Blood gas analysis  and chemistry tests should be monitored at least every 4 hours or more frequently if clinically indicated in patients treated with sodium bicarbonate. It is important to keep calcium and potassium within normal range and replete them if low to decrease the risk of cardiac arrhythmias.Other medications such as antiarrhythmics –38, non-In conclusion, the literature on the use of sodium bicarbonate in the management of sodium channel blocker toxicities is limited to animal research and case series; randomized trials are precluded due to ethical reasons. IV sodium bicarbonate should be considered in the cases of suspected sodium channel blocker toxicity associated with hemodynamic and ECG abnormalities, given the very high risk of adverse outcome without aggressive treatment . NeverthSalicylates are a group of pharmacological agents that include aspirin, bismuth salicylate, and local skin preparations such as salicylic acid and methyl salicylate  , 52. AspAnalgesics, including aspirin, were the most common etiology of all drug poisonings in the USA, with salicylate poisoning leading to a fatal outcome in 34 patients out of 2113 deaths reported in 2013 . The majPatients with salicylate toxicity typically present with tinnitus, gastrointestinal complications , hyperthermia (via uncoupling of oxidative phosphorylation), pulmonary edema, and mixed acid-base disorder  .Alkalinization with sodium bicarbonate is an essential component of management of the aspirin-poisoned patient. The first report in the English language medical literature of the positive effect of sodium bicarbonate in the management of salicylate-poisoned patient originates in 1948 .−) and uncharged  form: H+ + sal−  ⇔ HS. Uncharged molecules (HS), unlike charged molecules , can move easily across cellular barriers, including the blood-brain barrier and the epithelium of the renal tubule. Metabolic acidosis drives the above reaction to the right and increases the plasma concentration of HS, thereby promoting diffusion across the blood-brain barrier into the CNS. In patients with salicylate intoxication, the beneficial effects of sodium bicarbonate are mediated by the production of metabolic alkalosis that decreases the amount of lipid soluble salicylate and driving the above reaction to the left resulting in decreased penetration into central nervous system and in increased urinary clearance [Salicylic acid (HS) is a weak acid that exists in a charged  converting the parent alcohol into formaldehyde and glycolaldehyde, respectively. The metabolism of methanol and ethylene glycol disrupts cellular energy metabolism leading to cellular damage , 59. TheClinical presentations of methanol and ethylene glycol overlap, including central nervous system (CNS) symptoms such as headache, altered mental status, and seizures. Retinal toxicity and blindness are more specific for methanol; acute kidney injury and hypocalcemia are more typical for ethylene glycol intoxication. Laboratory testing and diagnosis are based on the presence of high anion gap metabolic acidosis, the presence of a serum osmolal gap , and measuring the levels of toxic alcohols .As in the management of other discussed toxidromes, the literature on the benefits of IV sodium bicarbonate originates from case reports and consensus guidelines , 59. BenIV administration of sodium bicarbonate may result in enhanced urinary excretion of certain chemicals through urinary alkalinization . The uriMetformin toxicity is another instance where sodium bicarbonate may be used . In rareIn conclusion, the data on the role of sodium bicarbonate in the management of the above-listed medications is even more limited and cannot be recommended as a first line.Based on the available literature and empiric experience, the IV administration of sodium bicarbonate appears to be beneficial in the management of certain pharmacological toxicities such as sodium channel blockers poisonings, salicylate intoxication, and ingestion of methanol and ethylene glycol. However, most of the data originates from case reports, case series, and expert consensus recommendations. The data on the management of metformin-associated lactic acidosis, chlorpropamide, methotrexate, and phenobarbital is even more limited. However, it seems very unlikely that randomized controlled trials assessing the impact of sodium bicarbonate will be performed due to ethical concerns.2 production), and worsening metabolic acidosis . Frequency of laboratory testing should be individualized. Blood gas analysis  and chemistry tests should be monitored at least every 4 hours or more frequently if clinically indicated in patients treated with sodium bicarbonate. It is important to keep calcium and potassium within normal range to decrease the risk of cardiac arrhythmias.The potential mechanisms of sodium bicarbonate administration include high sodium load, development of metabolic alkalosis with resultant decreased tissue penetration of the toxic substance, and its increased urinary excretion, while, on IV sodium bicarbonate, the patients must be monitored for the development of associated side effects including electrolyte abnormalities , progression of metabolic alkalosis volume overload, worsening respiratory status (volume overload and increased COPatients with oliguric/anuric renal failure and advanced decompensated heart failure should not receive IV sodium bicarbonate. IV administration of sodium bicarbonate represents only one aspect of the complex management of medication and chemical toxicities, and, for a thorough discussion of the management of these toxicities, the reader is referred to focused reviews.


