A considerable understanding of the fundamental cellular and molecular mechanisms underpinning healthy acute wound healing has been gleaned from studying various animal models, and we are now unravelling the mechanisms that lead to chronic wounds and pathological healing including fibrosis. A small cut will normally heal in days through tight orchestration of cell migration and appropriate levels of inflammation, innervation and angiogenesis. Major surgeries may take several weeks to heal and leave behind a noticeable scar. At the extreme end, chronic wounds – defined as a barrier defect that has not healed in 3 months – have become a major therapeutic challenge throughout the Western world and will only increase as our populations advance in age, and with the increasing incidence of diabetes, obesity and vascular disorders. Here we describe the clinical problems and how, through better dialogue between basic researchers and clinicians, we may extend our current knowledge to enable the development of novel potential therapeutic treatments.Much is known about the sequence of events contributing to normal healing.The two pathologies of wound healing are chronic wounds and scarring.We explain how the cell and molecular mechanisms of healing guide the therapeutic strategies.Drosophila as novel wound healing models.We introduce zebrafish and the fruit fly, We highlight unanswered questions and future directions for wound healing research. Wound healing after damage to the skin involves a complex interplay between many cellular players of the skin, primarily keratinocytes, fibroblasts, endothelial cells of vessels and recruited immune cells, and their associated extracellular matrix Fig.. In healTissue repair is a universal phenomenon across all multicellular organisms, and so we presume that many conserved mechanisms can be analysed in models more experimentally tractable than humans, and subsequently extrapolated back to the clinic for potential therapeutic benefit. Because of similarities to human skin, pig models of wound healing were initially used for investigating repair mechanisms,Much of what we know about the cellular and genetic players in wound healing and the relative time courses of the various phases of skin repair come from studies in mice. Transgenic and knockout mouse studies have provided opportunities to investigate the functions of many genes that turn out to have key roles during skin healing.Ap1, Fos and Jun,8The wound epithelium repairs both from cut wound edges and also from the stumps of hair and sweat gland appendages. Mouse wound transcriptome studies have revealed numerous genes upregulated after damage, and many of these gene inductions occur in the wound edge epithelium, extending back up to 70 or more rows of cells from the cut wound edge.−/− mice fail to change these adhesions and exhibit delayed healing.11Before migrating forward, wound-edge keratinocytes must change their cell-to-matrix adhesions. These adhesions will previously have bonded basal epidermal cells to the basement membrane, but during the repair process they must facilitate migration over a new wound-specific, fibrin-rich matrix. Several integrins are switched off in order for cells to detach from the basement membrane, and others now become essential for wound migration. For example, keratinocyte-specific knockout of β1-integrins in mice leads to severe retardation in wound re-epithelialization.Re-epithelialization is then activated by several driving growth factors, including hepatocyte growth factor (HGF) and one or more members of the fibroblast growth factor (FGF) and epidermal growth factor (EGF) families. Studies have shown that keratinocyte-specific knockout of c-met (HGF receptor) or FGF receptors 1 and 2 leads to severe retardation of the wound epidermis,14de novo from apparently nonfollicular epidermis, in a Wnt-dependent manner that appears to recapitulate embryonic appendage formation.18Generally, epidermal cells are lost following any skin injury and they must be replaced by cell proliferation, which occurs largely in an epithelial zone back from the migrating epidermal tongue.Many genes are also upregulated in the wound-edge fibroblasts. It was previously assumed that these cells were the sole source of the wound granulation tissue that became activated by exposure to various growth factor signals and are triggered to proliferate and migrate in synchrony with the advancing epidermis. Some of these cells transform into the contractile specialist cell, the myofibroblast, after exposure to transforming growth factor (TGF)-β and mechanical loading signals.23Studies of repair in embryonic model organisms including mice, and also in human patients undergoing fetal surgery, have indicated that prior to the onset of a wound inflammatory response, immature tissues are capable of scar-free healing.26There are now a plethora of mouse studies designed to test individually the function of most immune cell lineages in the wound repair process. For some lineages the jury is still out, but the current consensus is that early-recruited neutrophils largely deal with killing invasive microorganisms at the wound site,31Inflammatory cell recruitment and activation are a consequence of many signals that occur at the wound site, and some of the earliest of these include factors released by degranulating plateletsIn the clinic, it is presumed that the considerable vascular sprouting that occurs during any adult tissue repair process must play a pivotal role in healing, and there is much clinical anecdote that cutaneous innervation is important also. Neither of these episodes has been extensively researched in the context of repair, but much is known about the development of vascular patterning during embryogenesis, where we know that endothelial cell sprouting is driven by vascular endothelial growth factor, and macrophages are important in these episodes.43DrosophilaMuch of what is known about the molecular and genetic aspects of skin wound healing has been gleaned from studies in mice, alongside some descriptive clinical observations. But the tissues of mouse and man are opaque and neither organism is particularly genetically tractable. These limitations have encouraged wound healing studies in Drosophila embryo, for example, movies of haemocytes  that are mutant for each of the Rho-family small GTPases have revealed precise roles for these regulators of the cytoskeleton as fly macrophages undergo the wound inflammatory response.In the Drosophila have shown that there are many active cell-shape changes and junctional alterations as epidermal cells jostle several rows back from the wound edge, and this will focus attention away from the front row of cells, which have been considered the only key players until now.Drosophila wound models to identify differentially expressed genes and mutants that suffer impaired healing;wnt and Grh,Recent studies in Drosophila, with greater parallels to our own repair machinery. For example, rather than a single immune cell lineage, as in Drosophila, they have equivalents of all of our innate immune cells. Currently the most exciting insight from zebrafish studies of wound inflammation has been that reactive oxygen species like hydrogen peroxide can serve as immediate damage attractants to draw immune cells to wounds.55Translucent zebrafish larvae offer a phylogenetic step up from In addition to studies of inflammation, there are now new models of skin healing in adult zebrafish that reveal considerable parallels with mammalian wound repair, including similar, although faster, re-epithelialization, and transient scarring, all driven by conserved signalling pathways.Chronic wounds – diabetic foot ulcers, venous leg ulcers and pressure ulcers – do not adhere to the standard time course of cellular and molecular events that lead towards healing of a healthy acute wound Fig.. As an e57Frequently, hyperpigmentation as a consequence of melanocyte recruitment can occur at the wound site, and persist even after a chronic wound has successfully healed. At a molecular level, it seems that the chronic wound edge keratinocytes express a gene signature reflecting partial proliferative activation, with several cell-cycle genes – including the cyclins – upregulated, but with suppression of checkpoint regulators and p53; this might explain the epidermal hyperproliferation at ulcer wound edges.62Chronic, persistent inflammation is a hallmark of most chronic wounds,66With the growth of microbiome 16S ribosomal RNA sequencing opportunities, it is now possible to survey the full microbial flora of wounds, and early datasets are revealing some common genera between diabetic and venous leg ulcers, and significant differences also, whereas the microbial community across a sample of pressure ulcers appears to be the most variable.db/db) mouse), seldom make allowance for other important associations, such as age and wound microbial load. There is a strong case to be made for improving such models by layering on some of these additional influencing factors so that data can be more usefully extrapolated to the clinic. This would certainly lead to development of more optimal models (as reviewed by Nunan et al.It is also important to note that many models of pathological wound healing in mice, while accurately mirroring some of the systemic causes of impaired healing (e.g. the obese and hyperglycaemic diabetic (One of the mysteries in the field of tissue regeneration and repair is the heterogeneity among diverse organisms: some animals, including axolotls, can perfectly regenerate injured tissues and organs as complex as limbs, whereas others, like humans, replace damaged tissue with a connective tissue characterized by densely bundled orientated collagen fibrils called a scar. The degree of fibrosis after damage varies across organs and tissues and between individuals. In humans, perfect scar-free tissue repair has been described in fetal skin.In human skin, two types of scarring following injury are distinguished: hypertrophic scars and keloids Fig.. AesthetBoth hypertrophic scars and keloids are major therapeutic challenges for surgeons and dermatologists. Although multiple treatment regimens are practised, including silicone gel sheeting, pressure therapy, corticosteroids, cryotherapy, 5-fluorouracil, laser therapy and radiation, none of these is optimal and effective, and therapeutics based on molecular targets have not yet gone beyond clinical trials.In order to aid advancement of wound healing research in directions that will lead to benefits in the clinic, we need a good dialogue between clinicians and basic scientists. There follows just a few of the key unmet needs that might be worthy of research and provide clues as to prognostics and therapeutics for chronic wounds and for scarring.We know that almost all chronic wounds begin as a small cut or abrasion, and almost certainly begin the repair process as a normal acute wound. At some stage they stall, but of course this is likely to be some days or weeks or even months before the patient presents at the clinic. Unfortunately, we have little understanding of the time or stage in the normal cycle when stalling happens, and this may be crucial in developing therapeutics to reverse the failed process. There is a clear correlation between chronic wound duration and healing efficacy,It is now well understood that innate immune cells exhibit various phenotypes or activation states that can be either very antimicrobial or more dedicated towards nurturing of repairing tissue by their release of growth factors and cytokines. Learning how to manipulate or reprogramme the inflammatory response so it is most effective at staving off infection, and then able to switch to repair mode, and finally to resolve in a timely fashion to avoid the chronic inflammatory phenotype so common in persistent chronic wounds, would provide superb therapeutic tools. If we knew which microbe combinations and what host response led to the most stubborn non-healing wounds then we would have very useful prognostic indicators to guide which wounds need what treatment.It is generally believed that aspects of the acute wound inflammatory response drive scar formation at the time when skin wound healing is occurring – but can inflammation or its downstream consequences be modulated in ways that allow efficient healing but reduce scarring? One opportunity here might be to utilize the body's own inflammation resolution signals to drive early ‘shutdown’ of the inflammatory response.If inflammation causes hypertrophic scarring, then does even more inflammation cause the ‘overflowing’ keloid scar? Or is keloid scarring due to an inability of wound fibroblasts to respond to wound ‘stop’ signals and, if so, what are these? There are no animal models of keloid scarring, but there are opportunities for genome-wide association studies to identify genes that might predispose to keloid scarring, and these might also lead us towards more generic antiscarring therapies if the mechanisms of hypertrophic and keloid scarring are at all related.Much is known about the cellular and molecular basis of normal skin healing, but there are still avenues of research left to unravel that will guide us towards better prognostic indicators and better therapeutics for the various skin wound healing pathologies reviewed above.


