Dentoalveolar injuries are common and are caused by many factors. Dental trauma requires special consideration when a missing tooth or tooth fracture accompanies soft tissue laceration. A tooth or its fragment occasionally penetrates into soft tissue and may cause severe complications. This report presents a case of delayed diagnosis and management of a displaced tooth in the vestibule of the mouth following dentoalveolar injury. This report suggests that radiography can lead to an early diagnosis and surgical removal of an embedded tooth in the soft tissue. Dental trauma can result in a number of different injury types involving teeth and their supporting structures. Six types of luxation and seven types of tooth fracture have been described . The freThis paper reports a case of dentoalveolar injury in which a canine was embedded in the vestibule of the mouth and surgically removed from the soft tissue.A 46-year-old female was referred to the Department of Dentistry and Oral Surgery of Hakujikai Memorial General Hospital for clinical examination of the left maxilla with spontaneous pain. The patient had sustained an injury to the lower face 12 days earlier. She promptly consulted a neighboring emergency hospital because of laceration of the lower lip and gingiva of the maxilla. Thereafter, she was treated with suture of the lower lip under local anesthesia by a general surgeon and was instructed to put pressure on the bleeding gingiva with gauze. In addition, she lost the left maxillary lateral incisor and canine due to trauma. She could confirm the existence of one of the teeth, but the existence of the other tooth was unclear. No treatment or examination was provided for the missing teeth. She received prescriptions for antibiotics and analgesics and returned home. The bleeding easily stopped afterwards. However, because of swelling and pain of the left maxilla, the patient consulted our hospital.Her chief complaint at the time of the first medical examination was swelling and oppressive pain of the left maxilla . IntraorThe recognition and identification of an embedded tooth or its fragment are important because continuous movement and contraction of the muscles may dislocate the foreign bodies. Moreover, oral bacteria flora can infect the wound and deep tissues. Failure to remove an embedded tooth or its fragment in the soft tissue may result in persistent chronic infection, pus discharge, or disfiguring fibrosis . PreviouThis case report demonstrates the importance of an accurate patient history, physical examination, and radiographic evaluation of such a patient. When dentoalveolar injury occurs, both hard and soft tissue structures must be examined carefully for evidence of an embedded tooth.


Dental implants placement in the anterior mandible with flap or flapless technique is a routine procedure and is considered to be safe. However, serious life-threatening complications may occur. We report the first case of massive lingual and sublingual haematoma following postextractive implant placement in the anterior mandible with flapless technique. A 45-year-old female patient underwent placement of four immediately postextractive implants in the anterior mandible using flapless technique. During the procedure, the patient referred intense acute pain and worsening sign of airway obstruction, dysphagia, dyspnea, and speech difficulties. Bimanual compression of the mouth floor, lingual surface of the mandible, and submental skin was maintained for approximately 25 minutes in order to stop the bleeding. Computerized tomography highlighted the massive lingual and sublingual haematoma. The symptoms and signs had almost completely resolved in the next 48 hours. The prevention of these complications is mandatory with clinical and CT analyses, in order to highlight mandibular atrophy and to select carefully the correct length and angulation of bone drilling and to keep more attention to the flapless technique considering the elevation of a lingual mucoperiosteal flap to access the mandibular contour intraoperatively and to protect the sublingual soft tissues and vasculature in high risk cases. Placement of dental implants in the anterior mandible with flap or flapless technique is a routine procedure and is considered to be safe . HoweverA 45-year-old female patient underwent placement of four immediately postextractive implants into the sockets of four parodontally compromised mandibular incisors using flapless technique . When de submental artery, the largest branch of facial artery, is given off from this one just as that vessel quits the submandibular gland: it runs forward upon the mylohyoideus, just below the body of the mandible, and beneath the digastricus. It supplies the surrounding muscles and anastomoses with the sublingual artery and with the mylohyoid branch of the inferior alveolar artery; at the symphysis menti, the submental artery turns upward over the inferior border of the mandible and divides into a superficial and a deep branch. The superficial branch passes between the integument and quadratus labii inferioris and anastomoses with the inferior labial artery; the deep branch runs between the muscle and the bone, supplies the lip, and anastomoses with the inferior labial and mental arteries. The sublingual artery arises at the anterior margin of the hyoglossus and runs forward between the genioglossus and mylohyoideus to the sublingual gland. It supplies the salivary glands and gives branches to the mylohyoideus and neighbouring muscles and to the mucous membrane of the mouth and gums. One branch runs behind the alveolar process of the mandible in the substance of the gum to anastomose with a similar artery from the other side; another pierces the mylohyoideus and anastomoses with the submental branch [ incisive arteries [The soft tissues of anterior floor of the mouth, delimited by mandibular arch, are supplied by a rich anastomosing vascular rete with three sources of arterial blood: (1) the submental arteries, 2) the sublingual arteries, and 3) the incisive arteries. The the subl the inciarteries . These oSevere haemorrhage from this anastomosing plexus has been reported as a complication of dental and surgical procedures involving perforation of the lingual cortex and/or laceration of the adjacent soft tissues . In our Implant-based prosthetic rehabilitation in the anterior mandible is becoming a standard management option in partial or total edentulous patients. Flapless postextractive technique is one of the techniques used for implant placement in the intercanine area and is considered to be safe. However, severe and potential life-threatening complications, such as severe arterial bleeding and large-sized haematomas in the floor of the mouth, may occur. If, during the implant placement in the intercanine area, intense acute pain is noticed, haemorrhage and postdrilling progressive swelling, immediate suspension of surgical procedures, inside-outside bimanual compression on the floor of the mouth, Guedel pattern airway insertion, and local (haemostatic agent) and systemic (cortisone and tranexamic acid) medical therapy should be carried out. The prevention of these complications is mandatory with clinical and CT analyses, in order to highlight mandibular atrophy and to select carefully the correct length and angulation of the bone drill and to keep more attention to the risks linked to the flapless technique choosing the elevation of a lingual mucoperiosteal flap to access the mandibular contour intraoperatively and to protect the sublingual soft tissues and vasculature in risky cases.


Malnutrition and starvation's possible adverse impacts on bone health and bone quality first came into the spotlight after the horrors of the Holocaust and the ghettos of World War II. Famine and food restrictions led to a mean caloric intake of 200–800 calories a day in the ghettos and concentration camps, resulting in catabolysis and starvation of the inhabitants and prisoners. Severely increased risks of fracture, poor bone mineral density, and decreased cortical strength were noted in several case series and descriptive reports addressing the medical issues of these individuals. A severe effect of severely diminished food intake and frequently concomitant calcium- and Vitamin D deficiencies was subsequently proven in both animal models and the most common cause of starvation in developed countries is anorexia nervosa. This review attempts to summarize the literature available on the impact of the metabolic response to Starvation on overall bone health and bone quality. Starvation describes the most severe form of malnutrition, where a severe deficiency in energy intake evokes a metabolic response focused on the subsistence of the vital organs to allow for the survival of the affected individual. Nearly 805 million people are estimated to suffer from malnutrition. 25% of children experience stunted growth due to malnutrition, whilst approximately 45% of deaths in children under five can be correlated with starvation , 2.Starvation may be caused either by an insufficient caloric intake or an inability to properly digest food. Environmental circumstances such as draughts or other natural catastrophes affecting the agriculture, poverty, or forceful withholding in certain geopolitical circumstances such as war or political prison camps may contribute to the unavailability of food. This occurs most commonly in less developed countries. In more developed countries, the primary causes of starvation are medical. Diseases such as anorexia nervosa or depression which lead to a self-induced lack of food intake are not uncommon causes of starvation if the diseases are not diagnosed and treated correctly.The initial metabolic response to starvation does not differ physiologically from the postabsorptive phase in between meals which may usually be observed in a well-nourished human being , 4. The Starvation may occur for either limited periods of time followed by a return to a regular food intake or subsist over extended periods of time, thereby leading to a chronic adaptation to the low caloric intake or absorption.Starvation induced changes of the bone have been described and experimented with in various animal models.The most naturally occurring physiologic cause of starvation which can be observed in nature occurs during the hibernation of black, brown, and polar bears. Osteoblastic activity levels have been reported to decrease tremendously during hibernation, caused most likely by both immobility and starvation . NonetheProspective animal studies most commonly performed in a rat model have shed great light on the effect of energy restriction and starvation on fetal bone development in utero, associated hormones and consequences for the adult animal. Hermanussen et al.  demonstrOverall, the observations in wild moose and laboratory rats with regards to the metabolic bone response to starvation mimic human physiology more than the hibernating bear. A greater level of understanding of bear's ability to maintain their bone mineral density despite 5–8 months of immobility and starvation may inspire new studies investigating the effect of starvation on human bone.Malnutrition and starvation endured during famine may affect not only children and adults, but also fetuses in utero. The possibility of intrauterine programming of musculoskeletal disease developed in the adult human being was initially proposed by Lucas . It is gThe effects of periods of acute starvation in the child or the adult were discussed in several case series examining the potential effect of times of deprivation and malnutrition on the overall bone quality, incidence, and time of onset of osteoporosis, and risk of fracture. Immediate effects on overall bone health were reported by Winnick , detailiOne of the most commonly examined diseases with regards to its effect on bone health is anorexia nervosa, a psychiatric disorder more common in females than in males characterized by a self-induced restriction of caloric intake coupled with a variety of other possible symptoms such as distorted self-perception and compulsive eating rituals , 55. PosOverall, all studies examining the connection between starvation and the bone metabolism in laboratory animal models and humans found evidence of either developmental delays, stunted bone growth, decreased bone mineral density or decreased cortical strength. Given the importance of good bone health to the mobility and function of every human being, public health research investigating the prevention of starvation as well as research focusing on the optimization of therapeutic options for those who have endured periods of famine is in order.


