Hyperexcitability in the neural networks is one of the hallmark features of the epileptic brain and can manifest itself as recurrent short or long duration discharges . In rodeIn this study, we developed a branched computational model of CA3 region of hippocampus, consisting of a network of an astrocyte and a pyramidal cell with a feedback inhibitory interneuron. As both potassium and calcium ions have been shown to potentially affect neuronal hyperexcitability, the astrocytic model has both mechanisms - the clearance of potassium through potassium channels, and the influence of astrocyte in the synapse.Preliminary results show that in hyperexcitable systems with fully working potassium AHP channels depolarization discharges cease after less than a second , classifying them as short duration. With partial dendritic AHP channel blockade the duration of discharges increases, transitioning into long duration discharges . In the extreme case where all of the dendritic AHP channels are blocked, there is no cessation of the seizure-like state . We hypothesize that in hyperexcitable systems the postsynaptic AHP (and to a lesser extent the Nap) channels work in concert with glial cells to control the duration of depolarization discharges.


Inclination of the subtalar joint (STJ) in the transverse and sagittal planes may be highly associated with ankle sprain mechanisms. However, the validity and reliability of measuring inclination of the STJ axis of rotation (AoR) is not well established.The purposes of this study were to: 1) examine the validity of a custom made instrument (locator) to measure the STJ AoR on the basis of the STJ inclination measured by X-ray, 2) to measure the intra-tester reliability of the locator.Cross sectional study.Biomechanics laboratory.Twenty nine healthy male  and Nine health female  subjects were recruited for this study.No Intervention.Variables that were measured in this study were as follows: 1) Inclination of STJ AoR in the sagittal plane measured by radiographic images  of the foot in the sagittal plane. In order to collect radiological images of the foot, subjects stood with a tandem position and the STJ was placed in neutral position. Sagittal plane inclination of the STJ AoR were further analyzed using ViewRex  per McClay‘s method . Once thThe locator may be used in the clinical setting since validity verified by correlation was high and the intra-test correlation coefficient was large indicating consistent measurements. Along with the locator measurement, it is suggested that further study including motion analysis may provide more information regarding the relationship between inclination of STJ AoR and movement at the STJ.


The Titanosauria were much diversified during the Late Cretaceous, but paleobiological information concerning these sauropods continues to be scarce and no studies have been conducted utilizing modern methods of community analysis to infer possible structural patterns of extinct assemblages. The present study sought to estimate species richness and to investigate the existence of structures in assemblages of the South American Titanosauria during the Late Cretaceous. Estimates of species richness were made utilizing a nonparametric estimator and null models of species co-occurrences and overlapping body sizes were applied to determine the occurrence of structuring in this assemblages. The high estimate of species richness (n = 57) may have been influenced by ecological processes associated with extinction events of sauropod groups and with the structures of the habitats that provided abundant support to the maintenance of large numbers of species. The pseudocommunity analysis did not differ from that expected by chance, indicating the lack of structure in these assemblages. It is possible that these processes originated from phylogenetic inertia, associated with the occurrence of stabilized selection. Additionally, stochastic extinction events and historical factors may also have influenced the formation of the titanosaurian assemblages, in detriment to ecological factors during the Late Cretaceous. However, diagenetic and biostratinomic processes, influenced by the nature of the sedimentary paleoenvironment, could have rendered a random arrangement that would make assemblage structure undetectable. Sauropods constituted a group of Saurischian dinosaurs that were highly diversified, attaining large dimensions and wide geographic distributions Isisaurus and DiamantinasaurusTitanosauria constituted the most diverse sauropod lineage, represented by more than 30 known genera, widely distributed on nearly all continental landmasses during the Late Cretaceous Studies of Late Cretaceous South American Titanosauria have dealt predominantly with taxonomic and biochronological aspects, paleogeographic distributions, strategies of locomotion and behavior, reproductive and developmental biology, appendicular morphology, cranial morphology and phylogenetic systematics The structure of a vertebrate assemblage can be defined as nonrandom patterns in resource utilization among individuals that coexist in time and space Within this context, studies have shown that co-occurrence patterns are commonly attributed to competitive interactions or to environmental filters, and these patterns can be generated by historical factors, habitat associations, and/or species dispersal limits Considering the hypothesis that species co-occurrence in time and space will be determined and structured by their interspecific relationships, the present work sought to estimate the species richness of the South American Titanosauria during the Campanian and Maastrichtian ages (83.5–65 Mya) and to investigate the occurrence of structuring in this assemblage with respect to species co-occurrences and overlapping body sizes.The list of sauropods presented in this work  was prepChao1 = Sobs+F21/2F2, where Sobs is the number of species recorded in the assemblage sampled, F1 is the number of species represented by only one individual (“singletons”), and F2 is the number of species represented by two individuals (“doubletons”) The nonparametric estimator Chao1 was utilized to estimate sauropod species richness based on abundance data: SC-score index C-scores measure the mean numbers of units in a single block (checkerboard units – CU) for all pairs of species The EcoSim Module of co-occurrence was utilized to test the occurrence of nonrandom patterns of co-occurrence of the Titanosauria species recorded in the stratigraphic formations corresponding to the Lower Campanian to the Upper Maastrichtian in South America CU = (ri–S) (rj–S), where ri and rj correspond to the totals in a row, and S is the number of sites occupied by both species. The utilization of fixed row and column totals and column restrictions generate null matrices with the same number of occurrences of sites per species  and the same number of species per stratigraphic formation  as observed in the original data. The algorithm of sequential change repeatedly rearranges the original matrix, changing the sub-matrices that preserve the row and column totals, and is not very inclined toward type I or type II errors In a structured assemblage, the mean numbers of units in a single block should be significantly higher than the score expected by chance, according to a null model 10 transformed) for each species was derived from data available in literature The EcoSim Module of Size Overlap was utilized to determine the presence of nonrandom patterns of body size overlapping among species Segment length was calculated by the ordination of size estimates of the different species. These values represent the differences in body size between two consecutive species. Utilizing the variance in segment length as the size overlap metric, the overall tendency for the observations can be measured. A structured assemblage would have an observed variance significantly smaller than that seen in random assemblages (pseudocommunities). When the minimum segment length values (in meters) are selected, the smallest segment of the assemblage can be calculated by measuring the difference between the closest pair of species. This measure determines whether a minimum space between species is necessary for their coexistence in an assemblage. Thus, in a structured assemblage, the minimum segment length should be significantly greater than that expected by chance A total of 23 species were recorded in fourteen fossiliferous strata ranging from the Lower Campanian to the Upper Maastrichtian in different localities in South America . In relaC-score index was 1.96, which did not differ significantly from the mean expected by chance , whereas Puertasaurus reuili was estimated to be 30 m long The species themselves showed great variability with respect to their estimated sizes. The fossil record points to the South American continent as having had a diverse assemblage of Titanosauria, and estimators of species richness indicate an even greater species richness during the Late Cretaceous (Early Campanian-Late Maastrichtian). This high species richness was possibly influenced by the availability and occupation of ecological niches left by the diplodocoids sauropods after their extinction in the Late Coniacian, resulting in a rich diversity of forms and sizes within the clade Titanosauria The species richness could also have been related to the structural complexity of the habitats occupied by titanosaurian assemblages during the Late Cretaceous. Dinosaurs that coexisted during the Late Jurassic exhibit close associations with the characteristics of environments in which they lived, indicating the occurrence of structural patterns in those assemblages The results obtained by co-occurrence analyses of species richness demonstrated that the observed numbers of checkerboard units did not differ from random. This pattern is consistent with the hypothesis that the local coexistence of Titanosauria species during the Campanian and Maastrichtian in South America was not structured by ecological factors existing during the Late Cretaceous, such as resource limitations in the environment, interspecific competition, or predator-prey relationships.The coexistence of species in an assemblage can be limited by ecological interactions known to be negative, such as interspecific competition for spatial and trophic niches, the occurrence of aggressiveness between individuals of the assemblage, species that develop specific preferences for certain types of habitats on a wide geographic scale, or predator-prey relationships Random patterns in coexistence of Titanosauria species during the Late Cretaceous could have originated not through competitive interactions between species but through the influence of species showing specificity for a particular habitat type on a reduced spatial scale, distributions restricted to a particular period, endemism, or low abundances of some species Another important issue regarding the lack of structure in South American titanosaurian assemblages is the fact that species records in any particular formation can be influenced by factors such as taphonomic processes, the types of sedimentary paleoenvironment, and sampling efforts in fossil collecting. This latter aspect will be influenced by the numbers of paleontological explorations in each stratigraphic formation and by the environmental conditions at the sites where the fossiliferous strata are found .Paleoecological studies should emphasize the importance of taphonomic processes for the different types of sedimentary paleoenvironments, since these factors can influence the fossil records of one or more species in stratigraphic formations. Diagenetic and biostratinomic processes, influenced by the nature of the sedimentary paleoenvironment at the site where the animal died (which can hinder fossilization) and the transport carcasses to different assemblages, will determine the number of specimens preserved in place and, consequently, estimated species richness The analysis of size-overlapping in this study indicated a lack of structure in the Titanosauria assemblage, suggesting that the sizes of these dinosaurs were not a determinant factor for species coexistence in time and space. The random patterns attributed to body size overlapping among vertebrates in general may be due to local extinctions, non-limited food availability, or reduced population sizes Ecological differences between sauropod lineages could also have been associated with certain morphological attributes, such as body size and differences in dentition, shape of the necks and cranial morphology Competitive interactions for food resources and habitat utilization in bird assemblages can become reduced through morphometric variations related to the size and shape of the beak, the length of metatarsus, or body size Another important aspect that should be taken into consideration concerns possible historical effects on South American titanosaurian assemblages that occurred during the Late Cretaceous. The preference for, and utilization of, particular resources by Titanosauria lineages could have been strongly influenced by the evolutionary histories of the different clades. Phylogenetic effects include important processes that will determine the ecologies of large numbers of species (as opposed to putative interactions between members of the assemblage in terms of the utilization of available resources), reflecting the evolutionary histories of different lineages that diverged over millions of years It is possible to conclude that the species richness of Titanosauria during the Late Cretaceous in South America was influenced by various ecological processes associated with the extinction events of various sauropods groups during this period and habitat structures that provided support for the maintenance of high species diversity in the assemblage. The observed patterns of co-occurrence and size overlapping suggest the existence of random processes and a lack of structuring in this assemblage. It is likely that these processes originated from phylogenetic inertia, associated with the occurrence of stabilizing selection, and that extinction events and historical factors had important roles in the formation of titanosaurian assemblages during the Late Cretaceous, more than did strictly ecological factors. Nonetheless, diagenetic and biostratinomic processes  can cause random species distribution patterns, making structuring of those undetectable.Table S1Species of Titanosauria recorded in the stratigraphic formations of the Late Cretaceous in South America. The number of recorded fossils (n) and whole information were obtained from the matrix of data available in the Paleobiology Database (DOC)Click here for additional data file.