Lithium has been used as the gold standard in the treatment of major depressive and bipolar disorders for decades. Due to its narrow therapeutic index, lithium toxicity is a common clinical problem. Although risk factors for lithium intoxication seem to be well-described, lacking patient education and inexperience of treatment are assumed to contribute to the probability of lithium intoxication. A review of literature shows that the treatment of lithium intoxication has not been adequately studied or standardized. The aim of this literature review is to compile and present current evidence on the treatment of lithium intoxication and contribute to a standardization regarding general treatment recommendations as well as evidence on indication for extracorporeal methods. Against the background of this common and potentially life-threatening condition, the standardization of the treatment of lithium intoxication is definitely a task for the future. Since 1970, lithium has been approved and widely used as the gold standard for the treatment of acute episodes and maintenance treatment of bipolar disorder Nolen  and freqDue to a relatively narrow therapeutic index, lithium intoxication has been a common clinical problem  were returned from 1955 to 11/04/2015 using the search term “lithium intoxication AND case report”, but there were no meta-analyses or randomized, placebo-controlled trials that evaluated treatment methods in the management of lithium intoxication. Thus, we focused on relevant review articles and the few available larger case series to summarize the information available about treatment decisions. The lack of background data precluded a more systematic literature review.Lithium intoxication poses a substantial risk of permanent sequelae Nguyen . AgainstThe general approach to a lithium-intoxicated patient is similar to other poisonings, including airway management especially in cases of altered mental status, placing of a nasogastric tube and performing gastric lavage especially when patients present shortly after intoxication . Lithium dosage needs to be individually tailored. More importantly are all psychological interventions known to be effective in preventions of non-compliance Table  Vesterg.Table 2PIn summary there is insufficient information and inconsistent data concerning the indications and termination of hemodialysis in lithium-intoxicated patients. New sequential procedures with less stressful circulatory effects based on theoretical consideration of lithium pharmacokinetics are proposed, but need to be validated in larger studies. With regard to lithium intoxication, additional clinical observations, more comprehensive analyses and prospective treatment studies are urgently needed. To date, we only have available case reports, limited case series, expert opinions and some small retrospective analyses in cases which, against the background of a frequent and potentially life-threatening condition, are insufficient. Future research should aim at the development of standards for a differentiated lithium intoxication treatment.


The Human Microbiome Project defined microbial community interactions with the human host, and provided important molecular insight into how epigenetic factors can influence intestinal ecosystems. Given physiological context, changes in gut microbial community structure are increasingly found to associate with alterations in enteric neurotransmission and disease. At present, it is not known whether shifts in microbial community dynamics represent cause or consequence of disease pathogenesis. The discovery of bacterial-derived neurotransmitters suggests further studies are needed to establish their role in enteric neuropathy. This mini-review highlights recent advances in bacterial communications to the autonomic nervous system and discusses emerging epigenetic data showing that diet, probiotic and antibiotic use may regulate enteric neurotransmission through modulation of microbial communities. A particular emphasis is placed on bacterial metabolite regulation of enteric nervous system function in the intestine. The intestine has evolved efficient digestive, endocrine and immune functions in concert with its microbiota—a vast and complex symbiotic ecosystem comprising bacteria, viruses, fungi, protozoa, and archaea living in close proximity to the host . It is not clear whether enteric glia in mucosal sites also regulate enteric nervous system function, but this glial population is especially responsive to microbial signals , An emerging literature now supports the idea that normal intrinsic and extrinsic neurotransmission in the enteric nervous system is governed, in part, by bacterial-derived metabolites. However, with the exception of E. coli is a prominent bacterial species that generates bioactive nitric oxide in both the small and large intestine using different oxygen dependent mechanisms (Seth et al., Veillonella and Actinomyses spp which are active nitric oxide producers in entero-salivary secretions (Hyde et al., Altered metabolic activity of gut microbes has been implicated in aberrant regulation of enteric nervous system function, and in some cases clinical symptoms may be alleviated by altering microbial communities using prebiotics, probiotics and antibiotics (Hemarajata and Versalovic, Bacteroides fragilis induces excitability in myenteric AH neurons via signals that are linked to the presence of polysaccharide A in its outer membrane wall (Perez-Burgos et al., Lactobacillus reuteri is a probiotic bacterium that enhances colonic afferent excitability, in part through modulation of TRPV1 (Perez-Burgos et al., Lactobacillus reuteri has not been clearly characterized, this microorganism is a potent producer of histamine; an important neurotransmitter associated with pathology in the intestine where it regulates immune function, motility, permeability, and secretion (Hemarajata and Versalovic, Antibiotic use during early life is also reported to have lasting consequences on host physiology by altering intestinal microbiota composition and function (Cox et al., Environmental stressors also impact the host's ability to regulate intestinal physiology, e.g., immune surveillance of the gut microbiota is modulated by autonomic nervous system control of bacterial translocation from the colon. Although an expansive literature demonstrated stress-induced alterations to intestinal permeability and related activation of mast, neuronal and glial cells in the gut wall (Lomax et al., An emerging concept in intestinal disease associated with enteric neuropathy is that microbiota signals can mediate some of the effects, whether beneficial or detrimental. Preliminary studies implicate the enteric nervous system as an important regulatory signal of intestinal microbial community structure and function. Microbial communities themselves are prone to epigenetic signals that are associated with disease and may contribute to the disease pathogenesis by eliciting neurotransmitter profiles that interfere with enteric nervous system homeostasis. Microbial-derived neurotransmitters include regulators such as serotonin, histamine and catecholamines that operate in a coordinated manner with bacterial gaseous transmitters—hydrogen sulfide and nitric oxide—which are being independently pursued as intestinal therapeutics Savidge, . CarefulTS 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.


A growing body of evidence shows that cognitive processes in general, and causal cognition in particular, are variable across cultures  and Westerners (mainly North Americans and Western Europeans).In a move that proved remarkably generative, researchers theorized that contemporary East-West cognitive differences reflected epistemological orientations that could be traced back to Ancient Chinese and Greeks. Much like contemporary Eastern individuals, ancient Chinese philosophers were interested in continuity, changes, transformations, and dependence between objects, while Greek philosophers were interested in universal truths, formal rules, and discrete objects and entities. Further, ancient Chinese were interested in technological advances driven by pragmatic goals, while the Greeks valued intellectual endeavor for its own sake and were less concerned with concrete applications of knowledge (Norenzayan and Nisbett, This historical explanation assumes considerable psychological continuity within cultures across time. Yet accumulating evidence has begun to challenge the strong claim that contemporary cultural differences are rooted in ancient East-West philosophies (Varnum et al., If cognitive orientations also vary within cultures that share a single Ancient tradition, then this points to shifting cognitive patterns across time. On this perspective, a fuller account of the links between culture and cognition can be realized by including within-culture comparisons aimed at mapping historical trends.Adding an explicit diachronic dimension to current work on culture and cognition raises many methodological and theoretical questions. Methodologically, the main challenge facing researchers interested in within-culture historical trends is the lack of longitudinal data. Part of the problem is that cognitive psychologists, especially those working on causality, often pursue very specific theoretical questions and rarely use standardized measures or common procedures. Other fields are in a more advantageous position, having collected continuous time-series data long enough to detect trends. One widely debated example comes from research on general intelligence (Teasdale and Owen, Unfortunately, comparable data is not readily available to investigate similar shifts in cognitive dimensions. Longitudinal designs are rare among cognitive psychologists, but there are some documented cases of within-culture cognitive change. For example, in 1969/70 Patricia Greenfield brought a complex weaving task to Maya children and young adults in Mexico. Twenty years later she revisited the community and ran the same task with the same age groups (Greenfield et al., Another example comes from work on cognitive models of the environment and folkbiological reasoning with several cultural groups in the Peten rainforest in Guatemala (Medin and Atran, Such examples of research documenting cognitive changes within a culture are rare, because there is no systematic longitudinal data for the vast majority of cognitive tasks (Greenfield et al., Given this dearth of data, it becomes important to consider alternative approaches. Are there methods that can yield proxy measures of psychological variables when direct measurements are not available? The answer to such a question is limited only by the creativity of the researchers. One approach is to analyze ethnographic reports from different time periods and to draw inferences about a particular cultural group based on the descriptions. In one such analysis, Widlok  scrutiniMore recently, automatic text analysis has extended classical anthropological and archeological methods to infer psychological variables. Various methods of automated text analysis are now in use by psychologists (Iliev et al., Automated text analysis can be particularly useful for detecting historical trends in large corpora. One compelling demonstration comes from a study by Wolff et al. , who werApplying automated text analysis to study historical trends in causal cognitive processes may be more challenging than studying changes in knowledge content or social values, which seem more amenable to direct analysis via word frequencies. Still, some applications might be straightforward. For example, LIWC offers a causality-focused dictionary that could be used to measure cultural shifts in the frequency of causal language. Cognitive psychologists interested in historical trends can also develop specialized dictionaries guided by particular cognitive theories. Such an approach was used by Dehghani et al.  to compaThe field of cultural cognition traces its foundations to scholars who treated culture and history as complementary constructs (Vygotsky, 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.


