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This paper presents a research team's experience using a virtual steering group to manage a research project. The main research project was concerned with the evaluation and development of interprofessional working among health and social care staff across primary and secondary care in the United Kingdom, with a focus on older people receiving intermediate care. Intermediate care is a service aimed at preventing unnecessary hospital admission; supporting early discharge from hospital; and reducing or delaying the need for residential care in the community. Intermediate care covers multi-agency and interprofessional working across the continuum of care. We examine one aspect—the use of a virtual steering group, which is an innovative approach aimed at facilitating user and carer participation in the research in a supportive and less intimidating way. The research team includes academics, practitioners, older people and carers, and representatives from the voluntary sector—all are equal members. The team believes it is important to actively involve clients and their carers in the development and direction of research because they can provide a unique perspective ensuring that the research addresses issues of importance to them as service users. We examine and discuss the importance of preparation, support, and training to meaningfully engage in the virtual steering group and the direction of this research. The paper concludes by making recommendations about this model of involving service users in research. [ABSTRACT FROM AUTHOR]

Lifestyle factors have been identified as being very important in determining health in later life. Nutrition, exercise, and social environment all interact to promote, or to limit, opportunities for an active and healthy post-working life. Not only are rates of chronic illness and disability reduced through the promotion of healthy lifestyles, but also quality of life is maintained through the compression of morbidity. Governments in Australia, as in the European Union and North America, have highlighted the importance of behavioral change in health promotion strategies with the aim of having an impact on the health-related lifestyles of their populations. This paper examines the example of a group of older Australians, the “grey nomads,” who may present opportunities for examining health-related lifestyle changes. The term grey nomad refers to a portion of the older population in Australia who choose to use their later years and retirement as opportunities for travel and leisure, mainly within the confines of the Australian continent. As such, they are similar to groups in North America, such as the “snow birds,” who travel to the southern United States to escape the colder winters of more northerly latitudes. Similar seasonal migrations occur from Northern to Southern Europe. What all share in common is an active culture/lifestyle of attempting to “age successfully.” Grey nomads also participate in the creation of what can be termed postmodern communities, where they and other regular travelers may develop a sense of community feeling with others who are also regularly returning to the same spot year after year. Social support is highly predictive of health outcomes and such mobile communities may prove a positive factor in promoting good health. In this paper we examine whether the “grey nomads” represent a good model for improving health-related lifestyles in later life. [ABSTRACT FROM AUTHOR]

From a historical perspective, the studies that led to the isolation and characterization of the thymosins began in earnest in the early 1960s in the laboratory of Abraham White at the Albert Einstein College of Medicine in New York. In a 1966 paper in the Proceedings of the National Academy of Sciences, U.S., we first named these thymic-derived factors “Thymosins.” By 1972, the thymosin team had moved to the University of Texas Medical Branch in Galveston (UTMB) where an extremely talented group of young scientists and students succeeded over the next 6 years in preparing and testing a highly active partially purified calf thymus preparation, termed thymosin fraction-5 (TF5), which was amenable for scale-up and suitable for clinical use. In 1974, we received the first IND for a thymic hormone preparation from the FDA to begin a phase-I study with TF5 in children with primary immunodeficiency diseases at the University of California Medical Center in San Francisco. The immunorestorative and potentially life-saving properties of TF5 in clinical medicine were first documented in a landmark paper in 1975 by Drs. Arthur Ammann and Diane Wara in the New England Journal of Medicine. TF5 consists of a family of at least 40 mostly small acidic polypeptides, with molecular weights ranging from 1000 to 15,000 Da. This article will identify the key scientists and the milestones involved in the initial studies with TF5 that have led to the chemical characterization of the thymosins and to translational studies from the lab bench to the clinic. [ABSTRACT FROM AUTHOR]

This paper reviews a series of my heat transfer studies of on the so-called “self-rewetting” fluids, in which the Marangoni effect due to concentration gradient and the thermocapillary flow cooperatively result in a strong liquid inflow at the nucleation sites in the course of boiling. First of all, the background of the study and our first attempt at heat transfer enhancement in microgravity boiling are introduced. Succeeding fundamental vapor bubble experiments are then briefly depicted. The current progress for applications to space and terrestrial thermal management devices, the main topic of the paper, is described in more detail. [ABSTRACT FROM AUTHOR]

This paper reports the experimental and theoretical investigations of forced liquid flows through open capillary channels under reduced gravity conditions. An open capillary channel is a structure that establishes a liquid flow path at low Bond numbers, when the capillary pressure caused by the surface tension force dominates in comparison to the hydrostatic pressure induced by gravitational or residual accelerations. In case of steady flow through the channel, the capillary pressure of the free surface balances the pressure difference between the liquid and the surrounding constant-pressure gas phase. Because of convective and viscous momentum transport, the pressure along the flow path decreases and causes the free surface to bend inward. The maximum flow rate is achieved when the free surface collapses and gas ingestion occurs at the outlet. This critical flow rate depends on the geometry of the channel and the properties of the liquid. In this paper we present a comparison of the theoretical and experimental critical flow rates and surface profiles for convective dominated flows. For the prediction of the critical flow rate a one-dimensional theoretical model taking into account the entrance pressure loss and the frictional pressure loss in the channel is developed. [ABSTRACT FROM AUTHOR]

