Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke.Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger’s test were obtained to detect publication bias.We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate.This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA. Acute cerebral infarction is a major cause of adult mortality and disability, and its incidence will grow as population age, 2. It sPubmed, Embase and ScienceDirect were searched from January 1, 1979 to January 1, 2016 without language restrictions as follows:  AND  AND . Other potential studies were identified by consulting previous reviews and reference lists of retrieved records.The inclusion criteria were as follows: (i) using a filament or ligation mechanical stroke model; (ii) containing both rtPA and saline groups in non-transgenic animals, or both tPA deficient and wild-type groups in transgenic animals; (iii) reported means and their standard errors (S.E.) or standard deviations (S.D.) of infarction volume in the text. The exclusion criteria were as follows: (i) photochemical thrombosis or thromboembolic stroke model; (ii) review; (iii) conference abstract; (iv) human study; (v) dose of rtPA administration > 10mg/kg or timing of rtPA >6 hours.Data were extracted independently by two investigators (M.X.D. and Q.C.H.), and any differences were resolved by discussion with a third investigator (P.S.). We retrieved the following parameters from each included study: first author’s name, publication year, species, ischemic model, duration of ischemia, dose of rtPA administration, timing of rtPA, timing of assessment, infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological deficit sore, mortality rate, evaluation methodology and number of animals. Means, S.E. and S.D. for continuous measures were extracted from the text where possible or by use of a screen grab tool when they were represented in diagrammatic form. S.E. ca2 test and I2 statistic. An I2 of <25%, <50%, <75% and > = 75% represented low, moderate, high and extremely high heterogeneity, respectively. A meta-regression model was used to detect potential heterogeneity between the included studies based on moderators such as species, model, duration of ischemia, dose of rtPA administration, timing of assessment, timing of rtPA and STAIR score. Subgroup analyses of primary efficacy outcome were performed based on species (mouse versus rat), model (filament versus MCAO ligation), duration of ischemia (permanent versus transient), timing of rtPA (< = 3 hours versus 3~4.5 hours versus 4.5~6 hours), dose of rtPA administration (<10mg/kg versus 10mg/kg), evaluation methodology, and STAIR score (< = 3 versus > = 4). A sensitivity analysis was conducted using the leave-one-out method. Furthermore, publication bias was assessed using funnel plot, Trim and Fill method and Egger’s test. Data were analyzed using the RevMan5.3 (Cochrane Information Management System), Stata version12.0  and R version3.2.4. (www.r-project.org).Infarction volume was the primary efficacy outcome while BBB, brain edema, intracerebral hemorrhage, neurological deficit sore and mortality rate were the secondary efficacy outcomes. Statistical analysis process was described as before–31. BrieThe detailed flowchart of study selection was shown in A summary of the characteristics of the included studies was shown in I2 = 74%), afterwards, meta-regression (p = 0.276).The effect of rtPA on infarction volume used in each study was provided in gression  and subggression  were usegression . The fungression , and no I2 = 85%). Subgroup meta-analyses were performed to determine the sources of heterogeneity but failed (p = 0.120).Five included studies in t failed . The efft failed . More ret failed , and no I2 = 34%), and the effect was stable when sensitivity analyses were performed . The result was unstable when sensitivity analyses were performed (p = 0.140).SMD analyses  showed terformed . More reerformed , and no I2 = 43%) was moderate, and the effect was stable when sensitivity analyses were performed (p = 0.179).RtPA had significantly induced intracerebral hemorrhage, exhibited in erformed . The funI2 = 57%). Subgroup meta-analyses were obtained to detect potential moderator and the results were exhibited in p = 0.674).The effect of rtPA on neurological deficit score used in some studies was provided in p = 0.02). However, the heterogeneity was extremely high (I2 = 82%) but no source can be detected in subgroup analyses  levels after focal cerebral ischemia, 89. MMPRtPA had increased risk of intracerebral hemorrhage as well, probably due to BBB disruption. Intracerebral hemorrhage is the least treatable form of stroke and is associated with high morbidity and mortality from our former researches–97. We wThere are several notable limitations to this study. Firstly, it is a preclinical meta-analysis but not a clinical meta-analysis of randomized controlled trial. Although a large number of animal experiments have been performed on this issue, the quantity of human study is so small that it is difficult to get rid of rtPA’s thrombolysis property in human study. Secondly, heterogeneity still existed, even though we tried to determine the source of heterogeneity. It was probably because that tPA’s effect was not a primary end point in some studies.This meta-analysis reveals that both endogenous tPA and rtPA haven’t enlarge infarction volume, or deteriorated survival’s neurological function. RtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate. We conclude that rtPA can lead to neurological side effect independent on thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA. A PRISMA checklist for this article follows in supporting information part as S1 Table(DOC)Click here for additional data file.


