Aortic root occupies a central position in the fibrous skeleton with important relations to surrounding structures; therefore it is a challenge for surgeons enlarging the small annulus. We propose a low fidelity simulator to enhance the comprehension of the aortic root and the enlargement procedures.We used self-constructed models to simulate the aortic root. The related structures were constructed. Aortomitral angle of 120 degrees was created in the models. We performed three enlargement procedures 1. Manougian 2. Nicks 3. Nunez. Manougian and Nunez incisions were made through the commissure between the left and the Non coronary cusps (NCC) where Manougian extended through the anterior leaflet of the Mitral Valve (AML) while Nunez stopped proximal to the anterior annulus of the mitral valve. Nick’s incision was carried out through the middle of the NCC and also extending through the AML. Enlargements were carried out with a Dacron patch.Self construction of the Aortic Root and its related structures results in improving of 3D understanding of their relationship. The creation of the aortomitral angle leads to understanding the importance of maintenance of this angle after enlargement. Manougian and Nicks procedures resulted in the opening of the left Atrium (LA) and subsequent repair of the LA roof in addition to closure of the Aortic Annulus. While Nunez was simpler to patch as it did not require additional repairs.Low fidelity simulator is an excellent tool in broadening the knowledge of the familiarizing and performing different types of aortic root enlargement.


The development and application of standardised sets of outcomes to be measured and reported in clinical trials have the potential to increase the efficiency and value of research. One of the most notable of the current outcome sets was developed nearly 20 years ago: the World Health Organisation (WHO) and International League of Associations for Rheumatology (ILAR) core set of outcomes for rheumatoid arthritis clinical trials, originating from the OMERACT (Outcome Measures in Rheumatology) Initiative.The Cochrane Library. Reports of these trials were evaluated to determine whether or not there was a trend in the proportion of studies reporting on the full set of core outcomes over time. Researchers who conducted trials after the publication of the core set were contacted to assess their awareness of it and to collect reasons for non-inclusion of the full core set of outcomes in the study.A review of 350 randomised trials for the treatment of rheumatoid arthritis identified through This review suggests that 60-70% of trialists conducting trials in rheumatoid arthritis are now measuring the rheumatoid arthritis core outcome set. 90% of trialists that responded said that they would consider using the core outcome set in the design of a new study.This review suggests that a higher percentage of trialists conducting trials in rheumatoid arthritis are now measuring the rheumatoid arthritis core outcome set. Core outcome sets have the potential to improve the evidence base for health care.


Timing of initiating action is often critical for performance of voluntary behaviors. Appropriate times for initiating voluntary actions are considered to be acquired by reinforcement learning. In this learning process, exploration in the time domain is essential. The basal ganglia have been implicated in the initiation of voluntary movements. Recently, we proposed a biologically plausible mechanism for probabilistic timing of action initiation in the basal ganglia, and by computer simulations of the spiking neural network model we demonstrated the probabilistic nature of the action initiation of the model which supports active exploration in the range of several seconds . For fur


In addition to lacking dystrophin, this mouse also expresses a mutated version of the gene encoding LARGE, another important component of the DGC. The combination of these two mutations provides a model that demonstrates a severe neuromuscular phenotype and accurately mimics the symptoms of human muscular dystrophies. The authors also demonstrate that the model could be used to test the benefit of stem cell therapy to treat DMD and associated disorders. In a second study, Dean Burkin’s group provides insight into the mechanism underlying the beneficial effects of corticosteroid therapy in DMD and reveal potential candidates to target in future therapeutic approaches that might overcome the negative side effects associated with steroid use (1175page ). In their work, they utilise in vitro cultured myogenic cells and also a canine model of DMD that shows strong phenotypic similarities to human DMD patients, demonstrating that the use of multiple complementary approaches and model systems can allow complex disease mechanisms to be elucidated.Two research articles published in the current issue progress our understanding of Duchenne muscular dystrophy (DMD), a debilitating X-linked disorder characterised by progressive muscular weakness and degeneration. The disorder is caused by mutations in the gene encoding dystrophin, an important component of the dystrophin-glycoprotein complex (DGC) that connects intracellular proteins with the extracellular matrix and promotes muscle fibre integrity. In the first of the two studies, Mariz Vainzof and colleagues report a new mouse model for the disease in the form of a


Cells respond to changes in the internal and external environment by a complex regulatory system whose end-point is the activation of transcription factors controlling the expression of a pool of ad-hoc genes. Recent experiments have shown that certain stimuli may trigger oscillations in the concentration of transcription factors such as NF- Cells are dynamic environments constantly adapting themselves to internal and external stimuli. The response to such stimuli is a tightly controlled multi-step process from sensing the stimulus, usually by means of receptors present in the external and internal membrane, transmission of the signal across the cell by a cascade of protein modifications and protein-protein interactions, that activates specific transcription factors which, in turn, regulate the expression of target genes. Fine tuning regulations, e.g. post-translational and post-transcriptional modifications, take place at every step in process providing robustness against noise, specificity to the triggering stimulus and insulation between the different pathways.Recent discoveries have revealed that transcriptional regulation itself is a very complex process and genes are not just activated or deactivated by transcription factors. Rather transcription factors activate a pool of genes network motifs. Network motifs are patterns of connectivity that are present in a much higher frequency than in a network of similar dimensions but whose links between its nodes are generated randomly Some insights have been gained from identifying so called Among the network motifs feed-forward loops have been widely investigated both theoretically and experimentally and many of their properties have been described, such as persistence detection, protecting against transient loss of signals Oscillations have been observed for a long time in the most varied biological systems e.g. cell cycle For transcription factors the functional role of oscillations is not well understood. A number of studies provide supporting evidence that the oscillatory temporal dynamics of nuclear NF-In this work we theoretically and numerically investigate how the transcriptional activity of genes regulated by simple network motifs is affected by oscillations in the concentration of transcription factors. First we study and characterize quantitatively the properties of direct regulation. We then use and extend these results to understand the behavior of indirect two-step regulation and feed-forward loops, driven by oscillating transcription factors with varying period and temporal profile. The specific aim is to analyze how various characteristics of the oscillatory input signal (e.g. frequency and shape) can control differential expression of genes, that is not possible in the case of steady state responses. A better understanding of such mechanisms based on theoretical models can help identifying the functional role of experimentally observed oscillations in the expression of various genes. We focus on the genetic response produced by synthetic oscillatory input signals, where we can directly control the different characteristics of the signal.symmetric case in which In the following we present and analyze differential equation based models that link the temporal dynamics of a transcription factor Analytical solutions for the components of the considered mechanisms have been derived see  section We first studied the effects of oscillations on the average expression of a gene same see .The solution e value  .Although the specific solution ene  see :(3)whereWhen the concentration of the oscillatory transcription factor crosses the threshold of activation back and forth only once in each cycle of oscillation B)C)D)pulse generator promoting the expression of the gene As a representative of the IFFLs we illustrate the behavior of the IFFL-1 with an AND gate. In the IFFL-1 In the presence of an oscillating factor ncreased . SimilarThe response to changing the period of the oscillation of A)B)C)D)Oscillations are a widespread phenomenon arising in many biological systems Previous studies have investigated both theoretically and experimentally the properties of regulatory networks in relation to their topology. Alon and coworkers have demonstrated various properties of simple regulatory motifs like negative auto-regulation Under adequate stimulation oscillations in gene expression may involve a large number of transcription factors, propagating across different pathways and occur at different cellular levels In this work we studied the possibility of frequency dependent responses in simple gene regulatory schemes, that could be used in decoding information from time-dependent oscillatory signals, and to generate differential regulation of multiple genes controlled by the temporal dynamics of the same transcription factor.In the case of direct regulation the key factor regulating the gene expression is the fraction of time when the transcription factor concentration is above the activation threshold of a certain gene. As a consequence, modifying the frequency of oscillation cannot modulate the expression of a gene. Varying the amplitude of oscillation though, may cause changes in the duration of the activity of transcription factors and could regulate the average level. Such a mechanism might be ideal to regulate those genes whose average level of expression in cells and tissues should not change when the cellular environment is perturbed by a stimulus that gives rise to oscillations.For the two-step regulation the frequency of oscillation is capable of switching on or off the expression of the target genes. Increasing the frequency of oscillation of the regulating transcription factor causes the intermediate component to oscillate closer to its average value Thus increasing the complexity of the gene regulatory network provides the cell with more refined mechanisms for decoding information from the temporal dynamics, that is not possible in the case of steady-state responses with no temporal dynamics. We have identified distinct types of response behaviors depending on the parameters, for example: on/off switching of the gene expression in a frequency dependent manner, maintenance of a constant average expression, frequency dependent switching of the expression level between two distinct regimes. Moreover we have shown that, as Gene expression mediated by two-step regulation and FFLs could be advantageous in driving cell fate in those situations for which the transcription factor can regulate opposite cellular processes. NF-Future extensions of this work could consider how combining together several of these regulatory mechanisms affects the ability to decode information from the temporal dynamics of transcription factors in transcriptional networks with more complex topology. Another interesting possibility would be to consider gene regulatory motifs controlled by oscillatory input signals that depend on multiple stimuli, to explore how multiple information can be transmitted and recovered from the temporal dynamics of a single transcription factor. The inputs influencing the dynamics of an oscillatory transcription factor typically would modify not just the frequency but also other characteristics of the signals, e.g. average expression rate, amplitude of the oscillations etc. Therefore the frequency dependent responses that we described may be combined with or dominated by other changes occurring simultaneously.While in our models we focussed on the time-averaged response behavior of a stationary oscillating system, in many cases transient signaling and the timing of the gene expression is also important. Relevant information may also be encoded in the temporal profile of transient stimuli, that could lead to selective transient expression of different genes. Simple gene regulatory networks can also play a role in decoding such information as it was shown for example in the context of genes involved in cell cycle regulation Frequency dependent expression of genes regulated by NF-Supporting Information S1This supporting material contains the mathematical derivation of all the formulas presented in the main text. The numerical results obtained simulating Network Motifs with an OR gate stimulated by oscillatory transcription factors are shown and discussed extensively using the same framework introduced in the main text.(PDF)Click here for additional data file.