Our knowledge of the vestibular sensory system, its functional significance for gaze and posture stabilization, and its capability to ensure accurate spatial orientation perception and spatial navigation has greatly benefitted from experimental approaches using a variety of vertebrate species. This review summarizes the attempts to establish the roles of semicircular canal and otolith endorgans in these functions followed by an overview of the most relevant fields of vestibular research including major findings that have advanced our understanding of how this system exerts its influence on reflexive and cognitive challenges encountered during daily life. In particular, we highlight the contributions of different animal models and the advantage of using a comparative research approach. Cross-species comparisons have established that the morpho-physiological properties underlying vestibular signal processing are evolutionarily inherent, thereby disclosing general principles. Based on the documented success of this approach, we suggest that future research employing a balanced spectrum of standard animal models such as fish/frog, mouse and primate will optimize our progress in understanding vestibular processing in health and disease. Moreover, we propose that this should be further supplemented by research employing more “exotic” species that offer unique experimental access and/or have specific vestibular adaptations due to unusual locomotor capabilities or lifestyles. Taken together this strategy will expedite our understanding of the basic principles underlying vestibular computations to reveal relevant translational aspects. Accordingly, studies employing animal models are indispensible and even mandatory for the development of new treatments, medication and technical aids (implants) for patients with vestibular pathologies. Scientific research on the vestibular system has benefitted from studies on a wide variety of vertebrate species . SystemaNotably, based on their evolutionary proximity to humans, non-human primates have become a standard model for furthering our knowledge of basic vestibular processing and advancing translational research. In addition, advances in the generation of mouse lines with defined genetic backgrounds and/or transgenic lines, such as CRE, combined with viral-based optogenetics have provided new opportunities to probe the functional circuitry of vestibular pathways and gain insight into vestibular diseases or age-related impairments –8. HowevThe vestibular endorgans are located within the petrosal bone in close vicinity to the cochlea. This hidden location proximal to the auditory organ and the difficult access considerably delayed our understanding of the functional role of these inner ear organs. It was only in 1824, that Flourens  conducteAs for the semicircular canals, the initially assumed auditory role of otolith organs also remained unchallenged for a long time. It is noteworthy that this historical progression in our understanding is reflected in existing terminology, since otolith literally means “hearing stone”. Theoretically based investigations had deduced that the otolith endorgans sense linear accelerations including head tilts , 13, yetIn summary, a comparative approach including studies in vertebrate species from fish to mammals was essential to the progress that was made in the early vestibular research of the 19th century. In particular, the knowledge obtained following experimental lesions of semicircular canals, otoliths, and/or their nerves using different animal models has proven crucial for providing the important insight into species-specific adaptations of the endorgans and variations in their function relative to lifestyle, eco-physiological niche or locomotor dynamics.Head motion relative to space is detected and decomposed into individual vector components by semicircular canal and otolith organs . The semCurrent evidence suggests that vestibular endorgans across species have adapted to changes in the environment and body mass , indicatDuring ontogeny, vestibular reflexes are generally present after hatching/birth in precocial animals such as larval fish, amphibian tadpoles or certain avian species or as soon as the respective neural circuitry and/or cellular properties are mature in altricial species . While tHair cells in the vestibular system have long been a subject of functional studies using various vertebrate species including bullfrog , 38, turPrevious studies have shown that afferents supplied by type I hair cells, which are found in amniotes, tend to be more irregular Fig. a in theiOver the range of frequencies typically experienced during everyday behaviors , semicircular canal afferents encode head velocity while otolith afferents encode linear acceleration in mammals ranging from mice to primates –45. QuanOur basic understanding of the existence of these two peripheral signaling streams has also contributed to the development of clinical tests. In patients, high-frequency vibrational stimuli to the skull or air-conducted sound can be used to induce ocular vestibular-evoked myogenic potentials (oVEMPs) mainly originating from the utricular macula or cervical VEMPs arising from the saccular macula . These tCentral vestibular neurons play a key role in sensory–motor transformation of semicircular canal and otolith signals. Electrophysiological in vitro experiments in slices and isolated brain preparations have found two primary neuronal subtypes in the vestibular nucleus of rodents and guinea pig (type A and B neurons). These neurons distinctly differ in their resting discharge regularity, response dynamics and sets of ionic conductances . While eStudies in behaving monkeys have established two main functional classes of vestibular neurons Fig. a that liAs a general vertebrate pattern, afferent projections from vestibular endorgans largely overlap in the different central vestibular nuclei of all investigated vertebrate species including cat , pigeon Although afferents from all vestibular endorgans overlap to a large extent in the vestibular nuclei, 2°VNs exhibit a remarkable specificity in selecting their monosynaptic afferent input; most 2°VNs receive monosynaptic inputs from only one semicircular canal Fig. d–f or onIn everyday life, our vestibular sensors are activated by complex multi-dimensional motion patterns that simultaneously stimulate semicircular canal and otolith organs , 71. SinThe optokinetic reflex (OKR) works together with the vestibulo-ocular reflex (VOR) to stabilize gaze. The OKR is symmetric in monkeys and humans but asymmetric in mice, gerbils and rabbits –75 as weMost vestibular nuclei neurons in mice , rats  for the horizontal semicircular canal was described for the first time by Halmagyi and Curthoys . Today, Scientists and clinicians have long been fascinated by the capability of animals and humans to recover from the behavioral deficits after a loss of labyrinthine function , 10. In versus vestibular signals) at the level of vestibular nucleus neurons [Findings across a variety of animal models have further established that a common denominator of vestibular compensation is the induction of homeostatic plasticity. For example, postural recovery in frogs after unilateral labyrinthectomy depends on an altered efficacy of spinal reflexes provided that body-weight-supporting limb proprioceptive inputs are available . Interes neurons , 111–113 neurons  ), activ neurons , neck mu neurons  or an in neurons .Plasticity within vestibular pathways also plays an essential role in fine-tuning the coordination and accuracy of the VOR in response to environmental or developmental alterations. For example, adaptive changes in VOR performance are required to compensate for the mismatch between visual and vestibular stimuli caused by the magnification of corrective lenses worn during common visual conditions , 119. SuVestibular information is not only required for reflexive motor reactions but also vital for cognitive functions such as perception of self-motion, spatial orientation and body representation . Single-The vestibular cerebellum integrates vestibular and extra-vestibular information to make fundamental contributions to self-motion perception. The nodulus–uvula (lobules X and IX) is thought to create an internal model of spatial orientation that accounts for the physics of our world. Consistent with theoretical predictions , some neAscending projections from the vestibular nuclei and vestibular cerebellum terminate in regions of the thalamus , As illustrated in the previous chapters, studies using a wide variety of vertebrate species have been essential for furthering our knowledge of how the sensory organs in the inner ear detect head motion in space, how receptor cells transduce motion into voltage signals, and how the brain encodes and integrates these motion-related signals for accurate behavior and perception during self-motion. Notably, while some species are better suited than others to answer scientific questions on the organization and role of the vestibular system, others are better suited to establish the neural circuitry mediating higher order functions such as vestibular cognition. Vestibular research