The authors retract this publication due to concerns about the cell lines employed in the study.The study reports experiments looking at pathways involved in anoikis resistance in human adenoid cystic carcinoma; the experiments involved the use of the cell lines ACCM and ACC2. After the publication of the article, a reader raised concerns that these two cell lines may not originate from adenoid cystic carcinoma. The authors have completed a short tandem repeat analysis on the cell lines and this has revealed cross-contamination with other human cells, which compromises the relevance of the work to human adenoid cystic carcinoma, and thus the conclusions of the study.In the light of this, the authors retract this publication.


Toxicity caused by chemical mixtures has emerged as a significant challenge for toxicologists and risk assessors. Information on individual chemicals' modes of action is an important part of the hazard identification step. In this study, an automatic text mining-based tool was employed as a method to identify the carcinogenic modes of action of pesticides frequently found in fruit on the Swedish market. The current available scientific literature on the 26 most common pesticides found in apples and oranges was evaluated. The literature was classified according to a taxonomy that specifies the main type of scientific evidence used for determining carcinogenic properties of chemicals. The publication profiles of many pesticides were similar, containing evidence for both genotoxic and non-genotoxic modes of action, including effects such as oxidative stress, chromosomal changes and cell proliferation. We also found that 18 of the 26 pesticides studied here had previously caused tumors in at least one animal species, findings which support the mode of action data. This study shows how a text-mining tool could be used to identify carcinogenic modes of action for a group of chemicals in large quantities of text. This strategy could support the risk assessment process of chemical mixtures. Chemical risk assessment of mixtures is an important but challenging task for toxicologists. Unlimited variations of mixtures in our environment and knowledge gaps about toxic effects caused by chemical mixtures are examples of factors that make this process complex. Mixture effects can be described as caused either by additivity or interactions (such as synergistic or antagonistic effects) of the individual compounds  reports that the percentage of samples of fruits, vegetables and cereals with multiple residues increased by 11 percent from 1997 to 2007 (from 15 to 26 percent). In 2008, residues of two or more pesticides were found in 27 percent of the samples analyzed. The same proportion, 27 percent of samples containing multiple residues, was found in 2010. One sample of grapes was found to contain as many as 26 different pesticide residues   was gathered via a search (in August 2013) using the names of the pesticides. A computational tool, CRAB, was used to analyze the abstracts. The tool classifies PubMed abstracts automatically according to a MOA taxonomy. The MOA taxonomy captures the current understanding of processes leading to carcinogenesis and is based on two main categories: genotoxic and non-genotoxic MOA. The taxonomy is further structured into sub-categories according to a classification of Hattis et al.  are listed in Table We investigated the literature of human and animal Data from an analysis of apple and orange samples carried out in 2009–2010 was kindly provided by the Swedish NFA. Data shows that the majority of the tested apples and oranges contained several pesticide residues, 78 percent of the apple samples contained more than one pesticide and for orange samples this number was as high as 96 percent. The results thus show that two or more pesticide residues were freqently detected in apple and orange samples. For example, one apple sample contained residues of seven pesticides and in one orange sample 10 different pesticide residues were detected.Table The distribution of abstracts over the MOA taxonomy was analyzed in detail. The distribution of classified abstracts for the individual pesticides in apples and oranges is shown for 11 selected common MOA categories Figures . The disWe compared the MOA analysis by the CRAB tool with carcinogenic evidence and classifications for each pesticide Table . Common When all information on cancer classifications and published studies of the 26 pesticides was summed, it showed that the majority of the chemicals have evidence or classifications that suggest carcinogenic potential. The animal tumor data retrieved from published literature through PubMed shows evidence of carcinogenicity reported previously for 18 of 26 substances  for all pesticides permitted in food products intended for human consumption EFSA, . IndividThe CRAB tool has many advantages over manual literature analysis when large quantities of data need to be examined. The tool provides a rapid view of published literature and can point to carcinogenic MOA that groups of chemicals can have in common. We have previously conducted case studies to demonstrate how the text-mining tool can be used to support cancer risk assessment. For example, literature profiles of well-known carcinogens were compared with the known properties of each chemical and the classification results correlated well to what was previously known about these substances (Korhonen et al., Hazard identification and risk assessment of mixtures is a complex and challenging process. The study described here provides an example of how a text mining-based tool could support the analysis of large amounts of textual information to detect trends and patterns in data. A MOA analysis can identify common links between different chemicals which could serve as basis for hypothesis generation and direct further research and risk assessment of chemical mixtures.All authors were involved in the design of the study. Ilona Silins conducted the text mining experiments, analysis and the manual literature review. All authors contributed to the writing of the manuscript. All authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Spinal infections are an uncommon but significant clinical scenario that often requires aggressive medical therapy, sometimes leading to surgery . SurgerySiam et al.  report oThe authors stress the role of the superinfection of the local haematoma after surgery, and are convinced that the haematogenous route represents the main mechanism of infection of the adjacent disc. However, they also suggest that a direct infection of the adjacent disc space may occur by direct contamination during surgery because of the violation of the disc space by drilling or because of screw malpositioning .No role has been suggested by the authors for the use of titanium-based instrumentation, and in particular for the use of cages in these patients, even though their role in this surgery is still a major issue among surgeons. The use of metal implants in the infected spine has been avoided in the past because of the known adherence of bacteria to metal surfaces. However, experimental studies showed a variable bacterial adherence to different metal surfaces depending on biofilm formation and species. Titanium implants have been used in the setting of spinal infections, because these showed a reduced bacterial biofilm adherence; moreover, similar results and fusion rates were observed when titanium implants or bone grafts were used in surgery for spondylodiscitis .Of the eleven patients with positive microbiological findings described in the study, eight had a recurrence of the same microorganism with multiple antimicrobial drug resistance, and three had a superadded infection with another organism. The high recurrence of the same microorganism poses a question about the influence of the general health status of patients on the genesis of this disease . MoreoveTwelve out of the 23 patients in the study had no germs retrieved after cultural sample harvest, and the diagnosis of infection was made by clinical and radiological examinations. In orthopaedic surgery, a similar scenario is often observed in the case of suspected joint arthroplasty infections, and general guidelines have been implemented into clinical practice to improve the chances of isolating the responsible microorganisms ; however


