P = .03). The residual lesions that we could find with definitive histology of re excision specimens are related with lesions with ill defined profile. In 77% of the cases of re excision with tumoral residual the lesion was close to the new resection margin, thus the re-excisions couldn't achieve an adequate ablation of the neoplasm. Invasive or preinvasive nature of the main lesion resected for each case and the approach to the evaluation of the first resection specimen adequacy  don't affect the rate of tumoral residual in intraoperative re-excisions. In conclusion, our data are consistent with a low efficacy of intraoperative re excision in obtaining a complete removal of the tumor; intraoperative radiologic evaluation of the first resection specimen is however imperative in defining the effective removal of the target lesion.In the present study we considered the histology of 51 patients who have undergone breast conservative surgery and the related 54 re-excisions that were performed in the same surgical procedure or in delayed procedures, in order to evaluate the role of intraoperative re-excisions in completing tumor removal. In 13% of the cases the re excision obtained the resection of the target lesion. In this study, the occurrence of residual neoplastic lesions in intraoperative re-excisions (24%) is lower than in delayed re-excisions (62%;  Breast oncologic surgery is now widely focussed in conservative treatment with tissue sparing in order to obtain satisfying cosmetic results besides an adequate surgical resection –3. ObvioIn recent years, the role of the intraoperative evaluation of surgical specimen in resection margin control was assessed, but the literature is still limited and dissimilar. A group of recent papers on series of conservative resections for breast malignancies proved that the intraoperative examination of resection specimens is useful in decreasing the rate of second procedures, employing gross examination techniques , specimeAssuming that the re-excision procedures are useful tools in obtaining an adequate removal of the neoplastic lesions, thus reducing the risk of persistence of neoplastic foci in residual parenchyma, we believe it could be of interest to make an attempt at quantifying the amount of tumoral mass that lies beyond a margin that is considered close according to the ordinary criteria of intraoperative evaluation . The literature about this topic is still somewhat limited and is mainly based on delayed excisions: two recent works , 15 analThe present survey is based on the examination of histological material from a consecutive series of conservative resections that comprehended re-excision procedures, both in the context of the same session and in delayed surgical treatments. The main goal of this study is the assessment of the extension and of the morphological characteristics of the tumoral residuals in re-excision specimens to define both the role of the re-excisions (and mainly of the limited re-excisions) as a tool to obtain the complete removal of neoplastic lesions in conservative breast surgery and the potential employment of other therapeutic options in obtaining an adequate removal of the target area. As a consequent achievement, we planned to weigh up some of the issues that could be related with the occurrence of tumoral residuals, as the invasive or preinvasive nature of the lesion, the method of evaluation of the first resection adequacy, and the time occurring between the first resection and the re-excision.For the present study, we selected 51 patients consecutively treated in our institution with a preliminary conservative approach, subsequently extended with further (intraoperative or delayed) procedures. Since resection specimen radiogram is considered the most reliable technique of margin status evaluation in our structure, all the first resection specimens were conveyed to the radiology department for intraoperative evaluation, and most of the re-excisions were based on the radiologist's advice. Considering the main lesions reported in final histology for each patient, 28 infiltrating carcinomas , 19 in situ carcinomas (37%), and 4 (8%) benign lesions were resected. All the benign lesions were reported at final histology as sclerosing adenosis.The main histological characteristics of infiltrating and in situ carcinomas are resumed in 112 surgical specimens from 54 procedures (first resections and subsequent re-excisions) were evaluated in this study.Resection specimens were examined in radiology department using two standard projections. The presence of the target lesion in the radiograms was first ascertained; the margins were judged close to the target lesion when the lesion was eccentrically placed in the same mammograms.Space-oriented specimens were examined for the final histology. In the initial resections, the surgical margins were marked with one or two different colour inks. In the re-excision specimens, the new resection margins were inked. Consecutive sections of the area of the neoplasm closest to the surgical margins were obtained in large specimens while the whole tissue was processed in smaller specimens or, in the cases in which the lesion's shape was not clearly identifiable, on macroscopic examination. All macroscopically significant areas were processed. Resection margin was considered close when the distance from the lesions was equal to or smaller than 2 mm.Histological slices were reviewed by two different pathologists.2X test was used for statistical evaluations cited in the results section.52 patients were enrolled for this study, with 54 related re-excisions.We divided the re-excisions in accordance with the time of re-excision and with the method of evaluation that defined the surgical procedure.38 patients (74.5%) were re-excised intraoperatively: in 25, re-excision was supported by the radiological report of close margins after specimen mammogram and, in 13, direct re-excision was supported by clinical evidence of incomplete excisions during surgery; 3 patients of this group had delayed re-excisions performed after definitive histological report of close margins on first resection specimen.The remaining 13 patients (25.5%) had no intraoperative extension, since the ordinary method of immediate evaluation of first resection provided suggestions for further procedures, and were extended subsequently (with 13 related specimens) because of evidence of close margin on histology.The histological definitive diagnosis of the re-excisions specimens (considering the main lesion if the re-excisions consisted of more than one specimen) is reported in The overall occurrence of residual neoplastic lesions in re-excisions selected for this study was 19 out of 54 (35%).In the series of the intraoperative procedures concerning patient with neoplastic lesions, 5 (13%) were effective in removing the target lesion, 9 (24%) harboured residual neoplastic lesions, and 20 (52%) were reported as normal breast parenchyma or contained benign lesions at definitive histology. On the other hand, 4 intraoperative re-excisions (11%) were related to cases with definitive histological diagnosis of benign lesions. Among the 16 delayed re-excisions, 10 (62%) were effective in eradicating residual tumor.P = .03) even considering the re-excision in the patients with final diagnosis of invasive carcinomas .The rate of residual lesions was compared in the two groups of intraoperative re-excisions  and delayed re-excisions (10/16 re-excisions). The difference was statistically significant  in an area of in situ carcinoma in another case. In 3 of the 8 excisions, the in situ carcinomas were poorly differentiated sec Holland.Another re-excision harboured residual foci of a lobular carcinoma with invasive features.In 7 cases (77%), the residual lesion was close to the new resection margin.In order to assess the role of invasive features in the efficacy of re-excision, we evaluated the rate of residual lesions in re-excisions in the two groups of patients with final diagnosis of invasive carcinoma (13/28) and with final diagnosis of in situ carcinomas (6/17). We excluded re-excision from patients in which the re-excision led to the removal of the target lesion (5 re-excisions).P = .45) and ruling out (P = .45) the peritumoral in situ as residual lesion in resection for invasive lesions. No statistical difference in the distribution of the neoplastic residual lesions between the two categories could be stated, both considering .Similar results were obtained considering only the intraoperative re-excisions .We matched the 20 radiology guided re-excisions and the 9 surgeon guided re-excisions. No statistical difference in the rate of neoplastic lesions was ascertained in the two groups  of the re-excisions leads to the resection of the target lesions, supporting the usefulness of this practice in breast oncologic surgery.Considering the efficacy of intraoperative re-excisions in clearing residual parts of the main lesion, the histological definitive examination detected residual neoplasm in 24% of the cases. Interestingly, the rate of successful re-excision in this study is somewhat lower than the rate of occurrence in other studies available in the literature (see introduction) , 14–17. If we look at the morphology of tumoral residuals in limited intraoperative re-excisions that were confirmed as neoplastic lesions at definitive histology, mutifocal, ill-defined lesions  were detected, and in the 77% of cases the re-excisions were ineffective in completing the removal of the neoplasm, as the residual lesions were close to the new resection margin. Our data show that invasive or preinvasive nature of target lesion does not affect the rate of neoplastic lesions in re-excisions: it could be expected that the oncological adequacy of conservative surgery is dependent on lesion profile and on detection capability at radiological and clinical examination, more than on evidences of invasion.Postsurgical radiotherapy could be a good option in obtaining the local control of the residual lesion that we detected in our revision. A study on predictive factors of residual-positive re-excisions performed on 115 delayed resections  achievedP = .004) and limiting the analysis to cases with final diagnosis of invasive lesions. Placing these results in the background of the debate about the real implication of the finding of close margins, apart from the evaluation methods, our findings could not confirm the hypothesis of a higher rate of tumoral residual in immediate versus delayed re-excision for the absence of repair processes [According to our data, the efficacy of the intraoperative re-excisions  is lower than the efficacy of delayed surgery after histological examination of first resection specimen, both considering all the re-excisions with cases with final diagnosis of neoplastic lesion (excluding those which harboured the target lesion; rocesses ; on the Considering the evaluation method of the first resection adequacy, we could not ascertain any statistical difference between the efficacy of radiological evidence guided re-excisions and the surgeon's choice dependent re-excisions in completing tumoral excision. Probably, a larger number of cases are needed for a more accurate evaluation of these two techniques, but these results show that surgeon's evaluation of surgical bed has a pivotal role in removing neoplastic residual that are not evident in radiology. Concluding, this analysis suggests that intraoperative re-excisions are mandatory when the intraoperative examination doesn't confirm the presence of the target lesions in the first resection specimen, but is more questionable when the lesion is judged close to the resection margin. The lesions that were re-excised in the same surgical session were mainly ill-defined areas with foci of in situ carcinomas, and these findings suggest the employment of other therapeutic options, such as radiotherapy.Considering the adequacy of the resections, it must be underlined that the practice of conservative breast surgery must now face the recent theory of the “sick lobe” which asserts that conservative breast surgery must obtain the complete resection of the whole lobe involved in neoplastic disease . Followi