By pulling together results from five individual studies, we aim to enable the audience to explore how the overall narrative enables additional insight in to our understanding of development, effectiveness, and implementation of online interventions. Methods and results from studies will be explained and contrasted. The theoretical underpinnings of the development of Unitcheck, an intervention initially developed for UK university students, will be explored briefly before outlining results of three randomised control trials. The results of a study employing qualitative think-aloud methodology will then be presented. Evidence will be presented of the ability of Unitcheck to prompt users to actively engage with information presented, relating information to their own experience; resulting in an evaluation of their own drinking behaviour. Evidence will be presented of user's immediate cognitive and emotional reaction when comparing their own drinking with that of others. Next, we discuss how experiences with Unitcheck were applied to inform development of ChangeDrinking, an online screening and brief advice intervention for non-help-seeking individuals who have recently been hospital inpatients. The results of a study employing qualitative think-aloud methodology to understand how those identified as having substance misuse problems engage with ChangeDrinking will then be presented. The presentation will consider how context of implementation  shaped development of each intervention tool and subsequently impacted the evaluation process. The synthesis of the results of the think-aloud studies with randomised control trial results enables insight in to potential mechanisms for behaviour change. This paper will consider the implication of results for our understanding of the use of online brief personalized feedback interventions for modifying alcohol use.This presentation outlines the development and evaluation of two online brief personalized feedback interventions for alcohol use (


There is an exceedingly small group of microorganisms that are considered pathogenic in humans relative to the microbial biota—with literally just a few bacterial and viral agents that have the potential to cause disease when transmitted in aerosol form. This group of pathogens has adapted to circumvent the rigors of airborne transport to enter the respiratory system and induce infection. The changes that take place in the microbial composition during this process, including expulsion of bioaerosols from an infected host, is a multifaceted process that ultimately effects the underlying functionality of the organism and the induction of disease in the host target. Similarly, the nature of the aerosol source can be determinative of the size distribution of the pathogenic aerosols and thus affect the pattern of initial deposition in the respiratory system and the tissue/cell types most impacted by the pathogen.in vitro techniques and animal models for the purposes of further defining cellular mechanisms in aerosol-initiated disease pathogenesis. The resulting disease models have shown utility in medical product evaluations targeted to protecting or ameliorating the effects from an infectious mucosal/aerosol challenge. These aerosol disease models have been and continue to be an especially important consideration in biodefense-related research studies.The complexity of the mucosal response to infection within the respiratory system is affected not only by the number of infectious particles deposited, but the relative integrity of the microbial constituents contained in the aerosol particles. Conceptualizing and providing a description of the constitutive process of airborne disease transmission have given rise to recent research efforts using both This special issue brings together 11 articles that are diverse in content but are unified under a central theme of infectious disease aerobiology. This includes focused reviews that survey the current paradigm associated with airborne viral transmission of disease, as well as the benefits of directed alternative (aerosol) treatment of aerosol-acquired disease. The vulnerability of microorganisms in airborne environmental transport is also detailed in 2 of the 11 manuscripts contained in this special issue. Initial host response associated with exposure to airborne pathogens constitutes the majority of the articles included, with special emphasis on experimental infection as well as particle size-dependent disease pathogenesis.The first article Milton,  evaluateFrancisella tularensis. Microbial aerosol efficiencies can be negatively affected by prevailing lower relative humidity as well as the selection of growth media (MHb vs. BHI) used in bacterial propagation. Dabisch et al.  demonstrated differences in collection efficiency which can affect calculation of the delivered dose. These studies demonstrate the importance of microbiological and aerosol characterization when developing experimental animal models for respiratory infection.The next two articles present experimental data associated with microbial survival as it relates to the generation of laboratory-generated infectious bioaerosols for respiratory infection of animals. The first . The articles in this Research Topic are an excellent cross section of active research and topical reviews which will inform the reader of current technologies, gaps in knowledge, and opportunities for future research.


Total urogenital sinus mobilization has been applied to the surgical correction of virilized females and has mostly replaced older techniques. Concerns have been raised about the effect of this operation on urinary continence. Here we review the literature on this topic since the description of the technique 15 years ago. Technical aspects and correct nomenclature are discussed. We emphasize that the term “total” refers to an en-bloc dissection and not to the extent of the proximal dissection. No cases of urinary incontinence have been reported following this operation. It is yet too early to evaluate results regarding sexual function but it is likely that the use of a posterior skin flap to augment the introitus will minimize the development of introital stenosis. Persistence of the urogenital sinus (UGS) is a common feature of a variety of congenital anomalies, among them: (1) XX DSD, namely females exposed to androgens in fetal life; (2) as an isolated malformation unrelated to masculinization or rectal malformation and; (3) in persistence of the cloaca. Although there are important anatomical and functional differences among the different types of UGS the surgical techniques used for its correction bear similarities.The goal of the surgical correction of UGS is the creation of separate openings in the vulva for the urethra and the vagina with preservation of the function of both organs. Early surgical techniques involved complete or partial separation of the urethra from the vagina, at times preserving the sinus as the urethra and doing either a vaginal “pull through”  or creatIn 1997, Peña published a new technique for repair of the UGS in girls with persistence of the cloaca which avoided the separation of the urethra from the vagina. The technique involved the en-bloc mobilization of both structures to bring them down to the perineum creating separate openings. This maneuver saved time and reduced the number of complications in the eight children described and was called total urogenital mobilization (TUM) . By neceSubsequently, some authors expressed concerns that TUM may compromise urinary continence and bladder function  and a prMany reports on the outcome of TUM include patients with a variety of diagnoses which tends to make interpretation of results difficult.Here we review the published results of TUM in patients with XX DSD without associated anorectal malformations.Pubmed search under the headings: “UGS, vaginoplasty, feminizing genitoplasty, and TUM” was conducted. After collecting all abstracts, full length articles of those which included UGS mobilization in DSD patients were reviewed. Results regarding number of patients, diagnosis, urinary continence, and potential vaginal stenosis were recorded.The persistence of the UGS in cases of genetic females exposed to androgens in the first few weeks of embryogenesis is almost universal. In virilized XX individuals the urethra and vagina share a common opening but the urethra and vagina develop normally proximal to the persistent UGS. Therefore, the urethra proximal to the confluence is of normal length . The goaFollowing the description of the technique , Kryger More recently, Palmer et al. reported on the continence status of a population with mixed diagnoses which included CAH, cloaca, and primary UGS . Among tThe results of the literature search are presented in Table We analyzed the results of TUM performed to correct UGS in virilized females. Although many series in the literature include cases of CAH, cloaca and primary UGS, and other forms of DSD, it should be recognized that the variable anatomy and possible associated neurological anomalies may have a profound influence in urinary continence independent from the operation performed .The application of TUM to cases of virilized females has largely replaced the use of other procedures that required the separation of the urethra from the vagina. The advantages of this technique are clear; avoiding separation of the urethra from the vagina reduces surgical time and complications and may avoid potential damage to urethral innervation. Many authors mention the length of the UGS as a criterion to select the surgical technique. In fact, the length of the sinus may be irrelevant since much of its course is in the perineum, parallel to the surface. More important to predict the easy or complexity of the surgery is the distance from the confluence of the vagina and urethra to the perineal skin Figure . We routPosteriorly, the dissection should always be carried to the peritoneal reflexion to facilitate the descent of the posterior vaginal wall and the suture of the Ω flap. It is important to keep the posterior dissection close to the vagina in order to avoid disruption of the rectovaginal fascia which seems important for normal rectal function .We operate all those cases perineally in the dorsal lithotomy position. We see no advantage in the prone position which makes the vulvoplasty difficult. Furthermore, in cases of primary XX DSD, the use of the transanorectal approach is overly aggressive, hinders the use of a posterior flap and increases the potential for serious complications , 23.In short, data published since the description of TUM fail to demonstrate any adverse effect of the operation on voiding or continence.Interestingly, Davies et al. investigated 19 adult women with CAH of whom 16 had had corrective surgery in childhood. They found an incidence of urge incontinence of 68% and stress urinary incontinence (SUI) of 47%, significantly greater than in controls . It is nMost authors have combined TUM with a posterior flap of perineal skin to augment the circumference of the suture line and prevent introital stenosis , 25. TheGosalbez et al.  proposedPasserini-Glazel also avoided separation of the urethra from the vagina but instead of mobilizing the UGS sinus en-bloc his technique involved anastomosing the inverted distal UGS to the distal end of the vagina left in its original position . Lesma ePodesta and Urcullo  reportedIt remains to be determined whether the rate of introital stenosis with TUM and a posterior flap will be lower than that reported Bailez et al.  and moreWe recommend the parents of our patients that an examination under anesthesia should be conducted at the onset of puberty to evaluate the vaginal introitus.These girls need follow-up till adulthood to evaluate the adequacy of the vagina.No case of urinary incontinence has been documented after distal or proximal TUM performed as a primary operation. Although some reports suggest a low incidence of vaginal introital stenosis, no long term results with this technique have yet been published. Concerns about the use of TUM for the correction of virilized genetic females appear unfounded.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.