We read the paper by Gomes I et al i . with great interest.1 They showed the existence of patients with thiamine deficiency unrelated to alcohol consumption even in high-income countries, and that alerting healthcare professionals working in clinical practice to this fact contributed to improving the quality of medical care. Wernicke encephalopathy presented in the form of postoperative delirium in a patient with hepatocellular carcinoma and liver cirrhosis: a case report and review of the literature. Early detection and successful treatment of Wernicke encephalopathy in a patient with advanced carcinoma of the external genitalia during chemotherapy. [Extracted from the article]

This paper draws from three different bodies of research to discuss the hypothesis that age-appropriate experiences enhance brain and cognitive development throughout the life span. These age-appropriate experiences could be considered as the drivers of development at each age, including drivers to foster development beyond adult abstract thinking, as described in Piaget's formal operational stage. We explore how a nurturing caregiver is the driver in the first 2 years of life, how language learning is the driver from 3 to 10 years, and how problem solving is the driver in the teenage years. To develop beyond adult rational thinking, we suggest that the driver is transcending thought, which can result when practicing meditations in the automatic self-transcending category, such as Transcendental Meditation. [ABSTRACT FROM AUTHOR]

Work in the development and evaluation of mindfulness-based interventions (MBIs) for cancer care has been underway for the last 20 years, and a growing body of literature now supports their efficacy. MBIs are particularly helpful in dealing with common experiences related to cancer diagnosis, treatment, and survivorship, including loss of control, uncertainty about the future, and fears of recurrence, as well as a range of physical and psychological symptoms, including depression, anxiety, insomnia, and fatigue. Our adaptation, mindfulness-based cancer recovery (MBCR), has resulted in improvements across a range of psychological and biological outcomes, including cortisol slopes, blood pressure, and telomere length, in various groups of cancer survivors. In this paper, I review the rationale for MBIs in cancer care and provide an overview of the state of the current literature, with a focus on results from three recent clinical trials conducted by our research group. These include a comparative efficacy trial comparing MBCR to supportive-expressive therapy in distressed breast cancer survivors, a non-inferiority trial comparing MBCR to cognitive behavioral therapy for insomnia in cancer survivors with clinical insomnia, and an online adaptation of MBCR for rural and remote cancer survivors without access to in-person groups. I conclude by outlining work in progress and future directions for MBI research and applications in cancer care. [ABSTRACT FROM AUTHOR]

Fecal microbiota transplantation (FMT) is an emerging therapeutic option for Clostridium difficile infections that are refractory to conventional treatment. FMT introduces fecal microbes into the patient's intestine that prevent the recurrence of C. difficile, leading to rapid expansion of bacteria characteristic of healthy microbiota. However, the long-termeffects of FMT remain largely unknown. The C. difficile patient described in this paper revealed protracted microbiota adaptation processes from 6 to 42 months post-FMT. Ultimately, bacterial communities were donor similar, suggesting sustainable stool engraftment. Since little is known about the consequences of transmitted viruses during C. difficile infection, we also interrogated virome changes. Our approach allowed identification of about 10 phage types per sample that represented larger viral communities, and phages were found to be equally abundant in the cured patient and donor. The healthy microbiota appears to be characterized by low phage abundance. Although viruses were likely transferred, the patient established a virome distinct from the donor. Surprisingly, the patient had sequences of algal giant viruses (chloroviruses) that have not previously been reported for the human gut. Chloroviruses have not been associated with intestinal disease, but their presence in the oropharynx may influence cognitive abilities. The findings suggest that the virome is an important indicator of health or disease. A better understanding of the role of viruses in the gut ecosystem may uncover novel microbiota-modulating therapeutic strategies. [ABSTRACT FROM AUTHOR]

Diet has been known to play an important role in human health since at least the time period of the ancient Greek physician Hippocrates. In the last decade, research has revealed that microorganisms inhabiting the digestive tract, known as the gut microbiota, are critical factors in human health. This paper draws on concepts of cooperation and conflict from ecology and evolutionary biology to make predictions about host-microbiota interactions involving nutrients. To optimally extract energy from some resources (e.g., fiber), hosts require cooperation from microbes. Other nutrients can be utilized by both hosts and microbes (e.g., simple sugars, iron) in their ingested form, which may lead to greater conflict over these resources. This framework predicts that some negative health effects of foods are driven by the direct effects of these foods on human physiology and by indirect effects resulting frommicrobiome-host competition and conflict (e.g., increased invasiveness and inflammation). Similarly, beneficial effects of some foods on host health may be enhanced by resource sharing and other cooperative behaviors between host and microbes that may downregulate inflammation and virulence. Given that some foods cultivate cooperation between hosts and microbes while others agitate conflict, host-microbe interactions may be novel targets for interventions aimed at improving nutrition and human health. [ABSTRACT FROM AUTHOR]

Over the last 20 years, the Nestl'e Research Center in Switzerland and the International Center for Diarrhoeal Diseases Research in Bangladesh have explored the efficacy of alternative biological agents for the treatment of diarrheal diseases. This paper reviews the work of this collaborative effort, particularly on Escherichia coli phage therapy (PT), and discusses the development of the project, starting with the isolation of T4-like coliphages from the stool of diarrhea patients, their pilot plant amplification and purification, and the constitution and testing of a cocktail of T4-like phages in mice. A series of phase I clinical trials has demonstrated the safety of PT. Oral phage given without protection survived gastric passage and was recovered in the feces. Oral T4 phage cocktail was then tested in parallel to a commercial phage product in a phase II randomized, placebo-controlled single-center trial in Bangladeshi children hospitalized with acute E. coli diarrhea. It was found that oral phage did not perform better than the current standard of care by oral rehydration/zinc treatment. Furthermore, fecal E. coli pathogen titers were low and mixed infections were found to be frequent. Microbiota analysis showed a correlation between diarrhea and increased levels of Streptococcus, which raises fundamental questions on the causative agent of diarrhea that may explain PT clinical failure. [ABSTRACT FROM AUTHOR]