has particularly benefitted from its positioning at the intersection between basic and clinical science. For example, neural pathways mediating vestibular-driven reflex behaviors such as the VOR are relatively simple, and collective knowledge from studies using a wide variety of species have provided an excellent framework for understanding the physiology underlying clinical syndromes.Overall, we argue that in the future a reasonably balanced spectrum of animal models will continue to be required to increase our understanding of the vestibular system. Studies of ontogenetic aspects and developmental assembly of appropriate neural connections will require further work in model species that allow easy access to embryonic stages. For instance, genetic approaches and developmental manipulations can be combined with physiology in vertebrates such as fish, frog, chicken or mouse, even though recordings are rather difficult to perform in embryonic and early post-embryonic birds or mammals . With reFor studies of evolution and adaptation in the vestibular system and its cellular components, as well as the respective computations performed by early vertebrate ancestors or higher order cortical processing, an even wider range of vertebrate species is required , 67. ThiIn contrast, work in more advanced mammalian species including non-human primates will be required to further our understanding of how these circuits give rise to perception, cognition and behavior under normal conditions—knowledge essential for developing more effective health protocols to diagnose and treat the debilitating symptoms of vestibular disorders in patients. Decades of electrophysiological observations in non-human primates have already provided key insights as to how vestibular-driven sets of motor behavior and perception arise from neural circuit activity . NoFinally, it is important to emphasize that studies across a wider range of species will be required to facilitate translational vestibular research progress. For studies focused on efficient, high-throughput drug discovery , underst


Large for gestational age infants have an increased risk of obesity, cardiovascular and metabolic complications during life. Knowledge of the key predictive factors of neonatal adiposity is required to devise targeted antenatal interventions. Our objective was to determine the fetal metabolic factors that influence regional neonatal adiposity in a cohort of women with previous large for gestational age offspring.Data from the ROLO [Randomised COntrol Trial of LOw Glycaemic Index in Pregnancy] study were analysed in the ROLO Kids study. Neonatal anthropometric and skinfold measurements were compared with fetal leptin and C-peptide results from cord blood in 185 cases. Analyses were performed to examine the association between these metabolic factors and birthweight, anthropometry and markers of central and generalised adiposity.Fetal leptin was found to correlate with birthweight, general adiposity and multiple anthropometric measurements. On multiple regression analysis, fetal leptin remained significantly associated with adiposity, independent of gender, maternal BMI, gestational age or study group assignment, while fetal C-peptide was no longer significant.Fetal leptin may be an important predictor of regional neonatal adiposity. Interventional studies are required to assess the impact of neonatal adiposity on the subsequent risk of childhood obesity and to determine whether interventions which reduce circulating leptin levels have a role to play in improving neonatal adiposity measures.The online version of this article (doi:10.1186/s12887-015-0499-0) contains supplementary material, which is available to authorized users. Many factors, both maternal and environmental, are known to affect birthweight . Infant Not all LGA infants are born to diabetic mothers however. Women with normal glucose tolerance are also at risk of delivering larger weight babies at term . PreventBirth of a LGA or macrosomic infant presents a variety of obstetric and perinatal complications including increased risk of caesarean or instrumental delivery, transfer to a neonatal intensive care unit, shoulder dystocia , neonataWhile air displacement plethysmography is a validated form of adiposity measurement in neonates  this is Leptin is an adipocyte secreted circulating polypeptide hormone expressed in the adipose tissue  that wasC-peptide results from the transformation of proinsulin into insulin and was first discovered in 1967 with the discovery of the insulin synthesis pathway  and is aTo date, antenatal lifestyle interventions that target maternal nutrition and exercise in pregnancy have demonstrated limited effects on improving birthweight . HoweverThere is a paucity of literature investigating the link between fetal metabolic markers of obesity and more in-depth anthropometric measures of neonatal adiposity, which could provide valuable insight into the fetal origins of future obesity and metabolic disease. The only two studies we identified , 44 thatTherefore, the aim of this study was to determine the association between fetal metabolic factors and individual areas of neonatal adiposity, with a specific focus on fetal leptin and cord C-peptide in a cohort at high risk of macrosomia and early childhood obesity with a mean birthweight of greater than 4 kg.This is a follow on study of 185 infants born to women from the ROLO randomised controlled trial on whom cord blood C-peptide and leptin data were available as well as anthropometry at birth. Skinfold measurements were available for 147. The ROLO study was a randomised controlled trial of a low GI dietary intervention versus usual care among 800 non-diabetic, secundigravida women with a history of macrosomia, with the primary objective of reducing birthweight. Bloods including C-peptide and leptin were taken in early and late pregnancy and fetal sample from cord blood. Detailed methodology  and findn = 3) if any large discrepancy (>1 cm) was noted between the observers. Birthweight was measured on a Seca calibrated scales. A Seca lasso tape  predictors examined  which may explain why c-peptide was not determined to be an independent correlate of the anthropometry .These data confirm the association between cord leptin and individual markers of neonatal adiposity. While early pregnancy maternal leptin was associated with neonatal abdominal circumferences and neonatal subscapular skinfold thicknesses, and late pregnancy leptin levels with triceps skinfolds and the SS + TR marker, it is fetal leptin which is most significantly associated with birthweight, individual markers of regional adiposity and also markers of central and general adiposity. On multiple regression analysis, fetal leptin remained positively associated with neonatal anthropometry, independent of BMI, neonatal gender total gestational age or study group assignment. There was no significant difference in the degree of association between fetal leptin and the various individual markers of adiposity. This suggests that the effect of leptin on adiposity is generalised and not limited to central or peripheral adiposity as determined by the various markers measured in our study. Fetal C-peptide was no longer significantly associated with any adiposity measures however fetal C-peptide was strongly correlated with cord leptin (correlation coefficient 0.415, What remains unclear however is, if fetal leptin is higher in those with larger skinfolds and circumferences simply as it is secreted by the fetal adipose tissue or if it has a roll to play as a growth factor. Previous research has shown that neonates born LGA do indeed have higher levels of cord blood leptin than those born small for gestational age  and thatThis was a well characterised cohort from the ROLO study, which was a randomised controlled study examining neonates born to non-diabetic women with a history of a previous macrosomic child. As the ROLO Study did not find any difference in the birthweight  or adipoOur study has some limitations worthy of consideration. As previously mentioned, participants of the ROLO study were all secundigravida and non-diabetic. Although women who had previously been diagnosed with gestational diabetes were excluded, as genetics are known to play a role in the determination of birthweight, the cohort may have had a selection bias in choosing women who were more likely to have a larger birthweight baby.The intervention group in the ROLO study were instructed to change to a low GI diet. Although this intervention was shown not to affect birthweight or leptin concentrations, the reduced gestational weight gain among the intervention group  and consOur findings have contributed to a growing body of evidence that the fetal metabolic milieu plays a vital role in the determination of neonatal adiposity at birth in non-diabetic pregnancies and that fetal leptin may be a key metabolic factor to target in these pathways. Interventional studies are required to assess the impact of neonatal adiposity on the subsequent risk of childhood obesity and to determine whether interventions which reduce circulating leptin levels have a role to play in improving neonatal adiposity measures.