The international standardization of auricular acupuncture points (AAPs) is an important basis for auricular therapy or auricular diagnosis and treatment. The study on the international standardization of AAPs has gone through a long process, in which the location method is one of the key research projects. There are different points of view in the field of AAPs among experts from different countries or regions. By only analyzing the nine representative location methods, this paper tried to offer a proper location method to locate AAPs. Through analysis of the pros and cons of each location method, the location method applied in the WFAS international standard of AAPs is thoroughly considered as an appropriate method. It is important to keep the right direction during developing an International Organization for Standardization (ISO) international standard of auricular acupuncture points and to improve the research quality of international standardization for AAPs.  The third regional conference of the working group of the standardization of acupuncture points was held in Seoul, South Korea, in 1987  in Lyon,An international standard of AAPs is an inevitable requirement when the auricular diagnosis and treatment medicine develops for a long period and goes to a high level. Through more than 30 years of effort, great progress and achievements have been made in researches on the international standard of AAPs. Up to now, an international standard has been formulated and issued by the World Federation of Acupuncture-Moxibustion Societies. An International Organization for Standardization (ISO) international standard is also in development. Nevertheless, there are still debates on the location methods for locating AAPs, including location based on “points,” “subzones,” “coordinate,” and other methods.The corresponding author of this paper has been engaged in the study on the international standardization of AAPs since 1986 and had the honor to participate in the whole process of research work on the Chinese national standard of AAPs and international standard of AAPs. As the chief expert of the project, he finished the international standard for auricular acupuncture point , which wFrom perspectives of historical context of AAPs, clinical inheritance, and practice of AAPs, the understanding of the essence of points, advantages, and disadvantages of the following nine location methods for locating AAPs were analyzed, including (1) the location method based on points for the anterior of the auricle, (2) the location method based on subzones for the anterior of the auricle, (3) the location method based on the divided subzones according to anatomy of the anterior of the auricle, (4) the location method based on Nogier's Point Zero for the anterior of the auricle, (5) the location method based on the facial ties of the knee of the helix and lobe, (6) the location method based on both points and subzones of the anterior of the auricle, (7) the location method based on smaller subzones of the anterior of the auricle, (8) the location method based on subzones, points, and lines for the anterior and posterior of the auricle, and (9) the location method based on subzones, points, and lines for full cover of the anterior and posterior of the auricle. The analysis is described in detail with pictures so that readers can understand easily.No specific illustration of the location of AAPs can be found in Chinese ancient medical books  Figure  with the Essential Techniques for Massage. The superior part of the posterior auricle corresponds to heart, the inferior part corresponds to kidney, the middle part corresponds to spleen, the lateral side corresponds to liver, and the medial side corresponds to lung.With awareness of the limitations of the location method based purely on points, the Chinese academic circle in the late 1980s tried to locate AAPs according to the subzones. There were different zones on the auricle according to the anatomical structures of the auricle. Each zone was further divided into different subzones. The work began with the aim to locate AAPs at the ear lobe and concha where it was difficult to use points to locate these AAPs. The subdivision in vertical and horizontal lines of the ear lobe was published by Jarricot and Wong , who divIn 1990, Oleson and Kroening, scholars from University of California, Los Angeles, the United States of America, first located all AAPs at the visible surface of the anterior auricle according to the anatomy of the auricle in his article  Figure . Each suThis method was proposed in 1990 by Dr. Bossy at the international conference on AAPs held by the WHO Regional Office for the Western Pacific in Lyon, France, to solve the long-troubling problem of international standardization of AAPs. The zero point was set at the helix crus notch and the auricle is divided into four quadrants by the horizontal and vertical axis. AAPs were marked by the intersections of the latitude and longitude lines in each quadrant. Dr. Rouxeville  further This location method Figures , proposeThis method was proposed in 1988 by an article entitled “The Project of the Standardization of AAPs” by the China Association of Acupuncture-Moxibustion in the Journal of Traditional Chinese Medicine  Figure . The art Practical Auricular Acupuncture Therapy, was published by Shanxi Science and Technology Press of China in 1988 which further divided the previous subzones into a number of even smaller subzones to improve the accuracy of the location of AAPs The research on history, mechanism, and clinical application of auricular therapy has experienced a long process . The nomThe location method based on subzones according to the anatomical structures of the auricle, points, and lines for full cover of the anterior and posterior of the auricle is an appropriate method and is adopted by the WFAS international standard of AAPs. It is important to keep the right direction during developing an ISO international standard of auricular acupuncture points and to improve the research quality of international standardization for AAPs and of auricular diagnosis and treatment.


The corrosion behavior of zirconia in acidulated phosphate fluoride (APF) representing acidic environments and fluoride treatments was studied. Zirconia rods were immersed in 1.23% and 0.123% APF solutions and maintained at 37°C for determined periods of time. Surfaces of all specimens were imaged using digital microscopy and scanning electron microscopy (SEM). Sample mass and dimensions were measured for mass loss determination. Samples were characterized by powder X-ray diffraction (XRD) to detect changes in crystallinity. A biosensor based on electrochemical impedance spectroscopy (EIS) was used to detect ion dissolution of material into the immersion media. Digital microscopy revealed diminishing luster of the materials and SEM showed increased superficial corrosion of zirconia submerged in 1.23% APF. Although no structural change was found, the absorption of salts (sodium phosphate) onto the surface of the materials bathed in 0.123% APF was significant. EIS indicated a greater change of impedance for the immersion solutions with increasing bathing time. Immersion of zirconia in APF solutions showed deterioration limited to the surface, not extending to the bulk of the material. Inferences on zirconia performance in acidic oral