Capacity problems and political pressures have led to a rapid change in the organization of primary care from mono disciplinary small business to complex inter-organizational relationships. It is assumed that inter-organizational collaboration is the driving force to achieve integrated (primary) care. Despite the importance of collaboration and integration of services in primary care, there is no unambiguous definition for both concepts. The purpose of this study is to examine and link the conceptualisation and validation of the terms inter-organizational collaboration and integrated primary care using a theoretical framework.The theoretical framework is based on the complex collaboration process of negotiation among multiple stakeholder groups in primary care.A literature review of health sciences and business databases, and targeted grey literature sources. Based on the literature review we operationalized the constructs of inter-organizational collaboration and integrated primary care in a theoretical framework. The framework is being validated in an explorative study of 80 primary care projects in the Netherlands.Integrated primary care is considered as a multidimensional construct based on a continuum of integration, extending from segregation to integration. The synthesis of the current theories and concepts of inter-organizational collaboration is insufficient to deal with the complexity of collaborative issues in primary care. One coherent and integrated theoretical framework was found that could make the complex collaboration process in primary care transparent. This study presented theoretical framework is a first step to understand the patterns of successful collaboration and integration in primary care services. These patterns can give insights in the organization forms needed to create a good working integrated (primary) care system that fits the local needs of a population. Preliminary data of the patterns of collaboration and integration will be presented.


The Asthma and GERD are common medical affections and recent studies show that often they coexist (2). The GERD paper as leading factor of the asthma is an important subject, In addition, also exists the possibility that the asthma can precipitate the ERGE. This investigation purposed to demonstrate the interrelation between Gastroesophageal Reflux Disease and Bronchial asthmaThe Gastroesophageal Reflux Disease (GERD) is not associated with the increase the acid secretion, but by failure of the antireflux barrier with one basal hipotone of the inferior sphincter of the esophagus that can be because of the medicines like Xanthine, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), alcohol or anticolinergics By means of a descriptive and traverse study of the patients with bronchial asthma of the municipality Regla assisted in consultation of allergy of April - June 2011, being applied a survey to all the greater asthmatic patients of 20 years for clinical confirmation of the Gastroesophageal Reflux Disease.Demonstrating that 63.8 % of the asthmatic ones present GERD, being more frequents in females (64%) and on the group of 40 to 59 years old, the digestive symptom most significant was the postprandial fullness (94%), and digestive extra the cough (81%). The abundant food is the main factor of risk of the ERGE (69%).Most of the asthmatic patients suffer Reflux, being demonstrated the narrow relationship among these pathologies. It exists ignorance that the symptoms can be unchained by the GERD and that this last one is increased by Xanthine, NSAIDs, and abundant foods.


We address the problem of non-parametric estimation of the recently proposed measures of statistical dispersion of positive continuous random variables. The measures are based on the concepts of differential entropy and Fisher information and describe the "spread" or "variability" of the random variable from a different point of view than the ubiquitously used concept of standard deviation. The maximum penalized likelihood (MPL) estimation ,2 of theFrequently, the dispersion of measured data needs to be described. Although standard deviation is used ubiquitously for quantification of variability, such approach has limitations. For example highly variable data might not be random at all if it consists only of "extremely small" and "extremely large" measurements. Although the probability density function, or its estimate provide a complete view, quantitative methods are needed in order to compare different models or experimental results. In a series of recent studies, some alternative measures of dispersion were proposed. However, the estimation of these coefficients from data is more problematic. We present the obtained estimations of the dispersion coefficients based on the MPL method, which extends our previous study .


Mitochondria are the bioenergetic centers of eukaryotic cells that produce ATP through oxidative phosphorylation. A byproduct of oxidative phosphorylation is the generation of reactive oxygen species (ROS). Cancer cells exhibit high basal levels of oxidative stress due to activation of oncogenes, loss of tumor suppressors, and the effects of the tumor microenvironment Several studies have reported that a high frequency of clonal and, therefore, selected mitochondrial mutations are present in a variety of human tumors PLoS Genetics, Ericson and colleagues Cancer arises from a mutator phenotype and it has been established that the random mutation rate of the nuclear DNA of tumors is quite high Seven decades ago, Warburg discovered that mitochondria in cancer cells metabolize glucose by aerobic glycolysis and suggested that this was a result of impaired mitochondrial function that contributes to tumorigenesis Other explanations for the low frequency of random mitochondrial mutations in colon tumors include highly efficient DNA repair (for excellent review see HIF-1 and MYC, will emerge as new drug targets and molecular markers of prognosis and responses to therapy. In addition, targeting mtDNA repair proteins could serve as a potential alternative approach to kill cancer cells. The work of the Ericson et al. What are the implications of the findings of Ericson et al.


Culex spp. mosquitoes and birds as reservoirs host whereas humans and horses are dead-end hosts. Clinical symptoms of WN human infections range from asymptomatic or mild influenza like disease to severe neurological and meningoencephalitis syndromes.West Nile virus (WNV) is a flavivirus (Flaviviridae family) and its transmission cycle involves West Nile is a neglected emerging disease with major breakthrough in 1999 with the introduction of WN virus (WNV) in New York City and the subsequent spread to whole northern America over the last decade causing massive human and animals infection leading to some fatal cases. In Eastern Europe, circulation of WNV with recurrent emergences impacting human and animal health since 1996 is similar to the situation in the USA. Strikingly, in Africa WN appears to have a minor effect despite regular isolations from mosquitoes and vertebrates hosts. In addition, WNV exhibited a great diversity with eight different lineages among which only one (lineage 1) is found worldwide and 4 are present in Africa.Culex quinquefasciatus showed significant differences between strains of various lineages tested for infections, dissemination and transmission rates. Indeed the different strains can be classified as low, intermediary and high infection profile. Analysis of the transmission patterns with sequences of the strains suggest that glysoylation of the envelope protein of WNV, a key player in the virus entry in the cell, may play an important role. The implications of our findings are discussed in the context of global emergence of WN.In order to understand factors underlying the different patterns of transmission and processes involved in the emergence of WN in the different contexts, genetic diversity, phylodynamics and vectorial competence of WNV have been studied in Africa. Phylogenetic analysis based on partial and complete genome suggests an interconnection of zoonotic amplifications in Africa with emergence in Europe as well as replacement between lineages over time. Vectorial competence of lineages circulating in Africa for a domestic mosquitoes


Many aspects of a trial may be incompletely reported, including the outcomes collected and the full set of analyses undertaken. Selective reporting bias occurs when the inclusion of outcomes or analyses in the report is based on the results. We review and summarise the empirical evidence from studies that have assessed the selective reporting of outcomes and analyses and provide guidance to trialists to help reduce this problem.outcomes and ii) evidence for selective reporting of analyses. An international collaboration of experts will be brought together in July to discuss the available evidence alongside current reporting guidance for trials. Recommendations are being produced with regards to raising the awareness and safeguarding trial publications against selective reporting.Two systematic reviews of studies that have examined randomised trials for i) evidence for publication bias or selective reporting of From twenty studies, of which four were newly identified, the evidence in the first systematic review demonstrated an association between statistically significant results and publication. Statistically significant outcomes had a higher odds of being fully reported compared to non-significant outcomes (range of odds ratios: 2.2 to 4.7). A further seventeen studies consider aspects of selective reporting such as statistical analyses; subgroup analyses and composite outcomes.This work highlights the evidence of selective reporting and demonstrates the importance of pre-specifying outcomes, analyses and reporting strategies during the planning and design of a clinical trial, for the purposes of minimising bias when findings are reported.