BRCA mutationstatus in managing women with ovarian cancer, few patients are currently beingtested. The traditional means of selecting patients for BRCA mutationtesting using restrictive criteria will miss many women with a mutation. Toexpand access to testing and streamline the testing process, several centres inthe UK have been developing new models for BRCA testing. Trials withthese integrated models involving closer collaborations between genetics andoncology services are now under way. In addition to testing for BRCAmutations, there is also increasing interest in testing for other genesassociated with a predisposition to ovarian cancer. Advances in next-generationsequencing technology have resulted in the development of comprehensive genetictesting panels for use in the research and diagnostic settings. Interest is alsoincreasing in expanding testing for somatic mutations in ovarian cancer,particularly for genes such as BRCA1 and BRCA2, wherebymutations may allow more patients to benefit from targeted agents, includingpoly(ADP-ribose) polymerase inhibitors. In this review, the issues of who shouldbe offered testing, how testing could be delivered, when testing should occurand the technology and costs associated with genetic testing are addressed.Despite the increasing clinical importance of germline  BRCA1 andBRCA2 mutations, as well as when and how it should be carried out, arebecoming increasingly important for ovarian cancer patients in the UK. Over the lastfew years, greater public awareness of the genetic component of breast and ovariancancer has resulted in increasing patient demand for testing. This, combined with anexpanding range of clinical implications for ovarian cancer patients found to carrya BRCA1 or BRCA2 mutation, has presented a central role forgenetic testing. Recent studies have suggested that approximately 15% ofall ovarian cancer patients harbour a germline mutation in BRCA1 andBRCA2, few of whom are currently being offered testing , which offersfast, efficient, high-throughput testing at a considerably lower cost than witholder methods  recommends that all women with a10% chance of harbouring a BRCA mutation should be offeredtesting, and testing should be considered down to a threshold of 5% study in July 2013, to explore the feasibility and acceptability ofoffering direct testing for BRCA mutations in patientswith ovarian cancer. Oncology clinicians have been trained and certified to allowthem to obtain consent from patients for testing. Patients with non-mucinous ovariancancer or who have both ovarian cancer and another primary tumour (any age) areoffered BRCA testing at their appointment with the oncologist. The patientand the oncology clinician receive the results from the genetics department, andthose patients who carry a BRCA mutation then attend a genetics appointmentwith their results to allow detailed discussion and to have BRCA testingoffered for their relatives. In addition, patients can contact or be referred to thegenetics department at any time at their own request or at the discretion of theironcologist. This oncogenetic model of identifying patients with a BRCAmutation has provided a flexible, patient-centred, impartial, high-throughputapproach, which has resulted in considerable time and cost savings compared with astandard genetics referral  women with ovarian cancer who have a family history of breast,ovarian or colon cancer should have a genetic risk assessment; and (3)BRCA1 and BRCA2 mutation analysis should be considered in afamily where there is a 10% or greater risk of a mutation being present.The SIGN guidelines state that close collaboration between primary care andspecialist cancer genetics services should be encouraged, to enable efficientgenetic cancer risk assessments in individuals who are at medium or high risk.In November 2013, Scotland updated the Scottish Intercollegiate Guidelines Network(SIGN) guidelines on the management of epithelial ovarian cancer (SIGN 135) toinclude BRCAmutation. Even in those with clear, open criteria, it is likely that patients who domeet the criteria are not referred for genetic testing. Such under-referral ofpatients has been frequently reported in studies at specialist centres such as theMD Anderson Cancer Center in Texas, USA. It has also been reported in areas wheregenetic testing is more widely available, such as British Columbia and Ontario inCanada, where women can be referred for testing based on histology alone. Despitethis, reports indicate that only 20% of eligible women are referred fortesting. The uptake rate among those who are referred for testing is high,indicating that it is not patient reluctance that limits testing. This suggests thatit is not only the eligibility criteria, but the entire attitude towards testing forgermline mutations that needs to be considered.The information provided from the small number of English hospitals and the Scottishguidelines described here demonstrates that there is currently no consensus forgenetic testing of patients with ovarian cancer to identify a BRCAmutation testing has involved a combination of Sanger sequencing and multiplexligation-dependent probe amplification (MLPA). Direct Sanger sequencing allowsidentification of small variants (such as the deletion or insertion of singlebases); whereas MLPA identifies large variants, such as the deletion or duplicationof one or more exons. However, these methods are time consuming and costly, as theyrequire the gene to be divided into small fragments, each of which is individuallyamplified and sequenced  polymerase (PARP) inhibitors as that demonstrated inBRCA-deficient cells (Ovarian cancer is a genetically heterogeneous disease, with germline mutations inMRE11A in ovarian cancer (A range of multi-gene panels has been developed for use in the diagnostic or researchsetting, although use of these panels is not currently available within the UKNational Health Service. One of the major difficulties with cancer panels to date isthe reporting of mutations in cancer patients for genes in which there is noevidence of a causal link, such as BRAF, MTOR, MEK and AKT in ovariancancer. There is also interest in identifying patients with somatic mutations in DNArepair genes such as BRCA1 and BRCA2, as they may demonstratesimilar synthetic lethality to PARP inhibitors as that shown with germlinemutations. Somatic mutations have been reported in DNA repair genes in approximately9% of ovarian cancer, while BRCA1 promoter hypermethylation isreported in approximately 10% of high-grade serous and high-gradeendometrioid ovarian cancer (Somatic mutations in a range of different genes have been associated with eachsubtype of epithelial ovarian cancer. There is already interest in therapeuticexploitation of such somatic mutations, with trials investigating the role of drugstargeting BRCA1 or BRCA2mutation. The emphasis should therefore be placed back on the individual withovarian cancer to undergo testing to inform their management. Here, the integratedoncogenetic pathways have an advantage, with the oncology teams able to discuss theextent of the impact that knowledge of mutation status will have on anindividual’s care when obtaining informed consent. In order to moveforward to patient-centred, personalised cancer treatment in the era of targetedagents, genetic testing must now be considered an important part of the diagnosticprocess. In summary, it would be appropriate for all non-mucinous ovarian cancerpatients to be offered BRCA mutation testing at the time of theirdiagnosis, to inform and enable the most appropriate treatment decisions to be madefor each individual patient.For years, the primary advantage in ovarian cancer patients undergoing genetictesting was the identification of at-risk family members, who would then chooserisk-reducing interventions to modify their future risk of cancer. There are nowclear differences in the behaviour, response to treatment options and prognosis ofovarian cancer between those with and without a


Facial emotion recognition (FER) is essential to guide social functioning and behaviour for interpersonal communication. FER may be altered in severe mental illness such as in psychosis and in borderline personality disorder patients. However, it is unclear if these FER alterations are specifically related to psychosis. Awareness of FER alterations may be useful in clinical settings to improve treatment strategies. The aim of our study was to examine FER in patients with severe mental disorder and their relation with psychotic symptomatology.Socio-demographic and clinical variables were collected. Alterations on emotion recognition were assessed in 3 groups: patients with first episode psychosis (FEP) (n = 64), borderline personality patients (BPD) (n = 37) and healthy controls (n = 137), using the Degraded Facial Affect Recognition Task. The Positive and Negative Syndrome Scale, Structured Interview for Schizotypy Revised and Community Assessment of Psychic Experiences scales were used to assess positive psychotic symptoms. WAIS III subtests were used to assess IQ.Kruskal-Wallis analysis showed a significant difference between groups on the FER of neutral faces score between FEP, BPD patients and controls and between FEP patients and controls in angry face recognition. No significant differences were found between groups in the fear or happy conditions. There was a significant difference between groups in the attribution of negative emotion to happy faces. BPD and FEP groups had a much higher tendency to recognize happy faces as negatives. There was no association with the different symptom domains in either group.FEP and BPD patients have problems in recognizing neutral faces more frequently than controls. Moreover, patients tend to over-report negative emotions in recognition of happy faces. Although no relation between psychotic symptoms and FER alterations was found, these deficits could contribute to a patient’s misinterpretations in daily life. Facial emotion recognition (FER) is the capacity to interpret the emotions of others based on facial expressions . FER is Individuals with schizophrenia have problems in the perception of emotional states throughout the disorder . EmotionGiven the fact that psychotic symptoms occur transdiagnostically , it may Likewise, borderline personality disorder (BPD) is associated with trait elevation of psychotic symptoms. About 20–50% of patients with BPD experience psychotic symptoms  comparable to those in patients with psychosis from a point of view of the phenomenology, emotional meaning and their maintenance ,22.The purpose of the present study was twofold. First, we wished to compare possible FER alterations in a sample of FEP and BPD patients in comparison with a group of healthy controls (HC) and to examine to what degree FER alterations in patients is valence-specific, or restricted to particular emotions. To determine this, we first compared a group of FEP and BPD patients with HC for their capacity to precisely recognize facial expressions of the essential emotions. Second, we investigated associations between FER and positive, negative, depressive and disorganized symptoms in these 3 groups.The local ethics committee  authorized the study design. We obtained written consent from all patients of the study.The recruitment procedures for this study were described previously . Data weSocio-demographic and clinical variables collected in the sample have been detailed in a previous paper .Degraded Facial Affect Recognition Task (DFAR)  shows imThe Benton Facial Recognition Test (BFRT) , is a meIQ: The short form of the Wechsler Adult Intelligence Scale (WAIS)–III  was admiThe Positive and Negative Syndrome Scale (PANSS)  was usedStructured Interview for Schizotypy—Revised (SIS-R)  was admiThe Community Assessment of Psychic Experiences (CAPE)  was usedIn order to decrease differences between groups in IQ, we performed post-hoc analyses excluding from sample all subjects with IQ <70 (N = 8) and healthy controls with very high IQ . We have included analysis in whole sample as additional material  Tables.The descriptive statistical analysis was based on frequency tables, and means and standard deviations (SDs). The Kolmogorov-Smirnov test was used to test for deviation from normality. ANOVA with Scheffe’s method