In parallel with progress in understanding the canonical main olfactory system, a recent advance has accelerated elucidation of the structural organization and functional properties of the olfactory subsystems. These include the ganglion of Grueneberg, septal organ, and specific subsets of olfactory sensory neurons in the main olfactory epithelium. The emerging concept of the olfactory subsystems is that each subsystem expresses distinct classes of chemoreceptors and signal transduction molecules, and thereby detects distinct categories of odor or pheromone molecules. The chemical signals detected by the subsystems are sent via their axons to subsystem-specific domains in the glomerular map of the main olfactory bulb , which is released from conspecific mice under a threatening situation  . Therefore, respiration rhythm plays a key role orchestrating the information processing mode across a number of regions in the central olfactory system, which includes the olfactory bulb and numerous areas of the olfactory cortex  with high sensitivity . Because these olfactory sensory neurons project axons to the necklace glomeruli located at the posterior-most part of the glomerular map, they are called necklace olfactory neurons Luo, . These nThe septal organ is an island of olfactory epithelium located at the ventral base of the nasal septum. About 70% of olfactory sensory neurons in the septal organ respond to both odor stimulation and to mechanical stimulation, suggesting that they respond with spike discharges in synchrony with the nasal air flow even without odor input (Grosmaitre et al., The above discussions argue for the idea that at least some of the olfactory subsystems have an important role in detecting the timing of inhalation, exhalation, and air flow in the nasal cavity. Further experiments are needed to determine the functional role of each olfactory subsystem in detecting distinct phases of the respiration cycle. The timing of inhalation and exhalation plays a pivotal role in information processing in the central olfactory system (Mori et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Neurogenesis persists in adult mammals in specific brain areas, known as neurogenic niches. Adult neurogenesis is highly dynamic and is modulated by multiple physiological stimuli and pathological states. There is a strong interest in understanding how this process is regulated, particularly since active neuronal production has been demonstrated in both the hippocampus and the subventricular zone (SVZ) of adult humans. The molecular mechanisms that control neurogenesis have been extensively studied during embryonic development. Therefore, we have a broad knowledge of the intrinsic factors and extracellular signaling pathways driving proliferation and differentiation of embryonic neural precursors. Many of these factors also play important roles during adult neurogenesis, but essential differences exist in the biological responses of neural precursors in the embryonic and adult contexts. Because adult neural stem cells (NSCs) are normally found in a quiescent state, regulatory pathways can affect adult neurogenesis in ways that have no clear counterpart during embryogenesis. BMP signaling, for instance, regulates NSC behavior both during embryonic and adult neurogenesis. However, this pathway maintains stem cell proliferation in the embryo, while it promotes quiescence to prevent stem cell exhaustion in the adult brain. In this review, we will compare and contrast the functions of transcription factors (TFs) and other regulatory molecules in the embryonic brain and in adult neurogenic regions of the adult brain in the mouse, with a special focus on the hippocampal niche and on the regulation of the balance between quiescence and activation of adult NSCs in this region. Neural stem cells (NSCs) in the embryonic and early postnatal murine brain generate neurons and glia, including astrocytes and oligodendrocytes. The transition of proliferative and multipotent NSCs to fully differentiated neurons and glia is called neurogenesis and gliogenesis, respectively. Neurons are generated from early embryonic development until early postnatal stages, with only a few neurogenic zones remaining active in the adult  or a few types of neurons (granule neurons and periglomerular neurons in the V-SVZ)  of the telencephalon, the formation of the DG involves the generation of a dedicated progenitor cell source away from the VZ and in close proximity to the pial surface. This additional proliferative zone remains active during postnatal stages and eventually becomes the SGZ, which is the site of adult hippocampal neurogenesis Figure .The DG originates from the dentate neuroepithelium (DNE), also called primary matrix, a part of the VZ of the medial pallium that is in direct contact with the cortical hem (CH) and becomes clearly distinguishable from embryonic day 14.5 , characterized by rapid divisions and the expression of a series of neurogenic TFs  are produced early on by the telencephalic roof plate and later by the CH , although a more direct role of Tbr2, which is expressed by a small subset of NSCs, is not ruled out  drives the differentiation of IPCs into glutamatergic cells in the DG from development to adulthood  of the genes that are regulated between the quiescent and activated NSC states. Interestingly, a significant fraction of NFIX-regulated genes control cell adhesion, cell motility or extracellular matrix production  family have been implicated in the generation of neuronal and glial cells during hippocampal development. In particular, Tlx, also known as Nr2e1, is an orphan nuclear receptor that is involved in patterning of the embryonic telencephalon. Tlx is expressed throughout the telencephalic VZ, except in the dorso-medial region that will give rise to the hippocampus. Tlx expression remains low in neurogenic regions during late embryonic and postnatal stages and is upregulated only at adult stages  is a key component of the cell cycle machinery that controls the transition between the G1- and S-phases of the cell cycle, together with the other Cyclin D proteins (CcnD1 and CcnD3) and the Cyclin-dependent kinases  signaling has been shown to stimulate stem cell proliferation and neurogenesis in the adult DG, and this pathway has been proposed to mediate the stimulating effect of physical exercise (running) on neurogenesis  in the regulation of adult hippocampal neurogenesis has been the focus of several recent studies  and G protein-coupled GABAB receptors (GABABR), and the loss of both types of receptors increases stem cell proliferation in the DG , for instance, is segregated to the apical membrane in embryonic radial glia  is highly expressed in stem cells and non-neuronal cell types of the embryo, where it represses the expression of neuronal-specific genes : they are the source of instructive signals that determine the fate of neighboring stem cells. However, in contrast with stem cells in the developing brain that must cope with a continuously changing environment, adult stem cells are surrounded by a relatively stable niche. The V-SVZ and the SGZ niches share many common features. However, while the cellular and molecular composition of the V-SVZ niche has been relatively well investigated, we lack a similar level of understanding of the SGZ niche. Further studies of the signals and cellular interactions that control NSC behavior in the DG will be required before we can appreciate the similarities and divergences in the regulation and function of stem cells in the two adult neurogenic niches Figure .Genetic analysis of adult neurogenesis suggests that it is an unstable process, since removal of individual regulatory genes often results in dramatic changes in the behavior of adult stem cells. This inherent instability might reflect the strong impact that environmental cues have on stem cell activity. That defects in single quiescence pathways are sufficient to drive the cell cycle re-entry of subsets of stem cells also suggests that different pools of adult stem cells might receive and/or respond to different niche signals. Further investigations will determine whether adult NSCs in the DG are indeed heterogeneous and whether this is due to exposure to different niche signals or to intrinsic differences between distinct NSCs.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.


Despite the widespread use of repetitive transcranial magnetic stimulation (rTMS) in both research and clinical settings, there is a paucity of evidence regarding the effects of its application on neural activity. Studies investigating the effects of rTMS on human participants ] as the primary measure of changes in neural activity. Studies using MEPs to measure changes in the responsiveness of cortico-motor pathways however, cannot determine the source of observed changes, nor the manner in which individual neurons contribute to the overall effect. Often a “change in excitability” of motor pathways is described when MEP size is altered following rTMS. This term is somewhat misrepresentative however, as it is likely that changes in MEP amplitude represent a hybrid of changes of the intrinsic excitability of neurons within the activated pathway and alterations in the strength of the connections between these neurons. These processes occur through different mechanisms  amplitude (Aydin-Abidin et al., ex vivo slices. They found that increasing rTMS intensity resulted in a falloff in LTP then a suppression at high intensities which is somewhat surprising and could occur as a result of rTMS-induced damage to the brain. This highlights the need for additional investigation of the effects of rTMS intensity in animal models, and also demonstrates that rTMS applied to the cortex can influence the activity of subcortical structures such as the hippocampus. The latter was also displayed by Ahmed and Wieraszko (The intensity of rTMS is critical to the resulting effects on neural tissue, as it is for single pulses. Ogiue-Ikeda et al.  delivereieraszko  who descElectrophysiological studies such as those reviewed, provide much needed information on the effects of TMS pulses on neural responses. This information is an important step toward a clearer understanding of the effects of rTMS and the design of more efficacious protocols. What these studies do not provide however is an insight into the changes in intrinsic excitability and synaptic plasticity that may be occurring in the intact brain following rTMS. In order to obtain this kind of information, a different approach is required.Intracellular recording techniques provide information on both changes to neuron membrane properties that indicate alterations in intrinsic excitability and information on the strength of synapses in the recorded pathway. Unfortunately, the complexity of recording intracellular responses during TMS has made this a significant technical challenge (Matheson et al., NM drafted the manuscript. All authors critically reviewed and revised the manuscript and approved the final submitted version.NM was supported by a University of Otago PhD scholarship. JR received support from a Rutherford Discovery Fellowship from the Royal Society of New Zealand.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.