Anorectal melanoma is an uncommon and aggressive mucosal melanocytic malignancy. Due to its rarity, the pre-operative diagnosis remains difficult. The first symptoms are non-specific such as anal bleeding, anal mass or pain. Although anorectal melanoma carries a poor prognosis; optimal therapeutics strategies are unclear.Surgical resection remains the mainstay of treatment. The optimal surgical procedure for primary tumours is controversial and can vary from wide local excision or endoscopic mucosal resection (EMR) to an abdomino-perineal resection.A high degree of uncertainly exists regarding the benefit of radiation therapy or chemotherapy. The treatment of advanced melanoma is evolving rapidly with better understanding of the disease biology and immunology. Considerable effort has been devoted to the identification of molecular determinants of response to target therapies and immunotherapy. Anorectal malignant melanoma (ARMM) is a rare and highly malignant tumor with less than 5 year survival of 10% patients .ARMM is often misdiagnosed in about two thirds of patients and most often as haemorrhoids, adenocarcinoma polyps and rectal cancer . The typComparing ARMM with other anorectal carcinomas, tumour cells can exhibit multiple cell types characteristics , 7.The poor knowledge about aetiology, pathogenesis and genetics of ARMM makes difficult proper diagnosis, treatment and prognosis.ARMM accounts for only 1.3% of all melanomas and 16.5% of mucosal melanomas . The incLesions can affect anal canal, rectum or both, but the great majority of tumours are located with in 6 cm of the anal rim .Approximately 20–30% of ARMMs are amelanotic, can endoscopically resemble benign polypoid lesions, and unspecific symptoms can contribute to misdiagnosis , 13.Amelanotic lesions are frequent in mucosal melanoma . The incAmelanotic ARMMs can present some pigmentation at the periphery of the lesion and it is characterised by a worse prognosis because of the difficulty of diagnosis and the invasive nature , 19.The anal canal is derived from the hindgut proximally by the upper limit of the anal transition zone (ATZ) and the ectodermal proctodeum distally with the dentate line at the fusion point , 20.Melanocytes arise from neuro-ectodermal multipotent neural crest cells .Melanocytes can be found in the anal squamous zone, sometimes in the anal transitional zone and never in the colorectal zone. These potential cells migrate via the umbilical-mesenteric canal and later differentiate into specialized cells, which undergo neoplastic transformation. According to this theory, ileum that represents the distal end of the umbilical mesenteric canal should be the commonest of primary malignant melanoma of the small intestine . HoweverMelanocytes are melanin-producing somatic cells, which provide physiological functions .Melanin plays a key role in protection from stressors such as UV radiation, acting as sunscreen, or as metal ion and radical scavenger, energy transducer and also it can bind organic molecules and some drugs. Melanocytes in mucosal membranes are involved not only in antimicrobial defence, but also in the protective role of immune response and probiotics that may interact with the host , 25. ImmIn gastrointestinal barrier, melanocytes are important for structural changes in the epithelium, promoting the formation and the redistribution of some protein, in order to support the physical barrier; whereas in the mucous barrier, melanocytes induce mucin production in the Globet cells and up-regulates defensin production in the Paneth cells , 29.There are evidences supporting other non pigment-related functions of melanocytes such as antimicrobial and immunologicalmetabolic, endocrine, chemical and physical functions .Melanin is produced within membrane-bound organelles (melanosomes), which are transferred to the dendrites and eventually phagocytized by the keratinocytes. Melanoblasts, precursor cells to melanocytes, migrate during foetal development, throughout the dermis to the skin, the eye, the inner ear and the leptomeninges . The pigMelanocytes in the ano-genital give rise to melanomas that have a low mutation burden but highly rearranged genomes with numerous copy number changes, including multiple focused amplifications.Melanosomes are organelles of melanocyte important not only for melanin biosynthesis, but also because they contain proteins and enzymes useful to maintain melanosome structure and to the maturation of the immature pre-melanosome .The pathogenesis of anorectal melanomas is limited and obscure.There are several theories for the origin of malignant melanoma in the gastro-intestinal tract. Although anorectal contains no melanocytes, these cells have been occasionally found in the alimentary tract. Some authors suggest that malignant melanoma develops from intestinal Schwann cells. Other authors proposed that malignant melanomas originate from neural crest and during embryogenesis migrated to the basal layer of the epidermis and the hair follicles , 20, 33.The diagnosis of ARMM remains difficult for the non specificity of the symptoms and the diagnosis is frequently made after treatment for presumed benign disease, such as hemorroidectomy.The evaluation of the primitivity include presence of single lesion, absence of other primary site melanoma, no history of removal of melanoma or atypical melanocytic lesions, the presence of lymphocytes infiltration surrounding tumour mass  and abseet al. ..137].Little is known about the prognostic parameters, staging and treatment protocols  The anorThis tumour is characterized by aggressive behaviour, poor outcome as result of late diagnosis and fast tumour growth in the rich vascular and lymphatic supply of the ano-rectal mucosa .Considerable effort has been devoted to the identification of molecular determinants underlying melanoma chemo and immunoresistence . Today aThe biologic and clinical heterogeneity of cutaneous malignancies and mucosal melanomas provide a number of unique opportunities and challenges for preclinic and clinical studies.New targeted therapies (and immunotherapies) are under investigation for patients with both metastatic and primitive melanoma.Better understanding of genetic aberrations in mucosal melanoma could provide development of targeting and effective treatment –143.