Lysosomal storage diseases (LSDs) are a group of rare diseases in which the function of the lysosome is disrupted by the accumulation of macromolecules. The complexity underlying the pathogenesis of LSDs and the small, often pediatric, population of patients make the development of therapies for these diseases challenging. Current treatments are only available for a small subset of LSDs and have not been effective at treating neurological symptoms. Disease-relevant cellular and animal models with high clinical predictability are critical for the discovery and development of new treatments for LSDs. In this paper, we review how LSD patient primary cells and induced pluripotent stem cell-derived cellular models are providing novel assay systems in which phenotypes are more similar to those of the human LSD physiology. Furthermore, larger animal disease models are providing additional tools for evaluation of the efficacy of drug candidates. Early predictors of efficacy and better understanding of disease biology can significantly affect the translational process by focusing efforts on those therapies with the higher probability of success, thus decreasing overall time and cost spent in clinical development and increasing the overall positive outcomes in clinical trials. [ABSTRACT FROM AUTHOR]

The majority of hematopoietic stem cells (HSCs) are maintained in a quiescent state to minimize premature exhaustion induced by various stresses. However, quiescent HSCs are vulnerable to mutagenesis because of attenuated DNA repair and DNA damage response programs. Basal abundant expression of prosurvival BCL-2 proteins further endows HSCs with high resistance to apoptosis. In contrast, HSCs elicit strong activation of p53 upon DNA damage, resulting in enhanced activation of proapoptotic BCL-2 signals through p53. ASPP1, an apoptosis-stimulating protein of p53, is highly expressed in HSCs and preserves HSC pool integrity via selective induction of apoptosis. In this paper, we discuss the role of p53 and mitochondrial apoptosis in HSC regulation and introduce the current understanding of how p53 activity is regulated to achieve a good balance between maintaining the HSC pool and preventing hematological malignancies. [ABSTRACT FROM AUTHOR]

A broad set of brain regions has been associated with the experience and training of mindfulness. Many of these regions lie within key intrinsic brain networks, including the executive control, salience, and default networks. In this paper, we review the existing literature on the cognitive neuroscience of mindfulness through the lens of network science. We describe the characteristics of the intrinsic brain networks implicated in mindfulness and summarize the relevant findings pertaining to changes in functional connectivity (FC) within and between these networks. Convergence across these findings suggests that mindfulness may be associated with increased FC between two regions within the default network: the posterior cingulate cortex and the ventromedial prefrontal cortex. Additionally, extensive meditation experience may be associated with increased FC between the insula and the dorsolateral prefrontal cortex. However, little consensus has emerged within the existing literature owing to the diversity of operational definitions of mindfulness, neuroimaging methods, and network characterizations. We describe several challenges to develop a coherent cognitive neuroscience of mindfulness and to provide detailed recommendations for future research. [ABSTRACT FROM AUTHOR]

Increased organismic complexity in metazoans was achieved via the specialization of certain parts of the body involved in different faculties (structure-function complexes). One of the most basic metabolic demands of animals in general is a sufficient supply of all tissues with oxygen. Specialized structures for gas exchange (and transport) consequently evolved many times and in great variety among bilaterians. This review focuses on some of the latest advancements that morphological research has added to our understanding of how the respiratory apparatus of the primarily terrestrial vertebrates (amniotes) works and how it evolved. Two main components of the respiratory apparatus, the lungs as the 'exchanger' and the ventilatory apparatus as the 'active pump,' are the focus of this paper. Specific questions related to the exchanger concern the structure of the lungs of the first amniotes and the efficiency of structurally simple snake lungs in health and disease, as well as secondary functions of the lungs in heat exchange during the evolution of sauropod dinosaurs. With regard to the active pump, I discuss how the unique ventilatory mechanism of turtles evolved and how understanding the avian ventilatory strategy affects animal welfare issues in the poultry industry. [ABSTRACT FROM AUTHOR]

Interventions that improve health are often associated with longevity. Reduced growth hormone signaling has been shown to increase life span in mice by over 50%. Similarly, reductions in dietary intake of methionine, in rats and mice, result in life-span extension. Many factors affect metabolic health, mitochondrial function, and resistance to stressors, each of which influence aging and life span. This paper presents a comparison of these two interventions, as well as the results of a study combining these interventions, to understand potential mechanisms underlying their effectiveness in enhancing healthy aging. [ABSTRACT FROM AUTHOR]

Mouse B-1 cells are not only major producers of steady-state natural antibodies but also rapid responders to infections and inflammation. These discrete functions may be the outcomes of distinct environmental or developmental triggers that drive B-1 cells toward IgM production or an effector cell fate. Alternatively, distinct B-1 cell subsets may exist, which differ in their functional plasticity. In this paper, we summarize existing data suggesting that B-1 cells form a heterogeneous group of cells with distinct developmental requirements and nonoverlapping functions. Most spleen B-1 cells differ in development from that of bone marrow and peritoneal cavity B-1 cells, in that they develop in the absence of natural IgM. Functional heterogeneity is revealed by findings that B-1 cells in the bone marrow and spleen, but not the peritoneal cavity, generate natural serum IgM, while the latter are rapid responders to inflammatory and infectious insults, resulting in their relocation to secondary lymphoid tissues. A clearer understanding of the developmental and functional differences within the B-1 cell pool may reveal how they might be harnessed for prophylaxis or therapy. [ABSTRACT FROM AUTHOR]

