Introduction: As more infants are surviving at younger gestational ages, bronchopulmonary dysplasia (BPD) remains as a frequent neonatal complication occurring after preterm birth. The multifactorial nature of the disease process makes BPD a challenging condition to treat. While multiple pharmacologic therapies have been investigated over the past two decades, there have been limited advances in the field. Often multiple therapies are used concurrently without clear evidence of efficacy, with potential for significant side effects from drug-drug interactions.Methods: Systematic literature review.Conclusion: Although there is physiologic rationale for the use of many of these therapies, none of them has single-handedly altered the incidence, severity, or progression of BPD. Future research should focus on developing clinically significant end-points (short and long term respiratory assessments), investigating biomarkers that accurately predict risk and progression of disease, and creating appropriate stratification models of BPD severity. Applying a multi-modal approach to the study of new and existing drugs should be the most effective way of establishing the optimal prevention and treatment regimens for BPD. Bronchopulmonary dysplasia (BPD) has been traditionally defined as a chronic form of lung disease in neonates treated with oxygen and positive pressure ventilation for a primary lung disorder. As more neonates at the threshold of viability are surviving, BPD continues to be a persistent and prevalent NICU morbidity with approximately 15,000 neonates diagnosed in the United States each year. BPD also carries a higher risk of neurodevelopmental morbidity and  mortalitTable 1). Since the pathogenesis of BPD is multifactorial , a multidisciplinary approach is necessary for effective treatment. This article will discuss current pharmacologic approaches, which have not changed dramatically in the last 20 years. Often, many of these therapies are used concurrently with inadequate studies to define efficacy as well as the potential for significant side effects . Finally, experimental agents that are being investigated for the prevention of BPD and associated complications of this common neonatal disease will be introduced.Bronchopulmonary dysplasia was first described by ClinicalTrials.gov was queried for ongoing studies investigating pharmacologic therapies for BPD.Approximately 100 articles, including animal studies, human pilot studies, randomized controlled trials (RCTs), meta-analyses, and systematic reviews published on the PubMed database were evaluated for inclusion in this article. Additionally, Large volumes of intravenous fluids are often administered to premature neonates to provide adequate hydration and nutrition. Excessive fluid administration can be associated with pulmonary edema  and lead to increased respiratory support and ultimately BPD . Furosem2-agonist that is the recommended for the treatment of BPD with a strong component of reversible bronchospasm  is an inhaled βchospasm . It has chospasm . While achospasm . In summ2-agonist  is important in maintaining cell integrity and promoting tissue repair with deficiencies producing significant changes in the tracheobronchial tree . MultiplCaffeine treatment for the prevention of apnea of prematurity and BPD is currently the standard of care in most neonatal intensive care units . It has Pentoxifylline is a methylxanthine derivative and phosphodiesterase inhibitor with immunomodulatory and anti-fibrotic properties . It has Marked inflammation in the lung appears to play an important role in the pathogenesis of BPD, unifying many factors into a single common pathway. Therefore, it is reasonable to consider the use of corticosteroids in treating BPD. The use of corticosteroids can be further delineated based on route of administration.Historically, reviews of the use of systemic corticosteroids have investigated the effects of dexamethasone on BPD (treatment of existing lung injury as well as prevention) when administered during different time periods: early (<96 h after birth), moderately early (7–14 days after birth), or late  or longer-term clinical respiratory status . AdditioIt is well-recognized that infants with BPD can experience intermittent episodes of hypoxia which can promote secondary pulmonary vasoconstriction and pulmonary hypertension, adding to the complexity of BPD . This haSildenafil is a selective phosphodiesterase inhibitor that increases concentrations of cyclic guanosine monophosphate (GMP) and thus promotes pulmonary vasodilation. Animal studies of sildenafil have shown that it promotes alveolar growth, mitigates lung inflammation, and reduces pulmonary hypertension in hyperoxia-induced lung injury models . Small p2.Historically, surfactant administration has been administered shortly after birth for the prevention and treatment of respiratory distress syndrome (RDS). While early surfactant administration has not been shown to significantly impact the development of BPD, alterations in surfactant function have been reported in older patients with a variety of chronic lung disorders, suggesting a possible benefit to late surfactant administration in the treatment of BPD . AnalysiOxygen has a unique molecular structure that is capable of accepting free electrons generated by oxidative metabolism into its outer ring. Hyperoxia, reperfusion, infection, ventilator-associated inflammation, and inadequate antioxidant defenses can produce reactive oxygen species (ROS) which are toxic to living tissues. Clinical studies suggest that ROS are involved in the pathogenesis of BPD. Plasma concentrations of ROS  have been shown to be significantly elevated in the first week of life in infants developing BPD compared to infants who recover without the development of significant chronic lung disease . A strat3.CC10 is a 10-kilodalton protein secreted by non-ciliated bronchiolar epithelial cells (club cells) and is one of the most abundant proteins within the fluid lining the lung epithelium . CC10 haDecades after initially being described by 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.


Many microbial ecology studies have demonstrated profound changes in community composition caused by environmental pollution, as well as adaptation processes allowing survival of microbes in polluted ecosystems. Soil microbial communities in polluted areas with a long-term history of contamination have been shown to maintain their function by developing metal-tolerance mechanisms. In the present work, we review recent experiments, with specific emphasis on studies that have been conducted in polluted areas with a long-term history of contamination that also applied DNA-based approaches. We evaluate how the “costs” of adaptation to metals affect the responses of metal-tolerant communities to other stress factors (“stress-on-stress”). We discuss recent studies on the stability of microbial communities, in terms of resistance and resilience to additional stressors, focusing on metal pollution as the initial stress, and discuss possible factors influencing the functional and structural stability of microbial communities towards secondary stressors. There is increasing evidence that the history of environmental conditions and disturbance regimes play central roles in responses of microbial communities towards secondary stressors. Soil is known as a major sink for metals released into the environment. In many industrialized countries, soil pollution has become a serious problem . Metal p2 production pyrene and flooding stress applied as secondary stressors . This sun levels . The autn levels .et al. pyrene, salt, arsenic and flooding). The authors stressed that, without this knowledge, it would be difficult to pinpoint the factors determining the response of the community after the secondary stressors. We argue that knowledge about factors affecting the structure and the function of microbial communities is pivotal when attempting to predict the impact of secondary stressors on the stability of soil microbial communities.Previous “stress-on-stress” research in areas with long-term metal pollution history focused mostly on functional aspects of microbial communities, such as changes in respiration rates ,35,117 aet al.  showed hA number of studies published over the past decade highlighted the role of microbial diversity for ecosystem functioning ,119,120,It has been shown that microbial diversity is especially important for stability of narrow-scale functions, such as those associated with nitrification and denitrification ,125. GenSoil microorganisms perform many important functions, and the dynamics of different functional groups following the exposure to stressors can be different . Soil miet al. [−1) and unpolluted soils, Deng et al. [−1). They showed that the number of copies of 16S rRNA genes, microbial biomass carbon (Cmic), and substrate-induced respiration (SIR)  were more stable to additional metal spiking (CuSO4) than the number of copies of amoA gene and potential ammonia oxidation rate (classified as specific parameters).Contrasting results were observed when different microbial parameters were compared in the face of additional stressors. In general, previous studies indicated that the effect of stressors on the functional stability of the soil microbial community depends on the level of specificity of the function measured. It has been well documented that soil respiration is less sensitive to stressors than more specific parameters, such as enzyme activity. This is due to the fact that a wide range of organisms contributes to respiration, while only a small fraction of the total microbial community is responsible for nitrification ,112,135.et al.  reportedg et al.  studied Reports focusing on the responses of microbial communities towards a secondary stressor can be divided into two types. The first type consists of field observations after long-term (at least 10 years long) pollution with such metals as copper ,35,137, Previous studies have shown that the functional stability of microbial communities changes with soil properties ,116. SoiTo improve our understanding of the combined impact of metal pollution and secondary stressors on soil microbial communities, it is crucial to learn which microbial groups are selected in communities under strong pressure by metal stress and how associated costs of tolerance affect their responses in the face of additional stressors. There are several issues that still need to be addressed in order to evaluate the effect of metal pollution and secondary stressors on microbial communities in metal impacted soils. In this review, we showed that historical environmental conditions need to be considered when attempting to predict stability of microbial communities towards secondary stressors. Furthermore, microbial communities selected for metal resistance, in some cases, did not show a loss of their capabilities to cope with additional stress (due to acquired co-tolerance). Indeed, for some stress factors, the tolerance and resistance of soil microbial communities appeared elevated rather than decreased. Therefore, we may expect that if a microbial population has adapted genetically to long-term metal contamination, it may have higher tolerance and/or a higher ability to deal with additional environmental stressors. This is an important aspect for predicting responses of metal-tolerant communities to future environmental impacts, such as climate change, in areas with a long-term history of contamination.(1)The application of new DNA-based methodologies, allowing culture-independent assessment of microbial communities, has greatly enhanced our insights into the composition of these communities and their functional capacities.(2)There is increasing support that the historical environmental conditions and disturbance regimes are primary factors to influence microbial community stability towards secondary stressors. We argue that knowledge of factors controlling the composition and function of microbial communities is pivotal when attempting to predict the impact of secondary stressors on the stability of soil microbial communities. The potential influence of past events  on the development of community co-tolerance highlights the importance of historical factors in predicting the response of microbial communities to additional stressors.(3)Long-term “stress-on-stress” studies with single metals or defined mixtures may provide an integrated insight into the complex responses of soil microbial communities to secondary stressors at polluted sites. Following severe or long-term stress exposure, microbial community may not be able to recover within a short-term period.(4)The effect of soil physicochemical properties is important. The effects of metal pollution on microbial community structure is often confounded by natural soil properties such as pH and organic matter content.(5)Detailed knowledge on the functional and compositional properties of the microbial community prior to applying additional stressors may help to evaluate and interpret the microbial response to these stressors.(6)In contrast to DGGE and PLFA, far less attention has been given to sequence data to examine the direct or indirect interactions between microbial taxa in the face of stressors. We recommend that future “stress-on-stress” studies should investigate microbial communities under environmentally stressful conditions, using metagenomics and meta-transcriptomics together with carefully designed disturbance experiments and using different types of stressors. We expect that such studies will provide a deeper insight and clearer picture on whether predictable species assemblages occur following the combination of metal stress with other environmental stressors.In historically contaminated areas, functional redundancy buffers selective pollution effects, allowing soil microbial communities to perform their functional roles at relatively unchanged levels, despite the observed shifts in community structure. It may be, thus, difficult to evaluate ecological risks to such ecosystems based solely on measuring functional performance of their communities. In order to identify areas that are at high risk of losing their functionality due to pollution, microbial communities from such areas should be exposed experimentally to secondary stressors in order to see whether they show any reduction in functional capabilities. Such “stress-on-stress” studies should be designed with the following issues in mind:


Depletion of GRASPs in cells disrupts the Golgi structure and results in accelerated protein trafficking and defective glycosylation. In this minireview we summarize our current knowledge on how GRASPs function in Golgi structure formation and discuss why Golgi structure formation is important for its function.The Golgi apparatus is a central intracellular membrane organelle for trafficking and modification of proteins and lipids. Its basic structure is a stack of tightly aligned flat cisternae. In mammalian cells, dozens of stacks are concentrated in the pericentriolar region and laterally connected to form a ribbon. Despite extensive research in the last decades, how this unique structure is formed and why its formation is important for proper Golgi functioning remain largely unknown. The Golgi ReAssembly Stacking Proteins, GRASP65, and GRASP55, are so far the only proteins shown to function in Golgi stacking. They are peripheral membrane proteins on the cytoplasmic face of the Golgi cisternae that form  The Golgi apparatus is a membrane-bound organelle found in all eukaryotic cells, including those of animals, plants, and fungi, and functions as a central hub in the exocytic secretory pathway  only when the Golgi stack is disassembled ; depletion of dGRASP in S2 cells by RNA interference (RNAi) partially affected the Golgi structure but had no effect on tER organization  domain, which is more divergent Figure . GRASP oSo far GRASP65 and GRASP55 are the only known proteins with the properties required for Golgi stacking. A number of labs have tested these proteins; some support their roles in Golgi stacking, while others provided alternative functions including Golgi ribbon linking, transport of specific cargo across the Golgi stack, unconventional secretion, cell cycle regulation, apoptosis, and cell migration, which have been summarized in a number of reviews Wang, . Most retrans pairing over cis  than the distance between cisternae within each stack , suggesting that stacking is not absolutely required for cell survival. However, Golgi stacking is a pronounced feature in all metazoans and many unicellular eukaryotes, implying that it has important functional consequences. First, stacking may impact protein trafficking. The close spatial arrangement of cisternae in stacks minimizes the distance that molecules must travel; local tethering proteins facilitate vesicle fusion with Golgi membranes  but not in earlier sub-compartments.To a great extent, organelle function relies on its structure. However, why Golgi stack formation is important for its function has been remaining largely as a mystery in the field for many decades. Golgi cisternae do not normally form stacks in budding yeast  GRASPs are important Golgi structural proteins, (2) GRASP proteins may have multiple functions, and (3) there may be other proteins involved in Golgi structure formation. The use of GRASPs as tools to manipulate Golgi stacks has made it possible to assess the biological significance of stack formation. Significantly, there has been an increasing number of human diseases in which Golgi fragmentation has been observed, including autoimmune diseases (Fritzler et al., 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.


Depression is one of the major global health challenges and a leading contributor of health related disability and costs. Depression is a heterogeneous disorder and current methods for assessing its severity in clinical practice rely on symptom count, however this approach is unreliable and inconsistent. The clinical evaluation of depressive symptoms is particularly challenging in primary care, where the majority of patients with depression are managed, due to the presence of co-morbidities. Current methods for risk assessment of depression do not accurately predict treatment response or clinical outcomes. Several biological pathways have been implicated in the pathophysiology of depression; however, accurate and predictive biomarkers remain elusive. We conducted a systematic review of the published evidence supporting the use of peripheral biomarkers to predict outcomes in depression, using Medline and Embase. Peripheral biomarkers in depression were found to be statistically significant predictors of mental health outcomes such as treatment response, poor outcome and symptom remission; and physical health outcomes such as increased incidence of cardiovascular events and deaths, and all-cause mortality. However, the available evidence has multiple methodological limitations which must be overcome to make any real clinical progress. Despite extensive research on the relationship of depression with peripheral biomarkers, its translational application in practice remains uncertain. In future, peripheral biomarkers identified with novel techniques and combining multiple biomarkers may have a potential role in depression risk assessment but further research is needed in this area. Depression is a heterogeneous disorder with a spectrum ranging from minor/sub threshold to major depressive disorder (MDD)  and discuss its possible role in future, in management of depression.Two electronic databases (Ovid Medline and Embase) were searched for studies published between 1946 and Jan 2013 using the MESH terms “Biological markers” AND “Depression.” All original and review studies using peripheral biomarkers at baseline as a risk assessment tool for predicting future outcomes in patients with depression were included. Clinical outcomes pertaining to both mental health  and physical health  were included. Only studies published in English language were considered for inclusion. Studies related to animal, imaging biomarkers, cerebrospinal fluid biomarkers, and mood disorders other than depression were excluded. Studies which investigated the role of depressive symptoms and peripheral biomarkers independently in predicting adverse physical outcomes but did not examine the interaction between depressive symptoms and peripheral biomarkers, or in other words did not perform a sub-group analysis in patients with depression, were excluded. Studies that investigated changes in peripheral biomarker levels following treatment for depression and which didn't report any correlation between baseline biomarker levels and depressive symptoms were excluded as the aim of this review was to focus on the use of peripheral biomarkers at baseline or pre-treatment as a predictive tool of clinical outcome , rather than a change in biomarker level itself. The search strategy returned 1096 studies from two databases after excluding duplicates . The data extraction comprised of study sample size and country, type of study and setting, details of how depression was diagnosed and treated, follow-up duration, biomarkers assessed, clinical outcomes studied and potential bias in the results. The description of methodology used by included studies for biomarker measurement and the source of peripheral biomarker  was also reviewed in data extraction.n = 14) explored the use of peripheral biomarkers to predict outcomes in patients with depression. Fifteen papers were included for data extraction; which consisted of nine prospective cohort studies  exploring and supporting the cross-sectional relationship between depression and different peripheral biomarkers. However, only a minority of studies , neurotransmitter metabolism (n = 9), neuroendocrine (n = 8), metabolic (n = 4), and neurotrophic (n = 1) systems. All included studies assessed statistical significance based on the criteria of having a p-value less than 0.05. Twelve biomarkers were found to be statistically significant in predicting outcomes         statistic was presented only by 1 study, with AUC statistic for Dexamethasone suppression test (DST) reported as 0.65 for predicting increased incidence of cardiovascular deaths only for the male subset of their sample   and physical health were statistically associated with pre-treatment levels of peripheral biomarkers; however only two studies investigated outcomes related to physical health. Twelve different biomarkers related to five different biological systems  were found to have a potential role in predicting outcomes of depression. Despite extensive research on the biomarkers of etiopathogenesis of depression, there is limited published research exploring its translational application in clinical practice. Furthermore, the research is of generally limited quality and lacks clinical utility.The included studies have several methodological problems. The study sample size was small and follow-up duration was short in the majority of included studies. The majority of included studies used questionnaire scores using symptom count for diagnosing depression at baseline, while the gold standard interview technique for depression diagnosis was used only by a minority. Baseline severity of depressive symptoms assessed using symptom count is associated with higher rate of relapse in patients with depression  curve Cook, , which iThe use of prediction rules and biomarkers to inform clinical decision making is not a novel concept. It has been used in making management decisions in a wide variety of clinical scenarios such as patients presenting with high cholesterol, atrial fibrillation, chest pain, ankle injury, and intensive care  and depression suggested a dose-response relationship, with patients with mild depression showing higher HPA hyperactivity compared to controls but lower than that of patients with MDD (Stetler and Miller, In recent years, novel techniques in proteomics, metabolomics, genetics, and epigenetics have led to several new biomarkers being proposed in depression. Proteomic techniques have been used to identify nine differentiating proteins belonging to lipid metabolism and immune system from treatment naïve patients with depression, when compared against healthy controls (Xu et al., The term allostasis refers to the adaptive physiological responses organisms activate when homeostasis is disrupted during acute stress, real or interpreted threats (McEwen and Stellar, Our search strategy was limited to studies published in English language. A variety of other biomarkers such as genetic, imaging and CSF biomarkers may have a role in depression stratification by predicting clinical outcomes (Schneider and Prvulovic, There is a need for further research in this area, involving large scale studies with longer duration of follow-up, better characterization of patient populations and inclusion of patients with chronic diseases. An “ideal” scientific process for a biomarker evaluation in clinical risk discrimination has been highlighted in other fields such as cardiovascular disease, a similar approach can be adopted for biomarkers of depression (Welsh et al., Pre-treatment levels of 12 different blood based peripheral biomarkers related to five different biological pathways were found to have a statistically significant relationship with outcomes in patients with depression. Six different outcomes in depression were predicted using these biomarkers, pertaining to both physical and mental health, but the clinical implications remain unclear. It appears likely that peripheral biomarkers may have an important role in helping clinicians to stratify depression severity and to predict clinical outcomes. However, the available evidence has multiple methodological limitations which must be overcome to make any real clinical headway; in particular, interaction between these biomarkers, depressive symptoms and co-morbid physical conditions needs to be explored further.Literature search was carried out by Bhautesh D. Jani and Barbara I. Nicholl. Title, abstract and full text screening followed by reference and citation searching and data extraction were carried out by Bhautesh D. Jani and Gary McLean. All authors contributed to 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.