The case presented by the authors gives the opportunity to discuss the medico-legal issues related to lack of prevention of falls in elderly hospitalized patients.A 101 year old Caucasian female was admitted to a surgery division for evaluation of abdominal pain of uncertain origin. During hospitalization, after bilateral bed rails were raised, she fell and reported a femoral fracture. Before surgical treatment of the fracture, scheduled for the day after injury, the patient reported a slight reduction in hemoglobin. She received blood transfusion but her general condition suddenly worsened; heart failure was observed and pulseless electrical activity was documented. The patient died 1 day after the fall. Patient relatives requested a judicial evaluation of the case.The case was studied with a methodological approach based on the following steps: 1) examination of clinical records; 2) autopsy; 3) evaluation of clinicians’ behavior, in the light of necroscopic findings and a review of the literature.The case shows that an accurate evaluation of clinical and environmental risk factors should be always performed at the moment of admission also in surgery divisions. A multidisciplinary approach is always recommended also with the involvement of the family members. In some cases, as in this one a fall of the patient is expectable but not always avoidable. Physical restraint use should be avoided when not necessary and used only if there are no practical alternatives. A fall , an evenIt is estimated that about 14% of falls during hospitalization may be classified as accidental, due to environmental factors (e.g. slipping on the wet floor), 8% as physiological and unpredictable, due to sudden mutation of patient physical condition , and 78% of falls as physiological but predictable due to identifiable risk factors  [Risk patient identification is the first preventive step that should be considered. The systematic assessment of clinical and environmental risk factors must be implemented at admission and during hospitalization especially in case of modification of patient condition.The assessment of the risk of falling may be done through a systemic evaluation on individual and environmental risk factors -7 integrOnce you have identified risk factors it is essential that providers, patients and family/caregivers acquire the awareness of the risk of falling and work together in an integrated and consistent, careful application of multifactorial strategies.Interventions after risk assessment may reduce but not eliminate the risk of falling. A fall of a patient during hospitalization may have not only clinical consequences for the patient but also judicial consequences for the clinician.The case presented by the authors gives the opportunity to discuss the medico-legal issues related to falls in elderly hospitalized patients. A systematic review on the thematic of falls is beyond the purpose of this paper and we refer to the numerous national  and inteThe case was studied with a methodological approach based on the following steps: 1) examination of clinical records; 2) autopsy; 3) evaluation of physicians’ behavior, in the light of necroscopic findings and a review of the literature.A 101 years old Caucasian female was admitted to a surgery division for evaluation of abdominal pain of uncertain origin . She wasThe initial cognitive impairment associated to confusional states, the walking difficulties, the lack of personnel or family members capable of monitoring the patient during the night induced clinicians to use physical restraint and to ask nurses a more frequent evaluation of the patient. Bilateral bed rails were raised. During the morning of the next day of hospitalization, the nurse heard a noise coming from the room of the patient finding her on the floor. Immediate examination and instrumental evaluation allowed diagnosing a left femoral fracture and a slight concussion. TC scan excluded skull fractures or intracranial hemorrhages. A surgical treatment intervention was scheduled for the next day but during the afternoon the clinical condition worsened. Laboratory analysis revealed slight low levels of hemoglobin  and a worsening of neurological condition. The physician decided to transfuse the patient with two units of packed red blood cells. During the night a deterioration of the overall clinical picture was observed with dyspnea and bradycardia not responding to the treatments. Pulseless electrical activity (PEA) was documented; cardiopulmonary resuscitation measures were performed with no result. She was declared dead in the morning of the day after the fall.External examination showed at palpation signs of fracture of thorax and on the left lower hip. Section revealed a picture of cerebral oedema, bilateral rib fractures due to resuscitation, myocardial fibrotic areas, congestion and emphysema of the lungs, polyvisceral congestion, polydistrectual atherosclerosis.Histological examination confirmed the macroscopic findings, demonstrated the presence of interstitial myocardial fibrosis in absence of signs of recent myocardial infarct; significant areas of emphysema and congestion of the lung, areas of glomerulosclerosis were put in evidence.The cause of death was identified in cardio-circulatory arrest in cardiogenic shock, pulseless electrical activity in recent left femoral fracture, ischemic-hypertensive chronic heart disease, lung emphysema, chronic macrocytic anemia and previous old right femoral fracture.In Western countries, the aging of the population leads to an increase in the number of elderly patients admitted to hospitals or nursing homes. The growing number of medico-legal cases concerning professional liability  may reprThe methodological approach of evaluation of professional liability cases is based on the definition of damage to the patient (diagnosis of a disease or identification of the cause of death), on the analysis of the conduct of clinicians and on verification of causal relation between patient damage and the possible error of clinicians ,15.The identification of the cause of death requires a necroscopic examination . AutoptiIn our case the claim of malpractice was promoted by the relatives of the deceased. Prosecution was based on the hypothesis of a lack of fall prevention and on an incorrect use of physical restraint.According to the methodological approach clinical documentation analysis and autopsy were performed. The cause of death was linked with no doubt to the fall that triggered, acting on baseline patient health condition, a lethal pathophysiological evolution. Patient general clinical conditions were in precarious balance - she was very old and suffering from multiple diseases – and bleeding from fracture was considered a sufficient factor to alter patient precarious equilibrium with heart failure which hesitated rapidly in the death of the patient.With reference to the malpractice claim, the conduct of clinicians was considered correct. Initial cognitive impairment associated to transient confused states, urinary incontinence and walking difficulties were considered by clinicians as risk factors for fall. The awareness of risk of falling finds demonstration in the use of physical restraints. The clinicians considered properly the risk factors providing guidance to the nursing staff for the proper management of postural changes of the patient and of the aid to be provided during postural changes. Greater oversight of patients with more frequent rounds of inspection were established. The use of side rails during the night was considered a necessary measure to limit the ability of movement of the patient and nocturnal wanderings. This choice was widely discussed during the trial. According to prosecution, physical restraints such as bilateral bed rails, belts, and fixed tables in a chair should be always considered inadequate or wrong. Physical restraints are quite frequently used in geriatric division in Italy despite some evidences for their lack of effectiveness and safety -21. In UThe choice of using physical restraint was considered a forced choice in our case due to the high risk of fall and the lack of sufficient personnel to monitor the patient during the day.The case shows that an accurate evaluation of clinical and environmental risk factors should be always performed at the moment of admission of the patient also in a surgery division. A multidisciplinary and multicomponent intervention is always recommended also with the involvement of the family members. In some cases a fall of the patient is expectable but not always avoidable. In certain situations, the lack of adequate number of personnel, or of family members who may look after the patient, does not exclude the risk of fall. Physical restraint use should be avoided when not necessary and used only if there are no practical alternatives.CT performed the autopsy, contributed to the analysis and interpretation of the data, to the discussion of medico-legal issues and to the writing of the paper. FC contributed to the literature review, to the drafting and reviewing of the paper. BM, BA and CM gave their contribution to the analysis of the conduct of clinicians and contributed to the writing of the paper. All the authors read and approved the final manuscript.The authors declare that they have no competing interests.