Perhaps the greatest mystery is why the universe exists in the first place. How is it possible for something to emerge from nothing, or has a universe in some form always existed? This question of origins--both of the universe as a whole and of the fundamental laws of physics--raises profound scientific, philosophical, and religious questions, culminating in the most basic existential question of all:Why are we here? Discussion of this and related questions is presented in this paper. [ABSTRACT FROM AUTHOR]

From the discovery of new galaxies and nearly undetectable dark energy to the quantum entanglement of particles across the universe, new findings in physics naturally elicit a sense of awe and wonder. For the founders of modern physics--from Einstein and Bohr to Heisenberg, Pauli, and Bohm--a fascination with deeper questions of meaning and ultimate reality led some of them to explore esoteric traditions and metaphysics. More recently, however, physicists have largely shunned such philosophical and spiritual associations.What can contemporary physics offer us in the quest to understand our place in the universe? Has physics in some ways become a religion unto itself that rejects the search for existential meaning? Discussion of these and related questions is presented in this paper. [ABSTRACT FROM AUTHOR]

The holy grail of physics has been to merge each of its fundamental branches into a unified "theory of everything" that would explain the functioning and existence of the universe. The last step toward this goal is to reconcile general relativity with the principles of quantum mechanics, a quest that has thus far eluded physicists.Will physics ever be able to develop an all-encompassing theory, or should we simply acknowledge that science will always have inherent limitations as to what can be known? Should new theories be validated solely on the basis of calculations that can never be empirically tested? Can we ever truly grasp the implications of modern physics when the basic laws of nature do not always operate according to our standard paradigms? These and other questions are discussed in this paper. [ABSTRACT FROM AUTHOR]

The nucleotide analog NS5 B polymerase inhibitor sofosbuvir was approved by the U.S. Food and Drug Administration (FDA) in December 2013 for the treatment of chronic hepatitis C virus (HCV) infection in combination with ribavirin or peginterferon and ribavirin. Sofosbuvir was developed to meet an urgent medical need for shorter, safer, simplified, more effective HCV treatment regimens and to reduce or eliminate the need for peginterferon. New treatment regimens were especially required for patient populations with limited treatment options, including patients who had failed prior HCV therapy, those with compensated and decompensated cirrhosis, and those who were either intolerant of or had contraindications to interferon. Sofosbuvir plus ribavirin for patients with genotype 2 or 3 HCV infection was the first approved all-oral treatment option. Sofosbuvir is also the backbone of the first regimen available for patients awaiting liver transplantation to prevent HCV recurrence, as well as the first oral interferon-free regimen for patients coinfected with HCV and HIV. This paper describes the development of sofosbuvir up to its original FDA approval. [ABSTRACT FROM AUTHOR]

Opportunities exist for micronutrient fortification of condiments and seasonings to combat vitamin or mineral deficiencies. This paper reviews the available technologies for industrial processing of condiments and seasonings and their fortification with micronutrients. The industrial processes to manufacture commonly consumed condiments and seasonings, such as soy sauce, bouillon cubes, fish sauce, spices, and other relevant products, are described. The impact of processing on fortification is evaluated, considering both the type of vehicle and the fortificant used. The analyzed technologies represent effective strategies for mineral fortification, particularly with iodine and iron. However, fortification with vitamins has been more challenging, owing to sensory changes of the finished product and a poor stability of the fortificant when using certain vehicles. Therefore, more studies are needed in this area in collaboration with governments, the food industry, and vitamin suppliers. Despite the technical difficulties encountered, the current processing technologies for the production of condiments and seasonings can be adapted and refined to allow their successful fortification with micronutrients. [ABSTRACT FROM AUTHOR]

The growing base of information about ecosystem services generated by ecologists, economists, and other scientists could improve the implementation, monitoring, and evaluation of commodity-sourcing standards being adopted by corporations to mitigate risk in their supply chains and achieve sustainability goals. This review examines various ways that information about ecosystem services could facilitate compliance with and auditing of commodity-sourcing standards. We also identify gaps in the current state of knowledge on the ecological effectiveness of sustainability standards and demonstrate how ecosystem-service information could complement existing monitoring efforts to build credible evidence. This paper is a call to the ecosystem-service scientists to engage in this decision context and tailor the information they are generating to the needs of the standards community, which we argue would offer greater efficiency of standards implementation for producers and enhanced effectiveness for standard scheme owners and corporations, and should thus lead to more sustainable outcomes for people and nature. [ABSTRACT FROM AUTHOR]

Type 1 narcolepsy is a sleep disorder characterized by excessive daytime sleepiness with unintentional sleep attacks and cataplexy. The disorder is caused by a loss of hypocretinergic neurons in the brain. The specific loss of these neurons in narcolepsy is thought to result from an autoimmune attack, and this is supported by evidence of both environmental and genetic factors pointing toward an involvement of the immune system. However, definitive proof of an autoimmune etiology is still missing. Several different immune-mediated disorders targeting neurons are known, and many of these are believed to be caused by autoreactive CD8+ T cells. In this paper, we review the current knowledge on CD8+ T cell-mediated neuronal damage on the basis of our understanding of other autoimmune disorders and experimental studies. We identify major histocompatibility complex class I presentation of autoantigens on neurons as a possiblemechanism in the development of the disease, and propose T cell-mediated pathogenesis, with cytotoxic CD8+ T cells targeting the hypocretinergic neurons, as a central element. [ABSTRACT FROM AUTHOR]