for multiple comparisons was used to examine differences between the three groups in continuous variables, and Kruskal-Wallis test was used for non-normally distributed variables. For the comparison of categorical variables, chi-square tests, and Fisher´s exact test, when indicated, were performed.In order to analyse differences between groups in emotion recognition and to compare the type of misinterpretation during FER among the three groups, the ANOVA with Scheffe’s test for multiple comparisons or the non-parametric Kruskal Wallis test was used. Further on, the general linear model was used to analyse the differences in emotion recognition and type of misinterpretation during FER between the three groups adjusting for WAIS, age and sex.We carried out transversal within-group analyses. Associations between emotion recognition and symptom domain was analysed using the Spearman correlation coefficient.Statistical analyses were carried out with STATA version 12 .64 FEP, 37 BPD and 137 controls were assessed at baseline. Subjects with Benton test scores of less than 41 were excluded due to insufficient general facial recognition ability.Socio-demographic characteristics are shown in A significant difference between patient groups and HC on neutral face scores was found, as well as a difference on anger scores between HC and FEP patients. No significant differences were found between groups in the fear or happy conditions . In geneBPD y FEP groups had a much higher tendency to recognize negative emotions in happy faces. And BPD group had higher tendency to recognize also negative emotions in neutral faces as well. Moreover, after adjusting for other variables , results remained significant .FEP patients showed a significant tendency to recognize fear faces as neutral or happy.There was no significant association between emotion recognition and any of the different symptom domains in either patient group (correlation coefficients ranging from -0.23 to 0.22).FER alterations have been reported for various mental disorders and may predict poor social functioning. What remains unclear is how specific these alterations are and if certain patterns characterize particular patient groups. This study examined disorder-specific emotional alterations in two groups of patients in a comparison with HC.There were three main findings. First, our results showed poorer emotion recognition of neutral and angry faces in FEP and of neutral faces in BPD patients. Second, these alterations were not associated with (subthreshold) psychopathology. And finally, both patient groups tended to attribute emotional negative valence more frequently than HC to happy faces. Within the three groups, the level of positive symptoms was not associated with FER alterations. These FER alterations may be more prevalent in disorders with psychosis proneness rather than being associated to specific symptoms. This may imply that FER may be more a trait of psychosis rather than a state. However, it is possible that the statistical power of sample was not enough to detect such differences .Nonetheless, this study demonstrates that patients who are prone to psychosis (BPD), process emotions similarly to patients with psychosis (FEP). These findings may serve to support the hypothesis that such biases are related to interpersonal disability of these patients observed clinically, although hardly any study found a relation between emotion recognition and social functioning in the daily life of psychotic patients . We haveIt is also still unclear whether deficits in facial emotion identification in people with psychosis are general or valence specific. Although one of the most consistent findings across studies are deficits on negative emotions  ,36,37; iOur results indicate a worse FER in FEP and BPD patients, especially of neutral faces, and additionally of angry faces in psychotic patients. In general terms, we could state that there was poorer affect recognition of facial emotions on neutral emotion independently of cognitive performance in both groups of patients. These results suggest that patients with severe mental disorders display alterations in general emotion recognition.Moreover, happy faces were interpreted as negative in both groups at much higher frequencies than in HC. This tendency was also significant for neutral faces in BPD group. Hence, the ability of deducing emotional states from others may be compromised in these patients . Other sIn general terms, until now the reported findings do not make it clear whether the impairment is selective for concrete emotions, is selected for valence, or affects the whole domain of basic emotions. In this study, there was a clear alteration in FER in BPD patients in the recognition of neutral emotion as well as a negative misinterpretation of happy faces in both patient groups.Other authors ,44,45 foOur results indicate an alteration in recognition specifically of neutral faces in both groups, which could lead to perceive neutral emotions as negative and this can influence social interactions. Alterations in emotion recognition, although perhaps to a lesser degree, may cause negative misinterpretations of social-emotional situations. And misperceptions may lead to the avoidance of social situations or contacts and lead to problematic social behaviour.To study the nature of the associations between symptoms and social cognitive impairment in patients and HC, we performed a cross-trait within-group analysis. We did not find any association between symptom domains and FER alterations in FEP. The analyses also failed to reveal significant associations between symptom domains and psychopathology measures in BPD or HC.A previous study suggested an association between disorganized and negative symptoms and social cognitive performance in patients diagnosed with a psychotic disorder and, to a lesser extent, subclinical negative symptoms in siblings of patients diagnosed with a psychotic disorder . The lacTo the best of our knowledge, this is the first study to compare FER alterations in FEP and BPD patients in a comparison with HC. Studying individuals with FEP helps to minimize the influence of variables such as institutionalization, the long-term effects of antipsychotics and social deterioration, and could avoid variability due to the course of the illness .Our results are independent of IQ performance. This is consequent with the fact that performance on social intelligence tasks is not strongly influenced by IQ ; emotionBPD patients commonly suffer from other psychiatric comorbidities such as depression, PTSD or drug abuse. These disorders also relate with FER alterations. The possible effects of these comorbidities need to be taken into account as well . AlthougAnother limitation of the study is that we did not examine possible effects of psychotropic medication on emotion recognition. Although there have been a few studies reporting mild effects of psychoactive medication on FER , the recDivergences among previous studies with respect to the accuracy of FER alterations may have been the consequence of several factors including the use of different stimulus materials , differences in the intensity of the emotional expression, time limits and task instructions . As FertIn conclusion, FER is impaired in FEP and BPD patients, especially for neutral and angry faces. Moreover, patients tend to over-report negative emotions in happy faces. Alterations appear not only in FEP, but also in BPD, suggesting that discrepancies in the processing of integrated facial emotions may be related to transdiagnostic interpersonal hostility, and social functioning. This may suggest that differences in the patients’ higher order integration of emotional perceptions may be associated with the large variation in interpersonal dysfunction observed clinically.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 TableUnadjusted and adjusted analyses.(PDF)Click here for additional data file.S4 Table(PDF)Click here for additional data file.


That is, in order to process certain combinations of properties, each cortical stream cannot process complementary properties. Interactions between these streams, across multiple processing stages, overcome their complementary deficiencies to compute effective representations of the world, and to thereby achieve the property of complementary consistency. The two illusions concern how illusory depth can vary with brightness, and how apparent motion of illusory contours can occur. Illusory depth from brightness arises from the complementary properties of boundary and surface processes, notably boundary completion and surface-filling in, within the parvocellular form processing cortical stream. This illusion depends upon how surface contour signals from the V2 thin stripes to the V2 interstripes ensure complementary consistency of a unified boundary/surface percept. Apparent motion of illusory contours arises from the complementary properties of form and motion processes across the parvocellular and magnocellular cortical processing streams. This illusion depends upon how illusory contours help to complete boundary representations for object recognition, how apparent motion signals can help to form continuous trajectories for target tracking and prediction, and how formotion interactions from V2-to-MT enable completed object representations to be continuously tracked even when they move behind intermittently occluding objects through time.Neural models of perception clarify how visual illusions arise from adaptive neural processes. Illusions also provide important insights into how adaptive neural processes work. This article focuses on two illusions that illustrate a fundamental property of global brain organization; namely, that advanced brains are organized into parallel cortical processing streams with computationally  Imagine that the activation in response to the flash at the first position is decaying while activation is growing in response to a flash at the second position. Under these circumstances, the In summary, the space- and time-averaged cell responses to individual flashes do not change their positions of maximal activation through time. In this sense, nothing moves in response to a single flash. When a series of properly timed and spaced flashes is presented, however, the sum of their responses can produce a continuously moving peak of activity between the positions of the flashes. This is an emergent property of network interactions across multiple cells through time, rather than a property of any cell acting alone. The Motion ESP problem may thus be solved using the fact that the Gaussian response to the first flash is still waning—without causing a percept of motion—when the second flash occurs. The residual effect of the first flash as it combines with the waxing effect of the second flash enables the traveling wave to continuously interpolate variable ISIs and distances between the two flashes.In summary, illusory depth from brightness arises from the complementary properties of boundary and surface processes, notably boundary completion and surface-filling in, within the parvocellular form processing cortical stream. This illusion depends upon how surface contour signals from the V2 thin stripes to the V2 interstripes ensure complementary consistency of a unified boundary/surface percept, while also enabling figure-ground separation to occur. Apparent motion of illusory contours arises from the complementary computations of form and motion processing across the parvocellular and magnocellular cortical processing streams. This illusion depends upon how illusory contours help to complete boundary representations for object recognition, how apparent motion signals can help to form continuous trajectories for target tracking and prediction, and how formotion interactions from V2-to-MT enable completed object representations to be continuously tracked even when they move behind intermittently occluding objects through time. Lages and Heron  provide Many other visual illusions have helped to discover, and been explained by, adaptive mechanisms whereby our visual brains achieve their unparalleled achievements in perceiving, understanding, and acting upon a rapidly changing world.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.