Mitochondria play vital roles in oocyte functions and they are critical indicators of oocyte quality which is important for fertilization and development into viable offspring. Quality-compromised oocytes are correlated with infertility, developmental disorders, reduced blastocyst cell number and embryo loss in which mitochondrial dysfunctions play a significant role. Increasingly, women affected by metabolic disorders such as diabetes or obesity and oocyte aging are seeking treatment in IVF clinics to overcome the effects of adverse metabolic conditions on mitochondrial functions and new treatments have become available to restore oocyte quality. The past decade has seen enormous advances in potential therapies to restore oocyte quality and includes dietary components and transfer of mitochondria from cells with mitochondrial integrity into mitochondria-impaired oocytes. New technologies have opened up new possibilities for therapeutic advances which will increase the success rates for IVF of oocytes from women with compromised oocyte quality.The online version of this article (doi:10.1186/1477-7827-12-111) contains supplementary material, which is available to authorized users. Mitochondria play vital roles in oocyte functions and they are critical indicators of oocyte quality. Among the major mitochondrial functions is the production of adenosine triphosphate (ATP) to provide energy, but unlike in somatic cells, ATP in most mammalian oocytes is mainly generated through the glycolytic and Pentose Phosphate Pathway (PPP) rather than the oxidative phosphorylation (OXPHOS) pathway , 2 used Compared to our knowledge of mitochondria in somatic cells, relatively little is known about mitochondria in oocytes and in the preimplantation embryo but it is well known that mitochondrial dysfunction in the oocyte and embryo play significant roles in infertility and in developmental abnormalities –7.Fertility disorders have become a growing problem worldwide , 9, and The effects of mitochondrial dysfunctions as well as sub-optimal mitochondrial functions are correlated with meiotic spindle abnormalities. As will be addressed in more detail below, mitochondrial functions are important for the formation of meiotic spindles and for maintenance of the MII spindle before fertilization. Insufficient ATP generation will result in aneuploidy, a condition in which chromosomal segregation errors are frequently encountered. In human, oocyte chromosomal segregation is error-prone and these errors have been estimated to be about 15–20% ; revieweBased on the significant need to increase success rates in IVF clinics new strategies are in demand to overcome mitochondrial dysfunctions, but before therapeutic interventions can be applied the metabolic activities and dynamics of mitochondria in unaffected oocytes and embryos need to be understood more fully. Many aspects of mitochondrial function and dysfunction are still unexplored in oocytes and preimplantation embryos and many questions remain to be answered. This section will address our current understanding of mitochondrial dynamics and highlight the aspects that still need clarification.Mitochondria are multifunctional organelles with critical functions in cellular energy production, calcium homeostasis , cell siMitochondria are semiautonomous organelles that contain their own genome of ca. 16.6 kb circular mitochondrial DNA (mtDNA), encoding for 13 essential protein subunits of complexes I, III, IV, and V of the respiratory chain of the mitochondrial OXPHOS complexes as well as 22 tRNAs used in mitochondrial protein synthesis and 2 rRNAs (12 s and 16 s) that are necessary for the translation of mitochondrial subunits . A functIn addition to mitochondrial activity being dependent on overall mitochondrial dynamics and motility, mitochondrial activities depend on several specific mitochondrial features and characteristics that are important for cell cycle-specific functions and include the mitochondrial transition pore (mPT), membrane potential, localization and distribution patterns, and adequate amounts of mtDNA. Dysfunctions involve increases in reactive oxygen species (ROS) and calcium overload; reviewed in , 14–16.The mitochondrial permeability transition pore (mPT) is a nonselective and high-conductance channel composed of ANT, the voltage-dependent anion channel (VDAC), and cyclophilin-D . The mPTMitochondrial membrane potential (Ψm) results from mitochondrial activity, and is highly important for oocyte quality; conversely lowly-polarized mitochondria in oocytes result in abnormal embryos . SeveralIn somatic cells, mitochondria form a highly complex dynamic network and they undergo fusion and fission to accommodate the functional requirements of specific cell types. In most cell types mitochondria are translocated along microtubules to their functional destinations  using thAs mentioned in the introduction, in contrast to differentiated cells, early embryo cells, like pluripotent stem cells, contain mitochondria that display a round morphology and only few cristae Figure , generalOocyte maturation: Mitochondria are critically important for oocyte maturation and they are reliable indicators for oocyte quality achieved during the maturation process. Mammalian oocytes are arrested at the germinal vesicle (GV) stage in the ovary of the newborn which is the diakinesis stage of prophase I. These arrested oocytes remain at the GV stage until puberty, when follicle-stimulating hormone (FSH) induces development of small antral follicles into the pre-ovulatory stage. Oocyte maturation in the ovary continues with the resumption of meiosis from prophase I  and the extrusion of the first polar body (PBI) followed by initiation of meiosis II and oocyte arrest at the metaphase II stage of second meiosis. The number of mitochondria varies in different species but in most mammalian species mitochondria are closely located around the MII spindle , 52. ThiMeiotic spindle formation begins in most mammals at the center of the oocyte (reviewed in ) after nOocyte maturation is important for the establishment of oocyte qualities that allow for optimal fertilization and embryo development. During oocyte maturation, the oocyte grows and undergoes remodeling on cellular and molecular levels. This remodeling requires ATP likely supplied by mitochondria; thereby allowing timely and accurate cytoplasmic and nuclear maturation . MitochoThe oocyte arrested at the MII stage is the final product of oocyte maturation. On average, the mature mammalian MII oocyte contains approximately 100,000 to 200,000 mtDNA copies  and amouFunctional motor proteins and protein kinases that are needed for meiotic spindle assembly and chromosome alignment require ATP , and insFertilization: When the MII oocyte is ovulated it enters the oviduct where fertilization occurs. Fertilization initiates completion of meiosis II and is marked by extrusion of the second polar body (PBII) to achieve the haploid maternal contribution to the oocyte.Mitochondria are maternally inherited in mammalian embryos, and the MII oocyte contains all mitochondria for subsequent development to the blastocyst stage . The spePreimplantation embryo development: Remodeling of mitochondrial features is important for differentiation when increased energy is needed for embryo development. During preimplantation embryo development several changes take place in mitochondrial architecture as they transform from a simple spherical structure to begin displaying more complex morphologies, including well-developed cristae, a denser matrix, and an elongated or branched appearance. This more complex change in morphology is correlated with a bioenergetic transition from mainly glycolytic to aerobic OXPHOS metabolism. This transition includes an increase in the respiratory chain complex density and ATP production. Several proteins drive the mitochondrial differentiation process which have been determined to some extent , 2 but mMany of the studies on maturation, fertilization and embryo development have been performed in animal models such as the mouse, rabbit, bovine, and porcine systems and fewer studies are available for human; although this area of research is progressing more rapidly now because of the need for higher success rates in IVF clinics.As mentioned in section 1, oocyte quality is important for fertilization and development into viable offspring. Quality-compromised oocytes are correlated with infertility, developmental disorders, reduced blastocyst cell number and embryo loss, but the mechanisms underlying these effects are not well understood. Oocyte quality is achieved during the maturation process as addressed in section 1. Maturation defects can have several causes and many have been associated with mitochondrial dysfunction , 19 due Several metabolic changes or disorders such as obesity, diabetes, and aging among others, play a role in reduced oocyte quality. Metabolic disorders not only affect oocytes in the adult female but they also affect all oocytes produced in the developing fetus during pregnancy of the mother, as the adverse intrauterine environment directly affects oogenesis in the fetus and the embryo’s primordial germ cells from which the next generation develops .in vitro maturation and subsequent embryo development in pigs.As mentioned in section 1 sufficient oocyte maturation, both nuclear and cytoplasmic, is important to acquire fertilization-competency . The excessive reactive oxygen species (ROS) generation is closely associated with the oxidative energy production or calcium overload, which may trigger opening of the transition pore and subsequent apoptosis.Oocyte aging is strongly associated with mitochondrial dysfunction , 13, 17 ROS is generated during the production of ATP and it causes oxidative damage to mitochondrial DNA if not detoxified, which results in mutations and deletions of mtDNA. As repair enzymes for mtDNA are minimal, mitochondria are especially sensitive to oxidative stress-induced damage . The mutChromosomal aneuploidies are well known effects of oocyte aging but the time-dependent detailed cascades and specific mechanisms leading to loss of spindle integrity and aneuploidy are still being explored. A detailed cause and effect mechanism is not known. However, several aspects are clearly observed during the aging process and include decreases in motor protein functions as addressed above in section 1.Diabetes and obesity are two of the major causes for mitochondrial dysfunction , 98–100 Diabetes and obesity have become major concerns worldwide and have now exceeded the undernourished population with estimated numbers of 1.5 billion and 1 billion, respectively. Diabetes and obesity are both significantly associated with infertility and have contributed to the increase in patients seeking ART procedures in IVF clinics. Many of the mitochondrial