Type 1 narcolepsy is a sleep disorder characterized by excessive daytime sleepiness with unintentional sleep attacks and cataplexy. The disorder is caused by a loss of hypocretinergic neurons in the brain. The specific loss of these neurons in narcolepsy is thought to result from an autoimmune attack, and this is supported by evidence of both environmental and genetic factors pointing toward an involvement of the immune system. However, definitive proof of an autoimmune etiology is still missing. Several different immune-mediated disorders targeting neurons are known, and many of these are believed to be caused by autoreactive CD8+ T cells. In this paper, we review the current knowledge on CD8+ T cell-mediated neuronal damage on the basis of our understanding of other autoimmune disorders and experimental studies. We identify major histocompatibility complex class I presentation of autoantigens on neurons as a possible mechanism in the development of the disease, and propose T cell-mediated pathogenesis, with cytotoxic CD8+ T cells targeting the hypocretinergic neurons, as a central element. [ABSTRACT FROM AUTHOR]

Chemoresistance enables cancer cells to evade apoptotic stimuli and leads to poor clinical prognosis. It arises from dysregulation of signaling factors responsible for inducing cell proliferation and death and for modulating the microenvironment. In gynecologic cancers, p53 is a pivotal determinant of cisplatin sensitivity, while BCL-2 family members are associated with taxane sensitivity. Mitochondria fusion and fission dynamics are required for many mitochondrial functions and are also involved in mitochondria-mediated apoptosis, which is closely associated with chemosensitivity. Mitochondrial dynamics are controlled by a number of intracellular proteins, including fusion (Opa1 and mitofusion 1 and 2) and fission proteins (Drp1 and Fis1), which can be proapoptotic or antiapoptotic, depending on the cell types, status, and stimuli from the microenvironment. This paper describes the role of mitochondrial dynamics in the mechanism of chemoresistance and the evidence supporting a significant contribution of a hyperfusion state to chemoresistance in gynecological cancers. Moreover, we discuss our findings showing that enforced fission induces apoptosis of cancer cells and sensitizes them to chemotherapeutic agents. Understanding the regulation of mitochondrial dynamics inchemoresistancemay provide insight intonewbiomarkers that better predict cancer chemosensitivity and may aid the development of effective therapeutic strategies for clinical management of gynecologic cancers. [ABSTRACT FROM AUTHOR]

Human cell adhesion molecules (CAMs) are essential for proper development, modulation, and maintenance of interactions between cells and cell-to-cell (and matrix-to-cell) communication about these interactions. Despite the differential functional significance of these roles, there have been surprisingly few systematic studies to enumerate the universe of CAMs and identify specific CAMs in distinct functions. In this paper, we update and review the set of human genes likely to encode CAMs with searches of databases, literature reviews, and annotations. We describe likely CAMs and functional subclasses, including CAMs that have a primary function in information exchange (iCAMs), CAMs involved in focal adhesions, CAM gene products that are preferentially involved with stereotyped and morphologically identifiable connections between cells (e.g., adherens junctions, gap junctions), and smaller numbers of CAM genes in other classes. We discuss a novel proposed mechanism involving selective anchoring of the constituents of iCAM-containing lipid rafts in zones of close neuronal apposition to membranes expressing iCAM binding partners. We also discuss data from genetic and genomic studies of addiction in humans and mouse models to highlight the ways in which CAM variation may contribute to a specific brain-based disorder such as addiction. Specific examples include changes in CAM mRNA splicing mediated by differences in the addiction-associated splicing regulator RBFOX1/A2BP1 and CAM expression in dopamine neurons. [ABSTRACT FROM AUTHOR]

Bipolar disorders are common psychiatric disorders that affect 1-5% of the population worldwide. Major advances in the epidemiology, pathophysiology, and treatment of the disorders have recently occurred. The majority of published reports, however, originate from theWestern hemisphere, mostly Europe and the United States. There is a shortage of data from the Arab world on bipolar disorders. In an era of globalization and rapid communication, it is not clear to what extent research findings pertaining to one part of the world are by necessity applicable to other parts. Psychiatric disorders are known to be affected by the culture in which they occur, and knowledge of variations in illness presentation in different ethnic groups is also increasing. However, knowledge of variations affecting Arab populations remains quite limited. This paper provides a critical review of the literature on bipolar affective disorders in the Arab world, pointing to major gaps in knowledge and future opportunities to fill these gaps. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments forMDDprimarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant inMDD.We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with theNIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants. [ABSTRACT FROM AUTHOR]

The development of new antidepressants has had mixed results over the past decade, with several notable failures. This paper reviews a number of major initiatives in the development of new antidepressant agents. Traditional strategies to build on agents that have monoaminergic effects at the synapse (e.g., vilazodone and ketamine) have been complemented with efforts that have emphasized devices and brain circuits (e.g., deep brain stimulation and transcranial magnetic stimulation) or chemical agents that modulate neuroendocrine systems (e.g., glucocorticoid antagonists, mixed melatonin agonists/serotonin type-2 receptor antagonists). Interestingly, chemical agents, such as onabotulinumtoxin A, may affect brain circuits as well. We present data from recent studies in drug and device development--reviewing progress made, stumbling blocks encountered, and issues that need to be addressed in future studies. [ABSTRACT FROM AUTHOR]