environment can be elucidated from the study. Transformation occurs in both scenarios and is often ensued by a nucleation and growth process. This phenomena can lead to a cascade of events such as crack growth on the surface which is termed Subcritical Crack Growth (SCG) or static fatigue,,in vivo release of ceramic particles. Generally, ceramic particles are very inert and do not trigger adverse reactions, however there have been studies pointing to the ability of zirconia powder to cause inflammatory reactions due to the formation of zirconium hydroxideIn spite of the reported success, clinical reports of zirconia’s catastrophic failures do exist with significant biological and technical cost,,However, the formation of zirconium hydroxide has now been overcome with the sintering processHence, it is important to investigate and understand the effect of unfavorable acidic aqueous environment on the surface of newly incorporated materials such as zirconia. It has been also suggested that an aqueous environment with acidic conditions can accelerate the process of ageing with crack growth decreasing 20%-30% the prosthesis’ lifetimeHenceforth, this study focuses on the investigation of the surface characteristics of zirconia samples exposed to acidulated phosphate fluoride solutions (0.123% and 1.23%) for an extended time period of 11 d. This study is based on the hypothesis that an acidic aqueous medium in the oral environment can accelerate the process of ceramic ageing. This process can generate nucleation and propagation of cracks, in which fractures will result in dissolution of ceramic particles in the oral environment. Microscopic techniques were performed to understand the morphological features of the surface. X-ray diffraction (XRD) was employed to evaluate the crystal structure of the ceramic material because the change in the crystal structure is considered an indicator of material degradation. An electrochemical sensor was used to detect the presence of ceramic particles dissolution in the APF medium in which the samples were immersed. The overall goal of this study is to provide information on the performance of zirconia materials under simulated acidic oral environment.2, 3% trace elements) with diameter of approximately 0.15 cm and 30 cm in length. Acidulated phosphate fluoride (1.23%)  was used to prepare the immersion solutions.A non-porous zirconia ceramic rod was obtained from a vendor . Before immersion, all the samples were immersed in acetone and sonicated for 5 min.The cleaned zirconia rods were divided into four groups involving different immersion conditions as follows:Group 1: a zirconia rod not subjected to any immersion was used as a control.Group 2: a zirconia rod immersed in deionized (DI) water.Group 3: four zirconia rods immersed in 1.23% APF medium with each rod immersed in an isolated medium contained in separate glass vials.Group 4: four zirconia rods immersed in 0.123% APF medium in a similar manner to group 3. 0.123% APF was prepared by 1:10 dilution of the commercial topical agent.The sample bathed in DI water represented a neutral pH oral environment for the material. Different concentrations of APF solutions represented different acidic oral environment conditions. The test samples were stored in a 37°C room to simulate oral temperature. It has been mentioned in a previous study that 24 h of immersion would represent 1 year of exposure to APF solution for 4 min every daySurface morphology of zirconia rods from all the groups were analyzed at specific time intervals (“t”) . In addition, aliquots of immersion media from groups 2-4 were collected during the same time interval to verify the dissolution of zirconia particles release over prolonged exposure to acidic aqueous environment.o; and the weight of immersed zirconia rods every 24 h is indicated by WT.Mass loss and change in dimension were recorded to verify if dissolution of zirconia ions/particles could occur under the experimental conditions. Weight and dimensions (length and width) were recorded periodically for 11 d (264 h) for all specimens using a microbalance and caliper, respectively. Weight loss percentage was calculated using Equation 1. Where %∆W represents the percentage of weight loss; the initial weight of each specimen, before immersion, is denoted by WThe effect of APF solutions on the material surface was analyzed using different microscopy techniques. Surfaces of all specimens were imaged using digital microscopy , and analyzed by Scanning Electron Microscopy (SEM) , before and after immersion.Zirconia samples were ground using an alumina mortar and pestle. Powder X-ray diffraction  was used to determine the structure of the material pre- and post- immersion. Diffraction data were collected for a 2-theta range from 10 to 80 at 0.1 step size on a powder diffractometer equipped with a LYNXEYE detector with a power of 40 kV and 40 mA.The release of zirconia particles due to surface degradation in the immersion solution was analyzed with an electrochemical biosensor chip platform that quantifies particle dissolution using Electrochemical Impedance Spectroscopy (EIS). Aliquots of testing solutions were collected before and after the immersion of zirconia rods. After the immersion of rods, sample aliquots were collected from the testing media at different time intervals “t” hours (h) .per chip) was taken for the 1.23% APF gel due to the high viscosity of the medium. Where %∆Z represents the percent change in impedance; Zc and ZI represent the impedance value of the immersion solution before and after immersion of specimens, respectively.The EIS test was performed at a constant peak-to-peak voltage of 10 mV and a frequency of 250 Hz. The impedance of the sample of interest varies according to the conductivity of it, which depends on the concentration of ceramic particles in the electrolyte . Deionized (DI) water which was not subjected to any immersion was used as the control baseline. The ratio of change in impedance of the sample medium analyte from baseline was calculated to generate a percentage change in impedance (ΔZ). Percent change for impedance was determined using Equation (2). This allowed the data set to be averaged and the standard deviation to be determined over three runs on three separate EIS chips for the 0.123% APF solution. Only one EIS measurement  are evident and indicated by an asterisk (*). As the immersion time increased, so did the intensities indicating the presence of higher concentration of sodium phosphate. Additionally, these peaks are more intense for the samples bathed in 0.123% APF solution (2HPO4.2H2O)  .Sample aliquots of immersion media such as DI water, 1.23% and 0.123% APF over the specified intervals of time  were analyzed using a biosensor chip platform. Impedance values obtained from the biosensor showed a decrease in impedance, with increasing immersion time of samples in APF, as shown in The immersion study of zirconia rods in APF was performed to investigate the effect of an acidic electrochemical environment on the surface of zirconia. It was hypothesized that acidic aqueous environment provided by the topical agent can degrade the zirconia surface and accelerate the process of ageing, leading to micro-crack nucleation and propagation.in vitro,Examination of surface morphology of samples exposed to APF containing media showed visible discoloration