The functions of the medial geniculate body (MGB) in normal hearing still remain somewhat enigmatic, in part due to the relatively unexplored properties of the non-lemniscal MGB nuclei. Indeed, the canonical view of the thalamus as a simple relay for transmitting ascending information to the cortex belies a role in higher-order forebrain processes. However, recent anatomical and physiological findings now suggest important information and affective processing roles for the non-primary auditory thalamic nuclei. The non-lemniscal nuclei send and receive feedforward and feedback projections among a wide constellation of midbrain, cortical, and limbic-related sites, which support potential conduits for auditory information flow to higher auditory cortical areas, mediators for transitioning among arousal states, and synchronizers of activity across expansive cortical territories. Considered here is a perspective on the putative and unresolved functional roles of the non-lemniscal nuclei of the MGB. The medial geniculate body (MGB) is the main thalamic nucleus associated with audition, receiving direct synaptic inputs from the inferior colliculus  receives topographically organized projections from the central nucleus of the IC and projects to tonotopically-organized areas of the auditory cortex , AI and AII, via layer 5 of AI to MGBd and then to layer 4 of AII  areas, such as AI and PAF  also tend to be greater than inter-group connections , although the magnitude of these inter-group connections seems greater in primates compared with cats (Hackett et al., However, rather than forming the basis of a strict prediction, one might better approach these conjectures as a framework for deciphering future physiological investigations to consider both the corticocortical and corticothalamocortical routes as potential neural substrates in auditory forebrain operations. The question then of utility of these two pathways in auditory forebrain operations might be better construed as one of degree, rather than that of hegemony.A caveat to this notion of the non-lemniscal MGB nuclei as conduits for information flow to higher auditory cortical areas is the medial division of the MGB. Unlike the nuclei of the dorsal division, the medial division does not appear to be a major nuclear target of the giant, driver-like corticothalamic projections that establish the first leg of the corticothalamocortical pathway Figure . FurtherInstead then, the prevailing notion for the medial division of the MGB considers it to be part of the matrix system of thalamic nuclei, proposed by Jones  in his cIn this regard, the connections of the medial division of the MGB with the limbic-related nuclei in the amygdala position it uniquely to alter auditory forebrain networks in affective and emotional responses to aversive stimuli Figure . The samOverall though, it is clear that the operations of the non-lemniscal medial and dorsal division nuclei of the MGB extend and enhance the operations of the auditory thalamus beyond that of a simple relay for acoustic information entering the auditory cortical network. The ultimate challenge for future investigations will be to specifically parse their interrelated roles in global auditory forebrain processes and the emergent construction of holistic auditory percepts.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The Hodgkin and Huxley 1952) model of action potential (AP) generation accounts for many properties of APs observed experimentally and has been successfully used in modeling neurons of different types. In this model, however, the spike onset is much shallower than in experimental recordings from the soma suggesting different activation properties of sodium channels in the real tissue. To explain the origin of the observed sharpness (kink) in the spike onset three hypotheses were proposed: 1. Cooperative hypothesis: sodium channels cooperate in the axon initial segment, which makes their collective activation curve much sharper 952 model.To find out what is truly happening in the cell during the action potential, we investigated the active backpropagation and compartmentalization hypotheses by means of computational modeling and theoretical analysis. In order to differentiate the hypotheses, we varied systematically the morphology of the neuron and distribution of the ionic channels along the cell, and tested how they contribute to the appearance of the kink. We show that the kink at spike onset is primarily due to compartmentalization rather than to active backpropagation.


Objective: Due to the development of medical education in the past decade the role of teachers has changed and requires higher didactic competence. Student evaluation of teaching alone does not lead to considerable improvement of teaching quality. We present the concept of "Integrative Teaching Consultation", which comprises both the teacher’s reflection and own objectives to improve their teaching as well as data from students ratings.Methods: Teachers in collaboration with a teaching consultant reflect on their teaching ability and set themselves improvement goals. Then the consultant himself observes a teaching session and subsequently analyses the respective student evaluation in order to give meaningful feedback to the teacher.Results: The combination of student feedback with professional consultation elements can initiate and maintain improvements in teaching. Conclusion: Teaching consultation complements existing faculty development programs and increases the benefit of student evaluations.  Th. Thshiftlearning . At the learning , 6]. Th. Thshiftlearning , even exlearning . As an essential part of faculty development programs, workshops and seminars have been designed to improve teacher effectiveness. While the literature describes successful programs, their long-term effect and the sustainability remain unclear . The traThe "Integrative Teaching Consultation" (ITC) is a team of pedagogues and psychologists headed by a medical doctor. The aim of the ITC is to combine SETs with counseling and professional feedback in order to enhance the ability of teachers to translate the SET feedback into concrete measures of teaching behavior. Evidence on teaching and learning and principles of effective consultative feedback are used during consultation. This includes active involvement of teachers in the counseling process, the use of teacher self-ratings and feedback from teaching observations . StudiesAt the Medical Faculty of Heidelberg all departments receive additional feedback from the ITC on the basis of SETs. Successful lecturers receive positive feedback on their key factors of success. Lecturers with less positive evaluation results receive didactical advice to improve their teaching, as well as an offer for teaching consultation. The goal of the ITC is to support the teachers individually in order to improve their teaching and to strengthen their ability of self-assessment , which were complemented by practical training sessions and tutorials. One of the lecturers sought the support of the ITC in order to aim to adapt and improve his lectures and tutorials. On the basis of his reflections, the feedback and the SETs, he implemented concrete changes in his lectures and tutorials: learning objectives were clearly defined and communicated to the students in order to enhance the transparency of content and success criteria. Application exercises related to practice were integrated into the seminars to stress the importance of certain learning objectives and to uncover possible queries of the learners during the lecture. At the same time the content of the lessons was reduced. Tutorials were adapted with the help of assistant tutors who had received good evaluations in the past. The entire counseling process including teaching observation, pre- and post-processing extended over a period of 18 months.To analyze the effectiveness of the consultation process, the free texts of the students relating to the didactic lecture and the tutorials were analyzed using the method of Mayring . The texThe results (see table 1 If SETs alone do not lead to considerable improvement of teaching quality, it should not be the centerpiece of quality assurance. Combined with feedback interventions, the effectiveness of SETs can be improved. Our findings suggest that consultation on the basis of student ratings is an effective method for enhancing the teaching effectiveness of university teachers.This is based on the prerequisite that a long-term support of lecturers and disciplines is possible. The close connection between faculty consultant, faculty development and the SETs seems to be important. The concept of ITC may also be applied to other faculties. For the improvement of teaching quality, a teaching consultation should be integrated into the quality management of medical universities. Future research should attempt to clarify, what changes can be expected and which factor of consultation is notably relevant for lecturers and the curriculum. The authors declare that they have no competing interests.


In the last decades, the focus of vascular research has been on acute vascular events. The acute coronary syndrome with its dramatic acute clinical manifestations was in the centre of this whirlwind. The focus was on atherosclerotic plaque located in the intima, stenosis, rupture, acute occlusion and the very successful therapeutic interventions. This has eclipsed the other manifestations of vascular disease: stiffening of the vessel wall and arteriosclerosis. This stiffening leads to diminished windkessel function of the elastic vessels, water hammer damage to sensitive tissues and dysfunction of sensors located in the vessel wall. The effects of this stiffening are in general not acute but manifest themselves in the long and probably very long term.Many slowly evolving vascular manifestations of disease such as dementia, lacunar cerebral infarctions, chronic limb ischaemia and chronic heart failure could be caused by these mechanisms. The stiffening of the vessel wall is due to a mixture of intima proliferation, fibrosing and calcification, which is mainly located in the media layer of the vessel wall.Although these two processes of atherosclerosis and arteriosclerosis seem to be separate, they can probably occur sequentially or simultaneously and it is feasible that these processes interact with each other.The arteriosclerotic process has been mainly investigated with the pulse wave velocity (PWV) technique in hypertensive populations . This ulIn this issue, Kroner et al.  use suchKroner et al. looked at the stiffness of the carotid artery from the level of the origin of the common carotid artery up to the level of the petrous channel and found that the thickness of the artery in this pathway nicely correlates with white matter lesions. Yet, there is excellent literature showing that the really important part of the internal carotid artery from the point of view of pulse wave modulation is the carotid syphon, located just beyond the petrous channel running in the cavernous sinus . StiffenAnd lastly, why is this information important when the general belief is that we cannot change the process of stiffening? It has indeed long been thought that stiffening of the vessel wall with fibrosis and calcification is an unavoidable inert end stage of ageing and certain arterial diseases. However, it is increasingly becoming clear that the calcification component of stiffening is an active metabolic process very much resembling bone formation. The process of bone formation can be halted or even reversed and experimental medication to reverse fibrosis in the form of angiotensin type 2 receptor agonists is becoming available too. With this therapeutic prospect and to protect both grey and white matter, more knowledge about arteriosclerosis is needed. That knowledge should encompass morphology, histology and function of the vessel wall.None.None declared.


Micro(mi)RNAs are small non-coding RNAs that play critical roles in physiological networks by regulating genetic programs. They are conserved from worms to mammals and function as negative regulators of protein-encoding gene expression. Research on the role of miRNAs in pathophysiological conditions is very active since 10 years and several works evidenced that miRNAs play a key role in the regulation of immunological functions and the prevention of autoimmunity. I will discuss the involvement of miRNAs in the regulation of innate and adaptive immune functions and in the development of autoimmune disease. Focusing on the role of few miRNAs, I will emphasize the intertwined relationships between tissue homeostasis and immunity, and on how studying miRNAs in autoimmunity and immune-mediated inflammatory disorders will shed light on pathological processes and help identifying novel drug candidates and biomarkers.None declared.


Ayurveda has a personalized approach on dietetics. Requirement of food intake is assessed on the basis of constitution in healthy individuals. In an ideal condition instinct of the subject is the indicator of bodies needs to compensate deficient dosha. Assessment of quality of food is made subjectively through six tastes, attributes, potency and metabolized taste. Ayurveda gives more importance in regulates the digestive power than correction of the calorie of food. According to the change in space and time dosha predominance varies. This warranted a consideration in choosing the right diet. Ayurveda emphasized the need of healthy mind for the proper nourishment of body. Various processing methods alter the attributes of food. Hence the assessment of food quality is to be made at the time of dining. Ayurveda warns against the complications of food-food interaction due to wrong combination of good materials. Unhealthy diet practice is considered as one of the important reasons of disease. Hence the correction of diet itself is considered as treatment.


