Nitric oxide derived from endothelial nitric oxide synthase (eNOS) has been shown to be a major mediator of endothelium-dependent responses in cerebral blood vessels. Loss of a single eNOS gene is not associated with any apparent negative consequences on endothelial function in most blood vessels. In contrast, we have recently demonstrated that heterozygous eNOS gene deficiency in combination with a high fat diet is associated with marked impairment of endothelial function. These findings provide an important example of eNOS haploinsufficiency and one that directly impacts the cerebral vasculature. A major mechanism associated with the impairment of endothelial function with eNOS deficiency and a high fat diet appears to be related to increases in plasma IL-6 that serves to further reduce the bioavailability of NO either directly or indirectly via reductions in eNOS expression or activity and via increases in vascular superoxide. Taken together, these findings provide important insights into genetic and molecular mechanisms that promote endothelial dysfunction in response to a high fat diet in cerebral blood vessels with inherent reductions in eNOS gene expression, such as those due to eNOS gene polymorphisms. These findings also highlight the importance of eNOS+/− mice to study the effects of eNOS haploinsufficiency on cerebral blood vessels. While there appears to be some compensation for the loss of eNOS gene expression by neuronal NOS in cerebral arterioles there does not appear to be compensation for the loss of eNOS in the carotid artery, suggesting that endothelium-dependent responses in the carotid are entirely mediated by eNOS4.Endothelium-dependent responses of cerebral blood vessels are mediated in large part by nitric oxide derived from endothelial nitric oxide synthase (eNOS). For example, endothelium-dependent relaxation to agonists, such as acetylcholine, or changes in blood flow can be significantly reduced by pharmacological inhibition of NOS or genetic deletion of the eNOS gene7. Alterations in eNOS cofactor bioavailability  expression and reductions in L-arginine or tetrahydrobiopterin) can also result in reduced eNOS activity and thus negatively impact endothelial responses in cerebral blood vessels7. Once generated, NO bioavailability can be limited by increases in vascular superoxide. For example, the reaction of superoxide with nitric oxide produces peroxynitrite, which is a more oxidative molecule involved in nitration of proteins and DNA9. Superoxide-mediated inactivation of NO is a major mechanism of endothelial dysfunction in many diseases, such as atherosclerosis, diabetes, hypertension, and obesity11. Examination of vascular responses of cerebral blood vessels is clinically important, as endothelial dysfunction has emerged as a strong independent predictor of future cerebrovascular disease and events, such as carotid artery disease and stroke13.eNOS expression and activity is regulated at both the transcriptional and translational levels as well as by post-translational mechanisms including phosphorylation, acetylation and sumolyation14. The fact that the response to acetylcholine is normal is surprising considering that heterozygous eNOS deficiency is associated with a 50–60% reduction in eNOS protein14. We recently demonstrated that the majority of the response to acetylcholine in carotid arteries from +/−eNOS mice can be inhibited by L-NNA (a NOS inhibitor) and ODQ (an inhibitor of sGC)14. In contrast, responses to nitroprusside are almost completely inhibited by ODQ14. These findings provide pharmacological evidence that responses of carotid artery from +/−eNOS mice to acetylcholine and nitroprusside, like those in wild-type +/+eNOS mice, remain almost exclusively dependent on NOS and sGC and sGC, respectively. These data also suggest that there must be some compensatory mechanism(s), which serves to maintain a normal degree of endothelial function in the absence of a single eNOS gene.We, and others, have shown that heterozygous eNOS gene deficiency is associated with normal responses to endothelium-dependent agonists, such as acetylcholine, in the aorta and carotid artery15. sGC serves as the “NO receptor” in vascular muscle8. NO binding to sGC results in increases in intracellular cGMP formation and subsequent relaxation of vascular muscle through a protein kinase G-dependent mechanism8. Indeed, several laboratories have demonstrated that responses of carotid artery from −/−eNOS and +/−eNOS mice to NO donors, such as nitroprusside, are greater than those in wild-type (+/+eNOS) mice, suggesting that the sensitivity to NO increases in the absence of eNOS15. The increased relaxation that occurs in response to NO donors is greater in the absence of two eNOS genes compared to that in the absence of a single eNOS gene, suggestive of a gene dosing effect. Moreover, the increase in sensitivity to NO appears to be related to compensatory increases in sGC activity per se rather than increases in expression of the alpha or beta subunits of sGC15.At least two potential mechanisms have been described to account for normal vascular responses associated with a single eNOS gene. The first mechanism involves increased soluble guanylyl cyclase (sGC) sensitivity+/−eNOS mice appears to involve increased activity of eNOS itself. We recently demonstrated that despite the marked reduction in eNOS protein in +/−eNOS mice there appears to be a compensatory increase in eNOS phosphorylation at Ser1176 14, an eNOS phosphorylation site associated with enhanced eNOS activity as well as increased levels of NO7. An increase in Ser1176 phosphorylation would most likely be reflective of increases in upstream activity of protein kinase A and protein kinase B (Akt), two kinases that have been shown to phosphorylate Ser1176, decreases in dephosphorylation of Ser1176 due to reductions in PP2A expression or activity, as well as alterations in caveolin-1 and Hsp90, both important regulators of eNOS activity11. Additional studies are required to further define the specific molecular events that serve to maintain endothelial function in lieu of the normal complement of eNOS protein.A second mechanism that could also account for the normal responses to acetylcholine in −/−eNOS mice such studies do not appear to have a human correlate, as there is no evidence that homozygous eNOS deficiency occurs in the human population. While complete absence of eNOS may not occur in humans, a number of genetic polymorphisms have been identified in the human eNOS gene including in the promoter region , introns , and exons 21. Perhaps the best-studied eNOS polymorphism is the T-786C polymorphism, which is associated with reductions in eNOS gene expression as well as serum NO levels. The T-786C polymorphism is associated with increased risk of preeclampsia, coronary artery disease, and hypertension21. Surprisingly, much less is known regarding the association of the T-786C eNOS polymorphism and cerebral vascular function or disease. Thus, future studies will be extremely important in identifying those patients that may be at higher risk for cerebral vascular dysfunction and disease. Indeed, a few studies have begun to link the T-786C eNOS polymorphism with increased risk for intracranial hemorrhage24. While studies of vascular function in human cerebral vessels is currently limited, future studies in humanized mice or rats that express human eNOS gene polymorphisms will be particularly invaluable in studying the direct impact of specific eNOS polymorphisms on cerebral vascular function alone or in combination with other cardiovascular risk factors, such as aging and hypertension.Although a large amount of information regarding the role of eNOS in vascular responses has been obtained from +/−eNOS mouse is an excellent model to study the effects of inherent reductions in eNOS gene expression on responses of cerebral blood vessels. The +/−eNOS mouse with its 50–60% reduction in eNOS expression closely mimics the 50% reduction in eNOS expression associated with the T-786C eNOS polymorphism21. We have recently demonstrated, using +/−eNOS mice, that heterozygous eNOS deficiency in combination with 30 wks of a high fat diet  is associated with marked impairment of endothelial function in the carotid artery25. A high fat diet is closely associated with increases in plasma interleukin-6, a pro-inflammatory cytokine that has been shown to produce marked reductions in eNOS protein expression (in a dose-dependent fashion) as well as increases in vascular superoxide27.In lieu of humanized mouse models of eNOS polymorphisms, we propose that the +/+eNOS mice14. In contrast, IL-6 produced marked impairment of endothelium-dependent responses in carotid artery from +/−eNOS mice14. The impairment of endothelial responses by IL-6 was accompanied by increases in NADPH oxidase-derived superoxide. These data serve to link the increase in plasma IL-6 in +/−eNOS mice in response to a high fat diet and the impairment of endothelial function. These data provide an important example of eNOS haploinsufficiency that may have important clinical implications in terms of endothelial function and cerebrovascular risk in obese patients. Future studies in humans will be necessary to determine if eNOS polymorphisms alone or in combination with other cardiovascular risk factors predispose individuals to cerebral vascular disease and events, such as carotid artery disease and stroke.Moreover, in proof-of-concept experiments, incubation of carotid arteries with recombinant IL-6 had no effect on vascular responses in vessels from wild-type 29. We highlight an example of eNOS haploinsufficiency that occurs in the carotid artery in +/−eNOS mice fed a high fat diet. Based on these findings +/−eNOS mice appear to be an excellent model and one, which mimics the effect of eNOS polymorphisms in the eNOS promoter, such as those associated with reductions in eNOS protein expression. Future studies employing +/−eNOS mice will be critical to further our understanding of the specific cellular and molecular mechanisms that contribute to vascular dysfunction in cerebral blood vessels.In conclusion, loss of a single eNOS, while insufficient to impact endothelial function under baseline conditions, predisposes cerebral blood vessels to endothelial dysfunction in response to a high fat diet. Such findings serve as an important example of eNOS haploinsufficiency and may be predictive of greater cerebrovascular risk in obese patients with polymorphisms in the eNOS gene. While a number of eNOS polymorphisms have been linked to coronary artery disease and risk, much less is known regarding the impact of eNOS gene polymorphisms on the cerebral blood vessels and cerebrovascular disease