This paper highlights recent human neuroimaging and cross-species developmental and genetic studies that examine how fear regulation varies by age and the individual, especially during the period of adolescence, when there is a peak in the prevalence of anxiety disorders. The findings have significant implications for understanding who may be at risk for anxiety disorders and for whom, and when, an exposure-based therapy may be most effective. We provide proof of concept for targeting treatment to the individual as a function of age and genetics, inferred frommouse and human studies, and suggest optimization of treatment for nonresponders. [ABSTRACT FROM AUTHOR]

Depression presents a wide canvas for considering some approaches, issues, and problems in the study of major categories of mental illness in the context of current behavioral andmolecular neurobiology. The study of depression encompasses multiple interactions among psychiatry, neurology, and neuroscience, as well as interactions with a host of other disciplines. This paper considers issues from an American perspective and discusses topics including historical aspects of the ways humanity has struggled with depression; the growth of approaches, and the "wars" in psychiatry in the middle of the 20th century between different ideologies; the development of psychiatry as a behavioral science inclusive of many disciplines; current diagnostic systems such as the Diagnostic and Statistical Manual ofMentalDisorders (DSM-5) of theAmericanPsychiatricAssociation, and the ICD-10Classification ofMental andBehavioralDisorders of theWorldHealth Organization; the efforts to delineate subtypes of depression; the search for new neurobiological and behavioral targets in the context of the National Institute of Mental Health's Research DomainCriteria framework; and examples of potential future discoveries and disciplines thatmay ultimately improve treatment. [ABSTRACT FROM AUTHOR]

Schizophrenia is a major mental disorder associated with core neurocognitive impairments. The ability to recreate these deficits in animal models is limited, hampering ongoing translational drug development efforts. This paper reviews the use of electroencephalography (EEG)-based neurophysiological measures, such as event-related potentials (ERPs) or event-related spectral perturbations (ERSPs), as novel translational biomarkers for both etiological and treatment development research in neuropsychiatry. In schizophrenia, cognitive impairments manifest as deficits not only in high-level processes, such as working memory or executive processing, but also as deficits in neurophysiological responses to simple auditory and visual stimuli. Moreover, neurophysiological responses can be assessed even in untrained animals and are therefore particularly amenable to translational, cross-species investigation. To date, several sensory-level ERP measures, including auditory mismatch negativity and N1, and visual P1 and steady-state responses, have been validated in both human clinical investigations and animal models. Deficits have been tied to impaired neurotransmission at N-methyl- d-aspartate-type glutamate receptors (NMDARs). Time-frequency analysis of ERSP permits further extension of these findings from physiological to circuit/cellular levels of analysis. [ABSTRACT FROM AUTHOR]

Over the last few decades, neuroimaging techniques have advanced the identification of structural, functional, and neurochemical brain abnormalities that are associated with the increased risk, clinical course, and treatment outcomes of major depressive disorder (MDD). This paper reviews specific neuroimaging abnormalities that, on the basis of early studies, may discriminate between MDD patients who do or do not respond to current therapeutic modalities, such as antidepressants, cognitive behavioral therapy, or novel therapies. Differences in gray matter volume, white matter coherence, brain activity via structural and functional magnetic resonance imaging techniques, and concentrations of specific brain metabolites (as measured with magnetic resonance spectroscopy), are potential biomarkers discussed in this review. Given the heterogeneity of MDD, larger, multisite studies with increased statistical power will be needed to identify more precise imaging biomarkers of treatment response in MDD. [ABSTRACT FROM AUTHOR]

Vertigo, dizziness, and disequilibrium are common symptoms following concussion or mild traumatic brain injury (mTBI). Dizziness and vertigo may be the result of trauma to the peripheral vestibular system or the central nervous system, or, in some cases, may be due to anxiety, depression, or posttraumatic stress disorder; these mechanisms are not mutually exclusive. While most peripheral vestibular disorders can be identified by testing and examination, those without inner-ear causes that have persisting complaints of dizziness and motion sickness are more difficult to understand and to manage. Some of these patients exhibit features compatible with vestibular migraine and may be treated successfully with migraine-preventative medications. This paper reviews the nonotogenic causes of persisting dizziness, the possible mechanisms, and the pathophysiology, as a framework for patient management and for future research. [ABSTRACT FROM AUTHOR]

Meniere's disease is a poorly understood, disabling syndrome causing spells of vertigo, hearing fluctuation, tinnitus, and aural fullness. In this paper, we present a review of the histopathology, cytochemistry, and imaging of Meniere's disease. Histopathology is significant for neuroepithelial damage with hair cell loss, basement membrane thickening, and perivascular microvascular damage. Cytochemical alterations are significant for altered AQP4 and AQP6 expression in the supporting cell, and altered cochlin and mitochondrial protein expression. Current developments include imaging techniques to determine the degree and presence of endolymphatic hydrops, and future studies will endeavor to correlate the observance of hydrops with clinical findings. [ABSTRACT FROM AUTHOR]

It has been established that there is a relationship between chronic inflammation and cancer development. The constant colonic inflammation typical of inflammatory bowel diseases is now considered a risk factor for colorectal carcinoma (CRC) development. The inflammatory network of signaling molecules is also required during the late phases of carcinogenesis, to enable cancer cells to survive and to metastasize. Oxidative reactions are an integral part of the inflammatory response, and are generally associated with CRC development. However, when the malignant phenotype is acquired, increased oxidative status induces antioxidant defenses in cancer cells, favoring their aggressiveness. This contradictory behavior of cancer cells toward redox status is of great significance for potential anticancer therapies. This paper summarizes the essential background information relating to the molecules involved in regulating oxidative stress and inflammation during carcinogenesis. Understanding more of their function in CRC stages might provide the foundation for future developments in CRC treatment. [ABSTRACT FROM AUTHOR]