The identification and annotation of protein-protein interactions (PPIs) is of great importance in systems biology. Big data produced from experimental or computational approaches allow not only the construction of large protein interaction maps but also expand our knowledge on how proteins build up molecular complexes to perform sophisticated tasks inside a cell. However, if we want to accurately understand the functionality of these complexes, we need to go beyond the simple identification of PPIs. We need to know when and where an interaction happens in the cell and also understand the flow of information through a protein interaction network.Another perspective of the research on PPI networks is the study of their relation to disease. In disease conditions, mutations that alter the secondary structure of one protein might perturb its PPIs, as well. Thereafter many things can go wrong via cascading effects, caused by the inter-relatedness of the mutated protein to other proteins through the PPI network. Such perturbations could block the formation of a protein complex or lead to the formation of new protein complexes and the activation of abnormal signaling pathways. These events could alter the cellular transcriptome profile and further contribute to disease pathogenesis. That is why the maintenance of the proper structure and functionality of a PPI network is crucial for cellular homeostasis. Its disruption can cause complex effects and understanding them requires advanced methods for analysis.The aim of this Research Topic is to present novel findings and recent achievements in the field of PPI networks. Thematically, it is divided into two parts. First, we present methods for the identification and quantification of PPIs; second, we describe computational approaches to annotate interactomes and extract information related to disease prediction or disease progression.Suter et al. describe the application of next generation sequencing (NGS) for the characterization of binary PPIs. Authors present an accurate method to analyze yeast two-hybrid data by NGS and also interpret interaction data via quantitative statistics. They also discuss how this methodology can be used to discover differential PPIs allowing the identification of disease mechanisms .The first four articles deal with the identification and quantification of PPIs. In the first work, Yang et al. present methods that can determine the relative abundance of purified proteins in a sample enabling the identification of transient PPIs in different conditions. Additionally, when combined with proximity tagging methods, MS may illuminate spatial or temporal PPIs, especially those of signaling pathways whose perturbation may underlie human diseases . Meyer and Selbach indicate how MS can be used to identify dynamic changes in the interactome. Stable isotope labeling in aminoacids and affinity purification-MS can shed light on the dynamic behavior of proteins even at different stages of an experiment following perturbation. Authors also describe how MS may identify the stoichiometry of proteins in complexes. These methodologies can be employed to study the dynamic changes of PPIs under normal and disease conditions (Meyer and Selbach).The next two review articles describe mass spectrometry (MS) based approaches. Buntru et al. review novel cell-based assays for the detection of PPIs and discuss their strengths and weaknesses. Compared to traditional genetic or biochemical methods, these techniques provide quantitative information of PPIs even in the context of living cells. This information can be used to prioritize a large number of PPIs, allowing researchers to better describe the biological systems and improve our understanding of disease processes .In the next article, Alanis-Lobato describes computational mining tools to improve the reliability of protein networks and predict new interactions based on the topological characteristics of their components. He also provides examples on how the integration of clinical data can highlight disease modules in these networks or indicate similarities between diseases (Alanis-Lobato).The second part of the Research Topic is comprised of seven papers dealing with the annotation of protein interaction networks. Pelassa and Fiumara study the functional role of homopolymeric amino acid repeats (AARs) in proteins and their PPIs. AARs are considered to mediate PPIs and in some cases correlate with human diseases, such as polyglutamine expansions involved in Huntington's disease. The authors describe a computational screening of the human interactome and show that AAR-containing network components have a high degree of connectivity. They also indicate an overlap between AARs and interaction domains suggesting that AARs play an important role in shaping protein interaction networks (Pelassa and Fiumara).Lecca and Re present WG-Cluster, a novel algorithm for the detection of modular structures in protein networks. This tool combines network node and edge weight information of connected proteins improving the biological interpretability of a PPI. The authors also apply their technique in biological datasets from patients with colorectal cancer and indicate differentially active cellular processes in normal vs. tumor conditions (Lecca and Re).Chen et al.).In the next article, Chen and colleagues use the dynamical network biomarkers method to detect early disease signals in a breast cancer cell model. The authors pinpoint critical network changes and highlight a number of pathways associated with the pre-transition from the normal state to a cancer cell progression stage. They also suggest the use of these signals as targets for disease intervention .Theofilatos et al. argue about the challenges of computational analysis of PPI data and present future goals such as biomarker discovery or identification of pathogenic PPIs and their drug targeting. Authors also support that the integration of environmental or clinical data in protein networks will allow their in-depth study and the construction of personalized interactomes .In the last article of this topic, In the past decade, network biology focused on the representation of the binary interaction of proteins. Today, the field of PPI research capitalizes and hops above the establishment of such previous work and resources, identifies existing limitations, and proposes further avenues of investigation, as reflected in this Frontiers Research Topic. A tight connection between experimental and computational efforts is a hallmark of the articles that we present here, which set the tone that PPI research will follow in the next years. If anything remains unchanged, this is our awareness of the fact that diseases are often caused by the malfunction of large protein complexes. This holds as the main motivation of research in the field, which screams for more complete and reliable interactomes, ultimately crucial in order to identify relevant pathogenic mechanisms and design therapeutic intervention strategies.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.


Nucleosomes are the basic structural units of chromatin. Most of the yeast genome is organized in a pattern of positioned nucleosomes that is stably maintained under a wide range of physiological conditions. In this work, we have searched for sequence determinants associated with positioned nucleosomes in four species of fission and budding yeasts. We show that mononucleosomal DNA follows a highly structured base composition pattern, which differs among species despite the high degree of histone conservation. These nucleosomal signatures are present in transcribed and non-transcribed regions across the genome. In the case of open reading frames, they correctly predict the relative distribution of codons on mononucleosomal DNA, and they also determine a periodicity in the average distribution of amino acids along the proteins. These results establish a direct and species-specific connection between the position of each codon around the histone octamer and protein composition.