Clinical assessment in psychiatry is commonly based on findings from brief, regularly scheduled in-person appointments. Although critically important, this approach reduces assessment to cross-sectional observations that miss essential information about disease course. The mental health provider makes all medical decisions based on this limited information. Thanks to recent technological advances such as mobile phones and other personal devices, electronic health  data collection strategies now can provide access to real-time patient self-report data during the interval between visits. Since mobile phones are generally kept on at all times and carried everywhere, they are an ideal platform for the broad implementation of ecological momentary assessment technology. Integration of these tools into medical practice has heralded the eHealth era. Intelligent health  further builds on and expands eHealth by adding novel built-in data analysis approaches based on (1) incorporation of new technologies into clinical practice to enhance real-time self-monitoring, (2) extension of assessment to the patient’s environment including caregivers, and (3) data processing using data mining to support medical decision making and personalized medicine. This will shift mental health care from a reactive to a proactive and personalized discipline. Clinical assessment in psychiatry is usually based on findings from brief, regularly scheduled in-person appointments. Although critically important, this approach reduces assessment to cross-sectional observations that miss essential information about disease course and are subject to recall bias. The mental health provider makes all medical decisions based on this limited information.After an initial longer assessment, standard follow-up outpatient visits in a psychiatric clinic usually include a mental status examination, a brief update on the history of the patient’s present illness , an assessment of treatment effectiveness and potential side effects, and an updated diagnostic impression and treatment plan. All of this generally happens in under 30 minutes. Except in patients with severe mental illness or disabilities, family members or caregivers rarely attend these visits.As the duration of a psychiatric outpatient visit becomes increasingly shorter and intervals between appointments longer, it is essential to develop a form of assessment that can more accurately track patients’ symptoms between visits . One posOver the last decade, medical assessments have been supported by the increasing use and importance of EHRs that facilitate the portability of pertinent health information across providers and geographic locations. Interinstitutional EHRs further increase efficiency in medical services and provide complete and accurate medical information across providers in different institutions . HoweverInternet features have increased networking possibilities of EHRs, offering new options for patient monitoring. Integration of these tools into medical practice has heralded the electronic health  era, integrating new technologies into routine clinical practice. eHealth can also support patient self-monitoring, where both patient and caregivers can update a log of the patient’s mental and physical state between medical visits, potentially leading to more accurate assessment. For example, eHealth tools allow an endocrinologist to chart blood glucose levels between visits for a patient with a portable blood glucose meter. Similarly, a mental health clinician could have access to, and be able to chart, changes in sleep, mood, appetite, and other relevant data related to illness course between visits. These data can be collected through Web-based or mobile phone–based self-reports and other assessment tools and sensors. The clinician can take these data into account during the clinical decision-making process before or during the in-person visit.However, we need to go beyond eHealth and move to intelligent health . iHealth further builds on and expands eHealth by combining real-time self-monitoring with more contextual information from the patient’s environment and novel built-in data analysis tools to enhance medical decision making. The transition from eHealth to iHealth will require integration of comprehensive data from the patient’s environment, as reported by the patient or caregiver or captured through sensors in the patient’s living environment, and the use of artificial intelligence data-mining techniques to aid clinical decision making and provide more personalized treatment  and 2.iHealth will allow a mental health provider to receive real-time input from data-mining tools that will help guide clinical decision making. This is particularly important in the field of psychiatry, where the lack of biomarkers and objective biological tests means that most clinical decisions  are based on signs, symptoms, and behaviors reported to or directly observed by the clinician during the clinical interview. For example, a data-mining iHealth tool may generate a message to alert a clinician that a patient diagnosed with bipolar I disorder is showing a pattern of decreased sleep and increased activity that suggests the imminence of a manic episode. The clinician could decide, based on the alert and other available information, to have a member of the treatment team contact the patient to assess mood stability and determine whether a treatment change is warranted.In developing countries, iHealth could be used to increase access to specialized care for underserved populations. For example, a data-mining tool could generate data-driven personalized treatment recommendations for a given patient that would be implemented by a general practitioner .Below, we outline a novel iHealth model for clinical assessment and treatment in psychiatry based on (1) incorporation of new technologies into clinical practice to enhance real-time self-monitoring, (2) extension of assessment to the patient’s environment, and (3) data processing using data mining to support medical decision making and personalized medicine.By the end of 2014, there were almost 3 billion Internet users, two-thirds from developing countries, and mobile-broadband subscriptions reached 2.3 billion globally . With suThe emergence of smart homes and the development of sensor technologies allows the nonintrusive collection of activity data , allowinFuture studies need to assess the impact of the support provided by these smart home devices on patient outcomes and the sensitivity and specificity of the data collection devices. The cost-effectiveness of these new monitoring approaches also needs to be assessed. Furthermore, the ethical and legal aspects have to be addressed, taking into account privacy and medical confidentiality issues .Many psychiatric disorders are chronic illnesses associated with high levels of disability , making Studies have shown that caregivers and close contacts are reliable sources of information about patients with psychiatric disorders . TraditiThe new technologies described above, including PHRs and EMA, can easily include not only the patient’s own reports and activity but also those from a caregiver . CapturiInvolving caregivers in the clinical assessment may also help to decrease the caregiver burden, including physical and psychological stress, social pressure, and financial costs associated with care giving. Unfortunately, studies focusing on caregiver burden are scarce and have used small heterogeneous patient samples . IdentifWe are advancing toward a double paradigm shift. First, the integration of patient and caregiver data through EMA and PHRs into routine psychiatric assessment will give clinicians access to real-time reports and behaviors of patients and caregivers. Second, as described in the next section, the application of data-mining techniques to the EMA and PHR data will support and enhance medical decision making. These data can be analyzed using data mining tools in order to develop predictive models and personalized treatments. This will shift mental health from a reactive to a proactive discipline, leading to decision support systems for clinicians, as summarized in The traditional method of turning data into knowledge has relied on manual data analysis and interpretation of results in order to find useful patterns to support decision making. The enormous amount and complexity of the ecological data that can be obtained through EMA and PHRs ,25 make Data mining is a set of techniques that can be used to explore treatment and outcome questions in large clinical databases and help develop algorithms and guidelines for problems where controlled data are difficult to obtain. The data mining process includes several steps, including data selection, data processing, and machine learning (described below). Data mining techniques can be used to find relationships and patterns between EMA and PHR data and neurobiological data. As an example, experiments have shown that connections between momentary mental states and environments are sensitive to genetic effects, emphasizing gene-environment interaction . This maMachine learning techniques seek to answer the question: How can we build computer systems that automatically improve with experience, and what are the fundamental laws that govern all learning processes? Machine learning techniques allow processing of real-time observational information by continuously learning from data to build understanding and uncover previously unexpected associations and patterns in data . PredictDespite its many potential advantages over traditionally used psychiatric assessment tools, iHealth still faces several risks and challenges related to human factors. First, electronic monitoring devices are often experienced by physicians as financial, technical, or time-consuming threats. Furthermore, psychological barriers are also important to consider . With thIt could be argued that eHealth and iHealth may be most useful for severe and disabling psychiatric disorders, which are characterized by poor insight and often require significant involvement of caregivers and family members in the clinical care. Some examples could be major neurocognitive disorders (dementia), severe psychotic disorders (schizophrenia), or autism spectrum disorders. However, it should be noted that growing evidence suggests that family involvement and knowledge about the illness and regular contact between patients and caregivers improve outcomes across psychiatric disorders -36.Another limitation of iHealth is that it has been argued that some psychiatric conditions are not amenable to self-reporting . If a paIt may also be argued that requiring the patient to constantly keep track of their mental and physical state puts more responsibility and burden on them. Whether this would have positive or negative effects remains unexplored . eHealthData privacy concerns may deter patients from sharing personal data related to mental health, but data security procedures have been a routine part of data mining from the outset . Human fDespite the challenges and limitations iHealth may lead to improved clinically integrated decision-making tools and personalized medicine practice, tailoring medical treatment to each individual patient. Building on the advances in mental health assessment brought about by eHealth, iHealth will provide personalized clinical information outside of clinical visits and integration of real-time multimodal patient and caregiver data using data mining technologies. This will allow for more precise and effective clinical assessment and decision making. The ability to mine large databases for new hypotheses regarding clinical and environmental dynamic patterns of psychiatric illness through iHealth could also change clinical practice. These possibilities serve key public health needs and offer intriguing and novel opportunities for collaboration, knowledge production, and data analysis.