An articulated and partially preserved skeleton of an ichthyosaur was found in the Upper Jurassic (Upper Kimmeridgian) Katrol Formation exposed at a site south of the village Lodai in Kachchh district, Gujarat (western India). Here we present a detailed description and inferred taxonomic relationship of the specimen. The present study revealed that the articulated skeleton belongs to the family Ophthalmosauridae. The new discovery from India further improves the depauperate fossil record of ichthyosaurs from the former Gondwanan continents. Based on the preserved length of the axial skeleton and anterior part of the snout and taking into account the missing parts of the skull and postflexural region, it is suggested that the specimen may represent an adult possibly reaching a length of 5.0–5.5 m. The widespread occurrence of ophthalmosaurids in the Upper Jurassic deposits of western Tethys, Madagascar, South America and India points to possible faunal exchanges between the western Tethys and Gondwanan continents through a southern seaway. Ichthyopterygia is a highly successful group of marine reptiles that appeared in the Early Triassic (Olenekian) from a possible diapsid ancestral lineage, survived until the middle Late Cretaceous (Late Cenomanian) and had a worldwide distribution , 2. ThouDue to the extensive collections of ichthyosaurs from the UK and mainland Europe, historically the research on ichthyosaurs was biased towards the Laurasian continents. In the former Gondwanaland, the Jurassic ichthyosaur fossil record is very limited with most reports coming from the Middle and Upper Jurassic strata of Argentina , 7–9. UnIchthyosaurus indicus because of a deep concavity of the centra. I. indicus was considered nomen dubium by McGowan and Motani [Platypterygius indicus because of the morphological similarity of the teeth to Platypterygius and proximity of the two ichthyosaur fossil sites within the Karai Formation [Platyptrerygius also occur in Brachypterygius and thus suggested that the placement of teeth from the Karai Formation in P. indicus is tentative. Later reviews of Platypterygius species have shown that the vertebrae reported by Lydekker are referable to Ichthyosauria indet. as they lack diagnostic characters. Further it was felt that among the teeth only DUGF/41 can be referred to subfamily Platypterygiinae gen. indet. because of its square rooted cross-section and the rest should be placed in the order Ichthyosauria fam. indet. [In India, ichthyosaur remains have been reported previously from the Lower Cretaceous (Upper Albian—Middle Cenomanian) Karai Formation of the Cauvery Basin in South India –26. But d Motani . Five coormation . Zammit ormation  observed. indet. . AlthougThaumatosaurus indicus Lydekker [Katrolensis Ammonite Zone, equivalent of the Beckeri Zone of the Western Tethys, as representing the plesiosaur family Cryptoclididae. They also redescribed a plesiosaur mandibular symphysis from the Lower Cretaceous Bhuj Formation, Kachchh, housed in the Indian Museum, Kolkata. This specimen, initially referred to Thaumatosaurus indicus [Simolestes indicus [Steneosaurus were also reported from marls of the Chari Formation underlying the Dhosa Oolite about 10 km southwest of Bhuj [The Jurassic succession of the Kachchh Basin preserves rocks ranging in age from Aalenian to Tithonian but has yielded only a few marine reptiles. One plesiosaurian vertebra associated with a few fragmentary rib bones was documented from the Upper Tithonian to Neocomian Bhuj Formation from a site near Umia (Amiya) village and was assigned to Lydekker . Bardet Lydekker  describe indicus , 31, was indicus . Two lar of Bhuj . The relThe Kachchh Basin is a pericratonic E-W oriented rift basin on the western margin of India, which was formed during Late Triassic rifting between India and Africa . In the The Mesozoic rocks of Kachchh were first described by Wynne . HoweverKatroliceras lerense Spath, 1931 and Katroliceras sp. , one displaced possible right forefin, and non-preservation of hindfins, pectoral and pelvic girdles and part of the posterior tail bones may be interpreted in terms of scavenging, reworking, and partial burial of the skeleton with the exposed parts being subjected to disarticulation and decomposition . The verSuperorder Ichthyopterygia Owen, 1840Order Ichthyosauria de Blainville, 1835Family Ophthalmosauridae Baur, 1887Ophthalmosauridae gen. et sp. indet.Figs –12Partially preserved skeleton (KGMV 0501) consisting of premaxilla, articulated vertebrae, left forefin, and? right forefin. Two fairly well-preserved teeth (KGMV 0502–0503), one posterior caudal vertebra (KGMV 0504), three postflexural caudal vertebrae (KGMV 0505–0507), three isolated phalanges (KGMV 0508–0510) and two mandibular fragments (KGMV 0511–0512) found scattered around the articulated skeleton are considered to belong to KGMV 0501.Greenish-yellow shales of the Katrol Formation representing the Katrolensis Zone of the Upper Kimmeridgian age  exposed The studied specimen comprises a large, partial skeleton that is mostly articulated (KGMV 0501). The preserved skeletal remains include an incomplete premaxilla, articulated vertebrae of cervical, dorsal and pre-flexural regions, left forefin, possible right forefin all in articulation and isolated teeth, vertebrae of posterior caudal and postflexural regions, and phalanges possibly belonging to the articulated skeleton. Some of the anterior vertebrae, many of the caudal vertebrae and perhaps the pelvic remains are missing. The fin lying close to the vertebral column anteriorly is the left forefin in its original position with only a slight dislocation from the axial skeleton . The posThe incomplete premaxillary bone is 36 cm in length . The preThe broad groove between the palatal process and the facial part on either side is broad, deep and holds one tooth each (in cross section) Figs  and 5. TOne of the preserved teeth in the premaxilla is very robust  and has a worn rounded apex . This toPlatypterygius, its cross-section may have been circular or oval in shape. KGMV 0502 is similar to KGMV 0503 in the morphology of its crown and smooth dentine layer, but its basal cellular cementum layer is not preserved (Two teeth (KGMV 0502–0503) were found on the surface at the excavation site close to the anterior end of the articulated axial skeleton and probably belong to this specimen. KGMV 0503, the better preserved of the two teeth, has a crown with longitudinal striations that do not reach the apex, smooth and short acellular cementum (dentine) layer, and the basal elongated and flaring, porous cellular cementum with fine longitudinal ridges . In thisreserved . At the The preserved length of the axial skeleton is 3.6 m . The verOne large and three small vertebrae were collected as float during the excavation of the articulated skeleton. Based on the criteria used by McGowan and Motani  and KirtOne specimen (KGMV 0504) of the present collection of isolated vertebral centra can confidently be identified with posterior caudal vertebra. KGMV 0504 is anteroposteriorly flattened and disc-like (length of the centrum = 2.7 cm) Figs . In the There are three centra in the Kachchh ichthyosaur collection, which can be referred to the postflexural vertebrae Figs . KGMV 05One proximal shaft of an isolated rib lying dorsally and near to the posterior end of the vertebral column is double-headed and has an elliptical cross-section . The remExcept for the posterior region beyond the displaced? right forefin, the neural spines are preserved all along the dorsal surface of the vertebral column . They arA few clustered, short, rod-like bones of gastralia are found in the posterior region of the skeleton