under digital microscope . This observation was attributed to a grain structural change in the superficial layer, which may have affected light reflection on the surface of the material. Manufacturing marks evident on all specimens were considered to be manufacturing defects, since they were visible on the non-immersed control as well as shown in 3PO4 reflections in the XRD diffraction pattern  with 0.34% of HF, where its dilution to 0.123% APF will provide a fluoride content of 1,230 ppm,,Even though there was no change in the crystal lattice structure, both microscopic evidence and XRD results illustrated superficial surface degradation. Therefore, it was necessary to confirm the dissolution of zirconia particles in the immersion media. Sample aliquots of immersion media collected over specific interval of times were analyzed by an electrochemical biosensor chip platform. Electrochemical biosensor results showed more conductivity of the solution with increasing time, as illustrated in The results of this study clearly showed that the aqueous acidic environment was able to trigger superficial surface degradation with the dissolution of ceramic particles limited to the surface and did not affect the bulk crystal structure as confirmed by XRD, which was considered as an indicator for ageing (or) slow micro-crack propagation.,,The degradatation limited to the surface without affecting the bulk crystal structure could explain the clinical finding of no zirconia framework fractures experienced in well conducted clinical studies, resulting in overall prosthetic survival rates of 100% up to 5 yearsHowever, superficial surface degradation should not be neglected. Due to the roughness induced by fluoride and acidic environments, the top layer could promote plaque retention creating a stage for peri-implant diseases to ariseIt has also been suggested that formation of surface corrosion layers may influence the degree of degradation in addition to the effect of microstructure and environmental conditionsin-vivo oral environment can have fluctuations in pH, mastication forces, and other factors, that may further influence the materials’ properties and performance.Certain limitations exist within this study. This methodology provides an overview on the corrosive behavior of APF on zirconia in oral temperature. Nevertheless, in vivo are also exposed to mechanical factors such as occlusal forces due to mastication. It has been clearly stated that the mechanical properties of zirconia are affected under prolonged exposure in an aqueous medium. In the limited clinical evidences obtained so far, failure of zirconia has been primarily associated with fracture. Hence, future studies will include mechanical loading of zirconia in simulated oral environment to understand the interplay of mechanical and electrochemical factors that can accelerate degradation and fracture of the material.This study investigated the effect of acidic aqueous electrochemical environment due to a topical solution. However, the oral environment is comprised of complex electrochemical factors such as saliva, enzymes, a wide variety of bacterial species, along with fluctuations in the pH and temperature conditions due to food particles and beverages. In addition, dental restoration materials Immersed samples did not show any transformation of crystalline phase from monoclinic to tetragonal. Hence, it was concluded that the acidic medium was not able to trigger the ageing phenomenon. However, microscopic images detected superficial surface degradation. In the oral environment, superficial surface damage, due to acidic medium, can be further invigorated by cyclic occlusal forces which can have a direct effect on the bulk properties of the material. Future studies will focus on the synergistic effect of mechanical forces and acidic electrochemical environment, which may accelerate crack propagation resulting in fracture and failure of the zirconia core or chipping of the porcelain veneering layer.


His efforts to make the progress in the German-speaking countries regarding improvements in medical teaching visible in the international context were not only significant, but also successful. He was active up until the end on the GMA Committee for Accreditation and Certification and critically scrutinized learning objectives and their influence on the quality of medical education in his unfinished memorandum on the National Catalogue of Competency-based Learning Objectives for Undergraduate Medical Study (NKLM). Florian Eitel was an independent and occasionally uncomfortable thinker and debater, who placed great value on the clarity of definitions and concepts, and as such encouraged many to reflect and critically respond.Far too early at the age of 72, Professor Florian Eitel passed away on April 9Zeitschrift für Medizinische Ausbildung (ZMA). He saw to it that the journal, Medizinische Ausbildung, was published by the Thieme Verlag Stuttgart as a supplement to Das Gesundheitswesen. The first issue appeared in May 1998. He dedicated himself with vigor to the goal of having the journal listed in the international citation indexes and promoting the scientific debate within teaching and learning in the health sciences. His efforts bore fruit and the journal has successfully developed into the central journal for research in medical education in the German-speaking countries.To make this discourse heard, Florian Eitel rendered outstanding service to the Florian Eitel completed his medical studies in 1969 at the Saarland University (Homburg) and earned the title Dr. med. in 1971. Following his military service as medical officer, he worked in the surgical department of the University Hospital in Homburg/Saar and became a specialist physician for surgery and senior physician there in 1975. In 1977 he expanded his expertise to include trauma surgery. In 1981 he qualified as professor and followed his head, Professor Schweiberer, to Ludwig-Maximilians-University (LMU) Hospital in Munich. Since an occupational disease increasingly hindered him in his clinical practice, he established a specialty in theoretical surgery at LMU. In 1987 he was appointed adjunct professor and founded an interdisciplinary working group on university teaching. He has since served in many ways on diverse committees and projects at the national and international levels to improve medical education.Das Arztbild der Zukunft. An important role is played by the Munich Curricular Innovation Project (M-CIP) with its new, student-centered approaches to teaching.Florian Eitel very successfully secured funding for reform projects, thus giving impetus for the development of models that have been adopted and used by others. Particularly worthy of note is his committed participation in the Murrhardter Circle at the Robert Bosch Foundation, which to this day has formulated effective reforms in In 1996 Florian Eitel wrote in Medizinische Ausbildung that hindsight explains current situations and imparts knowledge and experience that can be meaningful for the future. This remains true today.Our deepest gratitude is due to Florian Eitel for his work and successful efforts to improve education and teaching. He will be missed as a colleague, comrade, and friend, and we will hold his memory dear in our hearts. To his family we extend our deeply felt sympathy and to him our unceasing commemoration.