Little previous research has explored what drives the diversification of national food supplies (DFS) across countries and regions. We construct and analyse a cross-country dataset linking a simple DFS indicator - the share of calories supplied by nonstaple foods - with structural transformation and agroecological indicators. Panel econometric models show that several indicators of structural transformation  are strong predictors of diversification within countries, yet time-invariant agroecological factors are also significantly associated with diversification, which appears to explain why some countries have exceptionally low or high DFS relative to their level of economic development. We discuss the implications of these findings for food and nutrition strategies. •Diversification of food supplies essential for improving nutrition.•First cross-country study explaining diversification of food supplies (DFS) with panel regressions.•Structural transformation indicators strongly predict DFS change over time within countries.•Yet several agroecological factors constrain diversification.•Countries facing these constraints require special policy attention to improve diets. Howeversupplies (hereafter DFS). After many years of focusing solely on calorie supplies, the Food and Agriculture Organization of the United Nations (FAO) recently added a simple DFS measure – the share of calories supplied by non-staple foods – to its expanded suite of food security indicators  containing data on the supply of calories, proteins and fats from different food groups  have been used to create a very simple measure of diversity of food supply which is our outcome variable: calories supplied from nonstaple foods, where staple foods include cereals and root crops. These data have well known weaknesses. Conceptually, they do not measure the composition of diets per se, but only food supply in aggregate, and much food may unequally distributed within a population. Empirically, the underlying quality of national data sources that go into FAOSTAT is often poor in low-income countries. Nevertheless these data remain the only comprehensive means of comparing the calorie content and diversity of food supplies across countries and over time. Moreover, while these data may be weakly associated with measured adult intake of particular foods , Fig. A1We use a wide range of indicators to explain DFS patterns and trends. We use private consumption expenditure per capita  for the period 1965–2010, with a sample of 557 observations, although the actual sample size used varies according to the model specification ( 3lpolyci command) to look for any nonlinear relationships in key parameters of interest. To econometrically explore factors that might influence DFS, we first estimate fixed-effects (FE) models to assess the associations between diversity of food supply (DFS) and four time-varying intermediate determinants , with trend effects represented by a vector of year dummy variables (T). These regressions are effectively difference-in-difference regressions, though a disadvantage of fixed effects models is that researchers are sometimes directly interested in the impacts of time-invariant factors. We therefore also utilize the correlated random effects (CRE) model, also called the Chamberlain-Mundlak model, following In terms of methods, we implement a variety of statistical techniques, via Stata version 14.0, to analyse these data. Graphically, we apply nonparametric techniques, specifically the local polynomial smoother with 95 percent confidence intervals  and in some cases at a much slower rate .5As the nonparametric results suggested, per capita consumption expenditure is a strong predictor of changes in diversity of food supply, even in terms of within-country effects. For every doubling of household consumption expenditure, calories supplied from nonstaples will go up by nearly 6 percent points, an association that is strongly significant at the 1 percent level in both FE and CRE regressions. However, other indicators of structural transformation are also highly significant. Indeed, point estimates of the partial elasticity of DFS with respect to urbanization are somewhat larger than that of consumption per capita (though not significantly so). Even more strikingly, the population aged 0–14 years has a large, negative, and highly significant association with DFS in both the FE and CRE models. Moreover, these associations are significantly larger than the coefficients on consumption per capita. Perhaps surprisingly, however, we do not find any significant association between the years-of-education variable and DFS.As noted in Consistent with economic theories of highly imperfect markets in underdeveloped rural settings, we observe some significant associations between DFS and various agroecological characteristics. Land suitability for crop production is positively and significantly associated with DFS, though the estimated partial elasticity is modest in magnitude (0.02). More strikingly, rural population density has a relatively large and negative partial elasticity of −0.11. We interpret rural population density as a proxy for land constraints, which may operate through several channels, such as feed constraints that inhibit production of animal-sourced foods, and a greater prevalence of small farms that push farmers into intensive cereal cultivation. Lowland areas have an insignificant association, but hilly and mountainous countries appear to have somewhat higher DFS. Groundwater depth has a negative association with DFS, but rainfall is also negatively associated with DFS.Finally, both models produce large coefficients of determination, suggesting that these specifications do a good job in predicting spatial and temporal variation in DFS. In the FE model the within R-squared is 0.62, suggesting that these four structural transformation indicators explain around two-thirds of the changes in DFS over time. The aggregate R-squared in the CRE model factors in the explanatory power of both time-varying and time-invariant factors, but it is worth noting that the time-invariant factors explain a high share of the total variation in DFS (56 percent). Overall, the results support We now use these regression results to analyse the predicted sources of DFS change over time using a simple decomposition at means technique, the results of which we report in 6In this section we engage in a series of robustness checks designed to establish the extent to which the results presented in the previous section stand up to alternative specifications and to a more confident causal interpretation.Next we estimate CRE and FE models where diversification of production as the dependent variable rather than diversification of total food supply. The difference between the two indicators stems from net imports, but Next, we consider a series of different indicators of agricultural and trade policies—tariff rate, agricultural tax and subsidy, price level of consumption, and public spending on agriculture. These indicators were not available for all countries and all years, and were therefore omitted from the results reported in the previous section. Another limitation is that these indicators is that yield little information on diversification specifically. For example, substantial proportions of government expenditures in developing countries are thought to be targeted towards staple grains. Grains-oriented policies could still help or hinder diversification, depending in part on whether they reduce the relative price of grains. A third limitation is that international policies – such as investment in international agricultural research – are also critically important, but very difficult to measure at a national level. Even so, we believe there is merit in exploring whether agricultural policy indicators bear any association with GFS.We find no effect of agricultural tariff rates on DFS, and do not find any association between the price level of consumption  and DFS, which might capture implicit taxation of tradable goods and services. However, we do find a small positive association between public spending on agriculture and DFS. Thus there is some evidence that greater public support for agriculture stimulates diversification, although the associations are modest and likely to be heterogeneous.7In this paper we set out to systematically explore what drives the diversification of food supplies across countries and regions, and over the course of economic development. We first show that a range of economic theories and evidence predict that food systems should diversify throughout the course of economic growth. Existing economic evidence on DFS and diets is largely confined to the indirect evidence provided by food demand analysis. Income elasticities estimated from such microeconomic studies suggest that diversification into animal-sourced foods and processed foods is more rapid than diversification into fruits, vegetables, and other crop-based foods. However, microeconomic theories of market failures in underdeveloped settings also predict that agroecological factors condition DFS given the high degree of perishability of many nutrient-rich nonstaple foods, and therefore the limited scope for trade in such foods.Both our descriptive evidence and our more formal regression models are consistent with these theories. We find strong support for Yet although economic transformation is clearly a very important driver of diversification, evidence herein suggests that some countries have unusually undiversified food supplies relative to their development levels. Descriptively, we note that many countries that are major consumers and producers of rice seem to have undiversified food supplies—examples being Bangladesh, Indonesia, Madagascar, Cambodia, and Laos. One explanation may be statistical in nature, particularly if stocks of rice are relatively large in some countries or simply overestimated (for a discussion on the difficulties of estimating rice stocks, see The analysis is this paper is subject to important limitations. It is well known that the FAO food balance sheets provide estimates that have considerable errors, some of which may be systematic in nature. While these inherent limitations in the quality of the underlying data and in the analytical methods used should not be ignored, it is worth reiterating that the regression analysis provides a series of results that are highly consistent with existing economic theory and evidence. Structural transformation is clearly a fundamental driver of the diversification of food supplies, which may provide one explanation as to why measures of economic growth and urbanization have been robustly associated with lower stunting rates in a wide range of studies (see At the same time, this finding poses many challenges for nutrition strategies, policies, and program design, because it illustrates the difficulties of diversifying food supplies and diets in the absence of prolonged economic growth and transformation. Moreover, while there are many nutrition programs that aspire to accelerate dietary diversification, it is still unclear whether such programs can substantially and sustainably improve diets without prolonged growth in incomes . In addi