Effective utilization of three-dimensional printing for tissue and organ engineering remains nontrivial. Here, Jordan Miller identifies key challenges and discusses conceptual targets on the horizon. How structure relates to function—across spatial scales, from the single molecule to the whole organism—is a central theme in biology. Bioengineers, however, wrestle with the converse question: will function follow form? That is, we struggle to approximate the architecture of living tissues experimentally, hoping that the structure we create will lead to the function we desire. A new means to explore the relationship between form and function in living tissue has arrived with three-dimensional printing, but the technology is not without limitations. In the 1960s field known as Bionics, many human tissue functions were considered analogous to basic mechanical and electrical systems, such as servomechanisms Since cells are the major functional unit responsible for biochemistry in the body, efforts to separate cells from their native environment in vivo and apply them therapeutically in extracorporeal devices have remained steadfast. In extracorporeal liver-assist devices, live cells can be loaded into bioreactor chambers outside the body and then connected in a closed loop with host blood circulation so that the biochemical benefit from cells in the device will positively affect the patient Cells loaded into extracorporeal devices or growing at the bottom of a Petri dish bear little resemblance to the exquisite anatomical complexity found in the human body. Organs like the lung, heart, brain, kidney, and liver are pervaded by incredibly elegant yet frighteningly complex vascular networks , leaving us without a clear path toward physical recapitulation of these tissues in the laboratory . HoweverAs we look toward the future, the prospect of using a patient's own cells to develop living models of their active biochemistry as well as functional, life-lasting cellular implants offers potentially revolutionary changes to research and healthcare. Stem cell biologists are uncovering exciting new ways to induce pluripotency Recent advances in 3D printing, a suite of technologies originally developed for plastic and metal manufacturing, are now being adapted to operate within the soft, wet environments where cells function best. Because 3D printing excels at producing heterogeneous physical objects of high complexity, biologists and bioengineers are gaining unprecedented access to a rich landscape of tissue architecture we've always wanted to explore.Seminal work in the 1980s by Ioannis Yannas and colleagues Thin tissues require comparatively few cells. One study implanted a thin construct of hepatocytes subcutaneously in rodents and the cells were observed to proliferate and function normally More subtly, the challenge is also one of cell density. More than 15 years ago, Laura Niklason and Bob Langer observed that "…gels seeded with cells have been limited by the fact that the resultant cell densities per unit volume that can be achieved are much lower than those observed in vivo…'' Yet, it's not clear which anatomical components are necessary and sufficient for tissue function and which are superfluous trappings. Do we need microtissues with multiscale vasculature, or are organ-on-a-chip systems Biologists and bioengineers are experts at adapting technologies developed in other industries for our own research endeavors. Techniques to organize or orient living cells on surfaces, for example, have come from modifying technologies from the microprocessor industry x,y,z) coordinate—termed "voxel'' (a portmanteau of volume and pixel)—within a given volume. Access to each voxel can make 3D printing rather slow: each time print resolution is doubled, the number of required voxels scales by a factor of eight , additive manufacturing starts from nothing and selectively builds, one layer at a time, an object of interest according to computer instructions. A dizzying array of technologies are currently in use, and all are potentially adaptable to engineering living tissues . An addiOne conceptual approach to adapt 3D printing technologies for biology and medicine is a substitution of the commonly used resins (such as acrylates) and plastics (such as acrylonitrile butadiene styrene) with biocompatible, nontoxic materials like polylactic acid (PLA) and polycaprolactone (PCL). Recently, this approach was used to successfully treat an infant in respiratory distress. Doctors used noninvasive anatomical scanning to map the tracheal defect, then designed and printed a tracheal splint made entirely from PCL To adapt 3D printing for the manufacture of living tissues, cells and extracellular matrix (ECM) are combined as ink in a process known as bioprinting. Inkjet printing In contrast to these additive cellular inks, temporary inks can be printed, encased, and then selectively removed later http://3dprint.nih.gov/) which may help to address this standardization problem. Protein crystallographers once wrestled with a similar challenge to define an all-inclusive file format for 3D data, resolved by the Research Collaboratory for Structural Bioinformatics (RCSB) open protein data bank (PDB) file format; nearly 100,000 protein structures have been centrally and publicly archived since 1971.Importantly, the ethos of the open-source software movement—making designs and code, like the Linux computer operating system, freely and legally available to anyone—has now bled into hardware designs and the software toolchain for 3D printers. The result is an explosion of more than 75,000 3D printers in operation worldwide by both researchers and hobbyists eager to help with focused scientific exploration Simplification of the hardware and software tools required for 3D printing mean the technology is becoming accessible even to non-experts. The diversity of interests in 3D printing, coupled with the wide distribution of printers themselves, mean a plethora of opportunities exist for applying 3D printing to biology and medicine .The dynamism of biology is exemplified with spatial signaling cascades such as Notch, Wnt, and Hedgehog, and the ability to reconstruct models of their behavior in vitro is progressing steadily, with exquisite genetic control To understand morphogenesis and cooperativity in large-scale tissues, we need techniques which can pattern cell populations to focus and understand their behavior Building physiologically relevant models of disease progression The promise of organ-on-a-chip systems The inexorable need for a continuous supply of oxygen and nutrients to maintain cell viability is a major limiting factor in the engineering of tissues containing living cells. Diffusion alone is sufficient for the growth of human cell aggregates up to several hundred micrometers thick; however, large cell aggregates develop necrotic cores. The challenge remains one of mass transport—how to get oxygen and nutrients in and waste products out of tissue constructs . Given tBulk perfusion of sponge-like macroporous tissue constructs in bioreactors can keep resident cells alive. However, seeded cells can secrete their own insoluble protein matrix into the porous void space, eventually restricting all mass transport To develop living tissue implants that can survive beyond the diffusion limits of oxygen in the interstitial fluids, we may need to construct new vascular networks that can be plumbed into the host vasculature and permit blood flow. Pre-vascularized implanted tissues can integrate into the host vasculature pO2, and pH). So, to solve transport questions in engineered tissues, it is likely that more than one architectural solution is possible Click here for additional data file.


Condition variation in endangered Gouldian and non-declining long-tailed finches was compared to populations of lesser-studied star and black-throated finches. Populations predicted to be vulnerable had patterns of muscle, fat and CORT levels similar to Gouldian finches, suggesting they are at a higher risk of future declines. Conservation agencies are often faced with the difficult task of prioritizing what recovery actions receive support. With the number of species under threat of decline growing globally, research that informs conservation priorities is greatly needed. The relative vulnerability of cryptic or nomadic species is often uncertain, because populations are difficult to monitor and local populations often seem stable in the short term. This uncertainty can lead to inaction when populations are in need of protection. We tested the feasibility of using differences in condition indices as an indication of population vulnerability to decline for related threatened Australian finch sub-species. The Gouldian finch represents a relatively well-studied endangered species, which has a seasonal and site-specific pattern of condition index variation that differs from the closely related non-declining long-tailed finch. We used Gouldian and long-tailed finch condition variation as a model to compare with lesser studied, threatened star and black-throated finches. We compared body condition (fat and muscle scores), haematocrit and stress levels (corticosterone) among populations, seasons and years to determine whether lesser studied finch populations matched the model of an endangered species or a non-declining species. While vulnerable finch populations often had lower muscle and higher fat and corticosterone concentrations during moult , haematocrit values did not differ among populations in a predictable way. Star and black-throated finch populations, which were predicted to be vulnerable to decline, showed evidence of poor condition during moult, supporting their status as vulnerable. Our findings highlight how measures of condition can provide insight into the relative vulnerability of animal and plant populations to decline and will allow the prioritization of efforts towards the populations most likely to be in jeopardy of extinction. Today's conservationists are often faced with the difficult task of promoting species recovery plans to a wide variety of stakeholders in order to fund conservation programmes . Often, Erythrura gouldiae) appear to be particularly sensitive to environmental change due to their specialized grass-seed diet and relatively rigid breeding and moulting schedules (Poephila acuticauda) and masked finches (P. personata) found in the same habitat did not display these changes in condition in response to seasonal, yearly or site-specific environmental change. Instead, these species tended to be in good body condition year round and had higher CORT levels when breeding compared with moult, as reported for many northern hemisphere passerines  share several characteristics with Gouldian finches, including living in similar habitats, having a moderately specialized diet of small seeds and strict timing of moult during 3 months each year (Poephila cincta cincta) feed on a larger range of seeds and other food, as well as having a more opportunistic moulting strategy compared with Gouldian or star finches  were sampled at two sites; Pormpuraaw, Queensland , an area of Indigenous-owned land, and Rinyirru (Lakefield) National Park , a conservation reserve. While Rinyirru is managed for biodiversity values, managers were not successful in excluding fire or grazing from most of the open grassland used by star finches, with both occurring at moderately high intensity; therefore, this population was predicted to be vulnerable to decline. Pormpuraaw contains patches of unburnt dense coastal forest vegetation, but extensive annual hot bushfires, weed infestations and moderate to high grazing levels in surrounding coastal grassland. Pormpuraaw was predicted to be less vulnerable to decline, due to the stable refuge habitat created by the ungrazed and fire-protected forest vegetation patches.Near threatened star finches  was sampled at Rinyirru National Park in grassy woodland near densely vegetated riparian habitat that sustains moderate grazing and burning levels. In this area of the reserve, almost no cattle were present and managers were successful in implementing patchy burning every 2–6 years, thus we predicted that this population was not vulnerable to decline. Threatened southern black-throated finches (P. c. cincta) were sampled at Laudham Park Station , a pastoral property with high levels of grazing and little fire. We predicted that this population was vulnerable to decline.The non-threatened northern sub-species of the black-throated finch (n = 60 for each species) are included in our analysis.Birds were passively captured within 4 h of sunrise using mist nets. No recaptured individuals from this or other studies were included in the analysis. Individuals were captured, measured, banded and released during two seasons: the late dry/early wet season, when birds are moulting (from November to early December 2007 and 2008), or the early dry/late breeding season (from May to June 2008 and 2009). During each visit to a study site, a minimum of 15 individuals of each species were captured and measured. In total, 240 finches  and muscle score based on the shape and relative volume of the pectoral muscles . Two standard CORT solutions (one high concentration and one low) were tested along with finch plasma, which had an intra-assay variability of <5% and an interassay variability of <5%.Haematocrit was measured after spinning blood in haematocrit tubes for 7 min at a force of 16 060r2 = 0.04 F1,238 = 23.70, P < 0.0001; Fig. Given that each finch in this study was blood sampled only once over a range of 5–60 min, we created a relative measure of CORT response to handling stress over time, running a linear regression using all CORT results against handling time and using the residuals in subsequent analysis. The regression was significant .For each of the four condition indices, a mixed model restricted maximum likelihood analysis was undertaken, with population type (vulnerable or not vulnerable), year  and season (breeding vs. moult) designated as fixed factors, and species designated as a random factor to account for general differences in measures among species (SAS institute JMP11.1.1). This ensured that the model was testing for differences in seasonal condition changes among predicted population types. Student's paired post hoc tests revealed that this trend was largely driven by significant differences found in the first year of the study and for vulnerable populations , coinciding with high June rainfall (>20 ml) recorded across all of northern Australia and during the middle of the dry season. Unseasonable rain can disrupt the abundance of grass seeds later in the year by promoting premature and extensive germination or burial of seeds that would otherwise be available to finches . Thus, iIn conclusion, it seems that not all eastern finches are as sensitive to environmental factors as Gouldian finches; we could infer that this is why the supposed non-vulnerable populations are persisting in the landscape while Gouldian finches have not. However, there are sufficient similarities in the pattern of seasonal variation in these measures for all species to identify food limitation as being a likely cause of their lowered condition indices. The reduction in muscle scores and increase in fat levels and CORT concentrations seen in all populations in late 2007 suggests that all finches responded poorly to a regional change in environmental conditions. In order to buffer remaining populations from similar unforseen detrimental circumstances, care could be taken to minimize nutritional stress during moult in the late dry/early wet season by increasing grass seed production in the remaining habitats of threatened species.Our findings highlight how measures of condition can provide insight into the relative vulnerability of vertebrate populations to decline and will allow recovery teams to allocate efforts to the populations most likely to be in danger of extirpation. Traditionally, gaining this insight would take many years of costly long-term population monitoring to complete. Our results provide evidence that short-term condition index studies may represent a useful alternative to determining the level of vulnerability among populations when long-term research is not feasible.This work was supported by the Australian Wildlife Conservancy, the Australian Research Council (grant number LP0668122), the University of Wollongong and the Northern Territory Department of Infrastructure, Planning and Environment and was administered and supported by Charles Darwin University. Additional funds were provided by the Stuart Leslie Bird Research fund and the Professor Allen Keast Award .Supplementary DataClick here for additional data file.