Antigen presentation is highly critical in adoptive immunity. Only by interacting with antigens presented by major histocompatibility complex class II molecules, helper T cells can be stimulated to fight infections or diseases. The degradation of a full protein into small peptide fragments bound to class II molecules is a dynamic, lengthy process consisting of many steps and chaperons. Deregulation in any step of antigen processing could lead to the development of self-reactive T cells or defective immune response to pathogens. Indeed, human leukocyte antigens class II genes are the predominant contributors to susceptibility to autoimmune diseases. Conventional antigen-processing calls for internalization of extracellular antigens followed by processing and epitope selection within antigen-processing subcellular compartments, enriched with all necessary accessory molecules, processing enzymes, and proper pH and denaturing conditions. However, recent data examining the temporal relationship between antigen uptakes, processing, and epitope selection revealed unexpected characteristics for auto-antigenic epitopes, which were not shared with antigenic epitopes from pathogens. This review provides a discussion of the relevance of these findings to the mechanisms of autoimmunity. Newly synthesized MHC II molecule associates with Ii, which targets it to specialized endosomal compartments (MIIC) where the Ii is proteolysed by cathepsins until only a fragment known as the class II-associated invariant chain peptide (CLIP) remains bound in the MHC II peptide-binding groove. Efficient displacement of CLIP from the MHC II groove requires the accessory molecule HLA-DM in human  . DM funce MHC II , 5. A pee MHC II , 7.immunodominant epitopes) that occupy the MHC II groove and are transported to the APC external membrane for stimulation of CD4 T cells.Another non-classical MHC class II accessory molecule is HLA-DO, H2-O in mice, and DO for short from now on. While discovered years ago, DO has recently been shown to play an active role in peptide exchange –10. Of iTo directly address specific questions regarding steps in antigen processing and the selection of immunodominant epitopes, we have developed a reductionist antigen-processing system for MHC II molecules that incorporates defined components and accurately predicts immunodominant epitopes from protein antigens . The sysUsing this minimalist system, we have discovered that the immunodominant epitopes from different antigenic sources are selected based on structural properties that allow them to form pMHC II complexes in high-relative abundance for presentation to T cells. Differential sensitivity to cathepsins and resistance to DM-mediated dissociation, equally play important roles. Unfit epitopes might be sensitive to DM-mediated peptide exchange, which results in their dissociation from the groove of MHC II, exposing them to the processing enzymes, cathepsins, and destruction. Those epitopes that fit the groove well form pMHC II complexes that are poor substrates for DM, and therefore, DM does not bind to them and displace them from the groove. Those pMHC II complexes remain intact and gain relative abundance over other epitope that when in complex with MHC II are good substrates for DM. Alternatively, a group of epitopes form complexes with MHC II that while being good substrates for DM and are displaced from the groove, are not digested away. Those epitopes are chemically resistant to cathepsin digestion. They may rebind to the MHC II groove, gain abundance, and become immunodominant epitopes. We found that the non-dominant epitopes are susceptible to both DM and cathepsins. They are often poor fits for the groove, and form DM-sensitive conformations, causing their displacement by DM. They are also sensitive to the cathepsins present in the environment, and are therefore digested away rapidly as they are dissociated from MHC II. As such, the non-dominant epitopes do not gain abundance, although they might be displayed at low-copy numbers on antigen presenting cell membranes.In general, processing of antigens cannot take place without the endocytic proteases or cathepsins. Cysteine proteases, aspartyl proteases, and serine proteases are the three major types of cathepsins studied for their roles in antigen processing , 13. TheOur recent studies  have shoAs discussed earlier, all auto-antigen-derived epitopes known as targets for pathogenic autoreactive T cells we tested resisted digestion by the cathepsins in the system. While some trimming of the epitopes occurred upon long exposure to our cathepsin mix, the core MHC II binding sequences remained intact. As such, we speculate that these auto-antigens, rather than being destroyed by the processing enzymes, are likely to rebind MHC II and presented to specific T cells. By this criterion, one might hypothesize that such epitopes would not be generated in the thymus, and T cells reactive to them would be less likely to be deleted . In the There are few known examples of auto-antigens that might fall in this unusual antigen-processing pathway. First, a member of the family of matrix metalloproteinases is gelatinase B (MMP-9) that is known for its role in generating collagen II fragments . It is fIn all, it seems that unlike pathogen-derived epitopes, auto-antigens rely on resistance to enzymatic digestion as key determinant of immunodominance, and while DM resistance can be an added as an advantage, it is not an absolute necessity. As such, it is likely that during inflammation auto-antigens are processed extracellularly, and binds MHC class II molecules displayed on the surface of paralyzed DC known for displaying large numbers of pMHC II on their surface .Several well-characterized auto-antigens have been reported to have multiple registers, i.e., peptide can fit the MHC II groove using two or more sets of anchoring amino acids. An excellent example is MBP(89–101) peptide that has two registers for binding to DR2a and DR2b , 44. Wheg7 binding epitope  epitope, digestion of insulin B7–23 epitope by the cathepsins mixture did not result in its destruction . The onl epitope , 46–48. lleagues , 50. WhiWe have discussed molecular mechanisms that foster the induction and development of autoimmune diseases using a minimalist cell free antigen-processing system. Abundant quantities of auto-antigens released due to tissue insults during inflammation, as well as the presence of a variety of proteolytic enzymes lead to generation of epitope fragments extracellularly. Insensitivity to further degradation by the processing enzymes appears as the key characteristic of auto-antigens. Inflammatory conditions and continuous processing of self-antigens by tissues resident dendritic cells may lead to their paralysis. Paralyzed DCs display large numbers of pMHC II on their surface some of which might exchange their peptides with the extracellularly processed epitopes from auto-antigens and emerge as targets for autoreactive T cells.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.