During brain development the neural stem cells are regulated by both intrinsic and extrinsic sources. One site of origin of extrinsic regulation is the developing choroid plexuses, primely situated inside the cerebral ventricles. The choroid plexuses are very active in terms of both secretion and barrier function as soon as they appear during development and control the production and contents of cerebrospinal fluid (CSF). This suggests that regulated secretion of signaling molecules from the choroid plexuses into CSF can regulate neural stem cell behavior (as they are in direct contact with CSF) and thereby neurogenesis and brain development. Here, choroid plexus development, particularly with regards to molecular regulation and specification, is reviewed. This is followed by a review and discussion of the role of the developing choroid plexuses in brain development. In particular, recent evidence suggests a region-specific reciprocal regulation between choroid plexuses and the neural stem cells. This is accomplished by site-specific secretion of signaling molecules from the different choroid plexuses into CSF, as well as brain region specific competence of the neural stem cells to respond to the signaling molecules present in CSF. In conclusion, although in its infancy, the field of choroid plexus regulation of neurogenesis has already and will likely continue to shed new light on our understanding of the control and fine-tuning of overall brain development. Neurogenesis, both in the adult and during development, occurs in a specialized environment established by both the neurogenic  and non-neurogenic cells within the neurogenic area, and from cells and compartments in direct contact with the niche  lining the ventricle . The processes of the NSCs span the entire thickness of the cortical wall and their nuclei move up and down in the ventricular zone (VZ) during the cell cycle  but they stay in contact with the ventricle via the apical process and the cilium responsive to elements present in CSF through-out the cell cycle. The NSCs divide and give rise to the next cells in the differentiation cascade, the transient amplifying cells, TAPs (yellow cells) or neurons (green cells). The TAPs are a heterogeneous population and vary in their morphology, location and abundance  are derived from plasma and are transferred across the choroid plexus epithelium by a subset of choroid plexus epithelial cells in a highly specific and regulated manner  and alterations in developmental neurogenesis  choroid plexus Figure . The choIn the adult, the choroid plexuses and CSF have several know functions such as: (i) protecting and regulating the internal environment of the brain via the blood-CSF barrier; (ii) secretion and modulation of CSF through the activity of the choroid plexus epithelial cells; and (iii) waste and metabolite removal, via the “CSF sink,” through the continuous production and then removal of CSF into peripheral circulation. During development two out of these three functions are already performed by the choroid plexuses; protection of the brain via the blood-CSF barrier and regulation of CSF composition via specific and regulated transfer and secretion (see more below). However, due to the lack of CSF reabsorption during embryogenesis, the removal of waste and metabolites does not occur . Ttr is known as the choroid plexus marker and is expressed in the mouse lateral ventricular choroid plexus from E11  choroid plexus has also been described  the choroid plexus was reduced in size but Cajal-Retzius cells were increased in number , resulting in a transient doubling of the size of the lateral ventricles  free passage of water and solutes between the cells has to be inhibited via the presence of tight-junctions , (ii) the capacity of water transport across the cells , and (iii) the presence of transporters and exchangers that can create an ionic or osmotic gradient that drives water across the epithelium. These criteria are of course all met in the adult choroid plexus via the presence of the blood-CSF barrier, the presence of the water channel AQP1 and the creation of ion gradients between blood and CSF via a multitude of ion transporters and exchangers  creates a pressure inside the cerebral ventricles. The requirement of this pressure for normal brain development was shown by a study in chick embryos (Stage18), where the intraventricular pressure was removed via insertion of hollow tubes into the ventricular system  or via changes in the secretion of molecules produced by the choroid plexuses themselves Figure . In the in vitro experiments. Here it was shown that isolated cortical cells can be maintained on embryonic CSF alone .The choroid plexuses appear whilst neurogenesis is occurring through-out the nervous system. This gives the potential for the choroid plexuses (via their modulation of CSF) to alter the behavior of the neural stem cells along the neuroaxis Figure , Box 1. With the advancement of region and time specific deletion techniques new strategies to isolate choroid plexuses involvement in neurogenesis are available. Along these lines, some recent work has demonstrated, via choroid plexus specific deletions, that molecules expressed in the choroid plexus have the capability to influence brain development at other sites. This was first achieved by deletion of Shh from the hindbrain choroid plexus (using the Wnt1-Cre), resulting in a more than 50% decrease in the proliferation of the neural stem cells in the nearby cerebellum and impaired GABAergic progenitor expansion  it not only significantly altered the size of the choroid plexus but also the relative expression of many secreted signaling molecules . We suggest that select tissues are prepared for certain signaling molecules, by the expression of not only receptors but also by the expression of modulators and inhibitors of the different signaling pathways. Thus, neurogenesis can be seen as a reciprocal process between the choroid plexus and the neural stem cells mediated via the CSF Figure .In conclusion, there is substantial evidence that there is indeed a role played by the choroid plexus-CSF-signaling axis in the modulation of developmental neurogenesis. However, much more remains to be discovered. The specific mechanisms by which the choroid plexuses modulate brain development both in terms of the choroid plexuses as whole organs as well as specific aspects of their functions  needs to be investigated. Further detailed studies of choroid plexus impact on different brain regions and developmental time-points would increase our understanding of the whole process of brain development. Understanding the role of the choroid plexus-CSF signaling axis and its impact on brain development can also lead to novel routes and mechanisms for treatment approaches for a multitude of developmental disorders and in the long-run also for application to adult neurodegeneration and brain injuries.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The hypothalamus is the higher neuroendocrine center of the brain and therefore possesses numerous intrinsic axonal connections and is connected by afferent and efferent fiber systems with other brain structures. These projection systems have been described in detail in the adult but data on their early development is sparse. Here I review studies of the time schedule and features of the development of the major hypothalamic axonal systems. In general, anterograde tracing experiments have been used to analyze short distance projections from the arcuate and anteroventral periventricular nuclei (Pe), while hypothalamic projections to the posterior and intermediate pituitary lobes (IL) and median eminence, mammillary body tracts and reciprocal septohypothalamic connections have been described with retrograde tracing. The available data demonstrate that hypothalamic connections develop with a high degree of spatial and temporal specificity, innervating each target with a unique developmental schedule which in many cases can be correlated with the functional maturity of the projection system. The hypothalamus is an important structure of the brain positioned as a higher part of the vegetative nervous system and a part of the limbic system. It is involved in realization of numerous neuroendocrine, endocrine, somatomotor and behavioral functions which help an organism to survive and adopt to the environment Swanson, . The bacCarbocianine dye tracing was introduced for studies of the brain connections since first works of Honig and Hume , 1989 anThe small dimensions of the hypothalamic nuclei at early developmental stages require very precise application of the marker, sometimes even single crystals of appropriate size were used  sections are the most appropriate for the analysis of DiI tracing results using conventional or confocal fluorescence microscopy. Frozen sections can not be recommended for the DiI tracing because of the fast lateral diffusion of the marker from the axon in any type of the mounting medium. This can be overcome only by mounting and drying cryocut sections without coverslipping  of the thalamus, the parvicellular division of the hypothalamic PV, the subparaventricular zone, the dorsomedial nucleus of the hypothalamus, the ventral lateral septum, the intergeniculate leaflet, the bed nucleus of the stria terminalis) on the first postnatal day (P1) with significant increase on P2–P3  and P10 in male rats but not in females although projections from the bed nucleus of stria terminalis (BSTp) to the preoptic region were revealed earlier on P4–P7 both in males and females  transported by their axons to the posterior pituitary   and arcuate hypothalamic nuclei in adult mammals . It is formed by collaterals of the MTeg as has been shown in adult rats with double tracer injections Mammillary body projections to the tegmentum Projections of parvicellular hypothalamic neurons  to the median eminenceProjections of magnocellular hypothalamic neurons (SO and PV) to the PL and median eminenceLateral septal projections to the preoptic areaProjections starting late prenatally and differentiating postnatallyProjections of accessory retrochiasmatic nucleus to the PLMammillary body projections to the anterior thalamic nuclei Projections from the tegmental nuclei to the mammillary body (mammillary peduncle)Projections of the accessory hypothalamic nuclei  to the posterior pituitaryProjections of the parvicellular hypothalamic neurons  to the ILProjections of anteroventral Pe to GNRH neurons around OVLTProjections developing postnatallyArcuate nucleus projections to the hypothalamic nuclei Arcuate nucleus projections to the BSTp and lateral septal nucleusProjections of anteroventral Pe to the BSTp, lateral septal nucleus and parvicellular PVSuprachiasmatic nucleus projections to the hypothalamic nuclei, lateral geniculate nuclei, BSTp and lateral septal nucleusGnRH neurons projections to the mediobasal hypothalamusProjections of the BSTp to anteroventral Pe and medial preoptic nucleusRetinal projections to the suprachiasmatic nucleusIt can be useful to distinguish three groups of hypothalamic projection systems according to the period of their formationThe 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.


Dear EditorThe recent paper on the methadone- and buprenorphine- related testicular toxicity  adds a dThe study is also consistent with the known interdependence of the germinal centres of the testis with the surrounding Sertoli cells, and the interdependence of the cellular elements with the basement membrane and vasculature. Therefore this highly provocative careful histolopathological study invites further careful mechanistic investigations. One also notes many reports of buprenorphine abuse. A comment from the authors on the very differing doses used in their rats from those usually employed clinically, would have been of interest.


The initial discovery of resistin and resistin-like molecules (RELMs) in rodents suggested a role for these adipocytokines in molecular linkage of obesity, Type 2 Diabetes mellitus and metabolic syndrome. Since then, it became apparent that the story of resistin and RELMs was very much of mice and men. The putative role of this adipokine family evolved from that of a conveyor of insulin resistance in rodents to instigator of inflammatory processes in humans. Structural dissimilarity, variance in distribution profiles and a lack of corroborating evidence for functional similarities separate the biological functions of resistin in humans from that of rodents. Although present in gross visceral fat deposits in humans, resistin is a component of inflammation, being released from infiltrating white blood cells of the sub-clinical chronic low grade inflammatory response accompanying obesity, rather than from the adipocyte itself. This led researchers to further explore the functions of the resistin family of proteins in inflammatory-related conditions such as atherosclerosis, as well as in cancers such as endometrial and gastric cancers. Although elevated levels of resistin have been found in these conditions, whether it is causative or as a result of these conditions still remains to be determined. Obesity is increasing worldwide at such an alarming rate that is has been classified as an epidemic . With thVisceral fat accumulation, or white adipose tissue, has been implicated as important risk factors not only for the development of type 2 Diabetes mellitus , but alsHere, we review the dissimilarity between rodent and human forms of resistin, and demonstrate how the function of resistin differs in rodent and human counterparts. We present the differences between both human and rodent resistin. We summarize the current knowledge of the signaling of resistin in humans, as well as the current hypotheses of the potential role of resistin in humans.White adipose tissue, one of the two types of adipose tissue found in mammals may represent the largest endocrine tissue of humans . ClassicA high percentage of genes expressed within visceral adipose tissue, about 30 %, are attributed to secretory proteins . The secIn lean individuals, white adipose tissue (WAT) storage of triglycerides is systematically regulated, controlling the release of anti-inflammatory cytokines such as Adiponectin , TransfoThe shift in cellular composition surrounding WAT sees a shift in the balance of anti-inflammatory macrophages (M2 phenotype) to pro-inflammatory macrophages (M1 phenotype)  ).The story of the resistin family of adipokines is very much of mice and men. Vast differences exist between these adipokine families across species in relation to existence, expression and tissue specificity. The lack of homology between human and rodent families of resistin adds to the intrigue of this family of cytokines.The physiological role of resistin and RELMβ in the pathogenesis of human disease remains to be determined, and leaves several questions unanswered. What is known is that elevated levels of both resistin and RELMβ are found in certain inflammatory-based disease states. Whether elevation of these adipokines is a cause or a consequence of the disease still remains to be determined. What causes its elevation if determined to be causative of an inflammatory condition? What is the effect of their elevation if found to be consequential to an inflammatory condition?The determination of a signalling cascade for both resistin and RELMβ should shed some light on the understanding of the role of these adipokines in human disease. Determination of the mechanisms of control of expression of these adipokines as well as determination of the functional receptor and effects on target cells would add invaluable insight into the biological role of these adipokines, in normal and pathological states.