The phase-response curve (PRC), relating the phase shift of the oscillator and externally given perturbation , is one Here we propose a systematic and efficient approach of estimating the PRC based on the recently developed method in signal processing called Compressive Sensing (CS) . CS is aUsing simulated and experimental data, we show that our CS-based method can produce a decent estimate of the PRCs particularly when the number of spikes is so small that averaging cannot help Fig. . Further


Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) are major components of the immune suppressive cells that potentially limit the effectiveness of an immunotherapy-based treatment. Both of these suppressive cell types have been shown to expand in tumor models and promote T-cell dysfunction that in turn favors tumor progression. In preclinical studies using transplantable mouse models, we observed that live attenuated bioengineered Listeria monocytogenes (Lm)-LLO immunotherapies have an impact on the suppressive ability of MDSC and Treg in the tumor microenvironment (TME), resulting in a loss in the ability of these cells to suppress T cells. This alteration of immunosuppression in the TME was an inherent property of all Lm-LLO immunotherapies tested and was independent of the tumor model. The virtually total loss in the suppressive ability of these cells in the TME was linked to a decrease in the expression of arginase I in MDSC and IL-10 in Treg. We are further investigating if the MDSC are differentiated into functional macrophages that increase antigen presentation within the TME in order to stimulate T cell immunity. Overall, this study provides insight into a potentially novel mechanism of action of Lm-LLO immunotherapies that may contribute to therapeutic anti-tumor responses.


The repression of competition by mechanisms of policing is now recognized as a major force in the maintenance of cooperation. General models on the evolution of policing have focused on the interplay between individual competitiveness and mutual policing, demonstrating a positive relationship between within-group diversity and levels of policing. We expand this perspective by investigating what is possibly the simplest example of reproductive policing: copy number control (CNC) among non-conjugative plasmids, a class of extra-chromosomal vertically transmitted molecular symbionts of bacteria. Through the formulation and analysis of a multi-scale dynamical model, we show that the establishment of stable reproductive restraint among plasmids requires the co-evolution of two fundamental plasmid traits: policing, through the production of plasmid-coded trans-acting replication inhibitors, and obedience, expressed as the binding affinity of plasmid-specific targets to those inhibitors. We explain the intrinsic replication instabilities that arise in the absence of policing and we show how these instabilities are resolved by the evolution of copy number control. Increasing levels of policing and obedience lead to improvements in group performance due to tighter control of local population size (plasmid copy number), delivering benefits both to plasmids, by reducing the risk of segregational loss and to the plasmid-host partnership, by increasing the rate of cell reproduction, and therefore plasmid vertical transmission. Mutual policing constitutes an important mechanism for the emergence and maintenance of cooperation through the repression of intra-group competition among a population of self-interested individuals. Existing models of mutual policing have been highly abstract and distant from the properties of real biological systems. In this paper, we construct a bottom-up, multi-scale computational model reflecting the biology of, perhaps, the simplest example of such a mechanism: replication control in non-conjugative plasmids, a class of vertically transmitted, molecular symbionts of bacteria. We simulate the emergence of plasmid copy number control through the co-evolution of two interacting plasmid traits: policing, realized as the production of trans-acting replication inhibitors, and obedience, expressed as plasmid-inhibitor binding affinities. We demonstrate and explain the intrinsic replication instabilities that arise in the absence of policing and we show how increasing levels of policing and obedience resolve these instabilities and improve both plasmid stability and host performance. The evolution of cooperation is a fundamental problem in biology: why help another individual to reproduce, if this comes at a cost to one's own reproductive success? This dilemma is reflected in the trade-off between an individual's immediate reproductive gains and its longer-term prospects of success as part of a collective, whose stability and overall performance is undermined by internal competitiveness. The eroding consequences of competition are exemplified by the “tragedy of the commons” A particularly elegant example of a policing mechanism for the repression of competition among individuals within a group is the replication control system of bacterial plasmids. Plasmids are extra-chromosomal DNA elements, organized as, typically circular, collections of discrete genetic modules The plasmid CNC mechanism encapsulates the two fundamental traits of standard generic policing models The CNC mechanism for the collective restraint of plasmid selfishness via mutual policing operates in a clear inter-specific context: plasmids often code for accessory adaptive traits that can provide their hosts with a variety of competitive selective advantages under particular environmental conditions The policing mechanism for the control of plasmid replication is subject to a dynamic evolutionary conflict between two levels of selection In this paper, we explore a range of social dilemmas facing non-conjugative plasmids carrying beneficial alleles. These dilemmas are present in the mechanistic interactions between selfishness, policing and obedience that determine the efficiency of the CNC system. More specifically, we use a mathematical model of the symbiotic relationship between hosts and plasmids in order to investigate how the conflict between intra-cellular selection (favoring plasmid recklessness with respect to replication) and inter-cellular selection  orchestrates the evolution of the plasmid-coded CNC mechanism.Our model for cellular growth and division (or death) is based on the premise that cell metabolism produces biomass and when this increasing mass reaches a certain threshold the cell divides. Specifically, let Changes in biomass rate see . As suchA wide range of mathematical models of varying specificity and complexity have been proposed for describing the autonomous replication of plasmids within a host, mostly based on the replication systems of plasmids R1 and ColE1 Parameters stable characteristic copy numberWe begin by focusing our attention to a single cell that contains a population of plasmids that are identical with respect to their replication profile. We initially ignore the stochastic nature of replication and cell division and consider the copy number to be a continuous variable, with both the host growth and the copy number described by deterministic differential equations see . Our modand  see . SubjectFor any configuration of plasmid replication parameters In the former case (NO-CNC), we observe that the system has a stable non-zero characteristic copy number for an extremely limited region of basal plasmid replication rates Our previous simulations demonstrated that, when stochasticity is ignored, there is only a limited range of The performance of a particular strain in such a stochastic simulation, in which hosts are infected by plasmids with identical replication parameter values, can be evaluated by calculating the average net host growth rate as the difference between the average host division and death rates. see also  and, as The stochasticities in plasmid replication and segregation upon cell division give rise to a distribution of copy numbers in the population that occur across all plasmid-infected hosts over the course of a simulation. We explored the effects of obedience  is obtained when we allow all three plasmid replication parameters tors see . In this low see , so thatWe also investigated the influence of policing costs to the evolution of collective restraint and the overall performance of the population, by introducing an additional cost term mids see .The positive effects of CNC are not limited to hosts but extend to plasmids as well. We evaluated the advantages of CNC for hosts and plasmids by comparing the results of our multi-cellular stochastic CNC simulations  of plasmids to the policing resource (replication inhibitor) that they themselves produce. Hosts in which plasmid obedience to policing is strong or under development, will outgrow fellow hosts in which obedience is weaker or absent, thus motivating the reinforcement of cooperation and the eventual establishment of the CNC mechanism.Text S1Detailed information about the plasmid profile used as well as about the methods and their implementation (i.e. the unicellular deterministic and multicellular stochastic simulations).(PDF)Click here for additional data file.


The different biochemical properties of Nit-ANigWT and Nit-ANigRec discussed in the paper were caused by a significant difference in the primary structures of these enzymes.The authors have retracted this article  due to t


Optical microscopy and multi-particle tracking are used to investigate the cross-correlated diffusion of quasi two-dimensional colloidal particles near an oil-water interface. The behaviors of the correlated diffusion along longitudinal and transverse direction are asymmetric. It is shown that the characteristic length for longitudinal and transverse correlated diffusion are particle diameter  The dynamic behavior of confined colloidal suspensions has recently received a considerable amount of attentions The diffusion behaviors of particles reflect the influence of the boundary conditions In this paper, we report an experimental measurement of the cross-correlated diffusion of colloidal particles near a water-decahydronaphthalene  interface. It is shown that for larger particle separation, along the line connecting the centers of the particles and the direction perpendicular to this line, the characteristic length is particle diameter Two types of colloidal particles, both with a diameter The experimental setup is shown as in Using an inverted Olympus IX71 microscope, the motion of the colloidal particles was recorded by a digital camera (Prosilica GE1050) at a rate of 14 frames per second. Each image sequence comprises 500 consecutive frames (taken over The PS monolayer is located at a higher position above the oil-water interface than the silica monolayer because the PS spheres are less dense and have a greater surface charge than the silica particles. The average distance The parameter Tracking individual particle's trajectory, we obtain particle's cross-correlated motion via the ensemble of averaged tensor products of the particle's displacements Typically,The mechanism behind the independence of To focus on the influence of the oil-water interface on the correlated diffusion coefficients, first, we averaged the curves of In the perpendicular direction, We compare our results with previous studies for the following boundary conditions: colloidal spheres dispersed in an unbounded 3D bulk, confined by a solid wall or at an air-water interface At first glance, the result that the decay rate of Similar to the mechanism of a membrane near a solid wall The HIs through path I entail that the cross-correlated motion is a function of tion of  . For a ldent of   for . InFor a very high area fraction We experimentally investigated the cross-correlated diffusion of colloidal particles near an oil-water interface that distinctly affects the correlated diffusion coefficient