dysfunctions that are known for aging oocytes are also seen in oocytes from diabetic and obese females: these include a decrease in membrane potential, reduced blastocyst formation with imbalances in TE and ICM cell numbers resulting in embryo loss, and several others; reviewed in , 103.in vitro fertilization (IVF) and embryo development in IVF clinics is the poor quality of mitochondria in oocytes of obese and diabetic women, of women at advanced reproductive ages, and of women with various other metabolic disorders. This limitation has stimulated a number of different approaches to overcome the defects and includes cytoplasmic transfer which refers to the supplementation of an oocyte with donor cytoplasm containing healthy mitochondria . While this approach had raised concerns as mentioned in the introduction [http://www.fda.gov/OHRMS/DOCKETS/ac/02/briefing/3855B1_01.doc). While different policies exist in different countries [One of the most challenging obstacles for achieving successful oduction  cytoplasoduction –29. Howeountries  and reseountries , 106 newountries , 88, 107Because many developmental disorders and diseases are associated with dysfunctional mitochondria  , 120. HeConsidering that numerous mitochondrial mutations, deletions, and nucleotide variations are found in quality-compromised oocytes and blastocysts  from womOther sources for mitochondrial transfer may include stem cell cytoplasm, as stem cell mitochondria display many of the characteristics that are known for embryonic immature mitochondria  have also been considered to improve mitochondria functions in quality-compromised oocytes . CoQ10 aDifferent from approaches to supplement mitochondria through cytoplasmic transfer are the approaches that are currently being discussed to eliminate inherited mtDNA mutations. To eliminate the transmission of mtDNA mutations to the offspring two oocytes from different females are needed and several approaches are possible.In one approach either the GV or the MII spindle and associated chromosomes are removed from the patient’s unfertilized egg containing the abnormal mitochondria and transferred into an enucleated donor egg containing healthy mitochondria. The donor egg now primarily contains the donor’s mitochondrial DNA but the patient’s nuclear DNA although some of the patient’s mitochondrial DNA is transferred along with the nucleus. This reconstituted egg now can be fertilized with the patient’s partner through the intracytoplasmic sperm injection (ICSI) procedure; thereby now containing the future parents’ nuclear DNA but mitochondria from the donor. The cleaving embryo with normal mitochondria and maternal and paternal genomes can then be transplanted into the patient’s uterus. This approach has also been characterized as “three-parent in vitro fertilization” but in fact the nuclear genetic material is only contributed by two parents. It is primarily used to prevent transmission of inherited mitochondria disease. This approach has been discussed extensively during the past year and resulted in approval by the Food and Drug Administration (FDA) . It had In another approach the patient’s egg containing abnormal mitochondria is fertilized with the partner’s sperm and allowed to develop to the patient’s zygote stage that still contains the abnormal mitochondria. The patient’s pronuclei are then removed and transferred to an enucleated donor egg containing healthy mitochondria. The reconstructed zygote is then processed further for transfer into the patient’s uterus.In a more recent approach the recipient oocyte is enucleated by removing the MII spindle; a donor oocyte is fertilized and the second polar body is removed and then transferred to the recipient oocyte , now conOther therapeutic approaches are actively being pursued to improve mitochondrial dysfunction and include approaches based on genome editing. For example, specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs have been reported  in whichThe past decade has seen enormous advances in potential therapies for quality-compromised oocytes that will particularly benefit women with metabolic disorders such as obesity, or diseases such as diabetes, or metabolic changes associated with aging. Dietary components such as CoQ10 and especially transfer of mitochondria from cells with mitochondrial integrity have opened new possibilities for therapeutic advances which will increase the success rates for oocytes of women with compromised oocyte quality. Optimal conditions for such transfers include that mitochondrial supplementation should be obtained from the patient’s own cells for optimal communication between mtDNA and nuclear DNA to maintain homoplasmy in offspring; using cells of ovarian or oocyte origin; and using mitochondria of high-quality cells without the risk to transmit deletions or mutations to the offspring. Stem cell mitochondria may be an optimal source for supplementation of quality-compromised oocytes.


While most experts agree on the limitations of neuroimaging, the unversed public—and indeed many a scholar—often valorizes brain imaging without heeding its shortcomings. Here we test the boundaries of this phenomenon, which we term neuroenchantment. How much are individuals ready to believe when encountering improbable information through the guise of neuroscience? We introduced participants to a crudely-built mock brain scanner, explaining that the machine would measure neural activity, analyze the data, and then infer the content of complex thoughts. Using a classic magic trick, we crafted an illusion whereby the imaging technology seemed to decipher the internal thoughts of participants. We found that most students—even undergraduates with advanced standing in neuroscience and psychology, who have been taught the shortcomings of neuroimaging—deemed such unlikely technology highly plausible. Our findings highlight the influence neuro-hype wields over critical thinking. Neuroimaging is on the rise, attracting attention from both academics and the popular media. Beyond transforming the neurosciences, human brain imaging has birthed neuroenchantment—a form of sub-judicious fascination with brain science. As scholars, reporters, consumers, and the general public increasingly come to appreciate the promise of imaging technology, a tendency emerges to overestimate the present state of knowledge and inflate our actual capabilities  participated in an experiment where a sham brain scanner, presuming to pass as new technology, allegedly allowed experimenters to unravel the thoughts of participants based on a measurement of neural correlates. We recruited 26 participants from an advanced undergraduate course focusing on the relative merits and shortcoming of different imaging techniques. These participants, with majors spanning psychology, neuroscience, and cognitive science, comprised the Neuro group. The professor in the course (AR) repeatedly harped on the present impossibility of mind-reading and tested this information on the final examination verifying that students internalized these points. He also spoke about his background as a mentalist—a magician who performs psychological tricks, such as mind-reading—and led class demonstrations to exemplify why the public often misinterprets these effects and takes them for genuine paranormal powers. The other 32 participants were undergraduate students unfamiliar with AR enrolled in courses unrelated to psychology, neuroscience, and cognitive science.Fifty-eight undergraduate students  = 2.81, p < 0.01] and less believing of the overall paradigm . Nevertheless, neuroimaging knowledge hardly offered an effective shield against the perils of neuroenchantment. Approximately 65% of neuroscience-educated individuals reported believing the paradigm. Furthermore, comparative analysis of data collected before and after the revelation of the pocketed information revealed that both Neuro and Other participants were more likely to believe the scanner could potentially deduce even more complex thoughts .Subjective ratings indicate that despite the current infeasibility of neuroscientific mindreading and the haphazard setup of our scanner, individuals were neither skeptical nor suspicious of the paradigm  formerly performed as a professional magician. For these participants, an encounter with technology that is purportedly capable of unveiling personal higher cognition eclipsed academic knowledge concerning the implausibility of such phenomena. Thus, here we show how our experimental context can lead individuals with various levels of expertise to accept science fiction as neuro fact.Human beings are infamously irrational when entertaining certain beliefs (Kahneman, First, although we deliberately crafted our experimental setup to elicit critical judgment by appearing absurd and ramshackle (see Figure Speculating beyond the present data, participants in our study appeared to concurrently agree with two conflicting worldviews. The first is the scientific stance of under-promise-&-over-deliver, which construes brain imaging as an imperfect but potentially powerful technique with a strong mandate for discovery. The second is the more popular over-promise-&-under-deliver mentality, which portrays brain imaging as an omniscient strategy for unscrambling the neural correlates of thought. Fueled by popular media and lay accounts, neuroenchantment further blurs fact from fad and leads to accepting tentative suppositions as indisputable fact (Racine et al., 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 cancer stem cell (CSC) hypothesis postulates that there is a hierarchy of cellular differentiation within cancers and that the bulk population of tumor cells is derived from a relatively small population of multi-potent neoplastic stem-like cells (CSCs). This tumor-initiating cell population plays an important role in maintaining tumor growth through their unlimited self-renewal, therapeutic resistance, and capacity to propagate tumors through asymmetric cell division. Recent findings from multiple laboratories show that cancer progenitor cells have the capacity to de-differentiate and acquire a stem-like phenotype in response to either genetic manipulation or environmental cues. These findings suggest that CSCs and relatively differentiated progenitors coexist in dynamic equilibrium and are subject to bidirectional conversion. In this review, we discuss emerging concepts regarding the stem-like phenotype, its acquisition by cancer progenitor cells, and the molecular mechanisms involved. Understanding the dynamic equilibrium between CSCs and cancer progenitor cells is critical for the development of novel therapeutic strategies that focus on depleting tumors of their tumor-propagating cell population. Physicians and scientists have wondered about the origins of tumors since the 18th century, when Giovanni Morgagni of Padua