Diseases/conditions with diverse etiology, such as hemoglobinopathies, hereditary hemochromatosis and menopause, could lead to chronic iron accumulation. This condition is frequently associated with a bone phenotype; characterized by low bone mass, osteoporosis/osteopenia, altered microarchitecture and biomechanics, and increased incidence of fractures. Osteoporotic bone phenotype constitutes a major complication in patients with iron overload. The purpose of this review is to summarize what we have learnt about iron overload-associated bone loss from clinical studies and animal models. Bone is a metabolically active tissue that undergoes continuous remodeling with the involvement of osteoclasts that resorb mineralized bone, and osteoblasts that form new bone. Growing evidence suggests that both increased bone resorption and decreased bone formation are involved in the pathological bone-loss in iron overload conditions. We will discuss the cellular and molecular mechanisms that are involved in this detrimental process. Fuller understanding of this complex mechanism may lead to the development of improved therapeutics meant to interrupt the pathologic effects of excess iron on bone. Nowadays, osteoporosis is a major public health problem, affecting millions of people worldwide, and it is expected to further escalate due to the progressive aging of populations. Based on demographic changes around the world and the incidence rates for hip fractures, it was estimated that the number of hip fractures occurring in the world each year will exceed 6 million by 2050  chains (α and β) causing various degrees of anemia  is a good predictor of fractures in thalassemia patients similarly to that of healthy subjects. Prevalence of low BMD is increasing sharply by age in thalassemia patients. For example decreased BMD is present in less than 10% of children with thalassemia (6–10 years) but more than 60% of the adult patients (>20 years) have low BMD, regardless of optimal treatment . SCD is one of the most prevalent genetic blood disorders worldwide affecting more than 300,000 annual births. SCD is associated with significant morbidity and shortened life span  is an inherited autosomal recessive disorder, caused by a single nucleotide mutation in the Hb β-chain coding gene      in Caucasian population is due to the Cys282Tyr mutation of the In the last 50 years evidence piled up suggesting the adverse effect of HH on joints and bones  mice had a phenotype of osteoporosis with low bone mass and alteration of the bone microarchitecture  mice  and receptor activator of nuclear factor κB ligand (RANKL) , which migrate to the site of injury, proliferate and differentiate. Osteogenic potential of these bone marrow-derived MSCs (BMSCs) is of crucial importance for proper remodeling and/or healing, which is highlighted by the recent discovery, that osteoporosis is associated with increased number, but low osteogenic potential of circulating MSCs (Dalle Carbonare et al., in vivo tracking of MSCs—increased intracellular iron content in MSCs and impaired osteogenic differentiation of human MSCs (Chen et al., Recently, Balogh et al.  showed t3 (Yang et al., The question whether excess iron affect osteoblast function arose more than 25 years ago, and initial studies showed that iron at high concentration diminish cellular proliferation and function of osteoblast-like osteosarcoma cells (Diamond et al., in vivo animal studies revealed that iron overload influence bone formation (Table −/− mice. Xiao et al. (In the last decade several on Table . Bone hion Table . Doyard on Table  also shoo et al.  found loo et al.  showed do et al.  showed tIron chelation therapy is the main treatment of patients with systemic iron overload (Fabio et al., Iron overload, can be of hereditary or acquired origin, is an excess iron in the body that can accumulate in vital organs. Iron overload increases the risk for liver disease, heart attack or heart failure, and endocrine disorders. Additionally, this condition is frequently associated with a bone phenotype; characterized by low bone mass, osteoporosis/osteopenia, altered microarchitecture and biomechanics, and increased incidence of fractures. Bone metabolism is a complex sequence of bone resorption by osteoclasts, and bone formation by osteoblasts. In order to maintain skeletal health, these processes should be very well harmonized. Excess iron disturbs the delicate balance between bone resorption and bone formation, resulting in bone weakening. Evidence suggests that both increased bone resorption, and decreased bone formation are involved in the pathological bone-loss in iron overload conditions.Iron overload, if it remains untreated, can cause premature death. Iron chelators are in the first line of therapeutic interventions to prevent iron accumulation in vital organs. With chelation therapy, the life expectancy of thalassemia major patients is vastly improved, whereas early treatment can confer normal life expectancy for patients with hereditary hemochromatosis. As life expectancy of patients with iron-overload increases, the prevalence of bone disease also increases, suggesting that the current therapeutic interventions cannot confer full protection for the bones. Further studies needed to investigate the effects of iron chelation therapies on bone metabolism. Fuller understanding of this complex mechanism may lead to the improvement of current therapeutic interventions meant to interrupt the pathologic effects of excess iron on bone.VJ conceptualized the article, performed the literature search, draw the figure and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


One problem with well-established executive function theories is that developmental disorders, brain injury, neuropathology, psychiatric conditions, and cognitive decline typically produce cross-cutting problems in social, cognitive, and emotional domains that seldom correspond to executive function models. Consequently, there is an argument that conceptual theories of executive function do not accord with clinical presentation .This research topic includes findings on the development of executive functions in childhood, adolescence, and early adulthood. Hsu et al. reviewed studies on the development and malleability of Executive Control (EC), which is defined as capacity to regulate cognitive processes for successful goal attainment. They concluded that targeted EC training interventions would likely benefit children from low socio-economic status backgrounds and those with attention-deficit disorders, although early findings are insufficient to warrant firm conclusions. The use of new neuroimaging techniques and better understanding of mechanisms underpinning EC training could further inform developmental interventions for targeted populations.One possibility is that cognitively controlled timing skills make some unique but distinct contribution to the development of working memory and executive functions. fluid intelligence. Royall and Palmer used a latent variable structural equation modeling approach to distinguish domain-specific variance in executive function and memory measures and shared cognitive variance defined by Spearman's g . When variance was accounted for across several memory and executive function measures, executive function ability overlapped with intelligence scores in a healthy elderly cohort. These findings have implications for classification and specificity of executive functions, measurement, and assessment and purported neural substrates. Similarly, impaired performance on a battery of executive function tests by schizophrenic patients was mostly explained by deficits in fluid intelligence Roca et al. Importantly, when fluid intelligence was partialled out multitasking and decision-making performance deficits remained indicating selective executive in addition to general cognitive deficits.This special edition includes evidence that performance on supposed executive function and memory measures may depend upon some shared process defined as Drabble et al. investigated the potential role of attentional control to self-harm in people with borderline personality disorder (BPD). However, the findings were surprising, high attentional focusing predicted self-harm history in those with high BPD features. In contrast, good attentional switching ability reduced the likelihood of self-harm. The notion of a potential moderating effect of attentional control on negative affect and self-harm in BPD individuals constitutes a new conceptualization of the condition. The review of extant evidence indicated that basal forebrain cholinergic system is a potential neural basis of executive attention . Collectively, data supported the notion that neuropeptide regulatory orexin neurons stimulate cholinergic frontal pathways and may provide the mechanism of executive attention, but a further detailed work is needed.Executive attentional control and working memory functions have been investigated in a range of psychiatric and neuropathological conditions. Liu et al. found that BPD patients had lower P3 amplitudes and longer N2 latencies than controls that were independent of working memory load likely indicating working memory dysfunction. Working memory abnormalities were also found in mild cognitive impaired (MCI) patients based on distant synchronization of the background network at rest and during working memory task performance . There was no significant difference between rest and working memory state in MCI patients when compared to controls indicating inefficient organization of the background network associated with cognitive impairment in patients. The neural locus of working memory networks was also explored in bilateral dorsolateral prefrontal cortices using a resting state functional connectivity approach mapped to working memory task accuracy in healthy controls . The findings revealed the functional connectivity between dorsolateral prefrontal cortex and anterior cingulate cortex, and right dorsolateral prefrontal cortex and fronto-insular cortex using spectral dynamic causal modeling. The connectivity of these regions governed working memory ability and differences in resting-state effective connectivity might explain individual differences in working memory ability.Working memory capacity was also investigated in BPD individuals using an event related potentials (ERP) paradigm. Kousaie et al. investigated the purported bilingual advantage on inhibitory control tasks in monolingual Anglophones and Francophones, and French/English bilingual young and older adults. Their findings did not show