Carers of individuals with social care needs , are subject to high levels of carer burden, social isolation and poor psychological outcomes. Carers’ worries and concerns include leaving the individual alone; risks of harm to the care-recipient; or household emergencies in their absence. At present there is a lack of research on the impact of telecare interventions on carer outcomes. It is feasible that carers’ anxieties and level of strain may be ameliorated with concomitant increases in quality of life, with the introduction of telecare systems for their care-recipient.This study investigates the secondary impact of telecare on carers, specifically whether the use of telecare reduces informal carer burden and social isolation and whether it improves carers’ psychological well-being and confidence in leaving the care-recipient alone.We report on the prospective analysis of a pragmatic controlled trial on carers of telecare users and controls within the WSD evaluation of telecare .Carers of individuals with social care needs were identified and recruited to the study via a combination of snowball sampling, light touch visits (to users) and self selection. Over 200 carers completed a questionnaire pack at baseline, and at short and long-term follow-ups; with roughly equal numbers of carers of recipients of telecare and recipients of usual care. The questionnaire pack included measures of quality of life (ICECAP), health related quality of life , psychosocial well-being  and care-giver strain measures .Multi-level modelling of difference in outcomes between carer groups and across time was conducted with appropriate covariates. Specific findings from the Telecare Carers Study are embargoed until these analyses have been peer-reviewed and accepted for publication.


The characteristics of time-driven simulation are a fixed-size simulation step and a fixed-size communication interval . The forThe time-driven environment of the simulator NEST  providesIn general, a time-driven simulator that supports the off-grid framework performs neural network simulations with the same precision and faster than an event-driven simulator . HoweverHere, we present algorithms which are guaranteed to detect all threshold crossings by supplementing the standard test for a super-threshold membrane potential at each check point and that exploit the information about the neuronal state at nearby check points. These additional tests need to be invoked whenever the membrane potential is sub-threshold, which means at virtually all check points. We develop sub-tests of increasing complexity and specificity, starting with simple sifting methods and ending up with a complex expression that faithfully indicates the existence of a threshold crossing between the last and the current check point. An analysis of the test specificities and computational costs results in a cascade of tests which locates all threshold crossings at a low computational cost.


The distribution of synaptic efficacies in neural networks takes fundamental influence on their dynamics and the modification of synaptic strengths forms the foundation of learning and memory. A prominent plasticity rule that has been observed in vitro is spike-timing-dependent plasticity (STDP). While first studied in glutamatergic synapses, recently also STDP of GABAergic synapses came into the focus of experimental and theoretical research .We study random balanced state networks of leaky integrate-and-fire neurons in the asynchronous irregular (AI) regime  that is When introducing excitatory STDP alone, parameters involving the maximal weight have to be fine-tuned in order to keep the network activity stably in the AI regime . For alm


The issue of missing data is present in every trial. Identification of the missing data mechanism is not straightforward; however it is essential to avoid bias. The mechanism of missing completely at random (MCAR) is seldom appropriate and the distinction between missing at random (MAR) and not at random (MNAR) is not straightforward. Follow-up reminder responses provide excellent source of information for investigating the issue.Improving postal response rates for patient-reported outcome measures often requires some kind of reminder process. Patient-reported outcomes from two stroke rehabilitation cluster randomised trials were used to investigate the usefulness of reminders in the identification of the missing data mechanism. In both trials, the reminder process was set-up from the outset. Missing data in these trials had an intermittent pattern. An approach by Fairclough (2010) was used to determine missingness mechanism.Covariates predicting non-response (from reminder-responders) were first identified to distinguish between MCAR and MAR mechanisms and participants outcome scores were added to model testing for inclusion to check for evidence of MNAR.The advantage of this method is that reminder-responses are considered to be similar to non-responders with the additional benefit of knowing the actual outcome. Furthermore, identification of covariates indicated by this approach can inform the choice of covariates for the appropriate method of data imputation.In trials with potentially high loss to follow-up, reminder strategies can be used not only to minimise loss to follow-up but offer valuable data to examine mechanisms of missingness and ultimately contribute to a robust final analysis.


Presented is further development of the architecture presented in  where a The neural network is built on integrate-and-fire spiking neurons with active dendrites (ADDS) and trained with STDP rule presented in . The ove


The global plan of reducing the number of new child HIV infections and a reduction in the number of HIV-related maternal deaths by 2015 will require inordinate political commitment and strengthening of health systems in Sub-Saharan Africa where the burden of HIV infections in pregnant women is the highest. Preventing HIV infection in women of child-bearing age and unwanted pregnancies in HIV-positive women forms the cornerstone of long-term control of paediatric HIV infections. To achieve the goal of eliminating paediatric HIV infection by 2015, health systems strengthening to address prevention of mother-to-child HIV transmission cascade attrition and focusing on the elimination of breastmilk transmission is critical. Understanding the pathogenesis of breastmilk transmission and the mechanisms by which antiretroviral therapy impacts on transmission through this compartment will drive future interventions. Identifying and retaining HIV-positive pregnant women in care and committed to long-term antiretroviral therapy will improve maternal outcomes and concomitant reductions in maternal mortality. Research assessing the natural history of HIV infection and long-term outcomes in women who interrupt antiretroviral therapy post-weaning is urgently required. Data on the outcome of women who opt to continue the long-term use of antiretroviral therapy after initiating therapy during pregnancy will determine future policy in countries considering option B+. The prevalence of antiretroviral resistance and impact on survival in infants who sero-convert whilst receiving neonatal prophylaxis, or are exposed to maternal HAART through breastmilk at a population level, are currently unknown. In addition to the provision of biomedical interventions, healthcare workers and policy makers must address the structural, cultural and community issues that impact on treatment uptake, adherence to medication and retention in care.