established autopsies as a routine procedure to determine why patients died. In 1863, the implementation of the microscope as a scientific tool lead Rudolf Virchow to speculate about the cellular origin of cancer when he observed that some tumor cells within pathological specimens seemed less differentiated than others, and in 1889 Stephen Paget proposed the seed-and-soil hypothesis, which provided an explanation for how tumors metastasize to distant sites. Discoveries in the early 1900’s by Peyton Rous and Theodore Boveri established that cancer can be caused by viruses and chromosomal abnormalities [The concept of stem cells applied to tumor initiation has been around for quite some time. Building on the breakthroughs of Morgagni and Virchow, pathologists increasingly recognized the histopathological heterogeneity within solid tumors. Furth and Kahn in 1937 and then others, using serial transplantations and limiting dilutions, showed that a single cell was able to propagate tumor xenografts that recapitulate the features of the original clinical tumor –4. FurthBeginning in the late 1970’s, the emerging discoveries of tumor suppressing and tumor promoting genes and their mutations constituted a conceptual paradigm shift that relegated the CSC hypothesis to a supporting role. In 1976, Nowell proposed that tumors are derived from a single cell, and that tumor progression is the result of acquired mutations that give the tumor cells an advantage  and seemIn the early 1990’s, groundbreaking work had been taking place in the area of hematopoietic stem cell research, namely the characterization of well-defined and validated surface markers that allowed for identification of undifferentiated cells as well as different lineages resulting from hematopoeitic stem cells –13. In tThe CSC hypothesis postulates that there is a hierarchy of cellular differentiation within cancers and that the bulk population of tumor cells is derived from a relatively small population of multi-potent neoplastic stem-like cells (CSCs) that play a particularly important role in maintaining tumor growth through their unlimited self-renewal, therapeutic resistance, and capacity to propagate tumors through asymmetric cell division –24 Figu.At a practical level, this hypothesis predicts that targeting the CSCs will more effectively treat tumors and prevent recurrence. Differentiation therapy has emerged as an approach to force tumor cells into lineages that are less efficient tumor propagators and more susceptible to treatment.As mentioned earlier, there is a growing body of evidence supporting the idea that the population of cells with stem-like potential exists in several types of cancer,19,20,25So rather than focusing on the cell of origin per se, the CSC hypothesis proposes a pragmatic approach and offers an “operational” definition of what constitutes a CSC. Regardless of the cell of origin, a tumor that conforms to the CSC hypothesis should be heterogeneous and contain a small population of multi-potent, relatively undifferentiated cells able to propagate tumors in transplantation models –29 and gGreat efforts have been put forward into understanding where CSCs come from. There are instances, such as intestinal cancers, where hierarchically organized tumors originate from normal cells ,31. In oThe term reprogramming, in the context of stem cell biology, is usually directly associated with the Yamanaka  experimeThis study highlights how under certain conditions cells can be induced to undergo a complete change of identity. Although the authors of this study focused on the implications of this plasticity for regenerative medicine purposes, one can envision a similar process taking place in tumor cells. By displaying this inherent plasticity, tumor cells can adapt to multiple environments and dynamically alter their dependence on specific signaling and metabolic pathways, features associated with metastasis and therapeutic resistance .As mentioned earlier, expression of a defined set of transcription factors is sufficient to reprogram mouse and human cells to an induced-pluripotent state. These iPS cells resemble embryonic stem cells since they possess the capacity to differentiate into all tissue subtypes . In cancThe high similarity in gene expression profiles of embryonic stem cells (ESCs) and high grade tumors  further Our findings that Nanog silencing inhibits the reprogramming capacity of c-Met signaling in GBM cells highlights Nanog’s emerging role in maintenance of CSCs . These rThe evidence presented so far argues that neoplastic cells are inherently plastic and transcription factors play critical roles in tumor cell fate determination through the process of reprogramming. We also proposed the possibility of neoplastic cells taking advantage of these capabilities in order to promote and maintain the tumor. But is there evidence that tumor cells can hijack this mechanism under physiological conditions and use it to their advantage? Under stress conditions, several cell types have the ability to de-differentiate in order to supplement the stem cell population to support tissue repair –61.Interestingly enough, it appears that tumor cells can take advantage of a similar process of “stress-induced reprogramming” and de-differentiate to a stem-like state with the capacity to maintain or even reconstitute a malignancy.For instance, glioma stem cells (GSC) are thought to reside in a hypoxic niche. Hypoxia stabilizes HIF2, which in turn can activate stemness genes that contribute to tumor initiation by reprogramming cells through a de-differentiation mechanism –65. As aIt is well-recognized that the microenvironment plays an important role in supporting stem cell populations within tissues. It is now well-established that discrete environmental niches exist  that provide molecular cues for maintaining stem-like states in selected cell populations ,64,66–68Hypoxia is a hallmark of the cancer microenvironment and plays an important role in inducing and maintaining neoplastic stem-like phenotypes in cancer . The hypThe perivascular niche has been found to play a particular role in supporting the tumor-initiating cell population of brain tumors ,75. CallThe evidence presented so far strongly supports the function of Yamanaka transcription factors induced by oncogenic signaling and microenvironmental cues as “drivers” of cancer cell reprogramming and stemness. These fate-determining transcriptional events are constrained by promoter accessibility which is determined by the influences of histone modifications on chromatin architecture and by promoter DNA methylation .DNA methylation is established by the de novo DNA methyltransferases (DNMTs) Dnmt3a and Dnmt3b, and is maintained through cell division by Dnmt1  in a proMany transcription factors bind DNA regions containing CpG sequences. It is thought that DNA methylation interferes with this process by changing the recognition sites at the cytosine residue. This process has been described for several transcription factors, including transcription factors with reprogramming capability –100. TheThe nucleosome is a fundamental building block of chromatin, consisting of DNA tightly associated with histone proteins . As mentReprogramming takes place in a step-wise manner in a process involving a dynamic interplay between transcription factor binding, changes in genetic signatures, and changes in the chromatin landscape during the transitions –110. A rAs alluded to earlier, the balance between open and closed chromatin structures determines genome-wide gene expression states, and altering this balance can result in transcriptional deregulation that leads to disease (e.g. cancer) . In factMicroRNAs (miRNAs) are short non-coding RNAs that inhibit gene expression by targeting mRNA for degradation or by blocking translation of target genes . These mGiven the potential implication in diagnosis and prognosis of cancer, several studies have focused on a cancer-specific miRNA signature  and, morReprogramming factors have been shown to promote expression of miRNA subsets in ES cells, implicating miRNAs in controlling ES cell identity . InteresThere is a growing body of evidence that associates stem cell properties with the tumor-initiating cell population in human cancers. This CSC population is highly relevant to the biology of tumors and understanding their contribution to tumorigenesis holds great promise in terms of cancer treatment. Identifying and developing ways to target the tumor-initiating population will improve the way we treat cancer. One caveat of this approach is that CSCs and normal stem cells have similarities, therefore it is very important to understand the differences between normal stem cells and CSC in order to design cancer-specific therapies. With the growing number of studies looking at CSC-gene signatures, one can’t help but wonder if in the near future we will be able to merge these data to identify CSC-specific mechanisms that are common among all the cancers with the hopes of identifying a “primordial tumor-initiating network”. This “ideal” situation would provide us with potential “magic bullets” to treat cancer.Our current knowledge of cell reprogramming mechanisms also opens the possibility that therapeutic approaches may inadvertently drive a subset of tumor cells toward a more stem-like and treatment-resistant state. This potential for “stress-induced de-differentiation” further highlights the importance of understanding the effects of current therapies not only when considering cytotoxicity, but also effects on de-differentiation and tumor-initiating potential. This hypothesis creates a new level of complexity and provides a plausible explanation for why tumors become resistant to therapy and recur. Understanding the specific microenvironments where these tumor-initiating cells reside will give us the option to target their niche as well as the specific cells themselves. Emerging data indicate there is a crosstalk between epigenetic modifications, miRNAs, and reprogramming transcription factors. Understanding the bidirectional regulation between these factors is becoming a new and interesting area of research. Identifying the components and circuitries that contribute to the generation of CSCs will allow us to design more rational therapies not only to target tumor-initiating cells, but to prevent them from appearing in the first place (e.g. cancer vaccines or therapies that block dedifferentiation). CSCs are extremely dynamic entities capable of adapting to different situations in order to maintain and propagate tumors, and although it appears that tumors arising in different tissues may have different cells of origin, one thing remains: understanding how transcription factor networks regulate tumor-initiating populations holds great potential for understanding tumor biology and advancing cancer therapy.