just anterodorsal to the preserved? right forefin . They arThe exposed surface of the left forefin  is consiThere is a second fin  located Three isolated phalanges were surface-collected from the site of the articulated skeleton (KGMV 0508–0510). One of them is rectangular in outline (KGMV 508), dorsoventrally thick and most likely a proximal one . Two of The Callovian and post-Callovian ichthyosaurs are generally included in the family Ophthalmosauridae , 46–50, The documented fossil record of Middle-Late Jurassic ichthyosaurs is highly skewed towards the western Tethys (Anglo-Paris Basin), North America, and Northern Europe . But recent reports of ophthalmosaurid ichthyosaurs from Argentina, Mexico, Cuba, Madagascar, Australia and now from India clearly indicate that the apparent restricted distribution is due to poor sampling in these parts of the world. In their classic work, McGowan and Motani  considerPlatypterygius, Undorosaurus, Brachypterygius and Maiaspondylus [A squared root cross-section of pondylus , 65, 66 pondylus . A compapondylus . The toopondylus .Aegirosaurus from the Early Tithonian of Germany [Aegirosaurus is widest at the distal end as in the Kachchh specimen [Aegirosaurus has a broad and distally less extended dorsal process situated at the proximal end of the humerus, an angulated distal margin, and more tightly packed fin elements which are to a large extent rectangular in outline. Cryopterygius kristiansenae from the Tithonian of Svalbard, Norway [Cryopterygius, however, the dorsal process of the humerus arises from the postaxial margin and its long axis trends anterodistally towards the midline and the fin is slightly asymmetrical.The little morphological information that could be deciphered from the proximal part of the left forefin distal to the humerus in its current state of preparation limits its comparison with other known ophthalmosaurids, but still some general conclusions can be made. In general, the outline of the forefin, being elongated and narrow anteroposteriorly, is comparable to that of  Germany . The humspecimen . However, Norway , has alsArthropterygius, Undorosaurus, Cryopterygius, Janusaurus, Sveltonectes, Maiaspondylus and Platypterygius. In Caypullisaurus, the distal end of the humerus is obliquely oriented to the long axis with a short angulation at the anterodistal end and the fin is long as in the Kachchh specimen  with a well constricted mid-shaft and a distal end more anteroposteriorly expanded than the proximal end differs from that of pecimen (: fig.5).lisaurus . In the tonectes , 59, 67 tonectes . In factal facet . But in Cryopterygius, Aegirosaurus and Brachypterygius. The phalanges of this specimen are rounded, widely spaced and dorsoventrally thick as in Ophthalmosauridae and their closest sister taxon Chacaicosaurus [Caypullisaurus, Platypterygius, Brachypterygius, Aegirosaurus and Maiaspondylus, the fin elements are rectangular in outline and tightly packed [Ophthalmosaurus icenicus though the fin is broader in its middle, distal to the epipodials in the latter. The distal end of the humerus is also nearly straight in O. icenicus as in the Kachchh specimen though angulated posteriorly in the former. The relatively dorsoventrally thick elements of the fins are characteristic of the family Ophthalmosauridae [Chacaicosaurus [The better-preserved left forefin of the Kachchh specimen has six digits as in cosaurus . In manyy packed . In the sauridae . Howevercosaurus .Ophthalmosaurus icenicus from the Oxford Clay. However, McGowan and Motani [In its shape, transverse width and height proportions, and location of the single rib facet slightly below the mid-height, KGMV 0504 compares very well with the one figured by Kirton (: fig.20 d Motani  noted thBesides using to distinguish between different groups of ichthyosaurs  and someThe two isolated teeth (KGMV 0502–0503) found on the surface close to the skeleton are embedded in the maroon-coloured ferruginous matrix and their surfaces were exposed during preparation. These teeth have finely fluted crowns with blunt conical apices and do not show any apical wear except for a rugose appearance and smoothening. KGMV 0502 displays a narrow strip (ribbon-like) of longitudinal wear on the enamel of the crown on its labiolateral face. Preliminary preparation of the premaxilla exposed one nearly complete large tooth . It has Dakosaurus, a metriorhynchid crocodile from the Late Jurassic of Europe, Young et al. [Dental wear surfaces due to attrition (tooth/tooth contact) or abrasion (tooth/food contact) on teeth are not very common in non-mammalian tetrapods . While sg et al.  noticed Dakosaurus. In contrast, the wear surfaces on the mesial and distal carinae and the semi-circular wear facet at the base of the crown characteristic of marine metriorhynchid crocodiles are not present on the premaxillary tooth of KGMV 0501. Examination of mosasaur, plesiosaur and ichthyosaur skeletons housed at the AMNH by Young et al. [In case of the premaxillary tooth of the Kachchh specimen, the apex is not broken but worn flat. There is another in-situ tooth in the premaxilla that shows a broken crown apex . It is, g et al.  revealedg et al. .According to the definition of Massare , the teeMiddle and Late Jurassic ichthyosaurs primarily represented by ophthalmosaurids have been widely documented from the western Tethys , the Boreal region  and North America . HoweverThe Jurassic ichthyosaurs from South America (Argentina and Chile) are shown to be closely related to those from the Tethys region , 74. BasArthropterygius in Northern Europe, Argentina and Canada suggested that the southern seaway might have become operational by the Late Tithonian and Berriasian.However, a second dispersal route extending from Iraq-Kurdistan, East Africa, western India, Mozambique, Madagascar, and eastern Antarctica to the interconnected rift grabens (Rocas Verdes Basin) of southern Patagonia was also suggested based on the presence of similar bivalve, belemnite and ammonoid faunas in the Upper Jurassic rocks of these areas , 86. TheThe Jurassic succession of the Kachchh Basin contains marine fauna that is very similar to that of Madagascar and therefore belongs to the Ethiopian or Indo-Madagascan faunal province. Based on the study of nautiloids, Halder  suggesteIndosphinctes, Oxfordian Larcheria [Nebrodites and Late Kimmeridgian—Early Tithonian Hybonoticeras [Tithopeltoceras and Durangites of the Mediterranean Province and Himalayites of the Mediterranean Tethys and Indo-Madagascan Province in the Late Tithonian fauna of Kachchh has been explained in terms of interprovincial migrations facilitated by high sea level [In the Jurassic fauna of Kachchh, there are several examples of episodic faunal exchanges between the Indo-Madagascan and the Mediterranean provinces. These include the Callovian reineckeiids , Indospharcheria , Kimmerioticeras . The appea level –107. Manea level .Corongoceras cf. C. lotenoense in the Tithonian of Kachchh and Virgatosphinctes, Blanfordiceras, Spiticeras