Pteronotus parnellii and Pteronotus quadridens) and in Rhinolophus rouxi. Recently, it was proposed that heteroharmonic target-range computations are a primitive feature of the genus Pteronotus that was preserved in the evolution of the genus. Here, we review recent findings on the evolution of echolocation in Mormoopidae, and try to link those findings to the evolution of the heteroharmonic computation strategy (HtHCS). We stress the hypothesis that the ability to perform heteroharmonic computations evolved separately from the ability of using long constant-frequency echolocation calls, high duty cycle echolocation, and Doppler Shift Compensation. Also, we present the idea that heteroharmonic computations might have been of advantage for categorizing prey size, hunting eared insects, and living in large conspecific colonies. We make five testable predictions that might help future investigations to clarify the evolution of the heteroharmonic echolocation in Mormoopidae and other families.Echolocating bats use the time elapsed from biosonar pulse emission to the arrival of echo (defined as echo-delay) to assess target-distance. Target-distance is represented in the brain by delay-tuned neurons that are classified as either “heteroharmonic” or “homoharmormic.” Heteroharmonic neurons respond more strongly to pulse-echo pairs in which the timing of the pulse is given by the fundamental biosonar harmonic while the timing of echoes is provided by one  of the higher order harmonics. On the other hand, homoharmonic neurons are tuned to the echo delay between similar harmonics in the emitted pulse and echo. It is generally accepted that heteroharmonic computations are advantageous over homoharmonic computations; i.e., heteroharmonic neurons receive information from call and echo in different frequency-bands which helps to avoid jamming between pulse and echo signals. Heteroharmonic neurons have been found in two species of the family Mormoopidae ( Echolocation allows bats to create perceptual images of complex night environments Griffin, . A key pPteronotus parnellii; O'Neill and Suga, Pteronotus quadridens, Hechavarría et al., Rhinolophus rouxi; Schuller et al., Myotis lucifugus; Sullivan, Eptesicus fuscus; Feng et al., Carollia perspicillata; Hagemann et al., P. parnellii and P. quadridens) and one species from the family Rhinolophidae (R. rouxi) delay-tuned neurons are activated by the combination of the FM component of the fundamental harmonic in the call and one of the higher harmonic FM components in the echo -FM echolocation  Mormoopidae is the only family of bats including both CF-FM and sCF-FM species.The “heteroharmonic computation strategy” (HtHCS) was first described in The evolution of echolocation has received much attention in the last decade. Recent molecular phylogenies  HtHCS was found in We discuss how brain adaptations, distinctive characteristics of calls- and echoes- and phylogenetic relationships in mormoopids could have led to the acquisition of the heteroharmonic target-range computation strategy in this family. We argue that the HtHCS provides mormoopids with behavioral and ecological advantages for categorizing prey-size, hunting eared insects, and living in large colonies. By conducting the analysis in the light of recent molecular phylogenies, we are able to explore the evolutionary relationships between HtHCS and CF-specializations. We present the hypothesis that in Mormoopidae, HtHCS echolocation evolved independently from long-CF echolocation, high duty cycle (HDC) echolocation and Doppler Shift Compensation. We make five specific, testable predictions that might help future investigations to decipher the evolution of the heteroharmonic echolocation in Mormoopidae and other families.The most commonly used approach to determine whether a neuron is tuned to echo-delay or not consists in presenting the animal with artificial  pulse-echo pairs with different delays. The response of the neurons is measured as the number of spikes fired by the neuron in response to each echo-delay. If the echo-level is also changed during the recording, then the neuronal response is represented in the two dimensional space of echo-delay and echo-level in the form of a delay response area (DRA). Delay tuned neurons respond only  to a few combinations of echo-delay and echo-level  is followed by one of the upper FM-harmonics in the echo  with a certain delay. Delay-tuned neurons are classified according to their best harmonic combination, i.e., the combination of pulse and echo harmonic that elicits the largest response. In P. parnellii, neurons tuned to combinations of FM1 and FM2, FM1-FM3, and FM1-FM4 have been found  in response to heteroharmonic pulse echo-pair combinations, i.e., FM1/FM2 and FM1/FM3. It has been suggested that neurons tuned to different harmonic combinations could provide information about targets with different acoustic properties i.e., preys of different sizes  is not an exclusive feature of heteroharmonic neurons tuned to echo-delay. For example, combination sensitive responses have been found in mice, birds, monkeys and homoharmonic bat species, among others . Only the family Mormoopidae includes both LDC and HDC species. Although useful as a first approach, classifying bats into FM-LDC and CF-HDC according to their calling strategy is not fine-grained enough to explore the evolution of target-range computation in mormoopids.The examination of call design could provide a better understanding of the evolution of the HtHCS for target-range computation in bats and specifically in the family Mormoopidae. Bats use a highly diverse repertoire of call designs. Biosonar call diversity is observed both across ] broadcast calls with three or more harmonics, as do the remaining Pteronotus and Mormoops species  contain two harmonics  use echolocation calls with one or two harmonics  uses the HmHCS  uses multiharmonic calls with harmonic overlapping  with two or more harmonics without frequency overlap. In addition, it is of advantage if the duration and curvature of the FM components are adjusted for acoustic focusing as a function of distance to target, in correlation with neuronal adaptations for the processing of call design as a complement of the target-range computation strategy. Also it could be predicted that bats that use HtHCS are capable of a precise control of call frequency and intensity. The latter will be explored in the following section.Echolocating bats dynamically change the acoustic parameters of calls  to cope with their environment and perceptual task. A closer view at the common principles used by HtHCS bats to exploit frequency and intensity of calls- and echoes- may help to assess the evolution of their target-range computation strategy. This section focuses on the analysis of frequency and intensity because both parameters are closely related in the heteroharmonic target-range computation strategy. The frequency spectrum of each call is determined by the amount of energy or sound intensity distributed between harmonics, and frequency and intensity are the two main parameters used to characterize the receptive field of delay-tuned neurons (see section Delay Tuning in Auditory Neurons of Different Bat Species).Tadarida brasiliensis  and from the maximum frequencies of the third harmonic . Distinction of insect size will be favored by individual auditory neurons responding to either the echoes from the second or the third harmonics , uses one of the lowest frequencies within the genus Pteronotus  is lowered in frequency and the echo's higher harmonics (FMx) is set at the species resting frequency. In contrast, the non-compensating smaller mormoopids should show best responses of delay-tuned neurons for combinations of the call's resting FM1 and the echoes' shifted FMx.Doppler shift compensation is not linked to the HtHCS. DSC involves lowering the frequency of the next echolocation call to compensate for the flight-induced increase in the frequency of echoes from a previous emission  as a promising feature that would support the HtHCS for target-range computation. In addition, both the most basal and one of the most recently evolved species of Pteronotus computes call-echo delay heteroharmonically  are gleaning bats that emit multiharmonic calls with faint fundamental harmonics, but showing frequency overlap  or to aid in the discrimination of different target sizes.If the ability of HtHCS computation characterized the ancestors of Noctilionoidea it may have prevailed at least in descendent species with limited frequency overlap between harmonics. The genera Noctilio and Macrotus are appropriate candidates to test this hypothesis.Intensity compensation is harmonic-dependent in mormoopids and other bats with HtHCS. Calls and echoes represent different harmonic interests for the heteroharmonic echolocator and therefore the rules describing the dynamic adjustment of call/echo intensity will distinguish one harmonic from the other.If the echolocation calls of mormoopids evolved to hunt eared prey, they will be relatively inaudible to moths if compared to calls from HtHCS bats of comparable size.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.


Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases.To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions.Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals  previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans.Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species . The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions.Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species. Over the past approximately 40 years, only around 600 chemicals have been tested by the NTPs in their two-year cancer bioassay and only about 5–6 times this number have been tested worldwide.There is push to use a broad array of biological data in toxicity testing to improve reliability and provide reasonably quick indications of animal and human toxicity of chemical compounds. The National Toxicology Program (NTP) 's High Throughput Screening (HTS) in vitro results from the various cell lines to the human in vivo context.The goal of toxicity testing is ultimately to protect human health. Even though the two-year cancer bioassay is performed on rats and mice, there is considerable data supporting its use to screen for carcinogens in humans An alternative to the cell-based assays in the HTS and ToxCast programs is the use of short term molecular data  from exposed animals or humans to predict future toxicity or carcinogenicity. Others have used gene expression data based classifiers that would distinguish a toxin or carcinogen from a non-toxin or non-carcinogen A characteristic of gene expression data is the very large features (genes) to samples  ratio. This characteristic contributes to the lack of identification of robust classifiers as demonstrated by In order to gauge quantitative predictive accuracy of a pathway-based prediction model we obtained gene expression data from the livers of mice dosed with 26 chemicals over a period of 90 days. All the 26 chemicals were tested in a two-year bioassay in the same strain of mice dosed via the same respective routes. Thus, the differential liver carcinoma and adenoma rates between treated and control animals from the results of the two-year bioassays are known. Using the data, we derived pathway-based models to predict the differential tumor rates at the end of a two-year bioassay. The use of a pathway-based model would result in a reduction of a model with around 6000 gene features to one with around 200 pathways in the KEGG database 1 mice are summarized in The chemical treatments used in the experiments on female B6C3FTo address the question of species extrapolation, gene expression and tumor data from chemical exposures in Fischer 344 rats were obtained from the literature The pathology review of the treated mice after 90 days of exposure to hepatocarcinogens did not identify liver tumors see . Hence, 2-transformed. The entire set of data sets associated with risk factors for liver cancer is summarized in Genetic risk factors in terms of single nucleotide polymorphisms associated with various human diseases including liver cancer are tabulated on databases like the Genetic Association Database The biochemical pathways used in the analysis in this paper were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database 4 randomizations , cN the number of chemicals . iz is given by ijZ is given by Specifically, the poly-3 statistic for a chemical obtained from the two-year cancer bioassays is assumed to be functionally related to the 90 day gene expression-based perturbation of the pathways :The framework of the so-called Super Learner CV.SuperLearner function implemented in the SuperLearner package. Specifically, the predictions for the chemicals in each of the 5 test sets (corresponding to the 5-folds) are derived from an additional 5-fold cross-validation of the remaining 20 or 21 chemicals in the 5 training tests.Five-fold cross-validation was chosen where the chemicals in each of the five folds were fixed (Table S3) and chosen so that distribution of high and low carcinogenicity values in each fold was more or less the same. Predictions for all the data sets were based on this 5-fold cross validation framework. In order to get ‘honest’ predictions for the chemicals with data from mice, because these chemical data are used to make predictions for the very same set of chemicals, two levels of 5-folds cross-validation was implemented using the The two year cancer bioassay carcinogenicity calls of the chemicals used in the mice and rats experiments along with the continuous predictions from the model ) derivedSL.randomForest.1_All in importance for each of the biochemical pathways used in the prediction model. The importance of a pathway is a measure of how much it contributes to increases the accuracy of the predictions.Different prediction models were evaluated in terms of their 5-fold cross-validated risk for fitting the model given by The model derived using the mouse data was used to predict the carcinogenicity in mice, rats and humans for the corresponding data sets. In this manuscript, the predicted values were treated as proxies for the continuous NTP carcinogenicity values in The false positives and false negatives in each of the three species at a level of specificity between 56–75%  is summarized are This paper presents results only for pathway-based prediction models. Gene-based prediction models were also evaluated and they showed a similar performance in terms of the AUC metric (data not shown) The importance measures for each of the pathway-based features are reported in The predicted dose response for the chemicals in The analyses involved in this paper worked with hepatocarcinogenicity prediction models trained using data from mice and extrapolated to data sets from rats and humans. Alternate models derived from rats to predict carcinogenicity in other species could be attempted. This was not attempted here because of lack of sufficient analogous two-year cancer assay data for the rat and human data sets. The model derived here used data for chemicals at their maximum tolerable dose (MTD) levels. It could be argued that responses at lower doses are the ones with the most human relevance. Again this was not attempted here because of lack of sufficient number of chemicals dosed at lower levels. One possibility of understanding chemical-specific low-dose mechanisms would be the availability to a relatively large epidemiological data set of exposed people . The mice have a relatively high background rate of developing HCC. In humans, HCC is thought to arise in a background of chronic inflammation, necrosis and regeneration, fibrosis and extracellular matrix deposition However, in the predictive toxicology context of the manuscript, in spite of the known differences in etiologies, our hypothesis is that gene expression levels of the precancerous lesions are the similar in mice and humans. This hypothesis is validated by the relatively high predictability of human hepatocarcinogenicity using an independently derived predictive model using 90 day gene expression data from B6C3F1 mice. Further, the work in Hoeneroff et al suggests that this hypothesis is not without justification. In their work the authors found similar gene expression profiles in cells from HCCs obtained from mice and human samples. The situation is analogous to the case of azoxymethane induced colon cancer In summary, we rigorously derive and evaluate a biochemical pathway based hepatocarcinogenicity prediction model. Among the set of alternate prediction models , random forests were found to perform the best in terms of cross-validated risk. The model used gene expression data from a given tissue at the end of a short term study to predict the risk for development of tumors at the end of a longer period of time. Specifically, the model is evaluated using gene expression data obtained from the liver of mice treated with a range of 26 chemicals over a period of 90 days. The model with the information on affected pathways derived using these gene expression data had sufficient signal to adequately predict the two-year liver carcinogenicity risk of the same chemicals as evaluated in the National Toxicology Program's two-year cancer bioassay. The fact that the model was developed at the biochemical pathway level allows one to reasonably expect conserved behaviors of the chemicals at the pathway level across multiple species. This belief was validated using the model developed for mice to predict results in humans and rats. This fact was observed in Figure S1Clustergram of transformed p-values ) representing the enrichment of the 216 pathways across the 26 chemicals treatments in mice, was generated using hierarchical clustering with the euclidean distance metric and average linkage to generate the hierarchical trees of pathways and chemicals using the Cluster and Tree view programs .(PNG)Click here for additional data file.Text S1Provides additional description of the microarray experiments, involved in mice and rats, the data for which are used in the analysis. Also provided are details of generation of (DOC)Click here for additional data file.Table S1List of rat hepatocarcinogen treatment groups from Auerbach et al., 2009.(XLS)Click here for additional data file.Table S2List of chemicals in  that were chosen to be in each of the 5 folds in the cross-validation analysis performed.(XLS)Click here for additional data file.Table S3List of various learning algorithms attempted in the SuperLearner package  and the cross-validated risk for the case of pathway-based continuous predictions.(XLS)Click here for additional data file.Table S4The list of pathways used as predictors along with their importance measures as reported by the random forests learning algorithm . The importance measures for each of the pathways are also reported.(XLS)Click here for additional data file.