Measures of climate change adaptation often involve modification of land use and land use planning practices. Such changes in land use affect the provision of various ecosystem goods and services. Therefore, it is likely that adaptation measures may result in synergies and trade-offs between a range of ecosystems goods and services. An integrative land use modelling approach is presented to assess such impacts for the European Union. A reference scenario accounts for current trends in global drivers and includes a number of important policy developments that correspond to on-going changes in European policies. The reference scenario is compared to a policy scenario in which a range of measures is implemented to regulate flood risk and protect soils under conditions of climate change. The impacts of the simulated land use dynamics are assessed for four key indicators of ecosystem service provision: flood risk, carbon sequestration, habitat connectivity and biodiversity. The results indicate a large spatial variation in the consequences of the adaptation measures on the provisioning of ecosystem services. Synergies are frequently observed at the location of the measures itself, whereas trade-offs are found at other locations. Reducing land use intensity in specific parts of the catchment may lead to increased pressure in other regions, resulting in trade-offs. Consequently, when aggregating the results to larger spatial scales the positive and negative impacts may be off-set, indicating the need for detailed spatial assessments. The modelled results indicate that for a careful planning and evaluation of adaptation measures it is needed to consider the trade-offs accounting for the negative effects of a measure at locations distant from the actual measure. Integrated land use modelling can help land use planning in such complex trade-off evaluation by providing evidence on synergies and trade-offs between ecosystem services, different policy fields and societal demands. The first scenario is a reference scenario that represents a continuation of ongoing economic and demographic trends and includes a number of important ongoing policy developments affecting land use. The second scenario is based on the same macro-level assumptions but includes a package of spatial policies that are related to adaptation measures. Both scenarios were evaluated with a series of models that translate scenarios of macro-economic change to spatial patterns of land use change. Finally four indicators of impacts on ecosystem services were calculated: flood risk, carbon sequestration, biodiversity and habitat connectivity. Based on these indicators the tradeoffs and synergies of the adaptation measures are evaluated. Figure 000–2030.increasing food and feed demand in emerging countries, i.e. the BRIC countries ;changing trade regimes because of increasing competitiveness of Asian and Latin-American regions;.changing environmental constraints because of resource scarcity and climate change  support , and current protected nature areas . In this way the reference scenario offers business-as-usual baseline conditions that allow a proper assessment of the impacts of policy alternatives.An alternative policy scenario was developed to evaluate the spatial planning of land use for the conservation of soil and regulation of water in connection to climate change. The macro-level socio-economic developments Table  and clim2 pixel is designated as experiencing an inundation of 50 cm or more in a 100 year flood event according to a map prepared by the EC Joint Research Center  under conditions of climate change. This assessment of potential river-flood risk does not incorporate the conditions of flood defence systems and the effects of upstream land use change on flood occurrence. Therefore, the indicator is especially meant to highlight those areas where new assets become exposed to flood risk. Flood risk from the sea is not included in the analysis.The second indicator used in this paper is an indicator of carbon sequestration. This indicator is based on a carbon bookkeeping approach that takes into account effects of soil and forest age on carbon stock changes. Emission factors are specified by individual countries and land cover types to account for differences in farming practice and ecosystem function across Europe. Details of the indicator are described by Schulp et al. .Two indicators are designed to capture the impacts of land use change on biodiversity at the spatial and thematic resolution of the land use modelling results. The first indicator is a measure of the suitability of the habitat for maintaining biodiversity while the second indicator aims to provide a measure of the connectivity of the habitats. Both indicators represent different aspects of habitat quality....The biodiversity indicator is a Mean Species Abundance (MSA) index which is derived from land use, land use intensity (agriculture and forestry), nitrogen deposition, spatial fragmentation, infrastructure developments and policy assumptions on high nature value (HNV) farmland protection and organic agriculture. The methodology used is based on the GLOBIO3 approach initially developed for biodiversity assessments at a global scale  natural area. The overall connectivity of an area is assessed by calculating the average resistance (or travel time) to reach the larger patches of natural vegetation from the smaller patches within a neighbourhood or administrative region. As the indicator is not including information on the quality of different land use types, it only offers an indication of the potential coherence of possibly valuable natural areas. The indicator has been defined in such a way to be as much as possible independent of the area of natural land use types in the region and solely capture the spatial arrangement. Therefore, also areas with a relatively small area of nature may still have a good connectivity if the green infrastructure is well-developed. Alternative indicators for landscape connectivity, such as the frequently used proximity indicator (Gustafson and Parker .Figure The maps indicate that the adaptation measures are not likely to influence the overall patterns of major land change processes in Europe in the coming decades. Land abandonment will still be concentrated in the most marginal areas and urbanization will take place in the already heavily urbanized regions. However, the adaptation measures will influence land change processes at selected locations and alter regional patterns of conversions. When analyzing the results in more detail the implications of the adaptation measures on land change patterns become apparent.An example of such regional differences in land use configuration resulting from the measures in the policy alternative is provided in Fig. 2 of new urban area is located in flood prone areas in the reference scenario while this area only amounts to 34 km2 in the policy alternative. The small increase in flood risk in spite of the restrictions on building in flood risk areas under the policy alternative is a result of the increase of the flood prone area during the scenario period while the land use policies are based on the area currently under risk of flooding.The flood risk indicator shows the success of the spatial policies in reducing the exposure to potential flooding Fig. . WithoutThe indicators of biodiversity and carbon sequestration are used to investigate if the adaptation measures lead to synergies with other ecosystem services. Figure In general a decrease in the resistance to reach habitats Fig.  is found....Adaptation to climate change consists of a wide range of measures related to different levels of governance. Measures range from local modifications of urban sewage systems to deal with higher peak flows to changes in national scale spatial planning policies and modifications in the common agricultural policy at EU level. In many of the measures land use plays a central role. Given that land use is central to the state of the environment and is linked to multiple economic sectors it is likely that policies in other fields will affect the effectiveness of adaptation measures while at the same time adaptation measures may provide synergies or trade-offs with other sectors. This paper presented a quantitative approach to analyze this mutual interaction between climate adaptation measures and other policy objectives in the context of a multi-scale analysis of land use dynamics. The results indicate that indeed the evaluated set of adaptation measures also impacts the other ecosystem services analyzed. In this paper only a small range of measures is analyzed and the impacts are assessed based on a limited set of indicators, only representing some of the ecosystem services provided in the study area. However, the approach allows for the evaluation of different scenarios and multiple impacts on ecosystem services (Kienast et alThe effectiveness of the adaptation measures in reducing flood risk are not analyzed in this paper. The flood risk indicator solely indicates the exposed assets using a flood risk map that accounts for changes in climate conditions. The results make clear that in the absence of adaptation measures the urban area under flood prone conditions is likely to increase strongly. Changes in the hydrological circumstances as result of improved retention and reduced run-off in the upstream parts of the catchments are not accounted for and may reduce flood risk. Accounting for such changes would require a dynamic coupling of the land use simulations with a hydrological model. Such an approach was taken by Hurkmans et al.  for analThe specification of the scenario options as an interactive process with the policy makers turned out to be a time-consuming process. However, during the specification an improved mutual understanding of the possible implications of the measures as well as an understanding of the capacities and limitations of assessment models to evaluate such measures was obtained. While initially defined in broad terms, the need for quantitative specification of the scenarios in the model provided a platform to discuss the more detailed implications of these policy themes for land use planning practices. In the end, the joint specification of the scenarios assisted the interpretation of the final modeling results because the policy makers had been involved in the process of specification which creates a feeling of ownership.The analysis presented in this paper shows that integrative analysis of the tradeoffs and synergies of policy measures in a dynamic scenario context can benefit the targeting and selection of adequate policy measures. The analysis provides information to support discussion between different policy fields and allows to better explore the potential synergies and avoid unforeseen trade-offs. The process of scenario and model specification as a collaborative effort revealed the challenges of effective science-policy communication. While simple straightforward answers and assessments were preferred by the policy makers the discussion of the specification and implementation of scenario options in the model helped policy makers to understand the need for a clear specification of the broader policy objectives to be able to assess their impacts. The presentation of results in maps helped to understand the complexity of the outcomes. Trade-offs and synergies between adaptation measures and ecosystem service indicators are location and context dependent and land change assessments therefore do not always provide crisp and uniform answers to the questions of policy makers. As such, the science-policy interface emerged into a joint learning process in which the role of specific policies in complex human-environment interactions becomes clearer to both scientists and policy makers..The approach presented in this paper is an example of operationalizing the ecosystem services approach to inform policy (Daily et alAs land use is both a driver and result of human-environment interactions it provides a proper platform for discussing the way we can best adapt to changes in the earth system and secure the ecosystem services provided by the land.


Neurons in the brain exhibit a broad spectrum of heterogeneities even within a given morphological or physiological class. In a recent modeling study, Mejias and Longtin investigated the effects of heterogeneity in the voltage threshold for spike generation on the dynamics of random networks of excitatory and inhibitory neurons  or quantities that are static in the time scales of interest (in experiments), and dynamical heterogeneity, which refers to measures of ongoing neuronal activity such as firing rates and correlations. The relationships between the two can be usefully explored in both directions: while Mejias and Longtin explored the dynamical consequences of different levels of biophysical heterogeneity (bottom-up), others started from experimental observations of dynamical heterogeneity, and investigated neuronal models that are consistent with the observed dynamics  in the presence of noise , both of which display important dynamical differences with respect to homogeneous all-to-all connectivity. We propose that a similar approach could be fruitfully applied to other forms of biophysical heterogeneity, and ultimately result in useful taxonomies of the different sources of biophysical heterogeneity, describing the dynamical heterogeneities they result in and the interactions between their effects. This level of understanding would facilitate the conceptual integration of different results and eventually lead to basic functional principles of neuronal processing beyond area- or species- specific details.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.