The debate over genetically modified (GM) crops has raged in Europe since 1996, but had barely risen above a whisper in the USA until recent labeling debates raised public attention. This article will explain GM crops and traits discuss safety assessment provide a view on safety from authoritative organizations discuss selected issues of current debate, and provide the author’s perspective as to why the public debate has drifted so far from scientific reality. The economic and environmental benefits of GM crops are beyond scope, but references are provided. GM food and feed undergo comprehensive assessments using recognized approaches to assure they are as safe as the conventional congener. Issues of food safety and nutrition, unrelated to the GM process, may arise when GM foods display novel components or composition. Unanticipated genetic effects in GM crops appear to be limited in contrast to existing variations among conventional varieties resulting from breeding, mutation, and natural mobile genetic elements. Allergenic potential is assessed when selecting genes for introduction into GM crops and remains a theoretical risk to date. Emerging weed and insect resistance is not unique to GM technology and will require the use of integrated pest management/best practices for pest control. Gene flow from GM crops to wild relatives is limited by existing biological barriers but can at time be a relevant consideration in gene selection and planting practices. Insect-resistant GM crops have significantly reduced use of chemical insecticides and appear to have reduced the incidence of pesticide poisoning in areas where small scale farming and hand application are common. Changes in herbicide patterns are more complex and are evolving over time in response to weed resistance management needs. Recent public debate is driven by a combination of unfounded allegations about the technology and purveyors, pseudoscience, and attempts to apply a strict precautionary principle. The public debate over genetically modified (GM) crops has raged in Europe since their introduction in 1996, but had barely risen above a whisper in the USA until the recent California  GM labelGM crops in use today  are largPrimary GM traits include herbicide tolerance, insect resistance, viral resistance, and nutritional enhancements. Herbicide tolerance facilitates the use of herbicides over GM crops , allowing the crop to remain uninjured while weeds are controlled. Tolerance to glyphosate is the leading commercial herbicide-tolerant trait. Glyphosate inhibits the EPSPS (enyol-pyruvate-shikimate-3-phosphate synthase) , the firCry  or VIP (vegetative) insecticidal proteins  derived from multiple strains of Bacillus thuringiensis (Bt) [Insect resistance is available in maize, cotton, soybean, and brinjal (eggplant) . Resistasis (Bt) . Bt is asis (Bt) . Alteredsis (Bt) .In the USA, GM crops are conjointly regulated by the FDA (food and feed safety), USDA (plant pest risks), and EPA  under an established inter-agency agreement . There iNo whole food category in history has been as thoroughly examined as GM crops—only chemical food additives receive greater scrutiny. Pre-market food and feed safety assessment is based on internationally recognized approaches and must demonstrate that GM crops are as safe as their conventional counterparts for food and feed use –12 and pFor GM crops with altered or novel compositional aspects , a comprehensive safety assessment is undertaken for any changes made, considering both individual health and population nutritional impacts. Unanticipated genetic effects can occur with any breeding technique, and the absence of relevant unanticipated effects can be demonstrated by studies to assure proper gene insertion, composition, and agronomic performance. Fifteen years of studies demonstrate considerably more variability among conventional crops due to genetics and environment than results from transgene insertion in a particular variety; recent genomics studies demonstrate that gene insertion produces minor perturbations of overall gene function compared to dramatic differences in expression across crop varieties, locations, and growing conditions (see below).Despite this scrutiny, concern is often expressed that no long-term studies with GM crops have been performed. While this is not correct , it is aBefore turning to the increasingly loud public debate on GM crops, it is worth pausing to identify some areas for which legitimate scientific concerns have been expressed. Few of these issues revolve around human health for precisely the reasons discussed above—currently implemented GM crops introduce DNA, RNA, and digestible proteins with a history of safe use into the diet following extensive regulatory review, and are thus unlikely to have associated safety concerns. The topics below are currently in public debate and thus of possible interest to readers. Given available space, this is not a comprehensive list and is not intended to suggest that other issues necessarily lack in scientific merit.Food-safety-related issues may arise in the context of GM crops with significant alterations in nutrient composition or with novel dietary components. These issues have little to do with GM technology as they relate primarily to impacts on overall dietary consumption patterns and the safety of specific food components. Appropriate safety assessment is nonetheless warranted. For example, the introduction of high-oleic, low-linolenic soybean oil for use in fast-food frying applications can reduce saturated fat intake . No new Similarly, the introduction of omega-3 fatty acid containing soybeans enhanced with stearidonic acid (SDA)  raises qUnanticipated genetic effects of GM technology have been alleged to raise food safety issues. It has long been recognized that conventional technologies  can also result in unanticipated phenomenon and that the risk of GM technologies falls within the range of risks entailed with conventional methods . In the Food allergy has also been raised as a potential issue in GM crops. GM crops are, of course, as allergenic as conventional crops as no allergenic components have been removed. As of this writing, there has been no documented occurrence of allergy to an inserted GM protein. Approaches to allergenicity assessment in GM crops have been reviewed elsewhere . By way A complete discussion of the environmental aspects of GM crops is beyond the scope of this paper, but a few recent issues are worthy of note. Given that medical toxicologists are likely less familiar with agronomic and environmental issues, references provided in this section are more introductory in nature.Agronomically important insect resistance to Bt toxins has emerged as a practical issue in corn rootworm management using single Bt genes for insect control in the upper Midwestern USA  and in pWeed management is not just a cosmetic issue for farmers—weed competition for resources in the field results in major yield loss if management issues are not properly addressed . Weed reAnother topic of debate is the possibility of gene flow , 39. GenGene flow from crop plants began approximately 10,000 years ago with the domestication of crops , 41, durPollen-mediated gene flow from GM to non-GM crops or to related species has also received significant attention . Pollen Pollen-mediated gene flow to non-crop species has been extensively reviewed . Gene flFinally, it is worth noting the current pesticide-use-reduction debate. A major advantage of Bt insect control has been a dramatic reduction in the need for conventional small-molecule insecticides over Bt commodity crops—most particularly corn and cotton , 32. ThiThe use of glyphosate tolerant crops initially produced a significant reduction in the use of non-glyphosate herbicides and in total herbicide use . In addiThese environmental issues are, on the one hand, real and quite worthy of discussion and debate. They are, however, extensions of ongoing issues already present in conventional agriculture. While there is a clear need to address these issues effectively, this does not appear to necessitate rejection of GM technology as a whole. Rather, the role of GM technology—and various conventional technologies—in agriculture should continue to evolve in response to an evolving environment and in response to continued technical and scientific developments, genetic, and otherwise , 32.Authoritative organizations such as the FDA, World Health Organization, AAAS, the Royal Society of Medicine, and the National Academy of Science have affirmed the safety of GM crops , 57–60. A second approach is to question the science underlying GM safety, often via misinterpretation of data obtained in inappropriate test systems. One recurrent example is the use of surfactant-containing preparations in cell culture systems, “proving” that glyphosate-surfactant products are endocrine disruptors since they impair hormone production. In fact, these systems demonstrate surfactant-mediated disruption of mitochondria, and the authors have simply chosen hormone production as a politically expedient endpoint for cellular asphyxia . Data frA third approach is to invoke the “precautionary principle.” As originally proposed, the principle stated that risk assessors and policy makers should take account of uncertainties and employ uncertainty factors when necessary to provide adequate margins of safety . The absGM crops have a more than 20-year track record of being grown and used commercially without a single human illness known to be caused by GM food or feed. Moreover, billions of animals have been fed predominantly GM diets for consecutive generations with no evidence that animal health and productivity were affected. The safety assessment paradigm for GM crops is robust and well established, and the approach has been confirmed by authoritative regulatory agencies and scientific organizations around the globe. These are, by far, the most thoroughly assessed foods and feeds in human history, and the National Academies of Science concluded that risk or unintended effects of GM technologies falls within the range of risks for conventional breeding technologies—which include forced inter-species crosses and radiation-induced mutagenesis . We can