Mimetics of secondary structure elements are one promising approach in the design of protein-protein interaction inhibitors, since secondary structure elements are very important recognition motifs in protein-protein interfaces. In helices and turns, the protein backbone provides a scaffold to present the sidechains in the correct orientation for the three-dimensional interaction motif. For both, scaffolds are known that resemble these backbone conformations and can be decorated with sidechains in the right position for mimicking the interaction motif . BenzodiHowever, identifying small chemical scaffolds that mimic turn structures is rather complicated. Turns are irregular structures with a wider variety of possible backbone conformations  and for The results of an exhaustive analysis of turn structures involved in protein-protein interfaces will be presented and the impact on the design of secondary structure element mimetics will be discussed. This is of particular interest since the secondary structure space of protein-protein interfaces is limited and similar interfaces with respect to secondary structure elements exists within proteins showing different overall folds and function . The ide


Various criteria to terminate resuscitation have been reported. EMTs in Japan are not permitted to terminate resuscitation in the field. The aim of this study is to test the hypothesis that ECG rhythm response to basic CPR and its duration may predict hospital death.The basal data were prospectively collected from 1,437 unwitnessed out-of-hospital cardiac arrests (OHCAs) that were resuscitated by EMTs without the ACLS technique in Ishikawa Prefecture  in hospital. The duration of EMT-performed CPR predicted the outcomes of the OHCAs that were unresponsive to the basic CPR Figure .Responsiveness to basic CPR and its duration may predict unavoidable death in hospital.


F-18 Fluorodeoxyglucose Positron Emission Tomography imaging (F-18 FDG PET) detects malignancies depending on the uptake profile of glycolysis of tumors; however, the role of FDG PET is limited in the evaluation of primary renal malignancy because of low FDG uptake by renal cell carcinoma and also because normal urinary excretion of FDG seen in the images. A patient with renal cell carcinoma whose FDG PET imaging study incidentally shows a photon-deficient mass in the upper pole of the right kidney is present here. The diagnosis is also validated by the histopathological findings of tumor necrosis, hemorrhage, and scars. It is well established that advances in F-18 FDG PET imaging may lead to early cancer detection, more accurate tumor staging and consequently adequate treatment, better monitoring of the disease and enhanced surveillance for recurrences after treatment. The role of FDG PET is limited in the evaluation of primary renal malignancy because of low FDG uptake by renal cell carcinoma (RCC) and because of the normal urinary excretion of FDG seen in the images.A 69-year-old man with a history of having undergone coronary artery bypass graft, cholecystectomy, cerebro-vascular accident with craniotomy and recent hoarseness of voice for eight months had recently invasive squamous cell carcinoma of vocal cord. CT of the neck without contract enhancement showed deformity of the larynx with thickening of the anterior commissure and right vocal cord which are characteristic of a mucosal lesion. He also suffered from new onset of changes in non-specific gastrointestinal symptoms. Therefore he underwent an abdominal CT with contrast medium which incidentally showed a heterogeneously enhancing exophytic mass projecting posteriorly from the upper pole of the right kidney . Four daA case of a photon-deficient area in the upper pole of the right kidney on FDG PET scan , which wRCC is a diagnostic challenge. Among all patients with RCC, 25%–39% are asymptomatic and the diagnosis is made from a radiological study obtained for the reasons.In the study of FDG PET in detection of RCC, Ak and Can reported that F-18 FDG PET may have a role in the diagnosis and evaluation of patients with RCC and primary staging of the disease.FDG PET is limited in the evaluation of primary urological malignancies including prostate and urinary bladder cancer.17In summary, a patient with renal cell carcinoma, whose FDG PET incidentally showed a photon-deficient mass in the upper pole of the right kidney is presented; this finding can be explained by non- uptake of the tracer by the tumor, and the histopathological findings of tumor necrosis, hemorrhage, and scars.


The Picardie region is one of the regions in which the incidence of methicillin-resistant Staphylococcus aureus (MRSA) is high  compared to the French national average .That is why the regional center for nosocomial infections control in 2012 made an assessment study on the actions and the resources involved in prevention and control of MRSA and Multi-Drug Resistant Bacteria (MDRB).The survey was proposed to 82 hospitals in the region using on-line or paper questionnaires forms. Data were entered and analyzed using Epi-Info 6.04d software.Overall 41 hospitals  participated in this investigation. 66% of them reported having a system of continuous monitoring of MDRB for the identification of clustered cases and 39% of the hospitals reported having a similar device for the identification of re-hospitalized cases. In addition, 63% of respondents indicated that they did not develop transmission means for the patients with MDRB to inform the hosting facility during a subsequent hospitalization. When a case of patients with MDRB occurs in a hospital, 88% of them track cases of re-hospitalized patients thanks to patient records and not via the administrative software. 57% of the hospitals reported to implement a policy of MDRB monitoring. More than half patients considered to be at risk  was concerned in the majority of sectors welcoming patients with emerging MDRB. The most frequently screened MDRB are respectively MRSA (46%), carbapenemase-producing Enterobacteriaceae (44%), glycopeptide-resistant Enterococci (44%) and extended-spectrum beta-lactamase-producing Enterobacteriaceae (41%).The components of the MDRB control which are collected within the hospitals of the region have shown critical points, especially in the monitoring of patients with MDRB. Specific policy focusing MDRB should be reinforced in the region.None declared