Children need physical activity and generally do this through the aspect of play. Active play in the form of organized sports can appear to be a concern for parents. Clinicians should have a general physiological background on the effects of exercise on developing epiphyseal growth plates of bone. The purpose of this review is to present an overview of the effects of physical activity on the developing epiphyseal growth plates of children.A National Library of Medicine (Pubmed) search was initiated using the keywords and combinations of keywords "growth plate", "epiphyseal plate", "child", "exercise", and "physical activity."Bone is a dynamic tissue with a balance of osteoblast and osteoclast formation. The normal functioning of the epiphyseal growth plate is an important clinical aspect. Much of the physiology of the epiphyseal growth plate in response to exercise includes the important mechanical component. Growth hormone, insulin-like growth factor I, glucocorticoid, thyroid hormone, estrogen, androgen, vitamin D, and leptin are seen as key physiological factors. While there is a need for children to participate in physical activity, clinical consideration needs to be given to how the epiphyseal growth plate functions.Mechanical loading of the bone is important for epiphyseal plate physiology. Exercise has a healthy function on the normal growth of this important biomechanical feature. Clinically, over-exertion in the form of increased load bearing on the epiphyseal growth plate creates an ideal injury. There is a paucity of research on inactivity on the epiphyseal growth plate resulting in stress deprivation. Further research should take into consideration what lack of exercise and lessened mechanical load bearing has on the function of the epiphyseal growth plate.Child; Physical activity; Epiphyseal growth plates; Bone; Exercise; Mechanical loading Bone has been described as a dynamic and highly interactive complex of many cell and tissue types . The epiThe purpose of this review is to present an overview of the effects of physical activity on the developing epiphyseal growth plates of children. A discussion of the physiological basis of epiphyseal growth plates will be included. Practitioners with a familiarity of the dynamic changes that can occur with the epiphyseal plate in normal children can ultimately lead to recognition of pathologic states , 8.As noted previously, skeletal growth at the epiphyseal plate is an active and dynamic process . The epiLongitudinal bone growth is primarily achieved through the action of chondrocytes in the proliferative and hypertrophic zones of the growth plate . LongituWithin the epiphyseal growth plate, chondrocyte proliferation, hypertrophy, and cartilage matrix secretion result in chondrogenesis . EndochoThe regulation of linear bone growth in children and adolescents comprises a complex interaction of hormones and growth factors . This prIn particular, for the majority of skeletal elements to develop and grow, the process of endochondral ossification requires a constantly moving interface between cartilage, invading blood vessels, and bone . An adeqThe balance between proliferation and differentiation in bone is considered to be a crucial step. It is a crucial regulatory step controlled by various growth hormones acting in the endocrine pathways . Growth Research with laboratory animals has provided most of the current information regarding estrogen's influence on the growth process of long bones, on the maintenance of cancellous bone mass, and on the architectural and cellular changes in bone . EstrogeAs previously noted, longitudinal growth of the skeleton is a result of endochondral ossification that occurs at the epiphyseal growth plate. Through the sequential process of cell proliferation, extracellular matrix synthesis, cellular hypertrophy, matrix mineralization, vascular invasion, and eventually apoptosis, cartilage continually is being replaced by bone as length increases . ParfittComprehension of the biomechanical aspects of bone allows one to conceptualize the physiological processes associated with exercise and physical activity on the epiphyseal growth plate. The mechanical influence on bone directly applies to the normal physiological functioning of bone. Longitudinal growth is controlled by local mechanical factors in the form of a feedback mechanism which exists to ensure that bone growth proceeds in the direction of the predominant mechanical forces . The indIn addition to the vital function of growth factors, it is known that mechanical forces stimulate the synthesis of extracellular proteins in vitro and in vivo and can affect the tissue's overall structure . AccordiOver the past decade, there has been a surge in the number of sports opportunities available to young athletes . Beyond The effects of exercise on the molecular nature of secreted human growth hormone (GH) or its biological activity are not well understood . Yet it Vascularization of the epiphyseal growth plate region represents a key mechanism for the coupling of two fundamental processes determining the rate of bone growth: chondrogenesis (cartilage production) and osteogenesis (bone formation) . Within A potential problem with physical activity and exercise on the epiphyseal plates is over-activity. Intuitively, it is the extent that over-physical activity may have on the growth plate resulting in injury. A better appreciation of how epiphyseal plate physiology works is seen in the response to trauma. Approximately 25% of adolescents have at least one recreational injury which is mostly minor reflecting only soft tissue trauma and abrasions of the skin . HoweverMost injuries in children's sports and activities are minor and self-limiting thus suggestive that children and youth sports are safe . Unlike The genetic potential for bone accumulation can be frustrated by insufficient calcium intake, disruption of the calendar of puberty and inadequate physical activity . While mThe clinical pathophysiology of excessive activity on the epiphyseal growth plates resulting in injury is one of the more prominent methods of understanding the effects of exercise on growth plate physiology. The immature skeleton is different from the adult skeleton with unique vulnerability to acute and chronic injuries at the growth plate . EpiphysGerstenfeld et al  summarizThe second and arguably the least discussed aspect concerning the epiphyseal growth plate is the role inactivity may play on the growth plate. Given the current interest in and rising rates of child obesity such interest in the growth plate should be considered. One of the implicated culprits in the child obesity epidemic is the lack of physical activity. It is known that epiphyseal growth plate activity controls longitudinal bone growth and leads ultimately to adult height yet numerous disorders are characterized by retarded growth and reduced final height either have their origin in altered chondrocyte physiology or display pathological growth plate changes secondary to other causes . PhysicaNonetheless, the recent concern over the increasing incidence and prevalence of obesity as seen in children gives rise to concern for the normal growth process. As previously indicated, functioning growth hormone (GH) and insulin-like growth factor (IGF)-I are essential for normal growth . HoweverIt may appear that, in some cases, genetic expression, through favorable conditions, can be maximally achieved throughout the entire period of growth . In thisThe epiphyseal growth plate is a dynamic entity. Growth is dependent not only on intrinsic factors such as hormones and other regulatory factors but on extrinsic factors. These extrinsic factors are based entirely on the biomechanical model. Exercise, a positive aspect for the epiphyseal growth plate needs to be moderated through carefully crafted activities especially during pubertal growth spurts. Obesity, a major problem among today's youth, can be attributed in part to a lack of exercise. Once activity is undertaken the potential for epiphyseal growth plate disturbances from too much activity may be a predisposing factor to growth plate dynamics. The effects of exercise on the epiphyseal growth plate needs further research to comprehend the entirety of this dynamic anatomical and physiological entity. Research in the area of the epiphyseal growth plate in some children who are sedentary needs to be addressed.


According to the geological characteristics of Xinjiang Ili mine in western area of China, a physical model of interstratified strata composed of soft rock and hard coal seam was established. Selecting the tunnel position, deformation modulus, and strength parameters of each layer as influencing factors, the sensitivity coefficient of roadway deformation to each parameter was firstly analyzed based on a Mohr-Columb strain softening model and nonlinear elastic-plastic finite element analysis. Then the effect laws of influencing factors which showed high sensitivity were further discussed. Finally, a regression model for the relationship between roadway displacements and multifactors was obtained by equivalent linear regression under multiple factors. The results show that the roadway deformation is highly sensitive to the depth of coal seam under the floor which should be considered in the layout of coal roadway; deformation modulus and strength of coal seam and floor have a great influence on the global stability of tunnel; on the contrary, roadway deformation is not sensitive to the mechanical parameters of soft roof; roadway deformation under random combinations of multi-factors can be deduced by the regression model. These conclusions provide theoretical significance to the arrangement and stability maintenance of coal roadway. Rc < 15 MPa) and weak cementation (argillaceous cementation). Hence, tunnels are mainly arranged in relatively stable coal seam. However, the shape of roadway is often seriously damaged after excavation due to the large deformation of surrounding rock which brings terrible impact on the production safety. Thus, it is urgent to grasp the deformation laws of the tunnel surrounding rock in order to seek reasonable constructing principle and supporting scheme.In recent years, coal industry is tending to transfer to the western area and most of the mining areas are mainly concentrated in Inner Mongolia, Shanxi, Gansu, Ningxia, Xinjiang and so on. The main rock layers of these areas are Jurassic and cretaceous soft rock strata with great thickness due to the special diagenetic environment and depositional history in western China –3. It isDeformation of coal roadway is actually determined by the global mechanical behavior of three body model composed of soft rock and coal seam, which shows obvious structure effect due to the different properties of rock layers. Wang and Feng  discusseFor a complicated compound structure composed of different rock layers with discrete lithology, it is difficult to establish the relationship between its deformation and influencing factors by an analytical expression. By comparison, the numerical method is more effective. However, large discreteness exists in various mechanical parameters obtained by geological exploration and indoor tests which bring difficulties to the parameters selection for numerical calculation, so the key problem to improve the numerical accuracy is to determine their value scopes and sensitivity according to tunnel deformation. Hou et al., Nour et al., Fenton et al., Gill et al., and Jia et al. –19 have In this paper, a compound system model composed of soft rock and coal seam is established firstly according to the geological conditions and construction characteristics in Xinjiang Ili mine, and then sensitivity analysis of mechanical parameters of each rock layer to the stability of coal roadway is carried out in order to find out the high sensitivity factors which have significant influences on roadway displacement. The conclusions obtained may provide some theoretical principles and optional methods for correct selection of simulation parameters, as well as improving the overall stability of coal roadway.The tunnel this paper had chosen is located in Ili forth mine in Xinjiang area. Soft rock strata such as mudstone and sandstone layers with low strength were encountered during the construction of transport tunnel. From the field monitoring data, the rates of roof subsidence and floor heave develop fast after excavation. As shown in q is the self-weight stress of overlying strata. The horizontal displacements of left and right boundary lines were restricted along with a fixed bottom. Due to the shallow depth of roadway, only gravity stress and horizontal stress are considered while ignoring the effect of tectonic stress.The layout of tunnel is usually passing through coal seam due to the characteristics of low stiffness, being easy to deform, and weak stability of weak cementation soft rock strata. For this, a compound physical model composed of soft rock coal seam was built as shown in Ur and Uf, respectively, were selected as the stability evaluation indexes. Let be the displacement of roof to floor U = Ur and Uf. For certain strata with specific thickness and buried depth, the main factors influencing the displacement of monitoring points are α = {E, C, φ, h}, namely, the deformation modulus, cohesion force, and friction angle of each rock layer as well as the depth of coal seam on the bottom of tunnel floor  stand for undetermined coefficients. The equivalent mechanical parameters have the following forms:Single factor analysis can only determine the influence law of a separate factor on the stability of surrounding rock, so it is difficult to establish the cross-influences of different parameters on the system feature. Thus, it is necessary to establish a multi-factors regression model for the system in order to make clearly the system sensitivity while multiple parameters change at the same time. For this, the system regression model is set as follows based on the influencing laws of each factor obtained in The unit type of each mechanical parameter is in line with Ef and h were changed simultaneously within their scope. It is easy to obtain the convergence displacements under the arbitrary combination of h and Ef. Similarly, the displacement responses can also be quickly established when other parameters change. The regression model provides theoretical basis for determining the optimal parameter combination which can minimize the tunnel displacement.h ≥ 2 m, so it should be fully considered in the arrangement of coal roadway.The tunnel displacement is highly sensitive to the depth of coal seam under soft floor. On the condition of specified thickness of each layer, the deformation of roof and floor tend to be stable when The mechanical parameters of coal seam and soft floor have significant influence on tunnel displacement; the direction of floor displacement will be changed by enhancing the stiffness of coal seam which can effectively prevent and control floor heave as well as decrease the roof subsidence; the damage state of side walls is determined by strength parameters of coal seam; therefore, the overall stability of roadway can be improved by the reinforcement of side walls. The roof subsidence can be obviously reduced by increasing the elastic modulus of floor. The floor displacement can be dramatically decreased by improving the floor strength which is closely related to the shear failure area of soft floor. The tunnel displacement is not sensitive to the mechanical parameters of soft floor.The multifactors regression model laid a theoretical foundation for seeking the best parameter combination and providing reasonable supporting to control the deformation of this kind of roadway.