Recently, a new journal, JEAAS  has been launched. The goal of this new interdisciplinary journal is to advance the field of animal sciences. A particular focus is the establishment and application of animal models for basic and clinical research . Theref


BioPsychoSocial Medicine editorial team would like to thank all reviewers who have contributed to the journal in Volume 9 (2015).The  Tetsuya AndoJapanShuji AouJapanKashif AzizPakistanHans-Christian DeterGermanyShin FukudoJapanMikihiko FukunagaJapanHirokazu FurukawaJapanYusuke HadaJapanMasahiro HashizumeJapanHirono IshikawaJapanYuko IshizakiJapanMotoyori KanazawaJapanKenji KanbaraJapanMichiko KanoJapanHiroe KikuchiJapanMasayo KojimaJapanHiroaki KumanoJapanMaría Torres LacombaSpainMariko MakinoJapanAstrid MüllerGermanyMasanori MunakataJapanShinichiro NagamitsuJapanJun NaganoJapanToshihiko NagataJapanMutsuhiro NakaoJapanShinobu NomuraJapanYuko OdagiriJapanMariko OgawaJapanKyoko OhashiUnited StatesTakakazu OkaJapanHirokuni OkumiJapanYoshifumi OkuraJapanAnnelieke RoestNetherlandsAmy RonaldsonUnited KingdomKen ShimizuJapanHideaki SoyaJapanNobuyuki SudoJapanNagisa SugayaJapanShu TakakuraJapanTakeaki TakeuchiJapanMasato TakiiJapanTetsushi TamekazuJapanYoshihisa WadaJapanJong Min WooSouth KoreaKazufumi YoshiharaJapanKazuhiro YoshiuchiJapanStephan ZipfelGermany


To assess the outcome of single stage dorsolateral onlay buccal mucosal urethroplasty for long anterior urethral strictures (>4cm long) using a perineal incision. From August 2010 to August 2013, 20 patients underwent BMG urethroplasty. The cause of stricture was Lichen sclerosis in 12 cases (60%), Instrumentation in 5 cases (25%), and unknown in 3 cases (15%). Strictures were approached through a perineal skin incision and penis was invaginated into it to access the entire urethra. All the grafts were placed dorsolaterally, preserving the bulbospongiosus muscle, central tendon of perineum and one-sided attachement of corpus spongiosum. Procedure was considered to be failure if the patient required instrumentation postoperatively. Mean stricture length was 8.5cm (range 4 to 12cm). Mean follow-up was 22.7 months (range 12 to 36 months). Overall success rate was 85%. There were 3 failures . Other complications included wound infection, urethrocutaneous fistula, brownish discharge per urethra and scrotal oedema. Dorsolateral buccal mucosal urethroplasty for long anterior urethral strictures using a single perineal incision is simple, safe and easily reproducible by urologists with a good outcome. Urethral stricture is a common disease encountered by urologist. Exact incidence in Indian population has not been reported. Reconstruction of long and complex anterior urethral strictures is technically demanding. Long anterior strictures with dense focal narrowing and scarred, extremely narrow urethral plates, fistula or infection are best managed with staged procedures , 2. ThosWe present our experience single stage urethroplasty with dorso-lateral onlay of BMG for long strictures of anterior urethra approached through a perineal incision.The study was conducted between August 2010 and August 2013. Approval was taken from the hospital ethical committee. Patients who presented to us with anterior urethral strictures (>4cm measured on RGU) were included in the study. Each patient was evaluated by detailed history, physical examination, uroflow with post void residual urine, RGU and VCUG, and other routine investigations necessary for surgery. A suprapubic catheter was placed pre-operatively in those presenting with acute retention of urine and/or with altered renal parameters. The cause of stricture was Lichen sclerosis in 12 cases (60%), instrumentation in 5 cases (25%), and unknown in 3 cases (15%).Exclusion criteria were previous failed urethroplasty, urethral abscess, urethral fistulas and a scarred and unsalvageable urethral plate.Uroflowmetry and measurement of post-void residue was done at 1 month, 3 months and 6 months after surgery and every 6 months for the first 3 years thereafter. Those who had a recurrence of voiding symptoms with an objective evidence on uroflow study underwent imaging and/or cystoscopy to identify the site of re-stricture. These cases were considered as treatment failures.Operation was performed under general anesthesia with nasal intubation. Two teams worked simultaneously, one at the donor site and other at the recipient site. Urethroscopy was performed using a 6-7.5Fr semi rigid (Karl Storz) ureteroscope and a hydrophilic (Terumo) guide wire was passed into the bladder. A 5fr ureteric catheter was guided over it and the ureteric catheter was secured with a stich on the glans. A midline perineal skin incision is made; the bulbar urethra is exposed, preserving the midline tendon of the perineum and bulbospongiosus muscle . The invThe penis is invaginated into the perineal incision and the involved segment of penile urethra is similarly dissected of corpora cavernosa along the left side. On the left side urethra is partially rotated and the dorso-lateral surface is incised exposing the lumen . The incThe buccal mucosa is harvested from the inner cheek . The inner cheek from just inside the labial angle up to the retromolar trigone is marked, keeping 0.5cm away from the opening of the Stensen duct, to obtain a buccal graft of 2.5-3cm width and 6-7cm length. We use a 26 gauge needle to infiltrate dilute (1:200000) adrenaline under the marked portion of the mucosa. The edges are incised, 2 stay sutures are placed at the distal corners of the graft using 3-0 chromic catgut, for traction. Once the graft is harvested, the raw area is allowed to epithelize secondarily. The graft is defatted, trimmed to an appropriate shape and used as an onlay. We do not perform a primary closure of the mucosal defect.The