Aim The aim of this study was to identify the communication methods and production techniques used by dentists and dental technicians for the fabrication of fixed prostheses within the UK from the dental technicians' perspective. This second paper reports on the production techniques utilised.Materials and methods Seven hundred and eighty-two online questionnaires were distributed to the Dental Laboratories Association membership and included a broad range of topics, such as demographics, impression disinfection and suitability, and various production techniques. Settings were managed in order to ensure anonymity of respondents. Statistical analysis was undertaken to test the influence of various demographic variables such as the source of information, the location, and the size of the dental laboratory.Results The number of completed responses totalled 248 (32% response rate). Ninety percent of the respondents were based in England and the majority of dental laboratories were categorised as small sized (working with up to 25 dentists). Concerns were raised regarding inadequate disinfection protocols between dentists and dental laboratories and the poor quality of master impressions. Full arch plastic trays were the most popular impression tray used by dentists in the fabrication of crowns (61%) and bridgework (68%). The majority (89%) of jaw registration records were considered inaccurate. Forty-four percent of dental laboratories preferred using semi-adjustable articulators. Axial and occlusal under-preparation of abutment teeth was reported as an issue in about 25% of cases. Base metal alloy was the most (52%) commonly used alloy material. Metal-ceramic crowns were the most popular choice for anterior (69%) and posterior (70%) cases. The various factors considered did not have any statistically significant effect on the answers provided. The only notable exception was the fact that more methods of communicating the size and shape of crowns were utilised for large laboratories.Conclusion This study suggests that there are continuing issues in the production techniques utilised between dentists and dental laboratories. Principles of dental team workingProsthodontics is a discipline that requires a synergy between the dentist and dental technician, in order to fabricate intraoral prostheses with acceptable fit, function and aesthetics.12However, a number of studies6789101112678910111213The first five years: a framework for undergraduate dental education.17Undergraduate training should theoretically prepare dentists with the required knowledge to provide fixed prostheses in a safe and predictable manner. However, a number of studies121The purpose of this cross-sectional study was to identify the communication methods and production techniques used by dentists and dental technicians for the fabrication of fixed prostheses within the UK from the dental technicians' perspective. Part one of this cross-sectional survey reported on the communication issues between dentists and dental laboratories.The details regarding materials and methods have been published in the first paper.The Dental Laboratories Association  was approached and approved the use of their database of e-mail contacts (782 addresses). A web-based survey tool, Opinio , was utilised for the administration of the survey and assimilation of data. Settings were managed in order to ensure anonymity of respondents.The data collected was presented as descriptive statistics and analysed using Fisher's exact test, the Mann-Whitney test or the Spearman's rank correlation . P-values of less than 0.025 were regarded as statistically significant. A significance level of 2.5% was chosen rather than the conventional 5% to avoid spuriously significant results arising from multiple testing.The null hypothesis was that factors such as the source of information used to answer the questionnaire, the location, and size of the dental laboratory, did not influence the communication methods and production techniques.The number of responses totalled 248, which yielded a 32% response rate. Sixty-eight respondents answered only some of the questions. The results presented in this paper pertain to the subchapters of general information, disinfection and suitability of impressions and production techniques. The subchapters and questions along with the results in parentheses are depicted in The results of the general information subchapter have been published in part one,The results of this study showed that a significant number of respondents (52%) considered that less than half of the impressions received from the dentist were clearly labelled as having been disinfected. Sixty-five percent of dental laboratories indicated that they routinely disinfected the impressions received from the dentist before pouring them up.The most popular impression tray used in the fabrication of crowns and bridgework was the full arch plastic tray, which was used in 61% and 69% of cases respectively. Custom made trays were only used in 10% of cases and quadrant plastic trays were the least popular. A significant number of respondents (17%) considered that the majority of final master impressions received were of poor quality and inadequate to use for a varied number of reasons including air voids, defects at the preparation margin and deformation of the impression material.The aforementioned results, pertaining to the disinfection and suitability of impressions, were not influenced by the size of the laboratory or the source of information with the exception of the responses about the inadequacy of the master impressions (p = 0.03), which suggested that the proportion of inadequate impressions was greater in the records group than the memory group.Regarding the adequacy of tooth preparations, the results of this study showed that, on average, 18% of respondents considered that they routinely received tooth preparations where there had been inadequate bucco-lingual tooth reduction. The analysis showed that the percentage was statistically (p = 0.01) higher (28%) in the records group compared to the memory group. With respect to occlusal tooth reduction, 26% indicated that they frequently encountered tooth preparations with insufficient reduction.The semi-adjustable articulator was the most frequently used (44%) in the fabrication of fixed prostheses followed by the simple hinge type (28%). This survey indicated that only 11% of the dental laboratories perceived that the majority of inter-occlusal records were accurate.The majority of respondents (68%) reported that they rarely received any particular guide, such as a diagnostic wax-up, or impressions from provisional restorations, in order to communicate the shape and size of the definitive restoration. Written instructions were the most widely used means of communicating the size and shape of crowns, and were often supplemented with photographs, drawings, or the use of diagnostic wax-ups . The staThe study also showed that dental technicians often had to decide on the type of material and the surface on which to use the material, as it had not been accurately prescribed by the dentist. Almost a quarter (24%) of dental technicians had to routinely choose both for the materials to be used for the fixed prostheses as well as the particular surfaces that needed to be covered with an aesthetic veneering material.For the fabrication of fixed prostheses, base metal alloys (52%) were the most commonly used, with high gold content alloys only used in 8% of cases .The most commonly requested combination of materials for the construction of both anterior and posterior crowns was metal-ceramic (69% and 71% respectively). All-ceramic crowns accounted for 29% of anterior cases and only 8% of posterior crowns. Metal-only posterior crowns were only used in 19% of situations. No significant statistical observations were noticed for the aforementioned results.This cross-sectional survey was undertaken to identify the communication and production techniques used by dentists and dental technicians for the fabrication of fixed prostheses within the UK from the dental technicians' perspective. The current publication reports on the production techniques used. The response rate of 32% was similar to previously published surveys101112613Personal bias may have affected the accuracy of the results as the majority of the information used to answer the survey questions was sourced from memory. Dental technicians could have exaggerated the extent of poor impression disinfection and suitability of the impressions, as well as potential issues in production techniques. Nevertheless, the statistical analysis showed that the source of the information did not play a significant role.The results of this study showed that a significant number of dental laboratories were receiving impressions from dentists that were not clearly labelled as having been disinfected. It was also shown that 65% of laboratories would routinely disinfect the impressions on their arrival. It seems that there is a lack of agreement between dentists and laboratories regarding decontamination and disinfection of dental impressions, even though clear guidelines have been made available via the British Dental Association.222324Full-arch plastic trays were the most frequently used impression trays for the fabrication of crowns and bridgework, and this confirms previous findings.611262729A concerning finding of this survey was that a high proportion of final master impressions were considered as inadequate for use by the dental technician. Most troublesome was the fact that the majority of the inadequate impressions presented with a combination of problems. Similar results regarding the frequency and aetiology of inadequate definitive impressions have been reported in previous studies711213233The lack of sufficient tooth preparation presents the dental technician with the difficult task of fabricating a crown or bridge with adequate form and aesthetics.113637To date there has been no research data on the use of articulators and occlusal records within commercial dental laboratories the UK. This particular survey showed that the semi-adjustable articulator was favoured in the fabrication of fixed crown and bridgework, being used 44% of the time. This type of articulator is also preferred in dental schools in the UK40The results of this study also showed that, in the majority of cases (68%), no guides were provided by the dentists for the fabrication of definitive prostheses. In cases that it happened, it was usually in the form of written instructions or photographs. Guides, such as the diagnostic wax-up, a copy of the provisional crowns, and occlusal aids, such as a custom incisal guide table should be provided by dentists.This survey concurs with previous ones6254The increasing cost of gold was reflected in the popular use (52%) of base metal alloys for crown and bridgework. This has also been a trend in other countries,74446There is still an apparent lack of protocol in the disinfection of impressions between the dentists and laboratories, thus creating a potential health riskPlastic full arch trays were the dentists' preferred choice of impression tray for recording master impressionsDentists frequently sent master impressions to the laboratory, which are not appropriate for the fabrication of fixed prosthesesMore use of diagnostic wax-ups and reduction guides to ensure adequate tooth removal should be used by dentistsThe dental technicians in the main did not trust the authenticity of the occlusal relationship records providedDentists frequently failed to prescribe the material to be used or the design of the prosthesis, incorrectly leaving the decision to the dental technicianMetal-ceramic crowns were still the most popular choice for both anterior and posterior units.Within the limitations of this UK based study, the following conclusions could be drawn:


Luteinizing hormone-releasing hormone (LHRH) neurons and fibers are located in the anteroventral hypothalamus, specifically in the preoptic medial area and the organum vasculosum of the lamina terminalis. Most luteinizing hormone-releasing hormone neurons project to the median eminence where they are secreted in the pituitary portal system in order to control the release of gonadotropin. The aim of this study is to provide, using immunohistochemistry and female brain rats, a new description of the luteinizing hormone-releasing hormone fibers and neuron localization in the anterior hypothalamus. The greatest amount of the LHRH immunoreactive material was found in the organum vasculosum of the lamina terminalis that is located around the anterior region of the third ventricle. The intensity of the reaction of LHRH immunoreactive material decreases from cephalic to caudal localization; therefore, the greatest immunoreaction is in the organum vasculosum of the lamina terminalis, followed by the dorsomedial preoptic area, the ventromedial preoptic area, and finally the ventrolateral medial preoptic area, and in fibers surrounding the suprachiasmatic nucleus and subependymal layer on the floor of the third ventricle where the least amount immunoreactive material is found. The luteinizing hormone-releasing hormone (LHRH) is a gonadotropin releasing hormone (GnRH), which acts on the pituitary hormones as a follicle stimulating hormone (FSH) and luteinizing hormone (LH), which act on the gonads, . The GnRThe preoptic area (PA) is part of the anterior hypothalamus and is confined to the anteroventral region of the third ventricle (AV3V); the PA is divided into, the medial preoptic area (MPA) and lateral preoptic area (LPA). The MPA makes its morphological appearance at eight weeks of gestation in humans and is located in the periventricular regions of the anterior hypothalamus covering the organum vasculosum of the lamina terminalis (OVLT) , 10. TheThe OVLT , 19 beloBrains from five female Wistar rats from Charles River Laboratories España S.A.  of 6 months of age were used. Rats were kept under lighting conditions of 12:12, and food and water were provided ad libitum. Rats were sacrificed at diestrus stage , and bef The sections of five coronal cephalocaudal anatomical levels of the anterior hypothalamus  were simThe immunohistochemistry slides were converted to digital images by using an LEICA DMRB photomicroscope with an LEICA DC 300 F camera (Germany). Image analysis was completed by ImageJ . The “mean gray value” was measured from the selected areas for all stained tissue. This value gives the average stain intensity in grayscale units for all threshold pixels. The immunohistochemistry statistical study was conducted using the IBM SPSS statistic 19 software (one-way ANOVA).Many LHRH fibers and neurons were found in different parts of the preoptic hypothalamus; the neurons presented a monopolar or bipolar morphology; the dendrites were uncomplicated, without branches and roofed with spines Figures . The distribution of LHRH cells and fibers is described with the use of the Paxinos and Watson atlas of the rat , the Paxa  till the level d, where the smallest amount of immunoreactive material was found  was found in the OVLT at the level as found .  The findings here agree with morphological studies which report that the GnRH neurons have long and simple uni- or bipolar dendrites typically covered in spines , 32. The In view of the prevailing significance of the GnRH neurons, it is necessary to know their anatomical localization to fully understand their structure and function in general, specifically in the sexual dimorphism. At the same time, it is unclear whether the medial preoptic area is a diencephalic or a telencephalic structure because the MPA is located in the anterobasal forebrain or prosencephalon during the early stages of its development. But in the following stages, when the diencephalon and telencephalon develop and differentiate from the prosencephalon, the preoptic area is anatomically localized in the anterior hypothalamus , 11, altc and d , and therefore, this is the terminology used in this study. Positive LHRH cells and fibers located in different parts of MPA and in OVLT such as dorsomedial preoptic area (DMPA), Figures  Figures , would cIn view of that described above, one could conclude that the exact denomination of the LHRH localization is peculiar; however, one could say that the greatest amount of LHRH immunoreactive material (LHRH-ir) was found in the OVLT and decreased cephalocaudally in the preoptic hypothalamus. LHRH immunoreactive material was found in the following parts: dorsomedial preoptic area, ventromedial preoptic area, and ventrolateral medial preoptic area, and in fibers surrounding the suprachiasmatic nucleus and subependymal layer on the floor of the third ventricle where the least amount of LHRH fibers and neurons was found.


Chronic migraine represents the most disabling condition among headaches, in particular when migraine is associated with drug abuse.Patients with chronic migraine (CM) coming to our centres are difficult to treat, both because of their refractory to antimigraine prophylactic treatment and for the combination of several comorbidities, that often need a multidisciplinary approach that leads to a multi-prescription of drugs.®) is an important therapeutic option both for its efficacy in the long term, and for the safety profile, due to the lack of clinically significant side effects.The treatment with OnabotulinumtoxinA (BotoxIn our Headache Centre we performed a retrospective study including a sample of 67 patients with a diagnosis of CM associated with drug abuse according to the ICHD-III (beta) classification. The patients were treated with OnabotulinumtoxinA according to the paradigm of the PREEMPT study (155 U to 31 injection sites) [The purpose of our study was to evaluate the duration of the Botox's efficacy in terms of headache days (HD), analgesic consumption (AC) and to assess the patients’ quality of life by some self-administered scales  and pain scale (VAS) .We recorded medical charts for 67 patients. However, we report the data concerning the results of only 57 patients since they represent the ones who were injected regularly every 3 months without interruption, some of them being injected up to cycle 7. Ten patients discontinued for regulatory reasons.Positive trend of the effectiveness of the treatment appears to be significant in all parameters evaluated as shown in the table This retrospective study confirms the safety and tolerability profile of repeated treatment with OnabotulinumtoxinA and shows a good consistency of the therapeutic effect over one year of treatment. The trend of the clinical parameters suggests other studies to further investigate the long-term efficacy of the treatment, as recently suggested by Pascual .Moreover, it is important to outline that in our sample we did not register any clinically relevant side effect, besides slight pain in the site of injection, and two cases of transient hypotension during the injection protocol, spontaneously reversed.Written informed consent to publish was obtained from the patient(s).


We propose some objective points which could enhance the internal validity of the study ( We have read the article entitled “Prevalence of marijuana use among university students in Bolivia, Colombia, Ecuador and Peru” with great interest . In factThere have been previous studies concerning the evolution of legal and illegal drug use in the United States ,3 and oti.e., those who did not participate). We would also recommend presenting weighted and unweighted estimates [Therefore, we suggest the authors present the participation proportion of each of the surveys to assess the internal validity of the study, and thus evaluate the potential selection bias in relation to the population not involved in the study (stimates .We suggest reporting the participation proportion for each survey and to present weighted and unweighted estimates.


In the recently published review article by Jagmag et al. , some cuThe pathological hallmark of PD involves the progressive loss of neurons in the substantia nigra pars compacta (SNpc) . Reserpine model was one of the first models to investigate the pathophysiology and to demonstrate the therapeutic efficacy of L-DOPA, which remains the gold-standard treatment for PD (Carlsson et al., Our research group has proposed that repeated administration of low doses of reserpine can mimic the progressive nature of PD (Santos et al., All authors participated in the preparation and discussion of the commentary. Designed and organized the illustration: AG.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.


In the Results section of the Abstract, the last sentence contains a typo. The sentence should read as the following: In contrast, the risk of typhoid fever did not vary geographically or with elevation among individuals more than ten years of age.


Vocal cord paralysis (VCP) can be caused by any process that interferes with the normal function of the vagal nerves or recurrent laryngeal nerves. It may be a first sign of extensive and severe pathology. Radiologists must therefore be able to recognise the imaging findings of VCP and know the course of the vagal and recurrent laryngeal nerves. This review focuses on the anatomy and imaging evaluation of these nerves and thereby the possible sites for pathology causing VCP. The imaging characteristics and imaging mimics of VCP are discussed and cases from daily practice illustrating causes of VCP are presented.Vocal cord paralysis may be the first presentation of severe pathology.• Radiologists must be aware of imaging characteristics and mimics of vocal cord paralysis.• Lesions along the vagal nerves and recurrent laryngeal nerves can cause vocal cord paralysis.•  The vocal cords play a crucial role in phonation. The muscles that are responsible for vocal cord movement are mainly innervated by the recurrent laryngeal nerves. The recurrent laryngeal nerves are branches of the vagal nerves. Vocal cord paralysis (VCP) can therefore be caused by any lesion along the course of the vagal nerves above the branching of the recurrent laryngeal nerves or of the recurrent laryngeal nerves itself. An offending lesion located in the brainstem or the skull base usually results in multiple cranial nerve deficits because at this level the vagal nerve is intimately related to other cranial nerves. Pathology involving the recurrent laryngeal nerves and/or the extracranial vagal nerves frequently results in isolated laryngeal symptoms. VCP most frequently affects one side but can be bilateral. Due to long anatomical course of the vagal and recurrent laryngeal nerves, there are many disease processes that can cause VCP. Surgery, malignancy, trauma, infection and inflammation can all result in VCP. A review of more than 800 patients showed that iatrogenic injury by mediastinal and neck surgery is the most important cause of VCP . Around Clinically, vocal cord function can be assessed by laryngoscopy, during which a stroboscopic light can confirm the absence of movement of the affected side. Symptoms of VCP include: hoarseness, vocal fatigue, loss of vocal pitch, shortness of breath and aspiration . HoweverThis review focuses on the anatomy and imaging evaluation of the vagal and recurrent laryngeal nerves and thereby the possible sites for pathology causing VCP. The imaging characteristics and imaging mimics of VCP are discussed and cases from daily practice illustrating various causes of VCP are presented.The vocal cords are located in a subsite of the larynx, called the glottis. The glottis includes the true vocal cords, the anterior commissure and the posterior commissure. From medial to lateral the vocal cords consist of the mucosal surface, the vocal ligaments and the intrinsic laryngeal muscles . The anterior commissure is the midline area where the cords meet anteriorly and where they are attached to the thyroid cartilage. The posterior commissure is the mucosal surface anterior to the cricoid cartilage in between the arytenoid cartilages. Posteriorly, the vocal cords are attached to the arytenoid cartilages and laterally to the inside surface of the thyroid lamina. The medial margins are free to permit the opening and closing of the airway. During quiet respiration the cords are in a relaxed, abducted state Fig. . Breath-The vagal nerve  exits bilaterally from the medulla oblongata just lateral to the oliva through the olivary sulcus. There are three nuclei within the medulla that receive and transmit information from and to the vagal nerve. The nucleus ambiguus gives rise to motor fibres to the larynx and is located just dorsally to the inferior olive, lateral and ventral to the lower part of the fourth ventricle Fig. . After eBilateral VCP is indicative of a central cause in the medulla oblongata . Acute oTo depict pathology in the course of the extracranial vagal nerves and the recurrent laryngeal nerves, we prefer contrast-enhanced computed tomography (CT) from the midbrain to the aortic arch including the AP window Fig.  15]. Wi. Wi15]. The most specific findings of unilateral VCP are , 16: (1)18F-fluorodeoxyglucose positron emission tomography (FDG-PET) exams of patients with VCP. In such cases, the PET may show increased metabolism in the unaffected vocal cord due to compensatory hypertrophy  the imaging characteristics and mimics of VCP, (2) the expected course of the vagal nerves and recurrent laryngeal nerves, and (3) the different types of pathology that can occur along their course.