Reports of clinical trials often include adjusted analyses, which incorporate covariate data into the analysis model. Adjusting for covariates can increase the precision of treatment effect estimates and increase the power of statistical tests, without the need to increase sample size. In individually randomised trials, the main reason to adjust for a particular covariate is that it is expected to be strongly associated with the primary outcome. The larger the association between covariate and outcome, the greater the increase in power achieved from an adjusted analysis.A valid analysis of a cluster randomised trial (CRT) must take into account the clustered structure of the data, for example by using a mixed effects model. The selection of covariates for an adjusted analysis of a CRT is more complicated because covariates exist at both the cluster level and individual level. Further, adjustment for an individual level covariate can affect the residual variance of the outcome at both the cluster and individual levels.Using results from simulations, and some analytic investigation, I show how the size of clusters and the intra-cluster correlations of the covariate and outcome affect power and precision in adjusted analyses of CRTs using linear mixed effects models. I also consider logistic mixed effects models and show how adjusting for individual level or cluster level covariates affect what treatment effect is being estimated.


CompARE is a pragmatic multicentre open-label phase III randomised controlled trial aiming to determine if intensification of treatment in intermediate and high risk oropharyngeal cancer (OPC) patients improves the definitive primary outcome measure of overall survival time. The trial evaluates three experimental arms separately against one control arm using a MAMS design, with three interim assessments of disease-free survival time. Experimental arms will be discontinued if they fail to meet the interim assessment criteria. The timing of these assessments is driven by the number of control events, with the study engineered so these occur approximately annually. The design characteristics will be presented.A potential additional experimental arm for treatment of OPC was proposed during CompARE initiation, and could be introduced into the trial after one year if approved. The straightforward implication is an increase in the number of patients required to recruit per year or an increase in trial duration. However in a complex MAMS design, a balance of multiple factors such as a feasible sample size, trial duration and appropriate number and timing of interim assessments with appropriate statistical error rates, have to be carefully considered.Using the nstage and artpep programs in Stata, a review of the operating characteristics of both the original design and expanded design with the new experimental arm was undertaken. The recruitment and statistical implications of the addition of the new experimental arm and an evaluation of the study duration to changes in recruitment predictions will be presented.


In vivo research carried out in various animal models as well as epidemiological and clinical data support the existence of a particular phenotype – osteoporotic OA. In fact, subchondral bone has become a potential therapeutic target in OA. Depending on the ratio between formation and resorption, subchondral bone remodeling can culminate in either a sclerotic or an osteoporotic phenotype. Patients with osteoporotic OA may thus achieve clinical and structural benefit from treatment with bone-targeted interventions.The identification of well-defined phenotypes along the course of the disease may open new avenues for personalized management in osteoarthritis (OA).  Arthritis Research & Therapy, Wang and colleagues demonstrate that osteoporosis aggravates cartilage damage in an experimental model of knee OA in rats [Subchondral bone has become a potential therapeutic target in osteoarthritis (OA). In a previous issue of  in rats . Interes in rats . The sigThe controversy regarding the relationship between subchondral bone quality and cartilage integrity originates from the complex biological and mechanical nature of the osteochondral junction . OA progThe effects of estrogen deficiency on the knee joint have been reported in various experimental animal models of OA. The findings obtained by Wang and colleagues on subchondral bone quality and articular cartilage damage support previous research carried out in rabbits, in which osteoporosis aggravated instability-induced OA . In thisThese findings in animal models could be translated to humans, and together with epidemiological and clinical data they support the existence of a particular phenotype – osteoporotic OA . Indeed,The original approach of using ESWT in OA by Wang and colleagues remains intriguing. These authors have reported previously that the application of ESWT to subchondral bone of the proximal tibia showed a chondroprotective effect in the initiation of knee OA and regression of established OA of the knee in rats. These effects were attributed to the ESWT multifunctional actions on cartilage and bone. Yet achieving such beneficial effects in this osteoporotic OA model suggests that the main mechanism of action of ESWT may be improving subchondral bone structure . HoweverIn summary, the study by Wang and colleagues further supports the existence of the osteoporotic OA subtype and the potential benefit of bone-acting therapeutic interventions. Consequently, the identification of patient phenotypes along with the discovery of specific therapeutic interventions targeting relevant pathogenic mechanisms during the course of the disease could lead to a personalized approach to the management of OA.


Allergens in food pose a risk to allergic consumers, especially if they are present in food without declaration or warning. While there is EU regulation for allergens present as an ingredient, this is not the case for unintended allergen presence (UAP). Food companies use precautionary "may contain" labels to inform allergic individuals of a potential risk from UAPs. However, the use or absence of precautionary label has a limited correlation with the level of UAP and consequently the risk of an unexpected allergic reaction. Allergen risk assessment using probabilistic techniques enables estimation of the residual risk after the consumption of a product that unintendedly contains an allergen.® . The allergens of interest were milk, wheat, peanut and hazelnut. The probabilistic model estimates the level of risk for objective allergic reactions posed to the allergic consumers in the UK and gives insight in the health implications of the measured unintended allergen levels.Previously, the UAP was determined among 500 packaged food products from 12 food groups in the UK, either containing a precautionary label or not . In the present study, the UAP results were combined with food consumption data from the National Diet and Nutrition Survey (NDNS) in the UK and the allergen-specific population threshold distribution in a probabilistic model. Data used for the threshold distributions were gathered during the scientific review of the VITAL® (mg protein) and the product specific consumption (kg).Also, the levels of UAP were compared to a product-specific action level (ppm) based on the reference doses as determined for VITAL® reference doses in evaluation of the use of advisory labeling in the UK.The results of this study will assess the public health risks posed by the levels of allergen cross-contamination found to be present in food in the UK retail market and will provide insight regarding the implications of the potential implementation of the VITAL


The European Paediatric Mycology Network (EPMyN) was launched in 2014 to create a European platform for research and education in the field of paediatric mycology. The EPMyN aims to address the lack of paediatric specific evidence and knowledge needed to (1) improve the management and outcome of invasive fungal infections in children and neonates and to (2) enhance and develop paediatric antifungal stewardship programmes. The European Paediatric Mycology Network (EPMyN) was launched in 2014 to create a European platform for research and education in the field of paediatric mycology. Its mission is to increase the knowledge of the epidemiology and pathogenesis and to improve the management of invasive fungal infections in neonates and children. The detailed objectives of the EPMyN are threefold: (1) to investigate the clinical epidemiology of invasive fungal infections in neonates and children, (2) to investigate new diagnostic and treatment modalities of fungal infections in specific paediatric groups, and (3) to create a forum for educating and training colleagues in the field of paediatric mycology.www.penta-id.org), a recognised level 1 network for paediatric infectious diseases in Europe by the European Networks of Paediatric Research at the European Medicines Agency (Enpr-EMA). PENTA-ID was developed from the well-established PENTA (Paediatric European Network for Treatment of AIDS) network, originally collaboration between paediatric HIV centres in Europe addressing relevant questions in the field of paediatric HIV. Numerous clinical trials of antiretroviral therapies in children have been successfully performed over more than 20 years and form the basis of current paediatric HIV treatment guidelines [The EPMyN is a member of PENTA-ID (www.ipfn.org), are the differences in management strategies , differences in the fungal epidemiology and in the risk factors associated with the development of invasive fungal infections (e.g. antibiotic prescription policies). A number of colleagues being a member of the EPMyN steering group are actively involved in the IPFN as well and this does reflect the complementarity of these two networks. In addition, developing and executing cross-Atlantic clinical research, taking into account the differences in regulatory, data safety and legal issues between the USA and Europe will enhance future collaborative activities aimed at a better understanding and improved outcome of invasive fungal infections in neonates and children.The need for EPMyNcan be found in the unique epidemiology of invasive fungal infections in neonates and children, differences in pharmacokinetics of antifungal agents and usefulness of fungal diagnostic measures compared to adults, and the lack of clinical phase-III trials to assess the efficacy of antifungal agents in the paediatric populations. The lack of paediatric specific evidence results in inappropriate use of diagnostic measurements and antifungals and hampers the development of paediatric antifungal stewardship programmes. Arguments favouring the EPMyN, in addition to the well-established International Paediatric Fungal Network (IPFN) led by colleagues in the USA  and the European Organisation for Research and Treatment of Cancer (EORTC). During this 2-day course, the participants were provided with state of the art lectures on the epidemiology, prevention, diagnosis and treatment of invasive fungal infections in neonates, children with primary immunodeficiencies, children with malignancies and those undergoing haematopoietic stem cell transplantation. Interactive case presentations with active involvement of the participants led to vivid discussions and revealed the absence of paediatric specific data to guide clinical decisions.Aspergillus fumigatus in the paediatric population.Current activities are focussed on collecting the necessary information about the management of invasive fungal infections in children and neonates from a large number of European centres. This information is collected by an electronic survey and the data is captured in the REDCap database. The results of this survey are expected to define specific areas of future research, to highlight gaps in paediatric specific knowledge in clinical mycology and will emphasise difficulties encountered in our daily practice which need to be addressed. In addition, specific surveys are being developed to obtain an enhanced insight in the epidemiology of invasive mould infections in the paediatric population, to describe the experience of fluconazole dosing in neonates with a focus on the use of higher dosages as suggested by recent pharmacokinetic studies –4 and towww.ema.europa.eu). Investigating new antifungals in paediatrics do require specific expertise compared to clinical trials in adults. A PIP need to consider an appropriate medicine’s formulation acceptable for use in children, the need of coverage of all paediatric age groups from birth to adolescence and how to measure its efficacy and side effects. The EPMyN within the PENTA-ID is able to cover those paediatric specific aspects and will provide in expertise needed.Next to these investigator-initiated studies, EPMyN aims to provide a platform for pharmaceutical companies to assist in developing and performing the studies as required in the so-called paediatric investigation plan (PIP) set out by the European Medicines Agency –Fungal Infections Study Group (EFISG) guideline for the management of invasive candidiasis in neonates and children was the first to be published •. In thiIn complementation of these guidelines, the development of an outline of a paediatric antifungal stewardship programme to be used as a format in individual European countries is under consideration. The need for a paediatric antifungal stewardship programme is directly related to the challenges encountered in the management of invasive fungal infections in neonates and children, the development of antifungal resistance and the high costs of inappropriate antifungal prescriptions. Invasive fungal infections are characterised by unspecific signs and symptoms in already extremely vulnerable children  transplants), poor-sensitivity of culture-based microbiologic tests, and the pressure to start treatment early due to the high morbidity and mortality of these infections. Most antifungals in paediatric settings are therefore prescribed for empiric/pre-emptive therapy. Suboptimal dosing of antifungals in neonates and children has been described and may contribute to suboptimal clinical outcomes •, 8. To Collaborative efforts in the field of paediatric mycology are critical to improve our knowledge and to facilitate research with the ultimate goal of improving the management and outcome of invasive fungal infections in children and neonates. The EPMyN has taken up the responsibility to provide a platform for research and education in the field of paediatric mycology. The activities undertaken by the EPMyN will facilitate the development of paediatric specific antifungal stewardship programmes built on increased evidence and knowledge.