in the Andes [Megacucullaea, a bivalve, considered to be endemic to the Indo-Madagascan Province, reached the Andes in the Late Jurassic [A two-way marine dispersal route between Kachchh and the Andes Basin via Madagascar and South Africa has also been visualized in view of the occurrence of he Andes , 106. SiJurassic , 107.Prior to the present ichthyosaur discovery, a cryptoclidid plesiosaur, a Middle-Late Jurassic plesiosaur widely known from western Europe, was documented from the Upper Jurassic Katrol Formation . This maOphthalmosaurus, Arthropterygius and Aegirosaurus.The present ichthyosaur find represents the first nearly complete articulated skeleton of an ichthyosaur from India and the first record from the Jurassic of India. It further expands our knowledge on morphological diversity and geographic distribution of Late Jurassic ophthalmosaurids, their dietary habits and palaeobiogeography. At present, the specimen cannot be positively identified with known Jurassic ichthyosaur taxa from other parts of the world because of its encrustation in ferruginous rock matrix, which conceals much of the morphological information. In its dental characters and vertebral and forefin morphology, KGMV 0501 is referable to the ichthyosaur family Ophthalmosauridae. However, the currently available limited number of characters is inadequate to establish generic or species level relationships within the family. In general, the morphology of humerus and forefin indicate close similarities with The preserved axial skeleton measures 3.6 m in length. If the partially preserved snout (36 cm), the missing posterior skull region and post-flexural tail are taken into account, the ichthyosaur from Kachchh may have had an estimated length of 5.0–5.5 m. In this respect, it may represent an adult animal that was comparatively large in size with respect to other Late Jurassic ichthyosaurs , 59. ItsAlthough the taxonomic position of the Kachchh ichthyosaur within the family Ophthalmosauridae is unresolved at the moment, it represents one of the few ichthyosaur finds from the Jurassic of the least explored former Gondwanaland. It adds to the already known ichthyosaur discoveries of Argentina, Madagascar, New Zealand, Australia, Antarctica and Chile thereby improving the fossil record of this group of marine reptiles from the former Gondwanaland. The presence of ophthalmosaurid ichthyosaurs in the Upper Jurassic of India, Madagascar and South America implies that a marine seaway possibly connected the western Tethys with South America via the Indian Ocean in the Late Jurassic facilitating faunal exchanges between Europe and Gondwanan continents. Identification of the Kachchh specimen below family level is crucial for understanding its phylogenetic relationships to contemporaneous taxa from the former Gondwanaland and Laurasia and consequent palaeobiogeographic connections. The articulated nature of the Kachchh ichthyosaur and the previous record of plesiosaur remains from the Kimmeridgian and Tithonian rocks of the Kachchh Mainland further indicates that focused research in remote areas of Kachchh may lead to more exciting finds in the future.


The number of granulocytes is maintained by a regulated balance between granulopoiesis in the bone marrow and clearance and destruction in peripheral tissues. Granulopoiesis plays a fundamental role in the innate immune response. Therefore, factors affecting the normal granulopoiesis lead to alterations in innate defenses and reduce the resistance against infections. In this study, we give a description on recent advances regarding the molecular and cellular events that regulate steady-state and emergency granulopoiesis, which are crucial processes for the generation of protective innate immune responses. Particular attention will be given to emergency granulopoiesis alterations in immunosuppression states caused by malnutrition and chemotherapy. The role of microbiota in maintaining a steady-state granulopoiesis and the immunological mechanisms involved are also discussed. Moreover, we describe the findings of our laboratory demonstrating that the dietary supplementation with immunobiotics is an interesting alternative to improve steady-state and emergency granulopoiesis, the respiratory innate immune response, and the resistance against respiratory pathogens in immunocompromised hosts. Bacteroidetes and Firmicutes  are detected by PRRs of innate immune system. In addition, bacteria and bacteria-derived products  are sensed by TLR-expressing endothelial cells. Consequently, the granulopoiesis and the neutrophils’ release into the circulation are produced by the increased amounts of G-CSF and GM-CSF . A large or TLR4 . An examimmunity . Therefoimmunity , 28, 29 11 granulocytes are generated each day during steady-state conditions in adults  is a drug widely used as an antineoplastic alkylating agent because of its significant therapeutic range and broad spectrum of activity to treat different types of cancer . For theIn the last years, a number of research project were meant to find alternative treatments to favor hematopoiesis, improve immunity, booster anticancer effects, and clear anticancer drugs . A long Lactobacillus casei CRL431 or Lactobacillus rhamnosus CRL1505, the recovery of the respiratory immunity in immunocompromised hosts was reduced from 21 to 7 days , which enables a prompt recovery of peripheral blood neutrophils after Cy-administration (Candida albicans (Some works have described beneficial effects of immunobiotics on myelosuppression and immunosuppression in Cy-treated mice, although no deep mechanistic studies were performed , 53–55 . Taking stration . These ialbicans . FurtherThis review exposes wide evidence that the gut microbiota regulates granulocyte homeostasis, and therefore influences the host’s innate immune response. Additionally, research from the last years demonstrated that the oral administration of immunobiotics improves the recovery of steady-state granulopoiesis and stimulate the emergency granulopoiesis in malnourished and Cy-immunocompromised host. Future research is needed in order to elucidate the mechanisms by which specific immunobiotic strains enhance the recovery of granulopoiesis in immunocompromised hosts. Although the use of colony-stimulating factors can reduce the increased risk of infections induced by chemotherapy treatments, they are also the cause of several important side effects including bone pain, low-grade fever, and fatigue. Interestingly, the results expressed provide the basis for new applications of immunobiotics in order to stimulate the production of neutrophils and other types of leukocytes in the BM which would strength the ability of the host to fight against infections, without the side effects observed for stimulating factors. Certainly, this immunobiotic effect would improve the quality of life of patients receiving chemotherapy.SS and SA wrote and approved 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.