The today’ s technologies allow an easy way to share information relevant to image by means of different tools. Many solutions are today available that allow to the cytologist to exchange digitalized information about glasses. It is thus arising the need of objective methodologies, such as the ones based on HTA that we have proposed in a previous study focused in tele-pathology , to inveIn a typical today’s architecture there ison-site-server with the scanner or alternatively a tele-pathology third-party-server , for the creation of the virtual glasses named Digital Slides (DS)s,a) an ’ centre  at http:andLight-client applications proprietary software tools  for the navigation on the DS which can be installed in remote clients.b) low cost (or free) This new methodology is rapidly largely spreading and it is becoming the core aspect of the formation for future qualified personnel and is more and more asking for user-friendly and effective ICT solutions.Tablet-technology-ICT-solution is recently widely increased as a user-friendly and effective tool to remotely share image information. Thanks to this technology it is possible to navigate into an image  using only the hand-fingers without typing the keyboard or the software interfaces’ keys. This way of image navigation is going to further improve the application of Telemedicine to DP and in particular in D-CYT with particular reference to the remote and/or cooperative decision and diagnosis in cytology.The The methodological flow clearly arises by inviting the reader to navigate in the Public WEB of the University of Leeds named “Virtual Pathology at the University of Leeds” where several digital-slides are available for public use at the URL :http://www.virtualpathology.leeds.ac.uk/public/common_slides.phpsubjectively consider thus the differences. It is thus clear that there is thus strongly the need of considering both the state of art of the Tablet technologies and the design of an objective methodology to assess the technology. The methodological flow faced thus the two basic issues:The reader can try to navigate the DS by means of a PC using the interface of Spectrum Web Viewer (by Aperio) or by means of a Tablet system using the fingers and Analysis of the state of art of the tablet technologies.• Investigation of HTA solutions [ to assess the technology (Tablet and applications of D-CYT) both in terms of performances and acceptance for the relevant introduction in Telemedicine [• olutions  to assesmedicine -8, [9,10wearable tablets, portable tablets and not-portable tablets.The analysis with the focus to D-CYT returned that the tablet technologies could be grouped into: wearable tablets comprehend the Smart-phones i.e the devices that can be embedded in a pocket  .1. Further issues relevant to studies of HTA, as from specific experience of mondial networks of HTA such as the EUNETHTA (2. Integration of specific studies on HTA over the NET, as the focus is the D-CYT is the communication over the WAN/LAN.Tablet technologies have been reviewed with the focus to the perspectives of the D-CYT. A HTA specific tool has been proposed to assess the performances and acceptance of the applications in D-CYT based on tablet technologies. Possibilities and limitations of the three different tablet technologies will be deeply investigated by means of the proposed HTA methodology on experts and students approaching the new scenario of digital-cytology.HTA: Health Technology Assessment; DP: Digital Pathology; D-CYT: Digital Cytology; DS: Digital SlideThe authors declare that they have no competing interests.DG MRG wrote the manuscript as major contributors. MP has prepared the review on the wearable and portable and not portable Tablet technologies and is currently caring the experimentation study. EG has reviewed and improved the scientific content and rationale of the manuscript. All authors have read and approved the final manuscript.


The Seal or Varnish study is a pragmatic randomised trial to evaluate the relative cost and effectiveness of pit and fissure sealants and fluoride varnish in preventing dental caries in high-risk children in South Wales. In partnership with the Cardiff & Vale UHB Community Dental Service (CDS), the trial utilises the infrastructure of an existing school-based dental programme to conduct clinical assessments/intervention delivery via mobile dental units.While this research naive setting is novel for a CTIMP, in accordance with the 2012 MRC/DH/MHRA joint guidance for risk-adapted approaches to the management of CTIMPs, the low risk nature of the interventions have allowed justification of several risk-based adaptations to the management and conduct of the trial. In addition, through the use of consultation exercises with a representative parents group, adaptations to the standard NRES templates for participant information sheets/consent forms have also been developed in an attempt to maximise uptake onto the trial.Employment of the risk-adapted approach has minimised additional administrative burden placed on the CDS in implementing the trial compared with the existing dental programme. The adaptations made to the consent process and participant materials have received positive feedback, however consent rates for the trial were found to be lower than previous years' response rates to the dental programme in the majority of schools.This trial represents one of the first experiences of employing a risk-adapted approach to management of CTIMPs, highlighting several areas for consideration when designing and implementing trials involving low-risk interventions in novel environments.


Auditory brainstem calculates horizontal direction (azimuth) of sound from the ITD . Jeffress proposed in 1948 that sound source azimuth is computed by a neural circuit consisting of an array of delay lines . We studWe present our current results as a case study showing multitude of roles of (random versus deterministic) spike timing in a neural circuit. In particular, either phenomenological (excitatory-excitatory and excitatory-inhibitory units), or electrophysiological (excitatory and inhibitory synapses) classification of individual elements of the circuit might be abstracted in an explanation stressing the neural computation in the circuit. We study various parameters of the MSO model and their influence on the output of the model. Finally we evaluate the performance of the model using the concept of ideal observer.


Critical dynamics in complex systems emerge at the transition from random to ordered dynamics and are characterized by power-law distributions of spatial and temporal properties of system events. The occurrence of critical dynamics in neuronal networks is increasingly supported by multielectrode array recordings of spontaneous activity in organotypic cortical slice cultures . System Here, we present three novel transfer-entropy  based meDynamics in our networks change from subcritical to critical to supercritical as the modular topology of the networks is progressively randomized Fig. . All thr


It has been known for some time that photoreceptors transmit more information when driven by stimuli which have 'naturalistic' statistical properties and that processing of naturalistic visual stimuli involves nonlinear transformations of the input signals. Until now it was not clear which statistical features of the stimuli the neurons are selectively 'tuned' to respond to. Another major difficulty was to elucidate the computational mechanisms which explain differences in coding naturalistic and Gaussian stimuli.Drosophila photoreceptor to fully characterize their underlying computational capabilities. The model was derived based on photoreceptor responses measured in vivo using naturalistic input stimuli, which the system experiences in its natural environment. In order to characterize the nonlinear transformations performed by photoreceptors we analytically computed the higher-order or generalized frequency response functions (GFRFs) of the identified nonlinear photoreceptor model. Using this approach, we demonstrate, for the first time that the observed increase in power of photoreceptor response, and shift towards higher frequencies as the mean light intensity increases, is the result of changes in the operating point of the photoreceptor, which produces a change in the shape of the magnitude of the frequency response functions. This suggests that the photoreceptor adaptation mechanisms are not tuned to fully compensate for the drop in intensity in order to achieve, in an efficient way - by exploiting the photoreceptor nonlinearity - a change in the shape of the magnitude transfer functions, which are optimal for the given mean intensity level.Here we used a functional model of Furthermore, we examined the significance of both local and non-local high-order phase correlations for fly vision. We simulated the photoreceptor model using synthetic stimuli sequences incorporating local phase correlations (edges) and non-local phase correlations (quadratic phase coupling) superimposed with Gaussian white noise. By decomposing voltage output of photoreceptor somata into linear second- and higher-order responses, we explain the nonlinear mechanisms responsible for coding the local and non-local higher-order statistical features in the stimuli as well as improving their signal-to-noise ratio.To validate the results, we carried out electrophysiological experiments using a specially designed stimuli sequence, which allows extracting the nonlinear component of the photoreceptor response directly from data, without a model.The frequency response decomposition employed in this study allowed us to reveal for the first time the quantitative relationship between the higher-order statistical properties of environmental stimuli and processing of these stimuli in fly photoreceptors. In light of the results, we argue that the goal of early sensory coding is to maximize sensitivity to higher-order statistical features of the stimuli that are behaviorally relevant to the animal whilst minimizing sensitivity to non-informative signals, to encode efficiently these features and increase their salience to facilitate further processing. Our framework elegantly explains the differences in coding of naturalistic and white noise signals and how this is achieved efficiently without a change in the response transfer function of the photoreceptor when the mean light intensity is constant. It also explains why and how naturalistic stimuli increase the rate and efficiency of information transmission.


The aims of this study are twofold: (1) the theory-based development of a patient self-report measure of physician warmth; and (2) the application of cognitive interview methodology to understand patients’ perception and interpretation of this new measure.A draft measure was developed based on an in-depth literature review of the concept of human warmth by a multidisciplinary expert group working in integrative medicine. Sixteen cognitive probing interviews were conducted to examine how patients from integrative and conventional medicine perceive and interpret this new measure and to identify potential problems. A content analysis of the interviews was used to evaluate findings.Findings indicate that the WARMOMETER is a short patient self-report assessment of physician warmth, which seems easy and intuitive to understand for every patient. In addition, most respondents were found to share a common concept of physician warmth.Verification of our study hypotheses and confirmation of the theoretical assumptions of human warmth give basic indications that the WARMOMETER seems to be a valid and sensitive patient self-report instrument for assessing the socio-emotional quality of physicians in integrative and conventional medicine. These first promising results of our cognitive interviews suggest that the WARMOMETER may also be used and further validated in future studies on the patient-physician relationship in integrative medicine, also with other healthcare professionals, e.g. nurses.