buccal mucosal graft is trimmed to an appropriate size and is spread and fixed (quilted) over the exposed half of the corpora. The edges of the graft are sutured to the corresponding edges of the opened urethral lumen using 4-0 polygalactin sutures  and 3c oTwenty patients were included in the study . Mean agMean follow-up was 22.7±4.105 months (range 12 to 36 months). Treatment was successful in 17 (85%) and failed in 3 (15%). These 3 patients presented with decreased flow rates of<9mL/sec after 1-3 months. VCUG revealed a stricture at the proximal end of the graft in 1 (confirmed by urethroscopy), meatal stenosis in 1, and 1 had recurrent stricture along the whole length of the graft.Recurrent stricture was treated by DVIU. Meatal stenosis was managed by a meatotomy. The patient who had recurrent stricture of the whole length was planned for revision urethroplasty but he lost follow-up.Other complications included scrotal oedema in 3 (17.6%), 3 patients (17.6%) had brownish discharge through external meatus and 2 (10%) patients had wound infection . One of BMG augmentation urethroplasty has become the standard of care for long urethral strictures. Whether to place the graft dorsally, ventrally or laterally is controversial. Dorsal placement of graft has advantage of using corporal bodies to provide a secure well vascularized graft bed that helps to prevent protrusion of the graft with resulting pseudo-diverticulum formation. In addition, this spread BMG fixation preserves graft width and hence urethral caliber . On the Later in 2008, Barbagli et al. showed that the dorsal urethral surface could be easily approached leaving the bulbospongiosum muscle and central tendon of the perineum intact, thus preserving the branches of perineal nerves from surgical injury. The bulbospongiosum muscle is primarily responsible for ejaculation because of its rhythmic contractions with other perineal muscles to expel semen from the urethra. It may also have an important role in expelling urine  may play an important role in determining stricture recurrence  was managed conservatively with scrotal support, and oral serratiopeptidase twice a day for 3 days. Three patients (17.6%) had brownish discharge through external meatus that was managed by gently squeezing the shaft from penoscrotal region till the meatus, which subsided in 3 days. This discharge was probably the collected blood that was retained in urethra during dissection. Two patients (10%) had wound infection and they were managed by regular dressings. One of these patients of wound infection had an urethrocutaneous fistula, which presented to us 3 weeks after catheter removal. He underwent reinsertion of suprapubic catheter & regular dressings. A VCUG done 3 weeks later showed resolution of the fistula tract, so the suprapubic catheter was removed. These patients of wound infection had prolonged hospital stay.Our results are comparable with those published by Kulkarni et al. in 2009, using the same technique (Dorsolateral placement of buccal mucosa graft for long anterior strictures is minimally invasive, safe and has good outcomes with short to intermediate length of follow-up. Further studies on larger series of patients are necessary to confirm that preservation of the one-sided lateral vascular supply to the urethra and its entire muscular and neurogenic support reduces the incidence of stricture recurrence, post void dribble and ejaculatory dysfunction.


Prior to colonoscopy, bowel cleansing is performed for which frequently oral sodium phosphate (OSP) is used. OSP results in significant hyperphosphatemia and cases of acute kidney injury (AKI) referred to as acute phosphate nephropathy  are reported after OSP use, which led to a US-FDA warning. To improve the safety profile of OSP, it was evaluated whether the side-effects of OSP could be prevented with intestinal phosphate binders. Hereto a Wistar rat model of APN was developed. OSP administration (2 times 1.2 g phosphate by gavage) with a 12h time interval induced bowel cleansing (severe diarrhea) and significant hyperphosphatemia (21.79 ± 5.07 mg/dl 6h after the second OSP dose versus 8.44 ± 0.97 mg/dl at baseline). Concomitantly, serum PTH levels increased fivefold and FGF-23 levels showed a threefold increase, while serum calcium levels significantly decreased from 11.29 ± 0.53 mg/dl at baseline to 8.68 ± 0.79 mg/dl after OSP. OSP administration induced weaker NaPi-2a staining along the apical proximal tubular membrane. APN was induced: serum creatinine increased (1.5 times baseline) and nephrocalcinosis developed . Intestinal phosphate binding  was not able to attenuate the OSP induced side-effects. In conclusion, a clinically relevant rat model of APN was developed. Animals showed increased serum phosphate levels similar to those reported in humans and developed APN. No evidence was found for an improved safety profile of OSP by using intestinal phosphate binders. As well as the known acute effects of OSP , the effects of OSP on serum PTH and FGF-23 levels and on the expression of NaPi co-transporter proteins in the kidney (NaPi-2a) were investigated. Finally, it was determined whether OSP induced side-effects could be prevented by intestinal phosphate binding using either lanthanum carbonate or aluminum hydroxide.ad libitum. At different time points  blood was drawn from the tail vein for the determination of serum phosphate.In a pilot experiment, 20 male Wistar rats  were randomly assigned to four groups (n = 5 per group) receiving a single OSP dose corresponding to (i) 0.4 g, (ii) 0.45 g, (iii) 0.5 g and (iv) 0.55 g phosphorus  by gavage. At different time points  blood was drawn from the tail vein in restrained, conscious animals for the determination of serum phosphate. In a second phase, the optimized OSP dose  was administered to 6 male Wistar rats  by gavage based on the standard OSP dosing regimen . Animals were fasted during the study period, but had access to tap water 2HPO4. 