This review aims to summarize these results with highlights on the pathophysiological function of the RAS under hypoxic conditions. It is concluded that the maladaptive changes of the RAS in the carotid body plays a pathogenic role in sleep apnea and heart failure, which could potentially be a therapeutic target for the treatment of the pathophysiological consequence of sleep apnea.The renin-angiotensin system (RAS) plays pivotal roles in the regulation of cardiovascular and renal functions to maintain the fluid and electrolyte homeostasis. Experimental studies have demonstrated a locally expressed RAS in the carotid body, which is functional significant in the effect of angiotensin peptides on the regulation of the activity of peripheral chemoreceptors and the chemoreflex. The physiological and pathophysiological implications of the RAS in the carotid body have been proposed upon recent studies showing a significant upregulation of the RAS expression under hypoxic conditions relevant to altitude acclimation and sleep apnea and also in animal model of heart failure. Specifically, the increased expression of angiotensinogen, angiotensin-converting enzyme and angiotensin AT The phys Figure . As suchArterial chemoreceptors in the carotid body are important for the rapid adjustment of respiratory and cardiovascular activities via the chemoreflex elicited by the sensory afferent activity of the chemoreceptor responding to changes in chemical stimuli in the arterial blood. The carotid body is a highly vascularized organ with blood perfusion far exceeding the needs of its local tissue metabolism. Thus, changes in arterial oxygen tension or pH, circulating humoral and locally produced signaling substances acting as paracrines or autocrines can readily diffuse to the chemosensory components of the carotid body. In addition to the response to hypoxia, hypercapnia and acidosis, the carotid chemoreceptor responds to Ang II because AT receptors are expressed in the chemosensitive glomus cell of the carotid body Allen, . Moreove1 receptors expressed in the glomus cells.The expression and localization of several key RAS components, notably angiotensinogen, which is an indispensable component for the existence of an intrinsic RAS, have been detected in the rat carotid body , which mobilizes the endoplasmic calcium to store and elevate intracellular calcium  of Ang IV , a biologically active peptide converted from Ang I and Ang II, respectively, by ACE2 and ACE. Recent study reported the expression of Mas receptors in the rabbit carotid body and also its decreased expression under a disease condition associated with heart failure  is increased by 2 folds in the carotid body of rats exposed to 10% inspired oxygen for 4 weeks (sustained hypoxia)  it increases the mRNA and protein level of angiotensinogen expressed in the chemosensitive glomus cell, and (ii) elevated the mRNA expression and enzymatic activities of ACE  associated with recurrent apneas closely related to pathophysiological conditions including sleep-disordered breathing, obstructive sleep apnea and hypertension . Hence, Ang II augments hypoxia-induced renal sympathetic nerve activity (RSNA) and there are significant increases in the expression of ATSleep-disordered breathing with central or obstructive sleep apnea is frequently observed in patients with heart failure. Sleep-disordered breathing has been known to have a negative impact on the CHF patient and so clinical treatment of sleep-disordered breathing could improve cardiac performance and long-term outcomes in these patients. Also, cardiac dysfunction may play a role in the pathophysiology of sleep apnea, although the interrelationship between heart failure and sleep apnea remains to be established (Caples et al., 1 receptor regulates the excitability of the carotid chemoreceptor. Hence, Ang II elevates the level of intracellular calcium in the chemosensitive glomus cells and the activity of carotid chemoreceptors. As a result, activation of the chemoreflex could be a peripheral control important for the physiological response to hypoxia and the maintenance of electrolyte and fluid homeostasis. In addition, the expression of AT receptors in the carotid body is regulated by hypoxia. In effect, sustained hypoxia induces an upregulation of AT1 receptor expression, which increases the sensitivity of the chemoreceptor response to Ang II. This regulation may be important in the modulation of the carotid body functions responsible for the hypoxic ventilatory response, for enhancing the cardiorespiratory response and adjusting electrolyte and water homeostasis during sustained hypoxia. Furthermore, RAS components are locally expressed in the carotid body and the increased RAS expressions are closely relevant to the pathogenesis of disease including sleep-disordered breathing and heart failure. Specifically, the upregulation of the expression of angiotensinogen, ACE and AT1 receptors could play a significant role in the augmented carotid chemoreceptor activity, via the increased activity of chemoreflex, contributing to the pathophysiology of sleep apnea and the sympatho-excitation that is central to the endothelial dysfunction and heart failure during the course of pathogenesis. Future studies in this direction warrant a better understanding of the pathogenic role of RAS in the carotid body in the disease associated with hypoxemia.Findings of expression and functional studies suggest that the ATThe 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.


Atraumatic avulsion of the tibial attachment of patellar tendon in adults is a very rare injury with only few published case reports. Here we are sharing the successful management and follow-up of a similar case with a different suture material for repair of the tendon, the FiberWire. We believe that the management we are discussing allows for early return to activity with good functional outcome. Isolated avulsion of patellar tendon from tibial tuberosity is very rare injury in the adults . Spontan52-year-old man, plumber by profession, presented at the emergency department with one day history of having sudden onset spontaneous pain and functional impairment of left knee while he was walking. The patient had history of hypertension. He had no history of taking medications such as corticosteroids or fluoroquinolones and did not remember having suffered any knee pain previously. On clinical examination effusion was present in knee. It was possible to palpate a gap between the distal patellar tendon and the tibial tuberosity and patient was not able to extend the leg. X-ray of the left knee showed a high patella and presence of calcification in the distal part of the patellar tendon . UltrasoPatellar tendon rupture occurs almost exclusively in males as a consequence of landing after a fall or a jump which produces a rapid contraction of the quadriceps muscle with a partially flexed knee or a consequence of direct trauma to the knee . Mostly Management of patellar tendon rupture varies from primary repair strengthened by cerclage augmentation and immobilization of the extension for 6 weeks , 4 to prPotential complications with use of FiberWire are rupture of the sutures, increased tendinosis by the sutures, and reduction of the strength in knee extension. One of the rare potential complications described in literature with use of FiberWire is reaction to the synthetic material leading to discharging sinuses. In our case, none of the abovementioned complications was observed.Avulsion of distal insertion of the patellar tendon is an extremely rare injury in adults that requires reliable fixation followed by supervised rehabilitation to get the best possible functional outcome. There are very few case reports in the literature describing surgical repair of these types of injuries. In contrast to conventional treatment options, our management of reinsertion of the tendon using transosseous suture with FiberWire is an attractive alternative treatment option that provides excellent resistance combined with good biocompatibility.