Levels of precursor proteins of collagen I and III are increased in fibrotic pulmonary diseases. This study determined whether the expression of precursors of type I and III collagen proteins would be increased in small and large airways of COPD patients in various stages of the disease reflecting fibrogenesis.The levels of precursor proteins of collagen I and III were studied by immunohistochemistry and quantified by image analysis in lung tissue of 16 non-smokers, 20 smokers with normal lung function, 20 smokers with stage I-II COPD and 8 ex-smokers with stage IV COPD.In large airways, the subepithelial layer which was positive for precursor proteins of collagen I and III was thicker in smokers and in stage I-II COPD compared to non-smokers. Large airways in stage IV COPD showed reduced expression of precursor protein of collagen I whereas precursor of collagen III was increased. The amount of precursor protein of collagen III was increased in small airways of smokers and stage I-II COPD but reduced in stage IV COPD.Precursor proteins of collagen I and III revealed different expression profiles in large and small airways in various stages of COPD. Smoking enhanced expression of both precursors in large airways with a positive correlation with pack-years. Repeated exposure to cigarette smoke induces persistent inflammation and oxidative stress in lungs, which leads to damage of lung parenchyma and airways and a process of continuous repair and remodeling . It is nThe small airways are the major source of airflow resistance  and thusThere are clear histopathologic differences between asthma and COPD ,11, i.e.Collagens are the classical components of the extracellular matrix. In lung tissue, collagen I is the most common collagen and it confers tensile properties while collagen III permits multidirectional flexibility, contributing to lung compliance . CollageCigarette smoke induces changes in lung tissue that are not simply destructive since the smoke can also trigger an active repair process leading to protein production and small airway remodeling. It is not known whether the destruction of lung parenchyma leads to the compensatory formation of connective tissue in an attempt to preserve lung tissue integrity. The aim of this study was to evaluate the expression of precursor proteins of type I and III collagen in small and large airways of COPD patients in order to determine if the expression of these proteins would change during the progression of COPD.2. COPD was defined on the basis of preoperative lung function: FEV1/FVC less than 70% and no reversibility (bronchodilatation effect less than 12%). The clinical characteristics were obtained from the patient records  undergoing resection for lung tumour were drawn for immunohistochemical studies from the archives of the Department of Pathology, Oulu University Hospital. Due to the fact that the resection of malignant tumors may theoretically have an influence on the adjacent structures, lung tissue specimens of non-malignant lung obtained during surgery for hamartomas were additionally included . In all, 33% of the operations were pulmectomies, 60% lobectomies and 7% bilobectomies. No wedge resections were included. Tissue specimens from tumor-free central bronchi and peripheral lung tissue were selected. The patients were not receiving any corticosteroid therapy  and did not suffer from an asbestos-related disease. In addition, lung tissue from 8 patients  undergoing lung transplantation due to very severe i.e. stage IV COPD were obtained from the Department of Pathology, Helsinki University Central Hospital. These patients were receiving either inhaled or systemic corticosteroid treatment and they were all ex-smokers. The lungs were fixed in inflation. The size of the each lung tissue specimen was approximately 1-2 cmFormalin-fixed paraffin-embedded lung tissue specimens were identified from computerized records. All material was re-evaluated by a pulmonary pathologist and a pulmonologist. Two tissue blocks from each patient were selected, one from the resection line with central cartilage-containing bronchus and the other from the peripheral lung. Four-μm sections were cut for immunohistochemical analyses. The sections were deparaffinized in xylene and rehydrated in a descending ethanol series. Endogenous peroxidase was blocked by incubating the sections in 3% hydrogen peroxide in absolute methanol for 15 minutes.The primary polyclonal antibodies to the amino-terminal propeptides of human type I procollagen  and type III procollagen  were produced as described previously ,19 and uThe immunohistochemical staining was performed as previously described ,17 usingAll membranous bronchioles with diameters less than 2 mm were analyzed. Digital photographs were taken using a Leica DFC 320 camera attached to a Nikon Mikrophot SA microscope, via Leica IM 50 software. The measurements made are shown in Figures The immunohistochemical expression of precursor proteins of collagen I and III was quantified by the image analysis method. Immunohistochemically stained slides of central bronchi and peripheral bronchioli were photographed digitally so as to include all of the chosen material described in the previous paragraph. The extent of positive expression was measured in large and small airways in each study case. The quantification was based on a measurement of the thickness of the subepithelial band expressing precursor proteins of collagen I and III at 30 random locations and the subepithelial area expressing these precursor proteins between the basement membrane and the inner smooth muscle border. Staining was assessed with an image analysis system using freely available software ImageJ version 1.24o developed at the National Institutes of Health, using the technique described by Kim et al .The statistical analyses were performed with SPSS for Windows software . Continuous data were compared using analysis of variance (ANOVA). When ANOVA results indicated that the groups differed, post hoc comparisons were performed using two-tailed t-tests. Categorical data were compared using Fisher's exact test designed for small sample groups. P-values less than 0.05 were considered statistically significant.The study protocol was approved by the ethical committees of the University of Oulu and Oulu University Hospital, Helsinki University Central Hospital and by the Finnish Natiolegal Board.Peripheral lung samples showed 1-3 transversely cut bronchioles (diameter < 2 mm) per case. Although bronchioles of stage IV (very severe) COPD were collapsed with a small internal lumen area, the other dimensions did not reveal any statistically significant differences between the groups . The precursor protein of collagen I positive subepithelial layer was thicker in the smokers and patients with stage I-II COPD when compared to the non-smokers. The patients with stage IV COPD showed diminished expression of collagen I precursor when compared with the patients with milder disease or the smokers . Figure  The subeThe expression of propeptides for collagen I and III was found to co-localise with spindle-shaped, alpha-smooth muscle actin positive, vimentin negative fibroblastic cells in small airways Figure  and largThis is the first study to investigate the immunohistochemical expression of precursor proteins of collagens I and III as quantified by an image analysis technique in non-smokers, smokers and patients with COPD at various stages of the disease. The levels of both proteins were increased in large airways of smokers and patients with stage I-II COPD. In contrast, precursor proteins were expressed differently in large airways of patients with stage IV COPD i.e. in these patients the amount of precursor protein of collagen I was reduced whereas that of collagen III was elevated. The present study also revealed that the increase of the precursor protein of collagen I and III in the large airways of smokers correlated positively with pack-years. No detectable expression of the precursor protein of collagen I was found in small airways, whereas the amount of the precursor protein of collagen III was increased in the bronchioles of smokers and in stage I-II COPD. Overall, the amounts of precursors of collagen I and III were increased in smokers and stage I-II COPD but tended to decline either in large or small airways in stage IV COPD.The accumulation of the precursor protein of collagen I could represent the synthesis of type I collagen which in turn offers protection from the distension and shearing effects of hyperinflation, while its absence may further contribute to alveolar wall disruption and emphysema formation in conjunction with other mechanisms. In contrast, the expression of the precursor protein of collagen III within small airways was increased in patients at stages I-II COPD and moreover, its amount correlated positively with the results of the lung function tests. The very thin subepithelial layer expressing collagen III precursor proteins in stage IV COPD may be attributable to decreased fibrotic activity in small airways in end-state COPD, and the combination of this defective repair of injured airways with elastin destruction which could evoke diminished compliance and disrupt the elastic properties of lung tissue. Decreased precursor protein of collagen III in stage IV COPD may also be due to the end-stage of the remodelling process, a diminished capacity of the lung cells to produce collagen III, and/or a shift in the balance towards degradation. The discrepancy in the expression profiles of the precursor proteins of collagens I and III reflects the fact that the regulative processes of these two collagens differ in COPD. In addition, there were few spindle shaped alpha-smooth muscle actin positive fibroblastic cells especially in the small airways but these cells co-localised with the expression of the studied collagen propeptides, suggesting that fibroblasts could well be one source of this newly synthesised collagen.We have previously shown that in the developing human lung, the precursor proteins of collagen I and III were expressed through all gestational ages and also in respiratory distress syndrome and bronchopulmonary dysplasia in a rather similar way both in bronchi and in the bronchioles underneath the airway epithelium  Thus, fiThe collagen III deposition which was accompanied by an excess of fibroblasts as detected in the large airways of patients with severe asthma was not observed in COPD . The myoin vitro conditions cigarette smoke can inhibit fibroblast recruitment, proliferation and extracellular matrix contraction [In our earlier studies, we found diminished levels of the rate-limiting enzyme of glutathione synthesis in smokers' lung  and thistraction  as well traction . The dentraction . It has traction .The limitations to this study include the lack of stage III COPD patients, since they have advanced airflow obstruction and operative treatment for their lung tumors is often not possible. Patients in the stage IV COPD groups were younger than those in the other groups, they were ex-smokers and they were heavily medicated often with both inhaled and systemic corticosteroids. Half of the patients with stage IV COPD had alpha-1-antitrypsin deficiency while the other half had normal levels of alpha-1-antitrypsin; however the histopathological destruction of lung tissue showed no difference between these two groups. In addition, no age-related change in the collagen content of the lungs of non-smokers has been found . Little Procollagen I and III are not specific to any fibrotic disease, since these proteins are components of both normal and enhanced remodeling. Our study confirms earlier reports in COPD patients that there is actual fibrosis beneath the basement membrane with increased collagen accumulation . The difWe conclude that smoking induces immunohistochemical expression of precursor proteins of collagen I and III in large airways of healthy and diseased lung and this change correlates with the pack-years. Moreover the amounts of both precursors exhibit variable expression profiles in large and small airways of patients with COPD in various stages of the disease. Accumulation of precursor protein of collagen III is increased in the small airways of patients with mild-moderate COPD but declines in end-state disease, possibly as a marker of the cessation of active fibrogenesis or as a result of enhanced degradation of the protein. These results suggest that smoking can induce the fibrogenesis of airways even in 'healthy' smokers with normal lung function. Furthermore, in COPD not only the small airways, but also the large airways display evidence of fibrogenesis. The effective treatment of the small airway disease in COPD will require a better understanding of the relationship between airway fibrosis and airflow obstruction, and also an awareness of extracellular matrix turnover and its regulation in smoking related diseases.The authors declare that they have no competing interests.TH participated in the design of the study and selection of patient material, performed the morphometric analysis, the statistical analysis and drafted the manuscript. VLK participated in the design and coordination of this study, selection of patient material, and helped to draft the manuscript. PP participated in the selection of patient material and analysis of immunohistochemical results, and helped to draft the manuscript. KS participated in the selection of patient material and helped to draft the manuscript. JR participated in the design of the study and provided the collagen precursor antibodies and helped to draft the manuscript, RK conceived the study, participated in the design of the study and selection of patient material, analysis of immunohistochemical results and helped to draft the manuscript. All authors have read and approved the final manuscript.This work was supported by grants from the Finnish Anti-Tuberculosis Association Foundation, Finnish Association of Respiratory Medicine, Sigrid Juselius Foundation, the Academy of Finland, EVO Funding of the Helsinki University Central Hospital and Oulu University Hospital, and the Jalmari and Rauha Ahokas Foundation.