Post-traumatic stress disorder (PTSD) is characterized by deficits in cognitive functioning, particularly cognitive control. Moreover, these deficits are thought to play a critical role in the etiology and maintenance of core PTSD symptoms such as intrusive thoughts and memories. However, the psychophysiological concomitants of cognitive control remain largely unexamined. In this article, we suggest that individual differences in heart rate variability (HRV), a physiological index of self-regulatory capacity, may underlie the association between cognitive control ability and intrusive cognitions in PTSD. We review evidence showing that individual differences in HRV at rest are related to prefrontal cortical activity and performance on a broad range of cognitive control tasks. We highlight the importance of inhibition as a mechanism by which HRV promotes successful cognitive control. In addition, we summarize recent research linking individual differences in HRV to performance on laboratory tasks that assess the ability to control unwanted memories and intrusive thoughts. We conclude by suggesting that future studies should examine the role of low HRV as a risk factor for developing PTSD. Traumatic experiences can greatly alter an individual’s cognitive, emotional, and physiological functioning as demonstrated by those with post-traumatic stress disorder (PTSD), who experience avoidance, hyperarousal, and re-experiencing symptoms . While cStudies using pharmacological and neuroimaging approaches demonstrate that prefrontal cortical activity is associated with vagally mediated HRV . For exaupdating and monitoring, attentional set-shifting, and inhibition. However, recent perspectives suggest that inhibition may be a “basic function” that underlies other aspects of cognitive control (Cognitive control refers to the mental processes involved in keeping desired information active while inhibiting irrelevant or unneeded information . While c control . Put ano control . Thus, aA growing body of research has found that individuals with higher levels of HRV at rest demonstrate enhanced performance on cognitive control tasks that require working memory, attentional control, and inhibition. Resting levels of HRV are also associated with performance on tasks that require attentional control . Park etWisconsin Card Sorting Task and the Color-Word Interference Task, two measures of general cognitive flexibility and executive function. Importantly, although resting HRV predicted general performance on the tasks, it was most strongly associated with aspects of the tasks that reflected inhibitory control (Consistent with perspectives that suggest a relationship between prefrontal inhibitory processes and HRV , 2009, s control . AltogetDeficits in cognitive control that have been observed in patients with PTSD appear to parallel those that have been associated with individual differences in HRV. However, it is worth noting that the association between cognitive control ability and PTSD is complex and evidence for broad cognitive control deficits in PTSD remains mixed. For example, while some have found that those with PTSD perform worse on neuropsychological measures that require a combination of sustained attention, inhibition of habitual responses, and set shifting, compared to trauma-exposed individuals without PTSD and healthy controls  others hRelative to other aspects of cognitive control, deficits in inhibitory control have been most consistently observed among individuals with PTSD . For exaIndeed, evidence suggests that deficits in inhibitory control are associated with elevated PTSD symptoms, particularly the experience of unwanted memories and thoughts . LaboratAlong these lines, researchers have investigated the association between cognitive control ability and suppression, a strategy commonly used to manage the experience of intrusive cognitions. Suppression is widely considered to be a maladaptive strategy as it sometimes serves to paradoxically increase the frequency of unwanted cognitions (for review see While there is growing evidence suggesting that the re-experiencing of symptoms and intrusive cognitions experienced by individuals with PTSD are associated with deficits in cognitive control, two issues remain unsettled. One question concerns the nature and organization of cognitive control deficits observed in PTSD. Specifically, it remains unclear whether these deficits are the result of disruptions in broadband cognitive ability or impairment in more specific functions such as inhibition. Another issue is that few studies have examined the psychophysiological correlates of cognitive control ability among those with PTSD. Adopting a psychophysiological perspective may provide greater insight into the relationship between cognitive control and the severity of PTSD symptoms and lead to new research directions focused on the etiology and treatment of PTSD. Individual differences in resting levels of HRV are associated with cognitive control ability, particularly inhibitory processes. Moreover, the neurovisceral integration model suggests that low HRV at rest may serve as an endophenotype for some forms of psychopathology, including anxiety disorders . By examGiven that individual differences in HRV index the degree to which the prefrontal cortex exerts a tonic inhibitory influence over subcortical circuits, one would expect that disorders characterized by psychological inflexibility and impaired inhibitory control, as is the case for PTSD, would also be associated with low resting levels of HRV. Indeed, a number of studies show that individuals with PTSD display lower levels of HRV at rest compared to healthy controls and trauma-exposed individuals without PTSD . BlecherIndividual differences in HRV influence the effectiveness of cognitive control processes involved in managing the experience of intrusive memories and thoughts. A recent study  examinedA large body of evidence suggests that PTSD is characterized by cognitive control deficits, which in turn have been linked to the re-experiencing of symptoms such as intrusive thoughts and memories. Moreover, these deficits in cognitive control are primarily the result of impaired inhibitory processes. Building from the common neural basis for cognitive regulation and physiological regulation of the autonomic nervous system, the neurovisceral integration model suggests that individual differences in HRV may be a peripheral marker of cognitive control ability. Indeed, low resting HRV is associated with poorer performance on tasks that require cognitive control processes, especially those that tap inhibition. Initial findings suggest that individual differences in HRV may also index the extent to which individuals are subject to re-experiencing symptoms such as intrusive thoughts and memories. Understanding the relationships among individual differences in HRV, cognitive control, and re-experiencing symptoms is critical, as it may help to refine theoretical models describing the etiology and maintenance of PTSD. Perhaps more importantly, identifying and manipulating the mechanisms that underlie PTSD symptomology may lead to improvements in preventative and therapeutic approaches. Because HRV is able to index the activity of brain networks that support goal-directed behavior, some have advocated its use as a research tool to better understand basic cognitive and psychopathological processes, such as those involved in the etiology and maintenance of PTSD . We echoIdentifying risk factors for developing PTSD has been a major focus of previous research. A number of studies have found that particular biological and cognitive individual characteristics observed prior to the onset of trauma heighten an individual’s risk of developing PTSD (for review, see The associations among HRV, cognitive control, and re-experiencing symptoms may also help to inform treatments for PTSD. If low HRV acts as a vulnerability factor for developing PTSD in the manner that we suggest, it follows that enhancing HRV through medical or psychological interventions may promote more effective cognitive control and thus reduced occurrence of re-experiencing symptoms. A number of interventions including mindfulness mediation , appliedIn this review, we sought to highlight the associations among individual differences in HRV, cognitive control, and re-experiencing symptoms that characterize PTSD. Empirical evidence suggests that these factors are intimately related, though we emphasize the importance of considering HRV given its role as a peripheral marker of organism adaptability and self-regulatory capacity. We hope that our suggestions, derived from a model of neurovisceral integration, will help researchers to develop hypotheses regarding the etiology and maintenance of PTSD symptoms.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 consumption of artificially sweetened processed foods, particularly high in fructose or high fructose corn syrup, has increased significantly in the past few decades. As such, interest into the long term outcomes of consuming high levels of fructose has increased significantly, particularly when the exposure is early in life. Epidemiological and experimental evidence has linked fructose consumption to the metabolic syndrome and associated comorbidities—implicating fructose as a potential factor in the obesity epidemic. Yet, despite the widespread consumption of fructose-containing foods and beverages and the rising incidence of maternal obesity, little attention has been paid to the possible adverse effects of maternal fructose consumption on the developing fetus and long term effects on offspring. In this paper we review studies investigating the effects of fructose intake on metabolic outcomes in both mother and offspring using human and experimental studies. The prevalence of obesity and diabetes has increased radically on a global scale over the past two decades to a point where these conditions are now considered to be “epidemic.” There are an estimated 312 million obese adults worldwide and at least 155 million children who are either overweight or obese . AdvanceCountries tend to undergo nutritional transitions from traditional grain-based diets to high-fat high-sugar diets as affluence increases and populations become more urban ; countriFructose is a naturally occurring sugar and the predominant monosaccharide found in honey, fruit, and some vegetables . It is aIn recent decades, human consumption of free fructose has increased with the introduction of both fructose and HFCS as manufactured sugars in many soft drinks and processed foods. It is now estimated that the average American consumes approximately 50 g of fructose on a daily basis  and sincA National Health and Nutrition Examination Survey (NHANES III), conducted in the United States between 1988 and 1994, included dietary fructose intake as a reported variable and its recent analysis found that on average fructose accounted for over 10% of daily caloric intake in adults and over 12% of daily caloric intake in adolescents, with a quarter of adolescents obtaining at least 15% of their caloric intake from fructose . The majHFCS may be present as different formulations consisting of a mixture of glucose and fructose. Commercial HFCS typically contains either 42% (HFCS-42) or 55% (HFCS-55) fructose mixed with glucose. This is biochemically different from sucrose in that fructose and glucose in HFCS are present in monosaccharide form rather than linked by a glycosidic bond to form a disaccharide , 26, 31 In the past, the characteristics of fructose absorption were not of particular interest because dietary fructose levels were relatively low. However, because of its commercial value, the significant introduction of fructose and HFCSs in processed foods and beverages, and the resulting increase in human consumption of free fructose, understanding the mechanisms of fructose absorption became increasingly important. Initially, rodent studies established transporter mechanisms showing that an active carrier-mediated mechanism of fructose uptake was present in rat small intestine , 34. StuStudies investigating acute responses to both sucrose and HFCS have found similar effects on glucose, insulin, leptin, and ghrelin profiles between the two sweeteners, which were intermediate between those induced by fructose alone and those induced by glucose alone . Both suFollowing an acute dose of fructose, the increased availability of intermediates in the glycolytic pathway leads to increased production of pyruvate and lactate, the end products of glycolysis . ImportaMuch of what is known about the long term effects of fructose has come from experimental studies in rodents. The fructose-fed rat is an animal model of acquired systolic hypertension and the metabolic syndrome . Early sNumerous pathways have been proposed to mediate the effects of fructose, including uric acid formation, inflammation, leptin resistance, and advanced glycation end products , 50–52. In humans, it can be difficult to isolate the effects of chronic fructose consumption, particularly over longer periods of time. Responses to a single dose of fructose alone are likely to be different from those elicited by a meal containing fructose and different again from those elicited by chronic fructose intake . FurtherOf the few studies that have investigated the effects of fructose consumption in human populations, many show changes related to lipid regulation. Fructose is more lipogenic than glucose and its consumption typically results