Although satellite cells have yet to be identified in cnidarians, muscle plasticity  in a regenerative context and its potential role during regeneration has started to be addressed in a few cnidarian systems. The development of novel tools to study those organisms has created new opportunities to investigate in depth the development and regeneration of cnidarian muscle cells and how they contribute to the regenerative process.The ability to perform muscle contractions is one of the most important and distinctive features of eumetazoans. As the sister group to bilaterians, cnidarians  hold an informative phylogenetic position for understanding muscle evolution. Here, we review current knowledge on muscle function, diversity, development, regeneration and evolution in cnidarians. Cnidarian muscles are involved in various activities, such as feeding, escape, locomotion and defense, in close association with the nervous system. This variety is reflected in the large diversity of muscle organizations found in Cnidaria. Smooth epithelial muscle is thought to be the most common type, and is inferred to be the ancestral muscle type for Cnidaria, while striated muscle fibers and non-epithelial myocytes would have been convergently acquired within Cnidaria. Current knowledge of cnidarian muscle development and its regeneration is limited. While orthologs of myogenic regulatory factors such as MyoD have yet to be found in cnidarian genomes, striated muscle formation potentially involves well-conserved myogenic genes, such as  Muscles, tissues specialized for contraction, are an essential component of the eumetazoan  body. They are involved in various functions of the body and are well characterized in various vertebrate and main non-vertebrate models , feeding and digestion through continuous peristaltic movements  . Interestingly though, in most of the free-swimming medusae, muscles are composed of striated epitheliomusclar cells. Despite the few muscle cell types found in cnidarians, there is a wide diversity of muscle systems in this phylum. In this section we describe briefly the diversity of muscle organization and muscle cell types described in the major groups of cnidarians.Hydra polyps. Hydra ectodermal and endodermal epitheliomuscular cells display, respectively, longitudinally and circularly oriented processes, called myonemes  and strong longitudinal endodermal muscles Figures .Aiptasia diaphana and Stomphia coccinea  the circular musculature found throughout the body wall, (ii) the longitudinal parietal muscles positioned at the junction between the mesenteries (reproductive and digestive structures subdividing the gastric cavity into chambers) and the body wall, and (iii) the longitudinal retractor muscles located on one side of the mesenteries. In many anthozoan groups, the retractor muscles are arranged in a bilateral manner along the secondary body axis , and constitute one of the landmarks of bilateral symmetry in these organisms   ra Figures , and . The other medusozoan groups lack an entocodon and their striated muscles instead, differentiate from the ectoderm of the subumbrella. In fact, a recent study showed that the striated muscles of the scyphozoan Chrysaora are produced anew during ephyra formation  of The development of vertebrate skeletal muscles is fairly well characterized at the molecular level, while a few factors involved in vertebrate smooth muscle formation have been identified, such as Myocardin, SRF and Capsulin  domain containing transcription factors, the Myogenic Regulatory Factors (MRFs), play key roles in vertebrate skeletal myoblast specification and differentiation. MRFs are notably able, when overexpressed, to transform fibroblasts into myoblasts , Pax3, Pax7, Six1, Six4, as well as their co-factors Eya1 and Eya2 , or showed ubiquitous expression (α-Actinin). Conversely, clear orthologs of Titin, the large protein which links Z-disk to thick filaments in bilaterians, could not be found. Most of the proteins regulating the organization of the M-line have yet to be investigated in cnidarians. Orthologs of Obscurin/UNC-89, giant proteins involved in M-line alignment in diverse bilaterians . The most parsimonious interpretation for this pattern is that they represent clade-specific adaptations. Indeed, phylogenetic reconstructions of Zoantharia , the longitudinal ectodermal muscles of scyphozoan and cubozoan polyps and staurozoans, and they represent the sole muscle type described in the parasitic groups Myxozoa and Hydra does not develop striated muscle at any stage of its simplified life cycle . Differently sized fragments of the jellyfish umbrella are able to rapidly restore the bell shape by a “morphodynamic process” and subsequently reform, at various degrees, missing structures such as the canals, tentacles and gonads  to rapidly regain a functional shape and pursue its development into adulthood  are oriented longitudinally  or the gene regulatory networks controlling endomesoderm development (Röttinger et al., Studies on cnidarians Figure  could heIt is however important to keep in mind that the embryological origin of cnidarian muscle cells is not the mesodermal germ layer, but either the endodermal or the ectodermal layer and, importantly, that cnidarian muscle cells are mostly epithelial. As for cnidarian epitheliomuscular cells, bilaterians myoepithelial cells originate from tissues of various developmental origins (Petersen and van Deurs, Nematostella (Bossert et al., wnt1 or notum (Adell et al., Recent work suggests that muscle contraction could play a primary role during the regenerative process, by promoting wound healing in The development of new molecular tools in a handful of hydrozoan and anthozoan species has already provided new insights into several long-standing evolutionary and developmental questions (Houliston et al., 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.