The comprehensive meta-analysis of Nine of the 10 studies Linear extrapolation is used in radiation protection if cohort strata pertaining to low doses and dose rates have low statistical power. There are, however, indications for non-linear protective effects of low doses delivered at low dose rates for end points related to athero-sclerosis in mice . MoreoveIn this context we note that in the 10 studies analyzed by Our results might have implications for issues of public health in the assessment of risk–benefit ratios for radio-diagnosis or radio-therapy. Thus, we encourage the use of multi-model inference techniques in the analysis of other cohorts. From our experience with the LSS cohort, we would expect lower risk estimates in the lower dose range with a more comprehensive characterization of uncertainties and improved support of the epidemiological data.


Deficits in decision-making have been repeatedly observed in various psychiatric disorders  as well as in frontal lobe patients. Such decision-making deficits are often assessed using the Iowa Gambling task (IGT) . The IGTRecently, these behavioral findings were successfully translated to animal research in a rodent version of the IGT, the Rat Gambling Task (RGT). In common with human studies, it was found that a third of a healthy population of rats exhibited poor decision-making performances . The ratHere we use a model of learning and decision-making in the RGT to answer the following questions: (1) how do the behavioral traits described above influence learning; (2) how is this manifested in terms of their decision-making performance?In order to model the learning and decision process of the RGT, we used a TD-learning algorithm . The modWe found that the model could account for the performances of good and poor subpopulations of decision makers. Additionally, the parameters defining the behavioral traits extracted from the model correlated significantly with those measured experimentally for the poor and good decision makers’ subgroups. The model was also able to predict the inflexibility of poor decision makers during reversal conditions.Our work supports the hypothesis that it is a combination of high scores for risk seeking, sensitivity to reward and cognitive inflexibility that lead to poor decision-making performances. According to the model, behavioral traits affect the learning process of the subjects by altering the estimated value of the received rewards and reducing their ability to reverse their initial estimations. This results in an incorrect perception of the environment, leading to an optimal decision-making according to their world representation but aberrant according to the real outcome of the task.


Aire gene can influence the transcription of such a large number of TRA genes within mTECs. From a mechanistic viewpoint, there are two possible models to explain the function of Aire in this action. In the first model, TRAs are considered to be the direct target genes of Aire’s transcriptional activity. In this scenario, the lack of Aire protein within cells would result in the defective TRA gene expression, while the maturation program of mTECs would be unaffected in principle. The second model hypothesizes that Aire is necessary for the maturation program of mTECs. In this case, we assume that the mTEC compartment does not mature normally in the absence of Aire. If acquisition of the properties of TRA gene expression depends on the maturation status of mTECs, a defect of such an Aire-dependent maturation program in Aire-deficient mTECs can also result in impaired TRA gene expression. In this brief review, we will focus on these two contrasting models for the roles of Aire in controlling the expression of TRAs within mTECs.The discovery of Aire-dependent transcriptional control of many tissue-restricted self-antigen (TRA) genes in thymic epithelial cells in the medulla  has raised the intriguing question of how the single  Aire gene can influence the transcription of such a large number of TRAs within mTECs . Most importantly, none of these cell lines express a reliable level of Aire at the protein level. However, large aspects of Aire’s action on TRA gene expression in the transcription model were deduced on the basis of the effects of lack of Aire expression in mTECs in vivo  and the opposite effects of Aire overexpression in mTEC-“like” cells in vitro . The reality is that there is still a fairly wide gap between these two experimental settings that needs to be bridged.The current prevailing view regarding the role of Aire in self-tolerance is that it is involved in the transcriptional control of many tissue-restricted self-antigen (TRA) genes in medullary thymic epithelial cells (mTECs) . In othein mTECs –7. Unforhigh) is another suggested aspect of the Aire-dependent mTEC differentiation program  but not fully competent for TRA expression, have a more globular cell shape and lack transcriptional machinery and/or activity for Aire-dependent TRA genes , and consequently the lack of Aire has little impact on their expression. It is still unknown why some (Aire-independent) TRAs are expressed from the immature stage(s), whereas (Aire-dependent) others are expressed only after they become fully mature. For this reason, it would be important to clarify the exact timing of Aire expression during the course of mTEC differentiation (Regardless of the models employed, there are several important issues related to the molecular regulation of TRAs within mTECs in the context of Aire. Obviously, the transcriptional control of TRAs is different from the regulation seen in their authentic tissues, as exemplified by differences in the transcriptional start sites of individual TRA genes . Althougin mTECs , 20 mighRA genes  (Figure ntiation . Neverthntiation , 22; Airntiation . In thisOne caveat of the transcription model is that expression of Aire and Aire-dependent genes does not always overlap at the single-cell level , 24, 25.involucrin gene was up-regulated possibly due to the transcriptional activity of Aire (in vivo systems suggesting that Aire is required for promotion of the mTEC maturation program. Thus, there is a need to understand the types of effects that can be expected according to the experimental systems employed.Involucrin is an interesting TRA in that it is sometimes used as an example of an Aire-dependent TRA that follows the transcription model: when cultured cell lines were introduced with an Aire-expressing plasmid, transcription of the endogenous  of Aire . However of Aire , 10. Thehigh/CD80high mTECs seen in Aire-deficient mice was considered to explain the lack of Aire-mediated proapoptotic activity, because loss of Aire did not result in augmented proliferation of mTECs (in vivo experimental systems.Regarding the role of Aire in the mTEC maturation program, an important issue that needs to be carefully investigated is whether or not Aire has proapoptotic activity. Introduction of Aire into cultured cells has been reported to result in apoptosis . Accordiof mTECs . Given tof mTECs . Once agin vivo models. Thus, our current understanding of the fundamental function of Aire still seems to be in its infancy, and the proposal and evaluation of different models would doubtless lead to further advances in this fascinating field of research.Finally, there is a need to discuss the implications of these two different models for the mechanisms underlying the defect of negative selection in Aire-deficient animals. In principle, the transcription model restricts the failure of negative selection in Aire-deficient mice to reduced expression of TRA gene products. In contrast, the maturation model suggests that Aire may affect the thymic microenvironment more globally than through simple control of TRA expression levels. Consequently, the maturation model allows for the possibility that regulation of TRA gene expression may not be the major defect of Aire-deficient mTECs responsible for impaired negative selection. Instead, other alterations in the function of mTECs lacking Aire might equally account for the defective negative selection in Aire-deficient mice. These changes could include processing and/or presentation of self-antigens within the mTECs , the proThe 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.


Respiratory diseases, including chronic obstructive pulmonary disease (COPD), are major causes of mortality worldwide , therefoIn this issue of the Journal Vitacca and Comini  analyze Understanding and improving patient-clinician communication about end of- life care is the key to high-quality palliative care . UsuallyAnxiety and depression may be important obstacles for frank and clear discussion on palliative and end-of-life care. In the frame of end-of-life care programs treatment of depression with drugs and/or psychological education, behavioural therapy, group and individual counselling may be useful.According to ethical and deontological principles in the frame of a medicine driven by agreed choices, doctors should respect patient’s willingness on the basis of either an informed consent or advanced directives. Advance directives and good advance care planning may represent an opportunity for improving the quality of palliative care for these patients. Nevertheless this mark of civilization is not available in all countries and somewhere patients are left at the mercy of doctors concerned more not to shorten life than to improve quality of life/death.Hospice and palliative care services represent an important opportunity for improving end-of-life care. Such services are again not available in all countries, and may be differently located within the same country. Furthermore clinicians caring for patients with chronic pulmonary disease not always know the best ways to utilize these services.In conclusion clinical decisions on end-of-life care must take into consideration the patient’s clinical and physical circumstances, preferences and likely actions to establish what treatment choice is available. Finally, clinical expertise makes the synthesis of all these considerations and recommends the treatment that the patient prefers . Therefo


There is an error in the byline noting the equal contribution of the authors. Only authors Anna Siebel and Monica Cubillos-Rojas are equal contributors.