The cerebellum contains the largest number of neurons and synapses of any structure in the central nervous system. The concept that the cerebellum is solely involved in fine motor function has become outdated; substantial evidence has accumulated linking the cerebellum with higher cognitive functions including language. Cerebellar deficits have been implicated in autism for more than two decades. The computational power of the cerebellum is essential for many, if not most of the processes that are perturbed in autism including language and communication, social interactions, stereotyped behavior, motor activity and motor coordination, and higher cognitive functions. The link between autism and cerebellar dysfunction should not be surprising to those who study its cellular, physiological, and functional properties. Postmortem studies have revealed neuropathological abnormalities in cerebellar cellular architecture while studies on mouse lines with cell loss or mutations in single genes restricted to cerebellar Purkinje cells have also strongly implicated this brain structure in contributing to the autistic phenotype. This connection has been further substantiated by studies investigating brain damage in humans restricted to the cerebellum. In this review, we summarize advances in research on idiopathic autism and three genetic forms of autism that highlight the key roles that the cerebellum plays in this spectrum of neurodevelopmental disorders. Autism spectrum disorder , is a behaviorally defined neurodevelopmental disorder that is estimated to affect 1 in 88 children and is diagnosed approximately four times more frequently in males than in females , 17% had below average intelligence (IQ 70–84), 25% had average intelligence (IQ 85–114), and 3% had above average intelligence (IQ > 115) Charman, . HoweverApproximately 90% of autism cases are classified as idiopathic while about 10% are caused by known gene mutations  olivocerebellar climbing fibers (CFs) that cross at the level of the inferior olive, travel through the inferior cerebellar peduncle and the cerebellar white matter, and “climb” onto the primary, secondary and tertiary branches of PC arbors. In development, CFs innervate the PC soma but as the PC dendrites arborize, these connections are replaced by basket cell perisomatic “baskets.” Each PC receives only one CF and in the human CFs can innervate up to 10 PCs along its ascent ; additional afferents arise in the anterior  spinocerebellar tract, cuneocerebellar tract , trigeminocerebellar fibers, lateral reticular fibers, and others. A massive projection arises from the cerebral cortex and travels through the pons (the cerebro-ponto-cerebellar tract) via the middle cerebellar peduncle. The topography of the cerebro-ponto-cerebellar projection has been well-established from tract tracing studies in primates , and other brainstem nuclei. Chan-Palay  describeWhat aspects of ASD could be most affected by cerebellar pathology? There have been several excellent reviews on this topic in recent years  subunit knockout mice, which display autistic behaviors and selective vermal hypoplasia  and social novelty testing . In addition, the GABRB3−∕− mouse in the DeLorey et al.  and develops and becomes fully foliated by 4 months gestation in humans, while development of the large cerebellar hemispheres (neocerebellum) lags behind that of the vermis by 1–2 months. Studies conducted on children that have undergone surgery for cerebellar tumors affecting the vermis have also been informative. Typical problems include cognitive impairment and flattened affect manifesting as increased irritability, impulsiveness, disinhibition, poor attention and behavioral modulation .Early neuroimaging studies of the cerebellum in ASD reported a reduction in the size of cerebellar regions including the vermis  near the 5′ promotor region of the FMR1 gene. Normal individuals have 5–55 CGG repeats whereas in FXS, repeat lengths of greater than 200 causes gene hypermethlyation and loss of the FMR1 gene product, Fragile X mental retardation protein (FMRP). FXS is associated with abnormal dendritic development and maturation of synaptic connectivity that contributes to the cognitive deficits  since boys with FXS and social anxiety show increased anterior, but not posterior vermis size  mouse is generally considered a good animal model of human FXS and has been intensively studied on the molecular, cellular, anatomical, and behavioral levels . Rett syndrome is a progressive neurological condition that presents early with autistic features, but then progresses to severe neurological and cognitive dysfunction. Rett primarily affects females where beginning at 12–18 months of age they regress, losing speech, and motor skills and suffer from additional problems including mental retardation, respiratory impairment, and seizures  and haploinsufficiency of either Tsc1 or Tsc2 is necessary and sufficient to induce an autistic phenotype in mice. These observations also overlap and are consistent with results from chimeric Lurcher mice which exhibit partial depletion of PCs during development and have been reported to display ASD characteristics such as motor hyperactivity, increased repetitive behavior, and deficits on a reversal learning task .- Human postmortem analyses are still limited by relatively small numbers of individual brains examined. Nevertheless, collectively these studies indicate a loss of PCs in a high percentage of cases with idiopathic autism. This finding is additionally supported by a more limited data set from published cases of FXS and TSC. The fact that PCs are the sole output of the cerebellar cortex, and that their axons project to the deep cerebellar nuclei which in turn project directly and indirectly to multiple forebrain regions, places this unique cell type in a strategic position in information processing and overall brain function.- Neurochemical studies in postmortem autism cerebella have revealed alterations in GAD65/67 in PCs, basket cells and in the dentate nuclei suggesting an imbalance of excitatory:inhibitory circuitry within the lateral hemisphere Crus II region. Further, cytoarchitectural abnormalities in the inferior olivary complex and in its inhibitory modulation from the dentate may lead to asynchrony of firing of inferior olivary neurons altering excitatory input to the remaining PCs. PCs bordering areas of absent PCs are hypothesized to be multi-innervated, thus affecting cerebellar output to high order association cortices.- Results from human imaging and neuropathological studies of TSC strongly support an important contribution of cerebellar pathology to the overall clinical picture including the autism spectrum characteristics associated with the disorder. Additionally, results from Tsc mice with mutations in Tsc1 and Tsc2 genes restricted only to PCs have been particularly enlightening. These studies complement human neuropathological findings demonstrating a reduction in PCs and provide strong support for an essential role of the cerebellum in ASD.- The demonstration by Tsai et al.  from the- Future human and animal studies of ASD should incorporate, and perhaps give priority to, assessing cerebellar parameters at the molecular, cellular, anatomical, physiological, and behavioral levels.The following questions arise delineating potential priorities for future studies to address:- Could reduced numbers of PCs, or even intact but dysfunctional PCs, be a feature common to many cases or forms of ASD? If so, this would represent a clear focus for future efforts in ASD research. In addition to the recent novel findings from mutant Tsc mice, the issue of the status of PC excitability and other physiological properties of PCs should be explored in other models of syndromic ASDs.- In light of PC loss in the autism cerebellum, how is the distribution of CFs affected? It remains to be determined whether the autism brain displays a PC multiple innervation pattern due to decreased PCs. This may contribute to sustain inferior olivary neurons, which are unaffected in number in the medulla in postmortem autism cases.- What is the relationship between the cerebellum and the basal ganglia in autism? Both structures are now known to participate in motor and non-motor functions, have indirect connectivity via the subthalamic nucleus, and, have reciprocal connectivity either directly or indirectly with similar thalamic nuclei and cortical targets. Could the two brain regions both participate in the alteration of fine motor control and high order cognitive behaviors in autism?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.