MEFV gene, which encodes the protein named pyrin , are associated with the autoinflammatory disease familial Mediterranean fever (FMF). Recent genetic and immunologic studies uncovered novel functions of pyrin and raised several new questions in relation to FMF pathogenesis. The disease is clinically heterogeneous reflecting the complexity and multiplicity of pyrin functions. The main functions uncovered so far include its involvement in innate immune response such as the inflammasome assemblage and, as a part of the inflammasome, sensing intracellular danger signals, activation of mediators of inflammation, and resolution of inflammation by the autophagy of regulators of innate immunity. Based on these functions, the FMF-associated versions of pyrin confer a heightened sensitivity to a variety of intracellular danger signals and postpone the resolution of innate immune responses. It remains to be demonstrated, however, what kind of selective advantage the heterozygous carriage conferred in the past to be positively selected and maintained in populations from the Mediterranean basin.Mutations in the  Autoinflammatory diseases are a group of genetically determined multisystem disorders caused primarily by the dysfunctions in innate immunity. These rare disorders are characterized by recurrent episodes of generalized inflammation and fever in the absence of infectious or autoimmune causes . FamiliaMEFV gene, which is composed of 10 exons and encodes a 781 amino acids protein called pyrin or marenostrin or TRIM20 (http://fmf.igh.cnrs.fr/infevers/). The FMF-associated mutations are predominantly located within exon 10 of the gene, and they primarily result in amino acid substitutions. The phenotypic variability of the disease is thought to be partially associated with particular mutations and allelic heterogeneity  I chain-related gene A has a modifier effect on the disease phenotype . Comparative analyses of amino acid substitutions in the ret finger protein (rfp) domain of pyrin among primates and diseased people have demonstrated that some human mutations actually represent the recapitulation to the ancestral amino acid states and these exist as wild type in other species . Inspectutations . The metutations . The autPositive selection to maintain the high frequency of the heterozygotes should be sufficiently strong to overcome the negative effects such as the increased morbidity and mortality rates among the homozygotes and compounded heterozygotes . There hMEFV encodes the protein called pyrin , which is supposed to play a key role in apoptotic and inflammatory signaling pathways. The protein belongs to the large family of proteins sharing a conserved domain structure with the tripartite motif (TRIM) consisting of an N-terminal RING domain, B-box domain(s) and a C-terminal coiled-coil domain  amyloidosis, which usually affects the kidneys. Amyloidosis is the result of tissue deposition of amyloid, which is a proteolytic cleavage product of the acute phase reactant serum amyloid A SAA; . Overpro alleles . Clinica alleles .MEFV mutations with different inflammatory pathologies, such as systemic onset juvenile idiopathic arthritis . The evidences for positive selection of mutations in the MEFV gene are given in several works cited in this review, and they have a strong support from the formal analytical approaches of population genetics. What remains unclear, however, why the mutations have been selected and maintained in the Mediterranean populations and what are the mechanistic explanations for the advantage at the biochemical level? In particular, we know well about the negative effects of the homozygous or compounded heterozygous mutant allele combination, which result in a higher morbidity/mortality rate. At the cellular level this genetics presumably results in the impaired assembly of pyrin inflammasomes, in the launch of excessive and extended inflammatory responses, and in a less efficient resolution of inflammation. Given the multiple functions of pyrin and the expected pleiotropic effects of mutations in the MEFV gene, the significance and contribution of each of these functions are difficult to ascertain in terms of clinical presentation in pathology or the heterozygote advantage at the phenotypic level. All we know at the clinical level is that the homozygous or compounded heterozygous state results in the enhanced and extended inflammatory response to some of the innocuous factors that are tolerated well and handled efficiently by the normal immune system. The diseased state is certainly disadvantageous  but we don’t know about the possible advantages conferred by the heterozygote state. Investigation of this previously ignored group could potentially reveal the characteristics and traits that were responsible for the selective advantage and maintenance of these mutations in the Mediterranean populations.Understanding the role of pyrin in innate immunity has progressed rapidly in recent years, uncovering its numerous functions in the cell from the formation of several supramolecular structures and inflammasome assembly, to sensing various intracellular danger signals, to mounting the innate immune responses, and to the resolution of inflammation (All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Sleep is critical for regulation of synaptic efficacy, consolidation of memories and learning. It has been proposed that synaptic plasticity associated with sleep rhythms could contribute to consolidation of memories acquired during wakefulness. It was suggested that in the active state of sleep slow wave oscillation, the hippocampal formation activates latent memories stored in the neocortex (replay) and induce permanent changes in synaptic conductances.In this study, we present a thalamocortical network model of the slow-wave sleep activity characterized by repeatable < 1 Hz) transitions between active (Up) and silent (Down) states of the network. The model consisted a layer of thalamic relay (TC) and reticular (RE) neurons in the thalamus as well as a model of cortical column with pyramidal neurons and inhibitory interneurons. All neurons were modeled based on the Hodgkin-Huxley kinetics. Spike-timing dependent synaptic plasticity was implemented to regulate synaptic efficacy. The slow oscillation was driven by intracortical dynamics; active states were initiated by the spontaneous miniature synaptic releases at different network sites [ Hz transWe found that the pattern of the active state propagation depended on the spatiotemporal pattern of activity on the previous cycle of slow oscillation and could be influenced by external input. Because of the refractoriness properties of the network, a probability of the next active state initiation was higher for the network site that initiated activity at the previous cycle. Furthermore, even weak external stimulation delivered to the network results in increase probability of up-state induction at the stimulation location. This suggests that spatially and temporally sparse hippocampal input could influence the spatiotemporal pattern of slow oscillation.Location of the initiation site and the pattern of active state propagation determined the relative timing of spiking in cortical neurons. When spike-time dependent synaptic plasticity (STDP) was implemented, there was a net decrease in synaptic strengths and, at the same time, an increase in the strength of specific synapses which were associated with the sequence replay. The change in synaptic weights between any two neurons was determined by the direction of active state propagation and by the distance between the neurons.Our study propose a mechanism of how interaction between cortically generated slow waves and sparse external input, possibly representing input from hippocampal formation, may lead to reorganization of synaptic strength during stage 3/4 sleep.


A mechanism must operate directly on the Achilles tendon which in effect introduces an obstruction to the outward movement of the Achilles tendon, but the features of this obstruction  are largely unexplored. We hypothesized that the obstruction arises from the differences in mechanical properties between muscle contractile tissue and non-contractile tissue. A possibility is that the pennate arrangement of muscle fibers results in a mechanical system which applies force vectors perpendicular to the muscle fiber axis, similar to that described for the action of intercostal muscle on the rib cage. The distal region of soleus (Sol) muscle has an unipennate arrangement, with fibers oriented between the posterior aponeurosis and anterior surface of the muscle. Although this configuration can constitute a constraint to the posterior movement of the Achilles tendon, the Kager’s fat pad, being non-contractile tissue, will be unable to actively develop any force and – render it mechanical incapable of constraining the movement of the tendon. If our hypothesis is true, the action of obstruction should be strongly synchronized to that of the tip of the Sol muscle as the ankle rotates.The anatomical location (x and y coordinates) and tissue movement (velocity) of Achilles tendon inflection point, which corresponds to the obstruction, and also those of the extremity of Sol distal edge were determined during passive and active contractions using MRI (n=6). A simple geometrical model was used to investigate how the position of the obstruction influences force and velocity gains.With increasing ankle angle, inflection point and extremity of the Sol distal edge moved in proximal and anterior directions Figure . The disThe Achilles tendon obstruction is likely to be emerged the location of boundary region between the Sol muscle and Kager’s fat pad when ankle positioned plantarflexion. Further, obstruction can provide a means of managing the tradeoff between force and velocity inherent in a finite power source and may effectively emerge in a location of terminal part of a joint such as foot or hand due to responsible for quicker movement rather than larger force exertions.


Several UMCG-wide implementation projects improving quality and patient safety have been organized to stimulate the (intrinsic) motivation to work safely in order to bring about the intended change. We deployed ‘change agents’ in various involved groups of professionals and trained them in supporting and stimulating their colleagues to work safely according to the latest evidence based guidelines. We will discuss the effects on implementation success of this strategy, using three examples of improvement projects, namely the implementation of a screening instrument for elderly patients to identify frailty, the Surgical Patient Safety System checklist (SURPASS) in the perioperative process, and the guideline Personal Hygiene.We used e-learning modules, instruction sessions, follow-up sessions, feedback, e-mail and the intranet to inform and instruct the change agents. We measured the effects on improving quality and patient safety by a pre-post evaluation of the degree of implementation, partly by individual completion rates of the checklist and the screening instrument and by observation of personal hygiene indicators. Furthermore, we investigated the influence of leadership and team climate on the effectiveness of deploying change agents  using vaThe study showed a positive effect of the change agent on the degree of implementation of the various innovations .A transformational leadership style of change agents resulted in higher usage rates of change recipients. Climate within the team in which the change agent acts also positively influences the degree of implementation. From the qualitative data we also learned that both the perceived status of the role by change agents themselves and the feedback received on the achieved degree of implementation seem to be affecting the success of a change agent in motivating and stimulating their colleagues to work according to the new guideline.Deploying change agents is an effective strategy in encouraging implementation of guidelines. The effect is larger when change agents show transformational leadership and work in a positive team climate. When change agents perceive their added value in implementation success they can motivate their colleagues better.