Many daily activities involve looking for something. The ease with which these searches are performed often allows one to forget that searching represents complex interactions between visual attention and memory. Although a clear understanding exists of how search efficiency will be influenced by visual features of targets and their surrounding distractors or by the number of items in the display, the role of memory in search is less well understood. Contextual cueing studies have shown that implicit memory for repeated item configurations can facilitate search in artificial displays. When searching more naturalistic environments, other forms of memory come into play. For instance, semantic memory provides useful information about which objects are typically found where within a scene, and episodic scene memory provides information about where a particular object was seen the last time a particular scene was viewed. In this paper, we will review work on these topics, with special emphasis on the role of memory in guiding search in organized, real-world scenes. [ABSTRACT FROM AUTHOR]

Attentional selection can be viewed as having two aspects: selection with respect to particular objects and selection with respect to particular categories. Both aspects are mathematically modeled in the theory of visual attention (TVA). In this paper, we expand the rate equation of the TVA and propose that the visual bias toward seeing an object x as a member of category i is a product of three factors: the expectancy (prior probability) of being presented with members of category i, the subjective importance (utility) of seeing objects in category i as members of that category, and the general level of alertness. Together, the three factors also determine the level of arousal in the visual system. The hypothesized multiplicative interaction between the three components of visual bias seems consistent with the function of an ideal observer and also paves the way for a Bayesian interpretation of the TVA. [ABSTRACT FROM AUTHOR]

Stroke remains to be a leading cause of disability. However, optimal strategies can prevent up to 80% of strokes. A large body of evidence supports many strategies for primary and secondary prevention of stroke. The purpose of this paper is to highlight recent major advances for management of modifiable medical and behavioral risk factors of stroke. Specific studies are highlighted, including those related to atrial fibrillation (AF), hypertension, revascularization, hyperlipidemia, antiplatelets, smoking, diet, and physical activity. Effective strategies include the use of novel oral anticoagulants for AF, antiplatelet therapy, and intensive lowering of atherosclerosis risk factors. [ABSTRACT FROM AUTHOR]

Cognitive training, physical activity, and exercise have often been reported to improve cognitive performance in older adults. This paper reviews some seminal and recent studies using these approaches to improve cognition and physical functioning in healthy older adults and in patients suffering from non-neurological chronic medical conditions. Results from cognitive training studies suggest that despite performance improvement in trained tasks, transfer effects appeared very limited. Surprisingly though, computerized dual-task training has been shown to improve balance and postural control in tests of physical functioning, suggesting that broad transfer can sometimes be observed. Physical exercise intervention studies generally found significant and large improvements in physical capacity, in some cognitive domains, and in quality of life. The benefits seem to be equivalent between frail and nonfrail participants. Overall, results reviewed here support the notion that cognitive plasticity for attentional control, as induced by cognitive training or physical activity and exercise, is preserved in late adulthood. Moreover, results of studies with patients at risk of cognitive decline also suggest that cognitive training and exercise interventions are promising nonpharmaceutical tools to help improve cognition in older at-risk individuals. [ABSTRACT FROM AUTHOR]

This paper describes principles underlying the evocation of emotion with music: evaluation, resonance, memory, expectancy/tension, imagination, understanding, and social functions. Each of these principles includes several subprinciples, and the framework on music-evoked emotions emerging from these principles and subprinciples is supposed to provide a starting point for a systematic, coherent, and comprehensive theory on music-evoked emotions that considers both reception and production of music, as well as the relevance of emotion-evoking principles for music therapy. [ABSTRACT FROM AUTHOR]

This paper reviews the mounting evidence for shared cognitive mechanisms and neural resources for rhythm and grammar. Evidence for a role of rhythm skills in language development and language comprehension is reviewed here in three lines of research: (1) behavioral and brain data from adults and children, showing that prosody and other aspects of timing of sentences influence online morpho-syntactic processing; (2) comorbidity of impaired rhythm with grammatical deficits in children with language impairment; and (3) our recent work showing a strong positive association between rhythm perception skills and expressive grammatical skills in young school-age children with typical development. Our preliminary follow-up study presented here revealed that musical rhythm perception predicted variance in 6-year-old children's production of complex syntax, as well as online reorganization of grammatical information (transformation); these data provide an additional perspective on the hierarchical relations potentially shared by rhythm and grammar. A theoretical framework for shared cognitive resources for the role of rhythm in perceiving and learning grammatical structure is elaborated on in light of potential implications for using rhythm-emphasized musical training to improve language skills in children. [ABSTRACT FROM AUTHOR]

Patients with prolonged disorders of consciousness (PDOC) stemming from acquired brain injury present one of the most challenging clinical populations in neurological rehabilitation. Because of the complex clinical presentation of PDOC patients, treatment teams are confronted with many medicolegal, ethical, philosophical, moral, and religious issues in day-to-day care. Accurate diagnosis is of central concern, relying on creative approaches from skilled clinical professionals using combined behavioral and neurophysiological measures. This paper presents the latest evidence for using music as a diagnostic tool with PDOC, including recent developments in music therapy interventions and measurement. We outline standardized clinical protocols and behavioral measures to produce diagnostic outcomes and examine recent research illustrating a range of benefits of music-based methods at behavioral, cardiorespiratory, and cortical levels using video, electrocardiography, and electroencephalography methods. These latest developments are discussed in the context of evidence-based practice in rehabilitation with clinical populations. [ABSTRACT FROM AUTHOR]