in immediate elevations in plasma triglycerides, despite the fact that it provides substrates for gluconeogenesis and glycogenesis. Fructose consumption favours triglyceride synthesis, particularly when glucose is also present. Studies of acute fructose intake have consistently observed elevated plasma triglycerides, and sometimes VLDL, in the 24 h period following a dose of fructose or a fructose-sweetened beverage , 53, 54.Fructose consumption also leads to hyperuricemia . The conWestern populations obtain >10% of their daily caloric intake from fructose ; thus, tIt is well established that fructose is an important energy source during fetal life, particularly in ruminants , 62; in Due to its inability to stimulate an insulin response, fructose was historically suggested as an alternative fuel source in diabetics . Early sTo date, there remains a paucity of data on the effects of dietary fructose intake during pregnancy and none that have examined long term effects on the offspring. What little evidence exists has been done using small animal studies.In early animal studies, female rats fed a 50% fructose diet during pregnancy and lactation demonstrated significantly elevated plasma glucose concentrations and elevated liver gluconeogenic enzymes during pregnancy . In earlα, and peroxisome proliferator-activated receptor-α [Work by Ching et al. showed that a maternal 60% fructose diet led to increases in serum triglycerides, FFAs, and insulin in offspring. This was concomitant with elevated hepatic triglyceride concentrations, increased expression of acetyl-coenzyme A carboxylase beta (ACC2) and carnitine palmitoyltransferase (CPT1a), and decreased expression of antioxidant enzymes and fatty acid binding protein, PPAR-gamma coactivator 1-ceptor-α .2+) handling, particularly during physiologically challenging conditions such as lactation, due to fructose induced reductions in synthesis of 1,25-OH2D3 [Zou et al. also used a supraphysiological fructose diet (63%) to show that maternal fructose intake results in fatty liver and glucose intolerance during pregnancy and lactation; although birth weights were not affected, weaning weights were significantly reduced in offspring of fructose fed dams . However25-OH2D3 .Most recently, it was demonstrated that the combination of chocolate and fructose consumption in pregnant dams resulted in increased total body fat and impaired liver function in offspring . HoweverStudies using lower fructose exposures have also reported significant changes in genes related to fatty acid biosynthesis and carbohydrate metabolism. Mukai et al. reported that a 10% fructose intake during rat pregnancy leads to the upregulation of maternal and fetal hepatic sterol regulatory element-binding protein- (SREBP-) 1c . More reWe have showed that maternal intake of fructose  during pregnancy results in significant elevations in circulating maternal fructose levels accompanied by maternal hyperinsulinemia. One of the most important and novel observations of this study was the marked sex-specific effects of maternal fructose intake on placental growth and fetal and neonatal metabolic profiles. We demonstrated in term rat fetuses that maternal fructose intake significantly elevated circulating plasma leptin levels in females  and thatSeveral studies have examined possible intervention strategies to negate the adverse metabolic effects associated with excess fructose consumption. One of the most studied interventions is that of the amino acid taurine with a number of studies reporting beneficial effects of taurine supplementation in the setting of fructose-induced metabolic disorders –87. Taurα and beneficially affect adipose tissue oxidative stress in rats with fructose-induced metabolic syndrome [α-lipoic acid ameliorates adverse cardiovascular and metabolic outcomes, possible via a reduction in lipid peroxidation [Resveratrol supplementation in the rat has been shown to restore many features of HFCS-induced disturbances including amelioration of vascular insulin resistance and endothelial dysfunction, possible by regulating eNOS and iNOS production , 94. Fursyndrome . Supplemxidation , 98. HowCurrently 36 million people die each year from noncommunicable diseases (NCDs) . ObesityAlmost two thirds of women of reproductive age in the United States are overweight translating to a marked increase in women entering pregnancy either overweight or obese. In 2006, >30% of Canadian women entered pregnancy either overweight or obese  and mateCurrent evidence in experimental animal models strongly suggests that high fructose intake during pregnancy and lactation leads to metabolic dysfunction in both the mother and the newborn. Increased liver weight and glycogen content and the presence of hyperinsulinemia and elevated plasma glucose and triglycerides may suggest that fructose can promote lipogenesis and induce a state of hepatic insulin resistance in the mothers. Although offspring appear to have early onset changes in metabolic regulation it is unclear whether phenotypic effects in the offspring are the direct effect of fructose transfer through the placenta to the fetus, the effect of fructose transmitted to the neonate during lactation through the mother's milk, or the result of adaptive responses made by the offspring in response to altered maternal metabolism. It is clear that further research is required to elucidate the mechanisms behind the effects of maternal fructose intake on the mother and the offspring and to determine consequences for the offspring in adulthood. per se difficult to delineate. The next few years will likely result in more cohort studies that are well-designed and controlled and which can effectively measure the impact of increased intake of manufactured sugars on metabolic outcomes in both mother and offspring.While experimental investigations into the effects of excessive fructose intake (and that of other manufactured sugars) on metabolic function and obesity have shown clear long term compromise, whether the same effects hold true in human studies is still contentious. No doubt this is fuelled by the complexity of the human diet, owing to increased intake of overall calories derived from not only excessive sugar intake but high fat intake as well, thus making assessment of the direct effects of fructoseOnly recently has excessive fructose intake become the focus of perinatal research; as maternal obesity and excessive weight gain during pregnancy continue to rise it is now imperative that we begin to understand not only maternal global nutritional impacts on fetal, placental, and offspring development but also specific components of today's diet. Together with controlled studies of maternal nutrition during pregnancy in women, we will begin to elucidate the mechanisms of action where a particular focus should be on sex-specific effects and on placental function.


Terfenadine and astemizole underwent regulatory restrictions in ’90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines.There is appreciable utilisation of antihistamines  with drug utilization data from 13 European Countries.We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance.Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals  and 6 in weaker signals . Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible.Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries  or with increasing consumption  deserve careful surveillance. This is especially the case of rupatadine, which was marketed in 2008 and shows steadily increasing use: e.g. Spain and Italy showed a consumption of 0.71 and 0.38 defined daily doses in the observed time-window. On the basis of our data, rupatadine was reported in 1 case of TdP and 4 of asymptomatic QT prolongation, reporting odds ratio resulted statistically significant, but in most cases known proarrhythmic drugs were co-prescribed. Information of its proarrhythmic profile includes also a Thorough QT study , which pHigh consumption of antihistamines in Norway and Sweden found in our study is in line with a previous drug utilisation survey , which pper se for confirmation through additional analytical studies or systematic review of clinical data with relevant meta-analyses, especially for rare events. Our specific methodology attempted to characterize statistically significant signals  considering additional qualitative information  and the clinical relevance of the event of interest  in order to prioritize signals for potential regulatory consideration .Intrinsic limitations of pharmacovigilance analyses are well known and should be briefly acknowledged here:  while moAlso drug utilisation data suffer from well-known limitations: discrepancy between supplied and actually administered drugs is common to all drug utilisation data collections. Moreover, in some countries, only reimbursed prescriptions can be collected, and reimbursement systems are heterogeneous across Europe. Also when Countries are able to collect sales data, hospital data could be missing, although for some drug classes  they represent only a low percentage of the total consumption. Despite limitations, the DDD system is a recognized tool for standardizing doses in drug utilization research and is currently recommended by the WHO for international drug utilization studies .Although also serious and rare European reports are submitted to the FDA, our data may be affected by specific drug marketing penetration . In addition, the characterization of signals is dynamic so that a given antihistamine may change strength of signal  depending on the availability of new pharmacovigilance data over time. This is particularly important for drugs classified as weak or borderline signals, which therefore require monitoring in the next years to fully appreciate their actual post-marketing safety profile.This study attempted to overcome the lack of information on exposed population in spontaneous reporting sources, by linking FAERS findings with drug consumption. It should be kept in mind that results derived from a combination of both data sources must be interpreted very cautiously, because information are obtained from separate databases, which are affected by different bias (see above). In addition, the link between drug utilization data and spontaneous reports is not straightforward. In most of the cases, adverse events track the magnitude of utilization, meaning that the volume of spontaneous reports largely mirror the prescribing trend. As a matter of fact, it should be acknowledged that antihistamines with strong signal are also largely and consistently used across Europe.However, the aim of our study was to approach pharmacovigilance data  in a population risk perspective and to provide risk weighting at the population level. Although pharmacovigilance and drug utilization data sources did not cover the same geographical area , we used these two dataset for different purposes: (a) FAERS, the largest public pharmacovigilance database, to accurately classify and characterize torsadogenic signals by antihistamines, and (b) European drug utilization data to map the overall antihistamine use .Combined analysis of pharmacovigilance and drug utilisation data can provide useful elements for clinicians and regulators in terms of population perspectives of safety concerns of drugs.Some antihistamines resulted in signals of torsadogenic risk and most of them are largely used especially in some European Countries.National Agencies should focus their attention on own peculiar uses of antihistamines and define strategies to minimise proarrhythmic potential, also in the light of their multiple place in therapy and the difficulty in monitoring their use by physicians because of the high frequency of self-medication. Educational initiatives focussed on recognition of patient susceptibility and possible differences in the potential risk among single agents should be addressed.