Loss of renal tissue and renal function results in an increase in function and mass of the remaining intact kidney tissue. A prominent example for this so called renal compensatory hypertrophy is the removal of one kidney  for instance in living kidney donors. Although it is well established that kidney size and function of the remaining kidney markedly increase in these patients and that these adaptations are a prerequisite for living kidney donation, several open questions regarding the regulation of the compensatory mechanisms remain. For instance the initial signals inducing the increase in glomerular filtration rate (GFR) are largely unknown. Based on previous studies demonstrating that I. the rapid increase in GFR post-UNx is mediated by a circulating factor and II. the cardiac natriuretic peptides ANP and BNP both are capable of increasing the GFR, we speculated that natriuretic peptides might be the long sought factor mediating the functional adaptation of kidney function in response to a loss of kidney tissue.Our observations in different gene targeted mouse models reveal that natriuretic peptide signaling via guanylyl cyclase-A is critical for the rapid increase in GFR which occurs within the first days post uninephrectomy. Thereafter, the functional adaptation and the hypertrophy of the remaining kidney is independent of the cardiac natriuretic peptides, so that GFR and kidney size are regularly elevated six weeks post-UNx even in the absence of GC-A. However, natriuretic peptide / GC-A signaling has a marked renoprotective effect in this chronic phase of renal compensatory hypertrophy, since it prevents podocyte damage and albuminuria. These beneficial effects of GC-A activation on renal integrity is independent of the blood pressure and is mediated via a direct effect on podocytes.Natriuretic peptide / GC-A signalling has at least two important functions in the renal adaptation to the loss of kidney tissue: It is critical for the rapid increase in the glomerular filtration rate in the first days after uninephrectomy and it ameliorates podocyte damage and albuminuria in the chronic phase of renal compensatory hypertrophy.


Synaptic plasticity mechanisms are usually discussed in terms of changes in synaptic strength. The capacity of excitatory synapses to rapidly modify the membrane expression of glutamate receptors in an activity-dependent manner plays a critical role in learning and memory processes by re-distributing activity within neuronal networks. Recent work has however also shown that functional plasticity properties are associated with a rewiring of synaptic connections and a selective stabilization of activated synapses. These structural aspects of plasticity have the potential to continuously modify the organization of synaptic networks and thereby introduce specificity in the wiring diagram of cortical circuits. Recent work has started to unravel some of the molecular mechanisms that underlie these properties of structural plasticity, highlighting an important role of signaling pathways that are also major candidates for contributing to developmental psychiatric disorders. We review here some of these recent advances and discuss the hypothesis that alterations of structural plasticity could represent a common mechanism contributing to the cognitive and functional defects observed in diseases such as intellectual disability, autism spectrum disorders and schizophrenia. Dendritic spines are the major site for excitatory transmission in the brain. They are usually contacted by en passant presynaptic terminals and most often surrounded by astrocytic processes, forming complex structures that dysplay a high degree of functional and structural plasticity. While most research attention has usually focused on the functional aspects of synaptic plasticity and their key contribution to learning and memory mechanisms, work in the last decade has clearly demonstrated the importance of the associated structural rearrangements. These consist of different types of morphological changes , affecting different partners  and taking place on different time scales (minutes to days), making them sometimes difficult to relate to the functional changes. These structural rearrangements are also tightly controlled by activity, they are usually NMDA receptor dependent, and have the potential to significantly affect the development and organization of local synaptic networks. Recent advances have started to unravel some of complex molecular mechanisms and signaling systems regulating these synaptic rearrangements, notably at the postsynaptic level. We will therefore mainly focus on these aspects in this review and highlight the multiplicity of mechanisms that may affect structural plasticity and the development of synaptic networks and thereby contribute to cognitive disorders.in vitro and in vivo studies have shown a high correlation between the size of the spine head, the size of the postsynaptic density, the size of glutamate-evoked responses and the stability of the spine , there appear to be two major structural types of changes that have been reported both in Identification of stimulated synapses within a network has been and still is one of the important limitations for understanding how activity and plasticity regulate synapse properties. This has been overcome in only a few studies using either 2-photon uncaging of glutamate to achieve local stimulation of identified synapses or calcium imaging coupled to electrical stimulation to reveal functional synapses. Although previous electron microscopic (EM) analyses had already suggested that LTP could be associated with morphological changes , regulators of Rho GTPases , srGAP3, Disc1, SynGAP), effectors of Rho GTPases (PAK3), as well as cytoskeletal regulatory proteins  or adhesion and scaffold molecules , intracellular mediators implicated in mTOR signaling  and regulators of protein synthesis  (Kumar et al., Functional synaptic plasticity properties, by quickly changing synaptic strength, allow fast adaptations of network activity which are critical for information processing. However, on a longer time scale, structural plasticity properties may allow a more significant and stable rewiring of synaptic networks through both the formation of new connections and the stabilization of specific contacts. These properties of structural plasticity are particularly important during development where they contribute to shape the structural organization of brain circuits through activity. Molecular analyses of these structural properties started to identify key signaling pathways implicated in these synaptic reorganizations, which also appear to be strong candidates for contributing to cognitive and psychiatric disorders. Hence a common denominator of developmental disorders could involve alterations in spine dynamics that would affect the connectivity and specificity of brain circuits. More systematic analyses of these properties and their functional consequences should allow a better understanding of how they affect information processing and this could eventually lead to new possibilities of treatment of these disorders.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The oral microbiome is composed of a multitude of different species of bacteria, each capable of occupying one or more of the many different niches found within the human oral cavity. This community exhibits many types of complex interactions which enable it to colonize and rapidly respond to changes in the environment in which they live. One of these interactions is the transfer, or acquisition, of DNA within this environment, either from co-resident bacterial species or from exogenous sources. Horizontal gene transfer in the oral cavity gives some of the resident bacteria the opportunity to sample a truly enormous metagenome affording them considerable adaptive potential which may be key to survival in such a varying environment. In this review the underlying mechanisms of HGT are discussed in relation to the oral microbiome with numerous examples described where the direct acquisition of exogenous DNA has contributed to the fitness of the bacterial host within the human oral cavity. The human oral microbiome is an incredible example of a species rich collection of micro-organisms living together primarily as a multispecies biofilm. The constant challenges the biofilm inhabitants have to cope with include interactions of co-operation and antagonism whilst the individual cells have to adjust to an ever changing onslaught of environmental perturbations. Availability of carbohydrate sources, temperature changes and the interaction with transient, non-oral species of bacteria are just a few examples of the challenges the individual members of the multispecies oral biofilm have to adjust to.There are many recent reviews concerning the actual numbers, and species composition, of bacteria within the human oral cavity and the reader is directed to these  occurring in bacteria from ecologically similar environments . A recent study on the genome evolution of the genus The oral cavity is by no means a static environment; rather it is an environment where diverse ecological pressures exist. As a portal to the distal part of the digestive tract the oral cavity is open to the environment and also has a variety of foods (substrates) pass through it. There is therefore a great deal of variability encountered in terms of physical, chemical and physicochemical characteristics.Bacteria will have to cope with multiple defense mechanisms within the oral cavity including, but not limited to the production of host antimicrobial compounds such as lactoperoxidase and lysozyme, bacterially derived antimicrobials and bacteriocins, production of immunoglobulins A, G, and M, mucus layers on mucosal surfaces and the constant shedding of epithelial cells. There are also relatively strong mechanical forces which result during chewing, talking and the movement of the tongue. Forces up to 150 Newtons (N) are generated whilst chewing foods such as meat whilst the maximal biting forces have been estimated to be between 500 and 700 N Wilson, . In addiVeillonella utilizing the lactate produced by cariogenic streptococci  have been shown to be exported from Escherichia coli in vesicles and furthermore have been shown to successfully transform Salmonella  via membrane vesicles into the developing biofilm and provides therefore an important source for genetic material via this novel mechanism  protein, a ribosomal protection protein which reversibly binds to the 23S rRNA subunit of the ribosome and prevents tetracycline binding therefore preventing protein synthesis, or removing a bound tetracycline molecule before binding itself  conferring macrolide, lincosamide and streptogramin resistance, Tn6009 encodes resistance to both inorganic and organic mercury by the action of MerA and MerB respectively and Tn1545 and Tn6003 both encode resistance to kanamycin via the product of aphA-3 , which is secreted and accumulates in the extracellular environment to trigger competence development in a quorum sensing dependent way , and compared to the commensals itself, S. mutans is highly H2O2 susceptible  and molecular oxygen (O2) to H2O2, carbon dioxide (CO2) and the high-energy phosphoryl group donor acetyl phosphate in an aerobic environment. Knock-out studies with putative pyruvate oxidase orthologs in S. sanguinis and S. gordonii confirmed SpxB as main H2O2 producer , which is considered a bacterial immune system. It is an adaptive and inheritable system which recognizes and destroys foreign DNA therefore preventing infection by bacteriophages, transposons and plasmids. It is an RNA based protection mechanism, which stores parts of the DNA of previously encountered bacteriophage, transposons and plasmids in the CRISPR chromosomal locus. The cell is therefore able to prevent potential harmful DNA of integrating into the chromosome by RNA interference using the stored information of the CRISPR (Gasiunas et al., The successful transfer of a new genetic trait is dependent on several events. In the case of eDNA, the genetic material needs to persist in the environment long enough to be taken up by a competent bacterium. The eDNA integrity and persistence is compromised by host and bacterial derived extracellular nucleases (Kishi et al., The increasing amount of evidence for HGT in the human oral cavity shows that these processes are important in the adaptability of the oral community. The nature of some of the evolutionary strategies involving HGT is much more complex than simple acquisition of DNA released from dead cells or acquisition of a plasmid or transposon from a donor member of the oral community. More evidence for this is found in oral metagenomes; it has recently been found that the incidence of CRISPRs and the numbers of MGEs associated with oral cavity derived metagenomes is far more than in the GI tract of man (Zhang et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