In humans and other animals, the locomotor and respiratory systems are coupled together through mechanical, neurophysiological, and informational interactions. At a macroscopic observer-environment level, these three types of interactions produce locomotor-respiratory coupling (LRC), whose dynamics are evaluated in this paper. A formal analysis of LRC is presented, exploiting tools from synchronization theories and nonlinear dynamics. The results of two recent studies, in which participants were instructed to cycle or exhale at a natural frequency or in synchrony with an external rhythmic sound, are discussed. The metronome was either absent or present (study 1) and close to or far from the natural frequency of the cycling and breathing systems (study 2). The results evidenced a stabilization of cycling, breathing, and LRC when sound was present compared to when it was absent. A decrease in oxygen consumption was also observed, accompanying the increase in sound-induced LRC stabilization. These results obtained with a simple rhythmic metronome beat have consequences for exercising while listening to music; the consequences are further explored here. [ABSTRACT FROM AUTHOR]

This paper brings together different perspectives on the investigation and understanding of temporal processing and temporal expectations. We aim to bridge different temporal deficit hypotheses in dyslexia, dysphasia, or deafness in a larger framework, taking into account multiple nested temporal scales. We present data testing the hypothesis that temporal attention can be influenced by external rhythmic auditory stimulation (i.e., musical rhythm) and benefits subsequent language processing, including syntax processing and speech production. We also present data testing the hypothesis that phonological awareness can be influenced by several months of musical training and, more particularly, rhythmic training, which in turn improves reading skills. Together, our data support the hypothesis of a causal role of rhythm-based processing for language processing and acquisition. These results open new avenues for music-based remediation of language and hearing impairment. [ABSTRACT FROM AUTHOR]

Precise control of movement timing plays a key role in musical performance. This motor skill requires coordination across multiple joints and muscles, which is acquired through extensive musical training from childhood. However, extensive training has a potential risk of causing neurological disorders that impair fine motor control, such as task-specific tremor and focal dystonia. Recent technological advances in measurement and analysis of biological data, as well as noninvasive manipulation of neuronal activities, have promoted the understanding of computational and neurophysiological mechanisms underlying acquisition, loss, and reacquisition of dexterous movements through musical practice and rehabilitation. This paper aims to provide an overview of the behavioral and neurophysiological basis of motor virtuosity and disorder in musicians, representative extremes of human motor skill. We also report novel evidence of effects of noninvasive neurorehabilitation that combined transcranial direct-current stimulation and motor rehabilitation over multiple days on musician's dystonia, which offers a promising therapeutic means. [ABSTRACT FROM AUTHOR]

Whereas much of research in music and neuroscience is aimed at understanding the mechanisms by which the human brain facilitates music, emerging interest in the neuromusic community aims to translate basic music research into clinical and educational applications. In the present paper, we explore the problems of poor pitch perception and production from both neurological and developmental/educational perspectives. We begin by reviewing previous and novel findings on the neural regulation of pitch perception and production. We then discuss issues in measuring singing accuracy consistently between the laboratory and educational settings. We review the Seattle Singing Accuracy Protocol-a new assessment tool that we hope can be adopted by cognitive psychologists as well as music educators-and we conclude with some suggestions that the present interdisciplinary approach might offer for future research. [ABSTRACT FROM AUTHOR]

Adults who engage in synchronous movement to music later report liking each other better, remembering more about each other, trusting each other more, and are more likely to cooperate with each other compared to adults who engage in asynchronous movements. Although poor motor coordination limits infants' ability to entrain to a musical beat, they perceive metrical structure in auditory rhythm patterns, their movements are affected by the tempo of music they hear, and if they are bounced by an adult to a rhythm pattern, the manner of this bouncing can affect their auditory interpretation of the meter of that pattern. In this paper, we review studies showing that by 14 months of age, infants who are bounced in synchrony with an adult subsequently show more altruistic behavior toward that adult in the form of handing back objects 'accidentally' dropped by the adult compared to infants who are bounced asynchronously with the adult. Furthermore, increased helpfulness is directed at the synchronized bounce partner, but not at a neutral stranger. Interestingly, however, helpfulness does generalize to a 'friend' of the synchronized bounce partner. In sum, synchronous movement between infants and adults has a powerful effect on infants' expression of directed prosocial behavior. [ABSTRACT FROM AUTHOR]

Arising from neural crest cells, neuroblastoma (NB) is the most common extracranial pediatric solid tumor. The clinical presentation of NB is heterogeneous, ranging from patients with asymptomatic tumor masses, who require minimal treatment, to patients with metastatic disease who are treated with multimodal therapies. Clinical outcome is also variable, with overall survival ranging from 98% to 100% in infants with stage 1 NB, to less than 30% in patients with stage 4 MYCN-amplified NB. More than 50% of patients show metastasis at diagnosis, with the involvement of different vascularized tissues, including the bone marrow (BM). In this paper, we focus on BM infiltration by NB cells, which is considered an adverse prognostic factor. In particular, we discuss the role of different biological factors that may favor the dissemination of NB cells in the BM, such as chromosomic abnormalities, gene amplification, transcription factors, cell-surface receptors, products of oncogenes, and, more importantly, cytokines and chemokines. In addition, we analyze different techniques to evaluate BM infiltration by malignant cells (i.e., flow cytometry, immunocytochemistry, and quantitative reverse transcriptase polymerase chain reaction). Finally, we review recent data regarding phenotypic and genetic characterization of BM-infiltrating malignant cells and characterization of the BM microenvironment in NB patients compared to healthy subjects. [ABSTRACT FROM AUTHOR]