Throughout the last decade, our understanding of the mechanisms involved in gene regulation has increased enormously, no more so than the role of non-coding RNAs (ncRNAs) in the regulation of gene expression  and how their levels change following exercise and under pathological conditions (Aoi and Sakuma, The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The rapid development of interventional procedures for the treatment of arrhythmias in humans, especially the use of catheter ablation techniques, has renewed interest in cardiac anatomy. Although the substrates of atrial fibrillation (AF), its initiation and maintenance, remain to be fully elucidated, catheter ablation in the left atrium (LA) has become a common therapeutic option for patients with this arrhythmia. Using ablation catheters, various isolation lines and focal targets are created, the majority of which are based on gross anatomical, electroanatomical, and myoarchitectual patterns of the left atrial wall. Our aim was therefore to review the gross morphological and architectural features of the LA and their relations to extracardiac structures. The latter have also become relevant because extracardiac complications of AF ablation can occur, due to injuries to the phrenic and vagal plexus nerves, adjacent coronary arteries, or the esophageal wall causing devastating consequences. There continues to be a lack of understanding of the pathogenesis of AF. Current evidence suggests that the pathogenesis of AF is multifactorial, because this arrhythmia may not only accompany a variety of pathological conditions, but also occur in a heart with no known structural abnormality, a condition known as “lone AF” . Recent From a gross anatomical viewpoint, the LA has four components : (1) a vAn anatomic septum in a heart is like a wall that separates adjacent chambers so that its removal would enable us to enter from one chamber to the other without exiting the heart. Thus, the true IAS wall is confined to the flap valve of the oval fossa. The flap valve is hinged from the muscular rim of IAS that, deriving from the septum secundum, is seen from the right atrial aspect of the interatrial wall . At its The major part of the endocardial LA including the septal wall and interatrial groove component is relatively smooth. The left aspect of the interatrial groove, apart from a small crescent-like edge , is almoThe walls of LA are nonuniform in thickness  and in gDetailed dissections of the subendocardial and subepicardial myofibers along the entire thickness of the LA walls have shown a complex architecture of overlapping bands of aligned myocardial bundles , 13 Fig. The terAlthough there are some individual variations, our epicardial dissections of the LA have shown a distinctive pattern of arrangement of the myocardial fibers . On the The epicardial fibers of the superior wall are composed of longitudinal or oblique fibers, (named by Papez as the “septopulmonary bundle” in 1920)  Figures that ariOn the subendocardial aspect of LA, most specimens showed a common pattern of general architecture. The dominant fibers in the anterior wall were those originating from a bundle described by Papez as the septoatrial bundle . The fibAtrial fibrillation is the most common sustained cardiac arrhythmia and is characterized by uncoordinated contraction of the atrium. It is still unclear whether the initiation and maintenance of human AF depends on automatic focal or reentrant mechanisms. Recent reports have shown the contribution of different atrial regions on the fibrillatory process and to the maintenance of AF, emphasizing the role of structural discontinuities and heterogeneous fiber orientation favoring anatomic reentry or anchoring rotors , 16. TheAlthough different mechanisms of AF exist, it is well established that the myocardial sleeves of the PVs, especially the superior veins, are crucial sources of triggers that initiate AF . CardiacNormal PVs anatomy consists of two right-sided and two left-sided PVs with separate ostia Figures  and 3. HThe presence of atrial myocardial tissue extending over the wall of the PVs has been confirmed both macroscopically and histologically by many investigators –31. In mSeveral studies have been designed to investigate and to compare the pathology of the PVs in patients with and without AF , 31. AltThe left lateral ridge (LLR) between the orifices of the left PVs and the mouth of the LAA is the most relevant structural prominence of the endocardial LA  Figures, and 8. Within the LLR, the oblique vein of Marshall runs, together with abundant autonomic nerve bundles  and a smLinear ablation connecting the inferior margin of the ostium of the left inferior PV and the mitral annulus, particularly when complete linear block is achieved, appears to increase the success rate of catheter ablation in patients with persistent or long-standing/permanent atrial fibrillation and prevent macroreentry around the mitral annulus or the left PVs . AlthougAdditional linear ablation lesions are created to improve the outcomes of PV isolation during AF ablation. In their study Cho et al.  using muThe LAA appears to be responsible for triggering AF in 27% of patients presenting for repeat procedures of catheter ablation . The LAAIn autopsy specimens and imaging studies, the LAA ostium is usually elliptical or round and in elliptical-shaped variant and its long axis is obliquely orientated relative to the mitral annulus , 53. TheIn some specimens (28%), muscular trabeculations can be found extending inferiorly from the appendage to the vestibule of the mitral valve . These eDue to the close proximity of the esophagus to the posterior wall of the LA, ablation procedures involving this region of the LA may cause esophageal damage and result in the formation of an atrial esophageal fistula  Figure . In an aThermal injury may involve the periesophageal vagal nerves, resulting in acute pyloric spasm and gastric hypomotility . The vagThe phrenic nerves lie along the lateral mediastinum and run from the thoracic inlet to the diaphragm . PhrenicThe intrinsic cardiac nervous system (ICNS) is a crucial regulator of heart rate, atrial and ventricular refractoriness, contractility, and coronary blood flow. Morphologically, the ICNS forms a neural ganglionated plexus that may be subdivided into epicardial and myocardial subplexuses. Several studies indicate that the ICNS is a complex of distinct subplexuses and that the cardiac ganglia are mainly distributed on (1) the superior surface of the right atrium, (2) the superior surface of the left atrium, (3) the posterior surface of the right atrium, (4) the posterior medial surface of the left atrium , and (5) the inferior and lateral aspect of the posterior left atrium and left PVs , 64. PosCatheter ablation has been shown to be an increasingly important therapeutic option for patients with paroxysmal, persistent, and chronic AF. Ablation techniques have evolved from rather limited initial approaches to quite extensive atrial interventions. The LA has a distinctive atrial appendage and an atrial body that comprises component parts that blend into one another. The patterns of general myocardial arrangement in the left atrial wall and the presence of interatrial muscle bundles may provide some anatomic background to atrial and interatrial conduction. Understanding the structure of the component parts and their relationship to one another and to other cardiac structures is relevant to interventional procedures inside and outside of the LA.


Conducting clinical trials in paediatric rheumatology has been difficult in the past mainly because of the lack of funding for academic studies and the lack of interest by pharmaceutical companies for the small and non-rewarding paediatric market. The situation changed dramatically few years ago with the introduction of the Best Pharmaceuticals for Children Act in USA and of a specific legislation for paediatric medicines development (Paediatric Regulation) in the European Union (EU).http://www.prcsg.org), covering North America, and the Paediatric Rheumatology International Trials Organisation (PRINTO at http://www.printo.it), covering more than 50 countries worldwide; the availability of validated measures to evaluate response to therapy, now called JIA American College of Rheumatology (ACR) criteria, accepted by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA); last but not least the advent of the biologic therapies  which have revolutionized juvenile idiopathic arthritis (JIA) treatment.The main reasons for success are: the availability of two large international non-for-profit networks working in close collaboration, such as the Pediatric Rheumatology Collaborative Study Group (PRCSG at Some problems however remain still to be solved: There is a need to harmonise all the regulatory aspects related to drugs that are used in the treatment of paediatric rheumatic diseases and in particular in JIA; the issue of me too drugs; the issue of proper pK studies; the ethics of drugs provision and of trial implementation; the implementation of proper pharmacovigilance systems.This presentation will review the reasons for success and the problems that still remains to be solved for conducting trials in JIA.None declared.