the expected bilingual advantage for executive task performance , or a bilingual disadvantage on language tasks when compared to monolinguals. One possible explanation of findings is the mediating effect of context and frequency of exposure to both languages on executive and language skills in bilinguals, indicating that purported cognitive advantage/and disadvantage warrants further investigation, particularly in relation to resilience associated with ageing.It has been revealed that speaking more than one language protects the executive functions in ageing. It is assumed that inhibition of one language whilst engaged in the other language confers an interference suppression advantage in bilingual individuals. However, available evidence also indicates that any executive control advantage is offset by poorer ability on language-specific tasks in bilinguals when compared to monolinguals. Wood and Worthington reviewed the literature on the purported link between executive function and socio-emotional functions in healthy ageing and post-traumatic brain injury (TBI) populations. They concluded that intact executive ability is crucial for appraisal and evaluation of social stimuli, and that the distinction between cognitive and socioemotional sequelae of TBI is no longer tenable based on current evidence. Torske et al. investigated whether social function problems were associated with specific executive impairments in children and adolescents with a diagnosis of Autism Spectrum Disorder (ASD) using parent-rated measures. Metacognitive executive functions contributed to social ability in young people with ASD and impaired social functioning potentially reflected poor behavioral regulation.There is an extensive literature on the role of executive function deficits to socio-cognitive behavioral problems, yet there is no overarching theoretical framework that delineates how executive deficits impact social functioning. Jasinska argued that it is time to reconsider whether inhibitory executive processes are conceptually different from response selection and execution. The evidence from neuroscience accounts of inhibitory control mechanisms indicate that response inhibition could be simultaneously classified as a control process and a prepotent response tendency. This conceptualization provides a potential new approach to treating disorders of inhibitory control. Inhibitory control was also poor in those with chronic neuropathic or radicular pain when compared to controls that may have been caused by the chronic experience of pain or secondary tendency to have higher anxiety and depression levels than controls . Problem solving executive ability was not affected by chronic pain in this cohort indicating selective effects of pain on cognition.process pure: supervisory, attentional, and control executive functions invariably operate across other lower-level functions and (ii), there are abiding issues of sensitivity and ecological validity with current standardized tests. To address these issues, a computerized cooking task was developed to evaluate whether an analogue of real world behavior requiring multiple executive functions reliably indexed ability in a control group when compared to standard neuropsychological measures . Task parameters distinguished executive ability from overall IQ, unlike several currently widely used measures, and difficult task levels tapped different executive and memory functions when compared to easier levels. Test analogues of real-world tasks are potential candidates for next generation executive function measures. Tanguay et al. investigated executive function ability using a Breakfast Task, an Activities of Daily Living scale, and real cooking activity with acquired brain injury patients and matched controls. Patients had significant problems with all aspects of the Breakfast Task when compared to controls, although real cooking activity did not correlate with task performance indicating that purported ‘real world’ tasks may not isolate and capture the same functions used in everyday behavior. McGuire commented on the importance of developing ecologically valid tests of executive function for clinical assessment but also emphasized the multi-sensory context of real world behavior, which at present cannot be captured in immersive or computerized tasks but remains a possibility for the future. Cipresso et al. measured executive function ability in Parkinson's disease patients with and without cognitive impairments and controls on a virtual version of the Multiple Errands test (VMET) and standardized executive tests. Patients made more errors on the VMET than controls and the task was more sensitive to detection of early executive deficits than standardized executive measures. Sensitivity and reliability were also problematic on another widely used SELF and OTHER rating scale of executive ability. McGuire et al. compared Self, Other, and clinician ratings on the dysexecutive questionnaire to investigate factor structure and inter-rater reliability of patients' ratings of deficits when compared to others' ratings of their problems. There was poor agreement between clinician and other ratings on the measure indicating that accurate reporting of patients' post-injury deficits was essential to maintain the reliability and usefulness of the scale. Other raters should be selected with caution when asked to rate patient's problems on the dysexecutive questionnaire. Overall findings presented in this research topic were promising for new ecologically valid measures of executive function but were less encouraging for current measures of executive function and their clinical utility.The measurement of executive functions remains problematic because (i), current standardized tests are not neural efficiency theory hypotheses that brain activity is attenuated in experts when compared to non-experts due to processing efficiency. When athletes and non-athletes were compared on a visuospatial executive task, athletes had faster reaction time responses but were not more accurate than non-athletes . FMRI data showed that athletes had reduced activation to multiple frontal, temporal, and cerebellar regions during task performance when compared to non-athletes indicating task-specific neural reorganization in experts. Young healthy males were assigned to either high-, moderate-intensity or a no-exercise group and cortisol levels, EEG activity and executive function performance were measured . Changes were seen in cortisol and P3 amplitude levels after resistance exercise along with enhanced executive function performance. The neural bases of these changes need further investigations, but effects may be associated with physiological arousal levels. Active participants also had better verbal working memory capacity, dual-task performance, and inhibitory ability when compared to a sedentary group . The authors concluded that chronic aerobic exercise can benefit cognitive and physical health across the lifespan.Finally, new approaches to enhance executive function ability are emerging associated with exercise and athleticism. The Tsai et al. investigated the effects of resistance exercise on executive function performance in healthy elderly males and controls, and measured insulin, growth hormone and homocysteine levels at baseline and 1-year intervention period. Performance improvements in the exercise group were associated with an increase in growth factor levels, improved P3 amplitudes (indicating better attention), and decreased serum homocysteine. Aside from the physical benefits, regular consistent exercise contributed to improved executive function and general cognitive health in a well elderly cohort.In other work, Collectively, the papers comprising this special topic reveal that executive function research is theoretically and methodologically diverse cross-cutting atypical, typical, and ageing populations. The neural bases of executive functions and working memory are receiving renewed interest using innovative and advanced imaging and modeling approaches. Importantly, new generation executive tests are emerging, that whilst in the early stages offer promise for speedy, sensitive process-specific clinical assessment. Finally, the relationship between cognitive and physical health reveals that healthy ageing need not be a process of gradual decline and executive functions, like cognition; generally, can be improved by enhanced physical health. Together these findings will hopefully stimulate new theoretical approaches and advances in the field.LB and NM wrote the editorial and were editors of the research topic.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.


Torday and Miller). The central question is: what self-organizing mechanisms in the human nervous system are common to all forms of life, and what mechanisms (if any) are unique to the human species?“Self-organization is the spontaneous—often seemingly purposeful—formation of spatial, temporal, spatiotemporal structures, or functions in systems composed of few or many components. In physics, chemistry and biology self-organization occurs in open systems driven away from thermal equilibrium” . The contributions in this special issue aim to elucidate the role of self-organization in shaping the cognitive processes in the course of development and throughout evolution, or “from paramecia to Einstein”  of regulatory mechanisms, under the dual criteria of minimizing surprise Friston,  and maxiAnnila argues that the most fundamental function performed by the nervous system is shared by all open systems and entails a generation of entropy, by extracting high-grade free energy from the environment and returning low-grade energy. As dictated by the second law of thermodynamics, cognitive processes seek out opportunities (paths) for consuming free energy in the least time. Evolution obtains progressively more efficient mechanisms for detecting and exploiting free energy deposits, culminating in consciousness that emerges in systems pertaining to the ability to “integrate various neural networks for coherent consumption of free energy…” .Street reviews discussions in the literature that examine the tension between—and synthesis of—information-theoretic and thermodynamics-motivated conceptualizations of brain processes. Tensions are rooted in the theory of information, designed to allow analysis of information transfer, irrespective of the physical processes that mediate transfer. Synthesis is necessitated by considerations of energy costs incurred in neuronal signaling. A consensus is anticipated, within a theoretical framework that views cognitive development as self-organization in the nervous system—seeking to minimize surprise, while incurring minimum energy costs.Torday and Miller discuss the conceptual framework needed for tracing evolution of the mammalian brain “from paramecia to Einstein.” The framework encompasses three key notions: (i) complex