The histopathological evaluation showed an infiltration of bone with tumor cells. Review No the literature revealed in previous cases of skeletal metastasis from gastric cancer in the tibia like this.We report a 41 years old man with rapidly growing and tender lump on the anteromedial surface of tibia. The patient had the history of gastrectomy and gastrojejunostomy due to gastric carcinoma. On admission, the Simple X-ray of lower extremity disclosed a slight thinning of the anterior cortex of tibia without cortical destruction. The whole-body bone scan with  Gastric cancer has not been recognized as a number of the group of common bone invaders consisting of lung, prostate, breast, thyroid and kidney cancers . Moreove A 41-year-old man came to orthopedic ward with the chief complaint of tender and painful lump on the anteromedial surface of his tibia in the proximal third which had been growing during previous 6 months. The patient was very cachectic and had the history of proximal gastrectomy and gastrojejunostomy which had been done 16 months ago due to gastric carcinoma accompanied with six sessions of chemotherapy and radiotherapy. In pathologic evaluation of the tumor in this operation, moderately differentiated adenocarcinoma with an-epithelial to-serosal extension and no lymph node involvement had been reported. In physical examination of the extremity, a firm and tender lump was seen with a diameter of 6 ∗ 4 cm which was firmly attached to the anteromedial surface of tibia. In simple X-ray an interesting feature was the slight thinning of the anterior cortex without cortical destruction which made the diagnosis of metastatic a bit unlikely . In wholPuri et al. in their report of three cases of gastric cancer presenting with distant metastasis, describe a case of metastasis to the left forearm in the form of soft tissue lump and another case of fibular metastatic lesion . KammoriEven though metastasis to bone is much more common in the axial skeleton and the roots of extremities, we should still expect to see them in unusual sites and from those cancers not so notorious in invasion to bone from.


Molecular footprints of phenotypic variation are usually explored by two different approaches in trees. On the one hand, association genetics is seeking for statistical correlation between SNPs and traits owing to the significant heritability that is usually observed in progeny tests. On the other hand, detection of outlier Fst values of single SNPs has also been implemented to account for the very large differentiation of traits that are observed in provenance tests. The rationale of both approaches is based on the extensive within or between population genetic variability that has been widely recorded in fields tests. While the cataloguing of candidate genes has steadily increased in trees, so has the inventory of their diversity in natural or breeding populations. There is now a rapidly growing body of experimental results showing a very large discrepancy between the expectations of both approaches and the SNP variation that is monitored in candidate genes. Most association studies show that single SNPs explain usually less than 5% of the phenotypic variation of the trait, while Fst values are at best of the same value than neutral markers. In my presentation I will explore the reasons of the decoupling between trait and gene variation, by focusing on the multilocus structure of traits, as compared to the monolocus SNP information. Indeed, association studies and Fst outlier detection are essentially based on single locus approaches, while traits are multidimensional structures. There are at least three properties of multilocus structures that will be investigated: cumulativity, interactions and covariation of gene effects. I will show that cumulativity and interactions may explain the discrepancy in the case of association studies, while covariation of gene effects (at the between population level) explain the missing Fst of genes underlying adaptive traits. These conclusions are supported by experimental results, theoretical background and simulation predictions.


Food safety is threatened by numerous contaminants, which can originate from environmental pollution, such as toxic metals and organic halogenated compounds; chemicals used in the production of food, such as pesticides and veterinary drugs; contaminants formed during food production and cooking; contaminants arising from food packaging, or natural toxins in food. Consumers’ perceptions of food-related risks have recently been investigated in the 2010 Eurobarometer. The highest concern was reported for pesticides in fruit, vegetables and cereals, with 72% of the respondents being very or fairly worried. Somewhat fewer people were worried about residues like antibiotics and hormones in meat (70%), pollutants like mercury and dioxins (69%), food poisoning from bacteria (62%) or putting on weight (47%).Adverse effects of environmental contaminants may be displayed as developmental toxicity and endocrine disruption, with fetuses and children being vulnerable target groups. One contaminant, which has attracted much attention, is bisphenol A (BPA) and there is a scientific controversy about the low-dose health risks of BPA. BPA is used in the production of polycarbonate plastics and epoxy resins. Human exposure is mainly from packaged food and beverages. BPA binds to estrogen receptors and also acts through other mechanisms on endocrine function. We have investigated effects of BPA on steroidogenic pathways in the human adrenocortical cell line H295R. Secretion of steroidogenic hormones and intermediates were affected at non-toxic levels of BPA. The effects were mediated by inhibition of CYP17 and CYP21 and expressions of steroidogenic genes were downregulated. This may be an additional mechanism behind the endocrine disruptive effects of BPA.One of the greatest challenges in toxicology today is in predicting the risks associated with chemical mixtures. The exposure to contaminants via the diet occurs as a mixture rather than as individual compounds. Thus, food safety is to a high extent dependant on possibilities to predict risks from mixtures. The two models most frequently used are concentration addition and independent action. The main difference between the two models is the assumption of mode of action of the chemicals in the mixture. In concentration addition it is assumed that the chemicals work through a common mode of action and can be regarded as dilutions of each other. In independent action it is assumed that the chemicals act independently via different mode of actions and the mixture effect is predicted by the probabilities of response of the individual chemicals. We have investigated mixture effects of food-related chemicals on secretion of steroids in the human adrenocortical cell line. The results have been compared to the predicted effects from the two prediction models. In general the chemicals acted in an additive manner on secretion of hormones, which could be predicted by both models.