Cancers initially reviews the role of AR in advanced prostate cancer, and then explores the potential importance of AR signaling in other epithelial malignancies. The first few articles focus on the use of novel AR-targeting therapies in castration-resistant prostate cancer and the mechanisms of resistance to novel antiandrogens, and they also outline the interaction between AR and other cellular pathways, including PI3 kinase signaling, transcriptional regulation, angiogenesis, stromal factors, Wnt signaling, and epigenetic regulation in prostate cancer. The next several articles review the possible role of androgens and AR signaling in breast cancer, bladder cancer, salivary gland cancer, and hepatocellular carcinoma, as well as the potential treatment implications of using antiandrogen therapies in these non-prostatic malignancies.The notion that androgens and androgen receptor (AR) signaling are the hallmarks of prostate cancer oncogenesis and disease progression is generally well accepted. What is more poorly understood is the role of AR signaling in other human malignancies. This special issue of  Cancers is to shed more light on the clinical significance of androgen/AR signaling, not just in prostate cancer, but also in other epithelial malignancies.Androgens and androgen receptor (AR) signaling are the hallmarks of prostate cancer oncogenesis and disease progression. While the medical literature is saturated by studies examining the role of androgens/AR in prostate cancer, less attention has been given to the potential importance of the AR pathway in other human malignancies. The goal of this special issue of This theme issue begins with a thoughtful summary by Schweizer et al.  introducThe second series of articles begins to address the role of AR signaling in other human cancers, with a focus on potential therapeutic implications. Rahim et al.  begin wiCancers, that they become informed about the role of androgens and AR signaling in the context of multiple different cancer types, and that this treatise will ignite further clinical research and therapeutic trials aiming to modulate the AR pathway in various human malignancies.We hope that the readership enjoys this this special issue of


Flavivirus discovered in Uganda in the 1940s. To date, three major ZIKV outbreaks have been reported. ZIKV infections have known to be primarily asymptomatic while causing mild illness in a few cases. However, the recent emergence and spread of ZIKV in the Americas has resulted in the declaration of “Public Health Emergency of International Concern” due to the potential association between the infection and prenatal microcephaly or other brain anomalies. In Brazil, a 20-fold increase in prenatal microcephaly cases and 19% increase in Guillain-Barré Syndrome (GBS) cases were reported in 2015, as compared to the preceding year. The probable deleterious effects of ZIKV infection prompt the urgent development of diagnostics and therapeutics. To this end, the existing evidences supporting the increasingly common prenatal microcephaly and GBS association and the current known ZIKV transmission dynamics, modes of detection (molecular and serology-based), and current control strategies are summarized in this review. This review also emphasizes the importance of understanding ZIKV transmission in order to design a sensitive yet cost and time-efficient detection technique. Development of an efficient detection technique would subsequently allow for better surveillance and control of ZIKV infection. Currently, limited literature is available on the pathogenesis of ZIKV, hence, focusing on the modes of ZIKV transmission could potentially contribute to the understanding of the disease spectrum and formulation of targeted treatment and control.Zika virus (ZIKV) is a mosquito-borne  Flavivirus belonging to the Flaviviridae family, is an emerging pathogen that is spreading rapidly across the Americas, raising concerns in the forefront of global healthcare , including the dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), tick-borne encephalitis virus (TBEV), and Japanese encephalitis virus (JEV) , a mosquito-borne e Ayres, . The virTo date, the exact ZIKV transmission dynamics have not been established. ZIKV has been isolated from humans, non-human primates, and multiple species of mosquitoes, suggesting a complex transmission network , hence, it is likely that the infection is underdiagnosed/underreported in a disease-endemic setting  and the structural viral protein E, it was found that although the ZIKV has the potential to affect the central nervous system, particularly in neonates, it however is not particularly related to other encephalitic viruses  are known to replicate in dendritic cells and subsequently disseminate to the lymph nodes and bloodstream , and mosquitoes. Antibodies against ZIKV have also been detected in vertebrates , hence, suggesting their potential role in the circulation of ZIKV  and DENV. A. aegypti mosquitoes are confined to the tropical and sub-tropical regions, hence, limiting ZIKV transmission potential , and A. polynesiensis (responsible for French Polynesia outbreak)   thus, making blood transfusion a novel potential mode of ZIKV transmission   for rapid ZIKV IgM/IgG ELISA detection are readily available in the market  technique in order to boost ZIKV RNA signaling . The growing threat of an explosive global spread of ZIKV has drawn an alarming interest among the scientific community to develop a suitable murine model for vaccine development /larvicides, is greatly emphasized due to the lack of vaccines and antiviral therapeutics against ZIKV . However, the potential of the virus to evolve and overcome the inhibitory effect of the endosymbiotic relationship must be taken in to consideration  as a preventive strategy is advised, particularly in tropical regions where the potential for ZIKV outbreak is more likely.Further studies could investigate the association between ZIKV infection and microcephaly/GBS through case-controls studies in order to rule out potential etiological confounding factors. Future studies could also explore other potential ZIKV reservoirs and further investigate the ZIKV pathogenesis pathways and host cellular response to aid the development of a robust detection assay, ZIKV vaccine, and antiviral therapeutics.AS collected data, compiled data and wrote the manuscript, SL edited and reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CMGDF and handling Editor declared their shared affiliation and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


A 44-year-old female was admitted to the emergency department complaining of gradually worsening headache over the previous few days, and a recent episode of amnesia. On admission, the clinical and neurological examinations were normal. The patient underwent unenhanced head computed tomography (CT) that revealed hydrocephalus and indirect signs of intracranial hypertension, with hypodensities around the cerebral ventricles (arrow) indicating transependymal migration of the cerebrospinal fluid (CSF) Figure . A roundColloid cysts of the third ventricle are benign tumors that accounts for 0.5–3% of primary brain tumors. As such, they can only be seen using cross-sectional imaging techniques. Most cases are found incidentally in middle age (the fourth decade), though some may be rapidly symptomatic and diagnosed in the pediatric age. The etiology of colloid cysts is still unclear. Their inner walls are lined with a single layer of epithelium that produces mucin, this ultimately determines the imaging properties of the cyst. On CT, the variable density of cysts depends on the respective proportion of fluid, cholesterol and protein within the cyst. Occasionally, the cyst misleadingly appears hypodense or isodense compared to the brain as in this case. Similarly, the signal of the cyst on MRI is variable . They arThe cysts are usually located on the roof of the anterior side of the third ventricle, between the fornices and behind the foramen of Monro. They may undergo slow growth due to the production of mucin. The subsequent displacement of these cysts towards the foramen of Monro causes obstruction to the CSF circulation, leading to acute hydrocephalus and raised intracranial pressure. The clinical presentation is non-specific but includes intermittent headaches, nausea, vomiting, loss of consciousness, amnesia and drop attack. Treatment of colloid cyst includes stereotaxic aspiration, endoscopic aspiration and microsurgical procedures. To this regard, the following characteristics may provide important information to the surgeon for the procedure of choice: hypodensity on CT and hyperintensity on T2-weighted sequences indicate low viscosity and suitability of stereotaxic aspiration.