multicellular organisms share fundamental organizational properties, with precursors in unicellular forms of life, (ii) the most basic property is the ability to extract energy from the environment and dissipate heat in a manner enabling homeostasis and processing of information and (iii) evolutionary improvements in homeostasis, self-maintenance and information processing derive from increased cellular collaboration (coherence). Within this framework, “life is cognition at every scope and scale” and “any cognitive action as a form of cellular coherence can be better understood as both an information exchange and reciprocally then, as energy conversion and transfer” (Torday and Miller).Campbell argues that Darwinian evolution can be expressed as a process of Bayesian updating. Conventionally, the ability to draw inferences and update Bayesian models has been attributed exclusively to (human) reasoning. The range of attribution can be expanded to include all organisms, by assuming that genotypes carry latent models of the environment receiving varying expressions in the phenotype. On that view, genetically transmitted models are the source of hypotheses (phenotype variations) subjected to confirmation  or rejection (extinction) by the environment. Changes in the phenotype over somatic time and the genotype over evolutionary time minimize surprise thus increasing the likelihood of survival of individuals and the species.Kozma and Freeman analyze alternations between highly organized (low entropy) and disorganized (high entropy) neuronal activities induced by visual stimuli. In rabbits implanted with ECoG arrays of electrodes fixed over the visual cortex, presentations of stimuli were accompanied by metastable patterns of synchronized activity—collapsing quickly into the background activity upon cessation of the stimuli. The authors define alternations between metastable patterns and disorganized firings as phase transitions and propose a “cinematic” theory of perception; treating alternations that spread across the cortex as successions of “frames” combined into perceptual units (percepts). Synchronized neuronal populations are identified with Hebbian assemblies, acting in a self-catalytic fashion: Interactions between assemblies maintain the cortex in the critical state, conducive to the emergence of organized (low entropy) structures, such as Hebbian assemblies.Stankovski et al. present novel findings concerning the coherence of neuronal assemblies. Assemblies oscillate within characteristic frequency intervals, with cross-frequency coupling serving to integrate assemblies into functional networks that span distant regions in the brain. In this study, cross-frequency coupling functions were reconstructed from EEG recordings from human subjects in the state of rest, with the eyes either open or closed. They review early evidence that closing the eyes triggers an increase in coupling strength. A novel method of analysis then allows them to determine variations in coupling strength across frequency ranges: crucially, they find that increases in the strength of inter-assembly coupling are accompanied by narrowing variation envelopes.Tang et al. recorded experience-induced changes in the connectivity of large-scale brain networks. Subjects were resting in a state of “mindfulness,” under minimal exposure to external stimuli. A comprehensive array of mathematical analyses was applied to the fMRI data. The analyses reveal statistically significant increases in connectivity between different brain areas. Many earlier studies have demonstrated increased connectivity in brain networks under external stimuli; however, according to this study, similar increases can be produced in the course of internally-induced, restful states.Werbos and Davis review progress to date in modeling cognitive functions, focusing on the neural net model of learning employing back-propagation algorithms. Neural nets represent learning as the acquisition of desired mappings between input vectors  and output vectors (desired responses), via iterative reduction of mapping errors. The model posits successions of calculations propagating forward and backward in the neuronal system, orchestrated by some global clock. Empirical substantiations of this model have been scarce—but new experimental findings and analysis are presented that speak to its biological plausibility.Perlovsky's “physics in the mind” research program tries to define the principles of cognition in a rigorous way (a la Newtonian mechanics). Some principles are suggested including mental modeling, vague representations, knowledge instinct, dynamic logic and dual hierarchy. A mental model is the basic functional unit of cognition, models are vague (lacking detail), while sensory inputs are crisp (rich in detail). Acquiring knowledge involves reconciling models and inputs in a process driven by knowledge instinct and employing mechanisms of dynamic logic. Model hierarchy has a counterpart in linguistic hierarchy .Newton analyzes composition of understanding and identifies three constituents: (i) imagery, (ii) the state of mental tension (surprise) caused by a novel situation and (iii) the state of tension resolution, provided by having worked out responses afforded by the situation. The feeling of having reached understanding (Aha!) precedes response execution and thus depends on factors other than external feedback . Execution involves some forms of bodily activities; so “understanding” is anchored in the mechanisms that control such activities. Understanding can then expand via mapping new situations onto those that are already understood.Yufik and Friston suggest that the same self-organization principle manifests in both the emergence of life and evolution of regulatory mechanisms sustaining life: Regions (subnets) in networks of interacting units  fold into bounded structures stabilized by boundary processes. Evolution expanded regulation mechanisms from conditioning to anticipatory planning—that is accomplished via self-directed composition and execution of mental models. Hebbian assemblies stabilized by boundary energy barriers  are produced by folding and phase transition in neuronal networks and represent (model) persistent constellations of stimuli (objects). Variations in packet responses (changes in the composition of responding groups and the order of their firing inside the packet) represent behavior. “Understanding” accompanies the composition of models representing behavior coordination (inter-object relations), as bi-directional (reversible) mapping between packets. Such reversible mapping underlies behavior prediction and explanation (retrodiction). Coordination establishes thermodynamic equilibrium in the volume of a model thus minimizing dissipation (costs) and enabling reversible execution. Expanding models and exploring new inputs necessary moves the system away from equilibrium. Regulation via anticipation and explanation is a uniquely human form of surprise minimization. The regulatory process is supported by verbalization and imagery but is driven by modeling. Arguably, mental modeling, i.e., coordination of packets  in the mental space builds on the neuronal machinery engaged in coordinating limbs and objects in the physical space.This concludes our brief survey of the articles offered in the special issue. To an outside observer, cars might appear to have the purpose of seeking out gas stations and converting fuel into heat and exhaust. A closer inspection will reveal intelligent regulators inside the cars  concerned with having enough fuel to reach the next station—and averting the “surprise” of finding the fuel tank empty. Other concerns—that contextualize this regulation—are the cost of fuel and the desire to keep the car running for the greatest distance possible. In the process, cars must maneuver in coordination with other cars, traffic rules and terrain. Such self-motivated, self-evidencing and self-regulated cars might be a plausible metaphor for minds embedded in a self-organizing nervous system.YY, BS, and KF contributed equally to this editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


All patients with hypertension are at increased risk for vascular events and hypertension is widely regarded as one of the most important risk factors for cardiovascular disease.2The role of the renin–angiotensin– aldosterone system (RAAS), even in the early stages of the cardiovascular continuum, is well-established, with positive results being obtained in clinical trials of cardiovascular event reduction using specific RAAS blockers.In hypertension management, tolerability is key to patient compliance and the long-term reduction of cardiovascular events. ARBs with placebo-like tolerability and efficacy in reducing cardiovascular and cerebrovascular events should be favoured in guidelines.3ARBs reduce blood pressure at least to the same extent as ACE inhibitors and more so in some cases. For example, the largest study undertaken to compare an ARB with an ACE inhibitor, the 1 600-patient Prospective Randomized Investigation of the Safety and efficacy of Micardis versus ramipril using Ambulatory blood pressure monitoring (PRISMA) study found greater blood pressure reductions from telmisartan than ramipril.4There is significant evidence of within-class differences among ARBs with respect to their plasma half-lives, lipophilicity and receptor-binding affinity. Drugs in the ARB class also differ in their antihypertensive efficacy.There is also increasing evidence that, as with ACE inhibitors, ARBs confer benefits beyond their blood pressurelowering effects by reducing morbidity and mortality in cardiovascular, renal and cerebrovascular outcomes through renin–angiotensin system (RAS) blockade.6Telmisartan is the only ARB that has demonstrated therapeutic equivalence to the ACE inhibitor ramipril in hypertensive patients at increased vascular risk. The patient population in this study (ONTARGET) is of particular interest as it is representative of the majority of hypertensive patients seen in everyday clinical practice.The findings from this study showed that telmisartan 80 mg per day was as efficacious as the proven dosage of ramipril (10 mg/day) in reducing risk of cardiovascular death, myocardial infarction, stroke and hospitalisation for heart failure in a broad cross section of highrisk cardiovascular patients. It achieved these results with far fewer side effects, resulting in significantly fewer patients discontinuing therapy.7In clinical practice, ARBs are linked to greater patient adherence and to better blood pressure control. For this reason, first-line ARBs can offer improved efficacy, greater compliance and reduced healthcare utilisation, which offset higher acquisition costs.Importantly, all ACE-intolerant patients who are at risk of diabetes, myocardiaI infarction, stroke or peripheral arterial disease should be switched to the ARB with proven benefit.