AbstractWell-organized acute and intermediate rehabilitation after stroke can provide patients with the best functional results. Several studies led to major changes in recommendations concerning remobilization therapies following stroke. Controlled studies including early mobilization in stands and training with partial body weight support on treadmills and "gait training" systems showed superior results compared to traditional treatment strategies. In case of spasticity and equinovarus and stiff knee pattern following stroke, botulinum neurotoxin A injections and/or casting enable the achievement of adequate alignment of the ankle for stance phase and allow the improvement of joint mobility during swing phase when restricted. It represents an emergency because once the lesion has installed there is no efficient therapy which can restore the function of the brain tissue [2]. The ideal medical therapy is the prevention of stroke. In addition, efforts have been made in order to precociously diagnose the installation of stroke, in order to be able to intervene during the evolution of a vascular thrombosis. This presupposes that the patients’ medical problems are discovered in the stage of asymptomatic atherosclerosis. Consequently, the therapy for the atherothrombotic disease with the affection of the extra- and intracranial vessels can be divided as it follows: stroke therapeutic primary prevention measures, measures of reestablishing the blood flow and stopping the pathological process in case of stoke, physical and neurological post-stroke rehabilitation therapy, measures of prevention of progression and repeating of the stroke (secondary prevention). These ideas have been also included in the Diagnostic and treatment guide for the cerebrovascular diseases, emitted by the Ministry of Health, 2009 [2]. The stroke is one of the main causes of chronic disability and death [2]. The thrombolysis done by administering TPA (tissue plasminogen activator recombinant) for 4,5 hours is a therapeutic option for ischemic stroke, which aims at reducing the disabilities which appear immediately after stroke [1]. The concept "time means brains" has appeared as a result of a research which showed that in the stroke in evolution, 1,9 millions of nervous cells die each minute [1]. In the case of the stroke of the vertebrobasilar system, an intervention can be made in 6 hours to remove the arterial thrombus (thrombectomy), by applying interventional radiology  [1].  The factors which influence the seriousness of the stroke are the following: localization, lesion size, lesion type [ Stages of neurological rehabilitation 4].  The functions restoration in the first months after a stroke mostly depends on the spontaneous healing, which is dependant on the compensation potential and the spontaneous plasticity of the brain [2]. In addition, the main purpose of precocious rehabilitation is cardiovascular rehabilitation training, reeducation of orthostatism, of feet coordination, of waking, of cognitive functions. Stroke rehabilitation is a process beginning during acute hospitalization and continues with later phases of rehabilitation. The important phases of stroke recovery are acute, subacute and chronic phases (more than 6 months post-stroke) [2]. The rehabilitation of the vertical position (orthostatism) and the walking must be started as soon as possible. The first mobilization of the patient should take place during the acute therapy of stroke [2]. For documentation of different neurological deficits and of severity of physical disability the best validated assessment instruments are the Barthel Index, Rankin Scale, Scales Ashworth (AS) and Ashworth modified (MAS) for spasticity, Mini Mental State Examination (MMSE) [ Locomotion rehabilitation 4].  The locomotion therapy mainly encompasses the rehabilitation of orthostatism and walking ability. The walking therapy is realized by an active training of walking which presupposes a frequent repetition. The training oriented towards "functional movements" used to ensure daily basic necessities has proved to be the most effective of all. Movements are "functional" when they allow us to reach an efficient, safe, adapted occupational behavior. The normal movement is possible due to the interaction between the musculoskeletal system and the central nervous system [5]. Different authors have stated that the critical speed  is of 110 steps per minute [6]. A severely affected patient can reach a number of 50 to 100 steps only if helped by 2 therapists. The training of walking on a walking tape with partial support of the weight with one or two therapists can reach the level of 300 to 400 steps per training. In case of a training supported by robotic equipment and with the help of a therapist, the patient can reach up to 800-1000 steps per therapeutic session. In case of an intense taking over of the walking activities by the equipment used, the rehabilitation process can be slowed because no exercises which involve the use of the patient’s potential are practiced anymore. When referring to walking tape exercises, the degree of difficulty can be progressively raised by establishing new tasks  [7].  Researches regarding the physiology of walking have shown that the spinal locomotion centers will be adequately stimulated only at a certain frequency of the steps; this way, a physiologic walking can appear [9].  The robotic locomotion training with the support of the lokomat can accomplish an intensive functional training , with the possibility of changing the training parameters according to the kinetic object established, as well as the use of a biofeedback and visual feedback of the results [10].  The application of the things learnt while walking follows after the training supported by the robotic equipment. The other purposes of this training are the following: the raise in the duration and speed of walking, the use of the escalator. The therapist will apply the training of walking outside the training room, as for example in the street, while trying different means of support  which compensate the neurological deficits and can ensure the independence of the patient [ Orthoses11].  The most commonly prescribed orthosis with a view to improving gate is an ankle-foot orthosis, but there are also orthoses for toes, knees, arms, elbow, fist/ hand or/and fingers. The orthosis for the ankle is recommended when the paresis of the dorsal flexion is present or when the spasticity of the flexors is important. In patients with foot inversion due to spasticity, the use of the orthosis allows the improvement in the symmetry of walking and can reduce the consecutive danger of a traumatism [8].The orthosis for the knee is most often applied in the precocious rehabilitation stage of walking. In case of knee extensors paresis, it helps in the knee joint stabilization. The knee hyperextension is dangerous in the spasticity of the extensors; the retroversion of the knee can lead to painful joint modifications in time [ Functional electrical stimulation 15]. FES  uses its effects on the intact neurons and incorporates the movement produced in a functional activity. FES has been used to help the weak or paralyzed muscles develop activities such as orthostatism, walking or movements of the arms, with the support of neuroprosthesis [12-14]. There are developed multifunctional advanced functional electrical stimulation systems that send low-level electrical impulses and can assist patients' functional movement, for example the Neural Electrical Stimulation System (NESS): H(and) 200 și L(imb) 300, 300 Plus [12].  During the precocious rehabilitation period, when the patient is still inactive, electrical stimulation can be used together with the physical exercises in order to maintain the muscular integrity. During the training of walking, it can be directly used the tibialis anterior muscles or the peroneal stimulation nerves at the level o the fibula end, which can lead to the improvement of the dorsal flexion function. The studies show an improved walking condition from the qualitative point of view. It seems that the use of electrical stimulation improves the post-stroke muscular force, as well as the endurance and the muscle force, if FES is administered together with the resistance opposed to the contraction generated by the electrical stimulation of the affected muscles [ Recovery and serial casting16]. Most of the times spasticity compels the muscle to remain in a contracted position which shortens it for long period of times; this way it may lead, also through consecutive muscle retractions, to the deterioration and limitation of functional mobility, the loss of the ability of performing routine activities, sometimes associated with severe pains which amplify the functional limitations, altering, in the same time, the quality of life. The joints of the elbow, of the wrist of the hand , of the toes and ankle are the ones which most often benefit from this treatment [16].  Serial casting  has been successfully used since 1989 in the therapy of spasticity of the arm and leg, having great results. The principle of action is the reduction of muscular hyperactivity, which influences in a positive manner both the vicious position of the leg/arm and the pain [20].  Opposition involuntary muscular hyperactivity that appears against an exogenic force, does not answer to BT therapy, just like posture apraxia, which sometimes mimics spastic conditions. Contracture can also answer to therapy and most of the times the pain is reduced. BT application is not recommended in the following cases: fixed contractures, bone deformities, patients who undergo an anticoagulant therapy. The botulinum toxin is efficient in the therapy of spasticity in upper neuromotor syndrome both in adults and in children [21]. In case spasticity is localized in fewer muscles, the local injections of botulinum toxin together with kineto-physical therapy can lead to substantial improvements. In spasticity, there is a need for a careful selection of the muscles and it is important that the injection of the spastic muscles is done strictly at the intramuscular level [18]:  BT therapy is indicated in spastic syndroms which have the following characteristics [ - dynamical (not fixed)  - especially in muscular hyperativity  - relevant for the daily activity  The use of BT in children presupposes attention to the following:  - the dose for muscles according to the body weight  - the whole dose for each patient according to the body weight  - the period of time between the injections. 12]. The BT-A and neuromotor electrical stimulation (FES) effects on the spasticity of the plantar flexor and the movement amplitude of the dorsiflexion in children with cerebral palsy, were also examined. The management of spasticity of upper limb with botulinum toxin therapy was examined in multicentric study and the most important goals for the clinical practice were defined [21]. What has been carefully paid attention to are the effects of the BT-A combined with FES injections, together with functional exercises on spasticity and the functions of hemiplegic patients. The results show that BT-A injections combined with electrical stimulation  for 3 days post-injection therapy can improve the functional capacities and spasticity in treated patients [ Social and professional rehabilitation 16].  An extra element, which is important in motor rehabilitation, is social and professional rehabilitation. This way, the rehabilitation and social reintegration therapy of a stroke patient, can be completed [2]. Its purposes are the following: skills , areas of activity (daily activities – DA), education, working, playing, social participation. The performances which are necessary to do some normal activities belong to the motor field , sensorial and perception field , the field of emotional regulation , cognitive field , communication and social life field . In his rehabilitation activity, the occupational therapist must take into account the internal organization of a person , the patient’s habits , will , and the entire cultural, social, spiritual, personal, time context [16]. In addition, occupational therapy has an important role in the rehabilitation process of a stroke patient [