Models of competitive template replication, although basic for replicator dynamics and primordial evolution, have not yet taken different sequences explicitly into account, neither have they analyzed the effect of resource partitioning (feeding on different resources) on coexistence. Here we show by analytical and numerical calculations that Gause's principle of competitive exclusion holds for template replicators if resources (nucleotides) affect growth linearly and coexistence is at fixed point attractors. Cases of complementary or homologous pairing between building blocks with parallel or antiparallel strands show no deviation from the rule that the nucleotide compositions of stably coexisting species must be different and there cannot be more coexisting replicator species than nucleotide types. Besides this overlooked mechanism of template coexistence we show also that interesting sequence effects prevail as parts of sequences that are copied earlier affect coexistence more strongly due to the higher concentration of the corresponding replication intermediates. Template and copy always count as one species due their constraint of strict stoichiometric coupling. Stability of fixed-point coexistence tends to decrease with the length of sequences, although this effect is unlikely to be detrimental for sequences below 100 nucleotides. In sum, resource partitioning (niche differentiation) is the default form of competitive coexistence for replicating templates feeding on a cocktail of different nucleotides, as it may have been the case in the RNA world. Our analysis of different pairing and strand orientation schemes is relevant for artificial and potentially astrobiological genetics. The dynamical theory of competing templates has not yet taken the effect of sequences explicitly into account. One might think that complementary sequences have very limited competition only. We show that, despite interesting sequence effects, competing template replicators yield to Gause's principle of competitive exclusion so that the number of stably coexisting template species cannot exceed the number of nucleotide species on which they grow, although one of the findings is that plus and minus strands together count as one species. Thus up to four different templates/ribozymes can constitute the first steps to an early, segmented genome: we suggest that other mechanisms build on this baseline mechanism. Gause (1934) in the Golden Age of theoretical ecology formulated the principle of competitive exclusion, proposing in effect what usually is being referred to as “complete competitors cannot coexist” We explicitly take into consideration the concentration of up to four different building blocks  and that the dynamics of these abiotic resources are not periodically forced, for example. We neglect replicase enzymes and assume that template and replica separate irreversibly upon completion of elongation. The kinetic effects are simplified to the extent that the elongation rate of template polymerization depends only on the identity of the inserted nucleotide and nothing else. We know that this is a crucial simplification but already with this rule different sequences may assume very different kinetic phenotypes. In agreement with this, we neglect secondary and tertiary structures.raison d'être for these assumptions is that we would like to demonstrate the effect of competition for resources of competing template sequences as simply and clearly as possible.  We deliberately want to see the dynamics of coexistence under irreversible exponential growth tendency, as a kind of worst case. The effect of the sequence diversity of templates on dynamical coexistence is not trivial. If there are two resources A and B, then it is trivial that sequences of The Some of the effects that we show in this paper are far from trivial. Our calculations show the effect of resource partitioning on template coexistence and shed more light on early molecular evolution, which surely was affected by sequence effects of template replicators.sequences) we formulated the dynamics of polynucleotide replication. Here we only explain the necessary basics of our formalism, for the mathematical model see To understand the mechanism of coexistence of template replicators ; we also introduce parallel strand polarity as opposed to antiparallel polarity (like in case of RNA replication). The difference between complementary and non-complementary pairing and parallel and antiparallel strand polarity is given in The following model of template replication models RNA replication, dealing with 4 monomers, complementary pairing and antiparallel strand polarity. We have investigated the coexistence of M1 With a given set of parameters (elongation constants M2 We have investigated the coexistence for each sampled sequence group for different numbers of complementary pairs (and stability of coexistence and that on four different monomers a maximum of four different sequence pairs could possibly coexist. Thus Gause's principle (against first intuition) limits the number of sequence pairs instead of individual sequences because of the dynamical coupling between the template and its complement . According to our exhaustive numerical results, we have found no case where more than two sequences could coexist, supporting our hypothesis. We have numerically integrated ODE systems until convergence or extinction of one of the sequences. The numerical methods and routines are the same as before. We have analyzed the coexistence of two sequences in two different ways  of coexistence of sequences can be deduced right from the order of monomers of the sequences according to a very simple rule . The rulA-s in its head; the latter behaves as having A-s in the head to yield coexistence  weighs more concerning the coexistence than the rear (tail). This is because during replication, earlier intermediates are present in larger concentrations than intermediates closer to the final step of the replication  the trinculeotide Mechanisms for template coexistence have been in the focus of models of primordial replicator evolution cf. . Here weRecently there has been an upsurge in interest in exo/astrobiology. It is in this context that we have deliberately presented results for homologous pairing also, even with parallel orientation of the strands. Although such configurations are not unheard of even in our world, we wanted to see how such features would in general affect dynamical coexistence of template replicators.We have obtained the fitness landscapes through a distribution of elongation and degradation rates. The main reason behind this is tractability: although the 2D structures as phenotypes of RNA molecules can be calculated for most cases, this does not automatically yield phenotypes in terms of replication rates. We are temporarily satisfied with the phenotype richness that our local rules provided see . What isIn each experiment, we integrated the system of Let us introduce two complementary sequences:The extension of the dynamics for more sequence pairs  is straightforward. The dynamics of the intermediates is independent for each pair and the dynamics of the monomers provides the coupling between the equations of different pairs of sequences. Because of the cross-coupling of equations, no analytical solution was found . For the numerical integration of the ODE system to find steady-state solutions we have used the CVODE code from the SUNDIALS project of the Lawrence Livermore National Laboratory Uniform degradation rates of sequence intermediates allow for a completely analytic approach. For the positivity test of concentrations, we introduce the following notation for the constants of the power sum of different signs.Let us assume that influx can counter degradation. In this case the condition of coexistence  of length . Lower left half: coexistence is marked by green, extinction of the first sequence pair by red and extinction of the second sequence pair by blue. Upper right half: stability of coexistence according to the leading eigenvalue . The upper triangle shows the stability measures of the sequences pairs from the lower one (mirrored and rotated (TIF)Click here for additional data file.Figure S2Coexistence plots of pairs of double-stranded sequences of length  (upper panel) and  (lower panel) using two monomers  in case of uniform degradation and identical elongation rate constants and non-complementary pairing. The green indicates stable coexistence, grey indicates structurally unstable coexistence, i.e. compositional identity , while pink indicates that there is no coexistence possible. Sequences along the axes are arranged first according to Hamming distance and secondly according to lexicographic ordering from more (TIF)Click here for additional data file.Figure S3Correlation plot of the fitness landscape as a function of Hamming distances for sequence pairs of length .(TIF)Click here for additional data file.Table S1Analysis of coexistence of  non-complementary pairs of sequences of length  according to method M1. Second column shows the number of scanned sequences (and the amount as a fraction of the whole combined sequence space). The third column shows the fraction of coexisting sequences in the scanned domain, i.e. the probability of coexistence of random sequence groups of size (XLS)Click here for additional data file.Table S2Analysis of coexistence of  non-complementary pairs of length  according to method M2. Second column shows the number of scanned sequences (and the amount as a fraction of the combined sequence space). The third column shows the fraction of coexisting sequences averaged over the scanned sequence groups and over 1000 random degradation rate sets for intermediates Click here for additional data file.Table S3Examples of coexistence for .(XLS)Click here for additional data file.Table S4Examples of coexistence for .(XLS)Click here for additional data file.Table S5Examples of coexistence for .(XLS)Click here for additional data file.Text S1Supporting text with sections on 1) Parameters for methods M1, M2, M3 and M4; 2) Analysis of non-complementary pairing with antiparallel polarity; 3) Analysis and analytical results of non-complementary pairing and uniform degradation rates; 4) Proofs; 5) Discussion of the fitness landscape; 6) Examples of coexistence of longer sequences.(PDF)Click here for additional data file.


Among the many achievements of the twentieth century the accelerating development of microprocessors and their capabilities is one of the most impressive accomplishments, influencing virtually every aspect of daily life. The impact of this new technological resource was (and still is) of particular importance for theoretical approaches in science and engineering. Although many theories , an increased awareness of the importance of the solvation is observed in literature in recent years consider alternative approaches in quantum chemistry, as have been summarized in a recent publication asking: Accuracy consideration and general applicability are not the only advantage of quantum mechanical computations over the use of empirical approaches: the majority of force fields can not (or not adequately) describe the formation and cleavage of chemical bonds. However, in recent years so-called reactive force fields  are another topic that received increased interest in recent years. NQEs are strongly linked to the computational treatment of hydrogen transfer reactions, which are of critical importance for many chemical disciplines such as catalysis and biochemistry. Due to the low mass of hydrogen atoms, nuclear quantum effects may have a significant impact on the reaction dynamics (Agarwal et al., Each of these grand challenges is strongly dependent on the development of improved computational facilities. Since it has been estimated that the progress in microprocessor technology will continue throughout the next decades, the formulation of improved approaches addressing the grand challenges will constitute a promising and exciting research activity in the future. It can be expected that theoretical approaches in chemistry assume a similar leading role in chemical science, as observed for theoretical methods in physics during the last century.


To present a group of anatomical findings that may have clinical significance.This study is an anatomical case report of combined lumbo-pelvic peripheral nerve and muscular variants.University anatomy laboratory.One cadaveric specimen.During routine cadaveric dissection for a graduate teaching program, unilateral femoral and bilateral sciatic nerve variants were observed in relation to the iliacus and piriformis muscle, respectively. Further dissection of both the femoral nerve and accessory slip of iliacus muscle was performed to fully expose their anatomy.Piercing of the femoral nerve by an accessory iliacus muscle combined with wide variations in sciatic nerve and piriformis muscle presentations may have clinical significance.Combined femoral and sciatic nerve variants should be considered when treatment for a lumbar disc herniation is refractory to care despite positive orthopedic testing. The recurrence of leg pain from lumbar disc herniations is a common post treatment clinical finding. Certain muscular and peripheral nerve variants may represent an unrecognized etiology in these cases and may affect the outcome of specific treatments. Recognition of these variations in normal anatomy may be useful to the clinician when treating the patient with refractory leg pain. The femoral nerve, derived from the second to fourth lumbar dorsal divisions, is one of the terminal branches of the lumbar plexus. MultiplThe sciatic nerve, formed from the ventral rami of the fourth lumbar to third sacral spinal nerves, leaves the pelvis passing both anterior and inferior to the piriformis or sometimes through the muscle. A 2010 Piercing of the femoral nerve by an accessory iliacus muscle in combination with bilateral variations in both sciatic nerve and piriformis muscle anatomy exemplifies the wide variability that exists within the lumbar and lumbosacral plexus. The clinical implications of these combined variants are discussed.During routine cadaveric dissection, bilateral sciatic and unilateral femoral nerve variants were detected. The course and muscular relationships of both sciatic nerve variants were studied. The femoral nerve variant was further dissected and was examined to determine its nerve root contributions and its branching pattern. Also, the accessory muscular slip of the iliacus muscle that was piercing the femoral nerve was dissected to determine both its origin and insertion points.On the right side, the sciatic nerve was split into the common fibular and tibial divisions proximal to the piriformis muscle, with the common fibular division passing above and superficial to the piriformis muscle and the tibial division passing inferior and deep to the muscle. On the left side, the sciatic nerve was also divided proximal to the piriformis muscle. However, the piriformis muscle was pierced and subdivided into two discrete bellies by the common fibular division, while the tibial division passed inferior and deep to the most caudal border of the piriformis muscle Figure. The rigIn the left iliac fossa, the femoral nerve emerged both lateral and deep to the psoas major muscle between the psoas major and iliacus muscles covered in iliac fascia. It was then pierced and divided into two separate divisions by an accessory slip of the iliacus muscle. Just proximal to the inguinal ligament, these two separate divisions rejoined and the femoral nerve passed as one under the inguinal ligament and then divided into its usual anterior and posterior branches Figure. The accThe sciatic and femoral nerves represent the two largest peripheral collections of lumbar and sacral nerve roots. There hStraight leg raise and femoral nerve traction tests are commonly performed orthopedic maneuvers done to ascertain the presence of a lumbar disc herniation,17. FemoVariants in lumbar and lumbosacral plexus anatomy should be considered when a symptomatic lumbar disc herniation is refractory to care. Recognition of these anatomical variants may lead to earlier intervention of physiologic testing, better treatment outcomes and improved patient satisfaction. Future studies examining the prevalence of these combined variants in the general population would be of interest to clinicians.Written informed consent was obtained from the deceased prior to the gift of body donation. All handling of anatomical specimens was in accordance with the institutions ethical policy for body donation for anatomical study and scientific purposes. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.PB conceived of the case report, assisted in reviewing the literature and drafting the manuscript. FS provided anatomical artwork, assisted in reviewing the literature and drafting the manuscript. DE assisted in reviewing the literature, drafting the manuscript and provided critical review. All authors read and approved the final manuscript.