Although nerve cell death is the hallmark of many neurological diseases, the processes underlying this death are still poorly defined. However, there is a general consensus that neuronal cell death predominantly proceeds by regulated processes. Almost 30 years ago, a cell death pathway eventually named oxytosis was described in neuronal cells that involved glutathione depletion, reactive oxygen species production, lipoxygenase activation, and calcium influx. More recently, a cell death pathway that involved many of the same steps was described in tumor cells and termed ferroptosis due to a dependence on iron. Since then there has been a great deal of discussion in the literature about whether these are two distinct pathways or cell type- and insult-dependent variations on the same pathway. In this review, we compare and contrast in detail the commonalities and distinctions between the two pathways concluding that the molecular pathways involved in the regulation of ferroptosis and oxytosis are highly similar if not identical. Thus, we suggest that oxytosis and ferroptosis should be regarded as two names for the same cell death pathway. In addition, we describe the potential physiological relevance of oxytosis/ferroptosis in multiple neurological diseases. Among all of the tissues in the body, the human brain is unique with regard to its complexity. About 86 billion neurons  that underlie neuronal death in different diseases of the brain. Within the last two decades, the dichotomy between apoptosis (previously meaning programmed cell death), and necrosis  has proven to be an oversimplification as a myriad of regulated cell death subroutines distinct from apoptosis have been described. These include necroptosis  polymerase 1 (PARP1) may lead to another distinct, non-apoptotic cell death paradigm called parthanatos   from 3H-arachidonic acid in cell lysates) was increased and LOX proteins were translocated to the plasma membrane. In addition, exogenous arachidonic acid potentiates oxytotic cell death. Currently, the precise LOX responsible for the 12-LOX activity is not clear. HT22 cells do not express ALOX15, ALOX12, or ALOX12b, but only ALOX15B  inactivation  was shown to be essential for cells undergoing ferroptosis  involved likely depend on the cell type, the current data support a model where GSH depletion leads to the activation of LOX, which then interacts with PEBP1 and binds to membranes, especially of intracellular organelles, where the cell death propagating lipid-ROS, oxidized phosphatidylethanolamines containing arachidonic or adrenic acid, are formed.The oxidized phosphatidylethanolamines that accumulate following activation of LOXs can be converted to their respective alcohols by GPX4  is among the targets of these LOX metabolites  cells, no changes in the susceptibility to oxytosis were observed in immature BAX−/− neurons compared to wild-type neurons  expression, which encodes cyclooxygenase-2 (COX-2), is prominently upregulated during piperazine erastin-induced ferroptosis , it seems that this idea needs to be carefully evaluated both Transition metals like iron can catalyze the oxidation of biomolecules by Fenton chemistry  with those generated from erastin-resistant and -sensitive human DU-145 cells   and iron accumulation and GSH loss have been repeatedly observed in autoptic PD SN , caspase 1 and 3 activation have been reported, and consequently caspase inhibition was shown to reduce motor neuron death , and mice expressing the first exon of HTT with increased CAG repeats showed shrunken, degenerating neurons, which did not display the nuclear fragmentation typical of apoptosis  (Li et al., Ballistic transfection of rat striatal slices with mutant HTT exon 1 induced loss of medium spiny neurons expressing mutant HTT that could be inhibited by ferrostatin-1 (Skouta et al., With regard to PD, it was reported recently that human differentiated midbrain neurons are uniquely sensitive to oxytosis/ferroptosis brought about by erastin treatment in comparison to insults that induce apoptotic or autophagic cell death (Do Van et al., In summary, multi-layered evidence strongly suggests that oxytosis/ferroptosis plays an important role in CNS diseases. We conclude that oxytosis and ferroptosis are one single pathway. Combining accumulated research performed under both terms will therefore accelerate our understanding of this type of cell death. Most importantly, more specific tools are needed to unequivocally demonstrate where and when neurons undergo oxytosis/ferroptosis in different CNS pathologies. This will provide the necessary framework for clinical trials with oxytosis/ferroptosis inhibitors that are under development for treatment of neurodegenerative diseases.JL: provided the concepts for the review and wrote much of it; PM: wrote a portion of the review and revised the manuscript critically for important intellectual content; GA: wrote parts of the manuscript, performed the gene expression analysis, revised the manuscript critically for important intellectual content; MC and AM: contibuted substatiantially to the conception of the manuscript and revised it critically for important intellectual content.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.


Comprehensive geriatric assessment (CGA) as a consultative service for older adults with complex medical and psychosocial challenges has existed for decades. However, studies have often showed inconsistent acceptance and implementation of geriatric recommendations by primary care providers (PCPs) raising doubts about the overall benefits of CGA in this setting. Press and colleagues investigated the patient- and provider-related factors that affect recommendation implementation, and like previous studies, they too found similarly low rates of implementation. In this commentary, we acknowledge the perennial challenges that exist to improving the acceptance of CGA in primary care practice, and we suggest an alternative target: medical sub-specialty practice. By highlighting three medical sub-specialty fields , which have demonstrated that CGA can be incorporated into their respective clinical practices, we argue that CGA may prove to have greater impact in these settings than in primary care. We also propose initial research steps that could further delineate the trends, outcomes, and next steps for such consultations. More than 3 decades have passed since the introduction of comprehensive geriatric assessment (CGA) into the clinical literature, and yet still today, we continue to debate CGA’s value, its role in the care of older adults, and why its acceptance by primary care providers (PCPs) has been so tepid. Intended to address complex medical and psychosocial problems and their impact on a patient’s function and quality of life, CGA has at best an inconsistent record of impact on PCPs and patient outcomes –4. Whilewhy some patients are more likely to have CGA recommendations implemented by PCPs than others is explored [In a study by Yan Press and colleagues, the very concept of explored . These iexplored , 7 demonThe question, “Why do PCPs who refer patients for CGA choose to not implement more than 50% of recommendations?” is neither new to clinical practice nor to the literature. It has been discussed by many in the past without leading to sustained changes in practice , 9. PresSimilar to their use in primary care settings, clinical practice guidelines in medical sub-specialty practice do not adequately address the complex medical and psychosocial needs of older adults. The wide heterogeneity in aging calls for individually tailoring sub-specialty care plans and a CGA can assist with that process. Medical sub-specialists may not have the training to address complex geriatrics issues, creating an arena for both increased need, as well as potentially increased responsiveness to CGA recommendations. While some fields have already welcomed CGA, others are just starting to recognize its potential value . We willOncology offers a natural opportunity for geriatrics collaboration given the complex decision making often involved and a common geriatrics goal to maximize function in older adults. Thus, oncology is one of the more studied examples of CGA in a medical sub-specialty setting , 11. SevChronic kidney disease (CKD) is a known contributor to increased rates of functional decline, frailty, and mortality in geriatric populations , 17. TheJournal of the American College of Cardiology acknowledged that geriatricians provide skills that “augment quality and capacity of cardiac specialists to meet the needs of their older patients” [Cardiology showcases a complementary approach to CGA within its sub-specialty by using geriatrics trained cardiologists to perform CGAs. A 2011 white paper from the atients” . The expatients” . Both coatients” . In a woThese three medical sub-specialties demonstrate the feasibility of integrating CGA into non-primary care spheres. But despite the above examples and evidence, a geriatrician’s perspective is not routinely sought in most medical sub-specialty practice settings. There are several possible explanations for this observation. There may be hidden boundaries that limit CGA to primary care. Perhaps the concept of CGA is poorly understood among sub-specialists or they have limited awareness of, and access to, CGA. Medical sub-specialists may not yet find the patient outcome data for CGA sufficiently convincing to routinely request it. These are hypotheses that are ripe for investigation to determine if CGA might be acceptable and ultimately effective in sub-specialty practice. Below, we outline three potential research phases that could advance our understanding of CGA and its potential applications in sub-specialty practice settings.why sub-specialists request CGA and implement its recommendations, then CGA could be redesigned to more effectively meet the needs of sub-specialists and their patients.One of the most basic investigations for sub-specialty practice CGAs would examine what would motivate sub-specialists to seek out and follow CGA recommendations. To this end, we would ask the following questions. What are common clinical questions that sub-specialists have for geriatricians? What types of recommendations are most useful for sub-specialists and their patients? What barriers would potentially prevent implementation? Any future studies would also want to compare the rates of implemented recommendations between PCPs and sub-specialists. The answers to these research questions might highlight a fundamental difference in how the primary care and sub-specialty worlds perceive CGA. Ultimately, if we can learn To successfully expand CGA to sub-specialty practice, issues of geriatrics workforce capacity will need to be addressed. Realistically, projections suggest there will not be enough fellowship-trained geriatricians in clinical practice to meet the demands of the rising number of patients requiring geriatrics expertise. This raises the question, “Do CGA practitioners need to be fellowship-trained geriatricians or can sub-specialists be taught the geriatrics knowledge and skills required to provide the key elements of CGA?” As nephrology and cardiology have shown, there is interest in adopting the latter model. Future studies would need to investigate the level of interest among sub-specialists to learn and perform CGA and the acceptance and inclusion of them within individual disciplines.Finally, if CGA within the broad realm of sub-specialty practice proves feasible and acceptable, the next step will be to determine if it can deliver meaningful patient outcomes and potentially cost savings. Similar to Temel et al.’s work on early intervention of palliative care consultation in oncology clinics, future studies could evaluate the effect on quality of life; they could also address the professional satisfaction of sub-specialists who work with CGA teams . ResearcDecades of experience with outpatient CGA targeted at PCPs and their patients has demonstrated inconsistent benefits to older patients and mixed reviews from providers. While there may still be much to learn that could lead to greater adoption of CGA recommendations in primary care, perhaps it is time to consider other applications of CGA. Since CGA attempts to incorporate a patient’s overall prognosis, functional status, goals, and comorbidities into a set of comprehensive recommendations there are many situations in sub-specialty practice where this approach could be applied. Therefore, rather than continuing to narrowly focus efforts on trying to make CGA work for PCPs and their patients, the geriatrics community should instead seek to learn if now is the time to move in a new direction. Evidence exists that CGA can be adapted to sub-specialty practice, but experience is limited and many questions remain unanswered. While the conundrum of why PCPs often elect not to implement CGA recommendations may never be solved, geriatricians can transition their efforts to a new audience that could potentially benefit patients, colleagues, and the health care system at large. CGA may never achieve universal implementation, but by identifying and focusing on the populations that would most benefit from the application of geriatric principles and the providers who are receptive to instituting those principles, the care of older patients could see marked improvement.