Itwas attended by 116 people from nine countries and granted promotional spaces forseveral non-governmental foundations dedicated to support children with heart disease inBrazil.The event celebrated the 15The three-day SLCCCP Congress was preceded by the 5th International Pediatric CardiologyResearch Symposium that provided a unique forum for original basic and clinical studiespresentations by junior and senior investigators from international and Braziliancenters. Among the eight junior presentations, one on lower extremity lymphatic vesseldynamics in patients with total cavo-pulmonary connection, presented by a medicalstudent from Denmark, was selected as the best paper and the author received an awardduring the Congress. The international senior speakers came from Aarhus, Denmark; Bonn,Germany; Buenos Aires, Argentina and Boston, USA, whereas three colleagues from SãoPaulo completed the program.On the morning of the last day, the International Symposium on Extracorporeal Circulationin Pediatric Cardiovascular Surgery, co-organized by Dr. Luiz Fernando Caneo, from InCorSão Paulo, wrapped up scientific activities. It covered recent advances in cerebralneuroprotection, anesthesia in cardiac surgery, safety protocols for extracorporealcirculation, and operating room teamwork. In addition to three national experts,Perfusion Clinical Coordinator at Boston Children's Hospital, Greg Matte, and Prof.Rodolfo Neirotti were the leading invited international speakers.The Congress' comprehensive scientific program included round tables on transposition ofthe great arteries (TGA), Ross and Ross-Konno operations, tetralogy of Fallot, Ebstein'smalformation, congenital heart disease (GUCH), congenitally corrected transposition ofthe great arteries (CCTGA), Fontan-Kreutzer operation, mechanical circulatory support,and interventional cardiology. The inclusion of international and Brazilian speakers aswell as two commentators from different countries in each round table was seminal toencourage discussion and enhance the audience interest.In addition, conferences, mini-conferences, special sessions, and oral and posterpresentations provided a diversity of captivating topics. Among them, the evidence-baseddemonstration that pediatric cardiac surgery humanitarian programs contribute to thehuman development index in emerging countries merits mention, an update of the WorldSociety of Cardiovascular Pediatric Surgery Database, a potpourri cardiac specimensdemonstration, evaluation of heart transplantation experiences in Argentina and Brazil,advances in imaging technology, respiratory syncytial virus prophylaxis, stem celltherapy, operability limits in patients with congenital heart disease and pulmonaryhypertension and intraoperative myocardial protection in the neonate. Other themes worthmentioning were an innovative investigation of the postoperative univentricular heartcirculation lymphatic physiopathology, with infrared fluorescence, results with apatient cohort submitted to lymphatic decompression surgery, "How to do it" surgicalvideos, an update on percutaneous arrhythmia ablation, and the pros and cons ofperforming adult and pediatric cardiac surgery under the same roof.The Society paid a much-deserved tribute to Guillermo Kreutzer, for his contribution tothe treatment of the univentricular heart, and invited Miguel Barbero-Marcial to presenthis lifelong accomplishments and reflections on the specialty.In the Society's Assembly many colleagues recognized the high standards of the scientificprogram, the Congress venue and the meeting organization. Furthermore, we were honoredwith the presidency of the SLCCCP during the 2017-2019 biennium, until the next meetingin Buenos Aires.After a special word of appreciation to the local nonprofit Sinhá Junqueira Foundationthat backed most of the meeting's budget, and before the farewell words by thepresident, took place a Posthumous Homage delivered by Edmar Atik, from Brazil, to PedroAntonio Sánchez, a cardiologist from Spain and one of the ancestors of the SLCCCP.The success of the meeting sends a valuable and persuasive message to the officials incharge of the Brazil's public health system. Considering that the vast majority ofpediatric cardiology and pediatric cardiovascular surgery centers were established instate capitals, mostly of them located in the coastal area, the up and coming centers,like ours, that more recently start practicing in the country's interior, must beproperly recognized and better nourished. Indeed, these new units deliver highcomplexity care for the local and regional population, and increase the capacity of theBrazilian national health system to assist patients from remote regions of thecountry.Ribeirão Preto, with the second largest affiliated tertiary hospital of the University ofSão Paulo, is one such example. Its pediatric cardiology group members have obtainedpostgraduate training in leading institutions abroad and are highly committed toimproving clinical results and academic achievements. All considered it is wise andtimely to start granting our centers and other similar centers the attention and longedfor the funding they need to expand and stand out.Perseverance and experience accumulated over 14 years of putting together an annualinternational meeting, a strong and official financial back up from a local privateinstitution, contributions from the University Hospital Foundation for Assistance andResearch ,medical industry and private organizations, as well as the seminal encouragement of theSLCCCP past presidents were our strongholds.Behind the scenes, in an era of resource scarcity, we must praise the spirit offriendship and cohesion from all the prominent international colleagues who promptlyaccepted to come to Brazil without any financial help from the Congress, the sameholding true for the Brazilian colleagues. The cooperation and suggestions of Prof.Rodolfo Neirotti, a native Spanish-speaking international leader of the specialty, andthe Danish group headed by Prof. Vibeke Hjortdal, the support of the Department ofCongenital Heart Disease and Pediatric Cardiology of the Sociedade Brasileira deCardiologia, and the Department of Pediatric Cardiovascular Surgery of the SociedadeBrasileira de Cirurgia Cardiovascular were also primordial.An in all, we must acknowledge the SLCCCP's widespread recognition by other importantpeer organizations and by its many Latin languages speaking teams, most of themsuffering the tribulations of being part of the underdeveloped world. By avoidingfavoritism and inequality, it became a cherished bastion to the advancement of knowledgeand highly praised and beloved by its fellow members whose generosity, truly unselfishbehavior, exemplary solidarity and an ever-increasing friendship allowed us to puttogether such a great event.The author wishes to thank Prof. Rodolfo Neirotti for revising the manuscript and for histhoughtful comments.