The microcirculation is a major topic in current physiology textbooks and is frequently explained with schematics including the precapillary sphincters and metarterioles. We re-evaluated the validity and applicability of the concepts precapillary sphincters and metarterioles by reviewing the historical context in which they were developed in physiology textbooks. The studies by Zweifach up until the 1950s revealed the unique features of the mesenteric microcirculation, illustrated with impressive schematics of the microcirculation with metarterioles and precapillary sphincters. Fulton, Guyton and other authors introduced or mimicked these schematics in their physiology textbooks as representative of the microcirculation in general. However, morphological and physiological studies have revealed that the microcirculation in the other organs and tissues contains no metarterioles or precapillary sphincters. The metarterioles and precapillary sphincters were not universal components of the microcirculation in general, but unique features of the mesenteric microcirculation. The microcirculation is one of the major topics in the study of physiology and histology. In current physiology textbooks, the general architecture of the microcirculation is frequently explained with schematic drawings depicting precapillary sphincters and metarterioles in addition to arterioles, capillaries and venules. Judging from the main text and figures with legends in relatively recent textbooks such as Johnson’s  Fig. 1)1) and BoSince the concept of precapillary sphincters and metarterioles is quite popular in physiology textbooks, one might expect that previous physiological investigations had revealed the existence of these structures in various tissues with reasonable certainty. Nevertheless, the existence of precapillary sphincters as universal components of the microcirculation has been questioned by some physiologists. McCuskey  pointed In the present article, we re-evaluated the validity and applicability of the concept of precapillary sphincters and metarterioles by reviewing the historical context in which these concepts were developed and accepted in four steps. In the first part, we investigated the historical process of how the schematics of these concepts was developed and incorporated into physiology textbooks. In the second part, we evaluated the validity of the concepts by examining the physiological literature on the microcirculation of the mesentery in which the concepts were originally proposed. In the third part, we examined the applicability of the concepts to the microcirculation of organs other than the mesentery. In the fourth part, we verified the structural counterparts of the concepts by examining the histological literature on the vasculature.We examined the available physiology textbooks from Haller’s “Primae Lineae Physiologiae” of 1747  to the mThe schematics of the microcirculation in the textbooks shown in Table Among the six schematics, two figures contained neither precapillary sphincters nor metarterioles, including figure 1 from Zweifach’s 1937 article  on the dOne of the six figures showed sketches of observations of the mesentery microcirculation with precapillary sphincters and metarterioles, namely figure 1 in Zweifach’s 1950 article  The other three figures represented an idealized microcirculation and contained both precapillary sphincters and metarterioles, including figure 1 of Chambers and Zweifach’s article from 1944  Fig. 6)6), figurThe other schematics of the microcirculation in the physiology textbooks did not use Zweifach’s article as the source for the figures and appeared to be original drawnings. The schematic in Berne and Levy’s physiology in 1967  and its The above survey indicated that the schematics of the microcirculation in the current textbooks of physiology relied on specific articles by Zweifach before 1953. In the following part, we will examine the literature on physiological research on the microcirculation, especially those by Zweifach, to evaluate the extent of applicability of the concepts of precapillary sphincters and metarterioles.A series of investigations by Zweifach utilized the mesentery of a few different animals for visualization of the microcirculation in vivo, beginning with Zweifach’s research in 1937  reportedIn introducing the new concepts of metarterioles and precapillary sphincters, Chambers and Zweifach  referredSummarizing the above literature survey, it must be concluded that the precapillary sphincters and metarterioles identified by several studies by Zweifachs provide enough evidence on the mesentery microcirculation, but their findings cannot be accepted as evidence for the microcirculation of the various tissues and organs in general.Zweifach provided four types of schematics including precapillary sphincters and metarterioles in three articles. The first type was in an article on the mammalian omentum and mesentery by Chambers and Zweifach in 1944  presentiHowever, the metarterioles and precapillary sphincters were topics of later physiological research on the microcirculation of various tissues and organs including the skeletal muscles –39, skinAfter the pioneering studies of Zweifach and coworkers, the structure and function of the microcirculation were studied in other organs such as the skeletal muscle, skin, heart, liver, kidney, intestine, etc. The microcirculation architecture was revealed to be quite diverse among organs and had specific patterns suitable to the functional demands of the individual organs.In skeletal muscle, the arterioles and venules branch successively to become the terminal segments that supply and drain microvascular units, respectively . The terIn the skin, the microcirculation is organized as two horizontal plexuses . One is In the coronary microcirculation, the small penetrating arteries give rise to arterioles at almost right angles, which take either longitudinal or oblique courses to the muscle fibers to give off capillaries around the muscle fibers . BetweenIn the liver, the hepatic arteries (HAs) and portal veins (PVs) divide successively into terminal HAs and PVs in the connective tissue stroma at the periphery of the hepatic lobules. The terminal PVs directly supply the sinusoids, while the terminal HAs drains into the terminal PVs and the proximal part of the sinusoids. The sinusoidal blood is drained via central venules into the hepatic veins . There aIn the kidney, the arteries enter the parenchyme and divide into the arcuate arteries at the corticomedullary boundary from which the interlobular arteries arise toward the cortical surface to branch off successively into the afferent arterioles to supply the glomerular capillaries in the individual glomeruli . The effIn the small intestine, the arterial and venous plexuses are formed in the submucosa . From thHowever, in the mesenteric microcirculation, the metarterioles have been recognized by the other authors as shunting arterioles . The bloThe metarterioles in the mesentery represent thoroughfare channels between the arterioles and venules and therefore can be regarded as a kind of arteriovenous anastomosis. These have been reported in various tissues and organs including the skin, skeleton, muscle, lung, heart, intestinal canal, kidney, brain, eye and ear . HoweverThe structure of the microvasculature has been repeatedly investigated in various tissues by means of three electron microscopy methods. By transmission electron microscopy (TEM), the smooth muscle cells and extracellular matrices of the vascular wall can be well visualized and analyzed, but it is usually difficult to identify the observed location within the three-dimensional branching of the vascular tree on the sectional planes. Thus, identification of precapillary sphincters may only be possible after repeated careful observations of the microvasculature with TEM. By scanning electron microscopy of vascular casts (SEM-vc), the three-dimensional branching pattern of the vasculature can be well visualized and analyzed, but it was practically impossible to identify the cellular composition of the vascular wall. The precapillary sphincter can be inferred by constriction of the vascular casts at the base of the vascular branches with SEM-vc. By scanning electron microscopy after removal of the extracellular matrices (SEM-rem), both the structure of the vascular wall and the three-dimensional branching pattern can be well visualized, but the cellular types can be identified only tentatively on the basis of cellular shape. The precapillary sphincters can be identified convincingly with SEM-rem.In a search of the literature, we found 36 morphological studies on the microvasculature in 16 kinds of tissues employing one of the three morphological methods Table . Six of Rhodin made detailed observations of the microvasculature employing TEM . The idePrecapillary sphincters were reported in the microvasculature of the heart with TEM and SEM-vc. Sherf et al.  describePrecapillary sphincters were reported in the microvasculature of the brain with SEM-vc by Nakai et al.  and CastAs shown above, the morphological evidence did not verify the existence of precapillary sphincters in the microvasculature of the muscular fascia, heart and brain. In the other 13 kinds of tissues, the precapillary sphincters were not observed at all with TEM, SEM-vc or SEM-rem. Our own observations of the microvasculature in the lung , kidney The arterioles received an abundance of aminergic (adrenergic) innervation in many organs such as the skeletal muscles –80, saliThe studies by Zweifach up until the 1950s revealed the unique features of the mesenteric microcirculation and provided impressive schematics of the microcirculation with metarterioles and precapillary sphincters. Fulton, Guyton and other authors introduced or mimicked these schematics in their physiology textbooks as representative of the microcirculation in general. However, morphological studies have revealed that the microcirculation in other organs and tissues contains no metarterioles or precapillary sphincters, and physiological studies on the microcirculation have used the terms metarterioles and precapillary sphincters differently. This reveals that the metarterioles and precapillary sphincters are not universal components of the microcirculation in general, but unique features of the mesenteric microcirculation. Therefore, explanations and illustrations of the microcirculation with metarterioles and precapillary sphincters can be regarded as inappropriate and misleading in physiology textbooks about the organs and tissues that aim to teach in general and not specific terms.