This minimizes research risks and avoids ethical problems that a randomized controlled trial (RCT) comparing PrEP to placebo would entail, particularly withholding care proven beneficial in other populations. On the other hand, observational studies yield less precise information than RCTs. This raises a broader question about the pace of research with pregnant women, as it typically takes many years after a drug’s approval for use in the general population to determine safety of the medication in pregnancy. Such delays can have the effect of making it impossible to ethically conduct an RCT with pregnant women, reducing the likelihood that the research community is able to obtain robust, pregnancy-specific evidence. While an observational cohort is potentially the most ethically and scientifically justified research design to study PrEP in pregnancy, earlier involvement of pregnant women in studies of newer preventives may lead to evidence that is more timely and robust.Though many women in need of access to HIV preventive regimes are pregnant, there is a dearth of data to guide these care decisions. While oral pre-exposure prophylaxis (PrEP) has been shown to prevent HIV infection in numerous high-risk populations, pregnant women have been excluded from all major prospective trials. We propose for ethical examination a theoretical trial—a prospective, observational study of PrEP for pregnant women at risk for HIV in sub-Saharan Africa—highlighting an ethical tradeoff that characterizes issues faced for advancing research in pregnancy. On the one hand, an “opportunistic” study design has certain ethical advantages: as formally construed, the research activity usually begins  Approximately 17.8 million women are living with HIV worldwide . AlthougPre-exposure prophylaxis (PrEP) has been shown to prevent HIV infection in numerous high-risk populations, yet little is known about its use in pregnant populations. Pregnancy has been an exclusion criteria from all major trials of PrEP in Africa e.g., , 4, and Future study, however, is uncertain due to debate about when and under what circumstances pregnant women should be involved in such research. The medications used in PrEP, including tenofovir (TDF) and tenofovir-emtricitabine (TDF-FTC) have been studied for PMTCT among pregnant women living with HIV and hepatitis B, and among women with incident pregnancy during PrEP trials; this limited data suggests these medications are generally safe in pregnancy –9, thougWe propose for consideration a prospective study of oral PrEP for pregnant women at risk for HIV in sub-Saharan Africa. While the case we propose is theoretical, a study is in fact currently under development by the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network, IMPAACT 2009 . IMPAACTafter decisions about use or non-use of PrEP are made in the clinical setting. Understood this way, the risks attributed to the research itself are minimal, limited to monitoring and follow-up; thus, the ethical and regulatory complexities of risk/benefit tradeoffs that often characterize interventional studies can be avoided. Second, an observational study avoids the ethical challenges that a randomized controlled study (RCT) comparing PrEP to placebo would entail, particularly withholding care proven beneficial in other populations. Indeed, a placebo-controlled RCT may now be difficult or impossible to justify given the robust evidence for PrEP in non-pregnant populations.Advancing the study of PrEP in pregnancy raises several ethical considerations in the current context, particularly ethical tradeoffs related to the choice of study design. An observational design has certain ethical advantages. First, the approach utilized is often “opportunistic”: as formally construed, research activity begins Yet, there are also disadvantages to such a design. Observational studies may not yield as precise data—particularly about rare events—as a randomized trial would. Thus, while an observational cohort can be an important workaround, it raises a broader question about the pace of research with pregnant women and the costs of delaying or avoiding prospective research, however ethically complex. Observational research in pregnancy most often occurs after licensure; estimates suggest that the determination of a medication’s safety during pregnancy takes an average of 27 years following the drug’s approval . Delays how clinical trials with pregnant women could be conducted, but when in the research and development cycle pregnant women should be included. Clearly, delaying enrollment of pregnant women in prevention studies allows accumulation of pregnancy safety data through inadvertent exposures, and also permits the research community to avoid the ethical challenges of intentional exposure of pregnant women to interventions whose risks and benefits are unclear. However, these delays can also raise new ethical barriers to the conduct of studies that would provide robust, pregnancy-specific data. Given the costs of delay, timely inclusion of pregnant women must be addressed in developing an HIV prevention research agenda that adequately and ethically attends to the interests of pregnant women and their future offspring.As we move forward in prevention efforts , it is important to consider not just There is an urgent need for HIV preventives during pregnancy; a prospective clinical trial of PrEP in pregnant women is an important step in meeting this need. While an observational cohort is potentially the most ethically and scientifically justified research design to study PrEP, earlier involvement of pregnant women in studies of newer preventives going forward may lead to evidence that is more timely and more robust. Addressing the ethical complexities of intervention research is therefore a pressing priority.


This Editorial introduces a special issue that illustrates a trend toward integrated landscape approaches. Whereas two papers echo older “win–win” strategies based on the trade of non-timber forest products, ten papers reflect a shift from a product to landscape perspective. However, they differ from integrated landscape approaches in that they emanate from sectorial approaches driven primarily by aims such as forest restoration, sustainable commodity sourcing, natural resource management, or carbon emission reduction. The potential of such initiatives for integrated landscape governance and achieving landscape-level outcomes has hitherto been largely unaddressed in the literature on integrated landscape approaches. This special issue addresses this gap, with a focus on actor constellations and institutional arrangements emerging in the transition from sectorial to integrated approaches. This editorial discusses the trends arising from the papers, including the need for a commonly shared concern and sense of urgency; inclusive stakeholder engagement; accommodating and coordinating polycentric governance in landscapes beset with institutional fragmentation and jurisdictional mismatches; alignment with locally embedded initiatives and governance structures; and a framework to assess and monitor the performance of integrated multi-stakeholder approaches. We conclude that, despite a growing tendency toward integrated approaches at the landscape level, inherent landscape complexity renders persistent and significant challenges such as balancing multiple objectives, equitable inclusion of all relevant stakeholders, dealing with power and gender asymmetries, adaptive management based on participatory outcome monitoring, and moving beyond existing administrative, jurisdictional, and sectorial silos. Multi-stakeholder platforms and bridging organizations and individuals are seen as key in overcoming such challenges. Görg Integrated landscape approaches (ILAs) or initiatives (ILIs)There is a great variety in how landscape approaches are conceptualized and labeled Pfund . A recenBuilding upon recent literature on ILAs and drawing from the contributions to this volume, this editorial first provides an overview of ILAs and how they differ from earlier approaches such as ICDPs and NTFP strategies that aimed to reconcile multiple aims. After this initial focus on ILAs, we move to ILLIs in areas such as forest and landscape restoration , the strategy was based on a sectorial focus on one or a few NTFPs, hardly considering trade-offs with other land uses, activities, or actor interests  are particularly lacking is the recognition that not all stakeholders will “win” all of the time  for Africa and 22%  and 7%  for Latin America and the Caribbean  and the dichotomy of top-down vs. bottom-up governance will likely be necessary to better account for the multiple conflicting processes occurring across tropical developing landscapes. ILAs need not be considered a departure from community-based conservation Berkes  or rightEvidence from the conservation literature has shown that strictly bottom-up approaches can produce perverse outcomes (Carpentier et al. Implementing landscape-level initiatives must confront the challenge of institutional and jurisdictional fragmentation and institutional rigidity, whereby in particular public actors adhere to their sectorial silos and jurisdictional powers (van Oosten et al. 2013; van Oosten et al. Several cases reported in this special issue illustrate such tendency toward polycentrism in ILLIs. In Ghana, this encompasses a combination of statutory and customary institutions in the implementation of natural resource schemes (Foli et al. Polycentric governance allows for flexibility, but also creates a coordination dilemma where one jurisdiction generates positive or negative externalities for other jurisdictions (Hooghe and Marks The papers in this special issue evidence the increasing recognition that global challenges such as sustainable production and livelihoods, biodiversity conservation, and climate change mitigation need to be addressed in a holistic and integrated manner at the landscape level. However, the sectorial silos, particularly in the public sector, are not easily broken down (e.g., Dale et al. Despite these encouraging signs, there are a number of other conditions that need to be fulfilled for ILLIs to evolve into integrated landscape approaches. These include, first, the need to create a sense of urgency of a commonly shared problem at the landscape level. As several cases have shown (e.g., Dale et al. Participatory monitoring of progress and outcomes of landscape approaches and landscape-level initiatives is key to adaptive management and the capacity to deal with the dynamics inherent in landscapes, but data collection is often costly and time-consuming (Sayer et al. c.f. Meinig This special issue illustrates a trend toward greater synergies in objectives and actor configurations in natural resource management and value chain governance. Starting with product-focused approaches in the NTFP sector aiming at combined development and conservation outcomes, the current trend is toward landscape-level initiatives and integrated landscape approaches that consider and negotiate trade-offs between different land uses and objectives. Despite design principles that suggest a common umbrella (Sayer et al. Supplementary Material