2 H2O  and NaH2PO4. H2O (Merck) in a weight ratio of ∼1:2.3.The composition of the OSP dose was based on the therapeutically used Fleet Phospho-soda ,12,40 anad libitum.30 male Wistar rats  were randomly assigned to five experimental groups (n = 6 per group): (i) a group receiving 1000 mg lanthanum carbonate  followed by OSP corresponding to 0.4 g phosphorus , (ii) a group receiving 289.5 mg aluminum hydroxide (suspended in 0.1% CMC) followed by the same OSP dose , (iii) a group receiving 1000 mg aluminum hydroxide (suspended in 0.1% CMC) followed by the same OSP dose , (iv) a group receiving vehicle (0.1% CMC) followed by the same OSP dose and (v) a control group receiving vehicle followed by water by gavage. Based on the standard OSP dosing regimen, two OSP doses  were administered with a time interval of 12 hours. Animals were fasted during the study period, but had access to tap water Lanthanum carbonate, aluminum hydroxide (or vehicle) and OSP (or water) were administered through separate gavages to avoid phosphate binding prior to arrival in the intestine which would not reflect actual intestinal complexation.At different time points  blood was drawn from the tail vein in restrained, conscious animals for the determination of a series of serum parameters. At sacrifice (6 hours after the second OSP dose), animals were anaesthetized with 30 mg/kg sodium pentobarbital  via intravenous injection, opened through a midline incision and exsanguinated through the aorta abdominalis. The left kidney and intestinal tract were removed and slices of renal tissue were fixed in neutral buffered formalin (FNB) for 4 hours, rinsed with 70% isopropanol and embedded in paraffin for (immuno-) histology or digested in 65% nitric acid for chemical analysis. The content of the entire colon and terminal 5 cm of the ileum was collected to examine bowel cleansing.Experimental procedures were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the University of Antwerp Ethics Committee (Permit number ED2011-68).Serum phosphate (mg/dl) was measured using the Ecoline Phosphate FS assay (DiaSys). Serum calcium (mg/dl) was determined by flame atomic absorption spectrometry . Serum creatinine (mg/dl) was measured using the kinetic alkaline picrate (Jaffe) reaction. Serum intact PTH (Immutopics) (pg/ml) and intact FGF-23 (Kainos Laboratories) (pg/ml) were both determined using ELISA kits.Besides visual observation of diarrhea, bowel cleansing was examined by collecting the bowel content of the entire colon as well as the terminal 5 cm of the ileum in a 15 ml centrifuge tube during sacrifice. Water was added up to a volume of 14 ml and content was vigorously mixed. Subsequently, the tubes were centrifuged at 3000 rpm (1620 g) for 45 minutes and the percentage of visible insoluble bowel content  was used as a measure of bowel cleansing. Renal calcifications were visualized by Von Kossa staining. Deparaffinized 4 μm tissue sections were incubated in 5% silver nitrate for 45 minutes. Slides were rinsed in water, incubated in 1% pyrogallol for 3 minutes, rinsed with water, fixed in 5% sodium thiosulfate for 1 minute and counterstained with hematoxylin/eosin. In each section CaP deposits were quantified histomorphometrically using Axiovision 4.5 software (Carl Zeiss). Renal calcification is expressed as area% and was calculated as the ratio of Von Kossa positive (pixel²) on renal tissue (pixel²) area.Renal crystal content was also quantitatively assessed by measuring calcium and phosphate content in renal tissue digestion solutions. Briefly, transversal slices of renal tissue were weighed after removal, digested in 65% nitric acid at 60°C overnight and diluted in 0.1% lanthanum nitrate to eliminate chemical interference during subsequent spectrometric analysis. In this solution total calcium content was measured by FAAS (Perkin-Elmer) and total phosphate content using the Ecoline Phosphate FS assay (DiaSys).Immunohistochemical staining was performed on FNB-fixed, deparaffinized renal sections for NaPi-2a. Heat-induced epitope retrieval was performed by microwaving the sections (2x 5 min) in 0.1 M citrate buffer (pH 6.0). The tissue sections were then blocked with normal goat serum (20% in TSB with 1% Triton X-100) for 20 min and incubated overnight with polyclonal rabbit anti-human NaPi-2a . Biotinylated goat anti-rabbit (Vector Laboratories) was used as secondary antibody. Avidin/biotinylated peroxidase complex  was added as signal amplifier and 3-Amino-9-ethylcarbazole  was used as substrate. The sections were counterstained with hematoxylin. Sections in which the primary antibody was omitted were used as negative controls.Data are either presented as mean ± standard deviation, individual values or as median (range). Differences between multiple time points for each group were determined by the Friedman test, followed by a Wilcoxon-signed-rank test. Comparisons between the groups for each time point were assessed using a Kruskal–Wallis test, followed by a Mann–Whitney-U test. Values of p<0.05 were considered significant. Spearman correlations were made between the renal calcium and phosphate content and the histomorphometrical calcification score and between the serum parameters . Statistics were performed with SPSS Statistics 20.0.Administration of a single OSP dose resulted in significantly increased serum phosphate levels for all tested doses  and induced diarrhea in all animals, reflecting efficient bowel cleansing. However, because of the mortality in the groups receiving 0.5 g and 0.55 g phosphorus (20% and 80% respectively), it was decided to use the lowest dose (0.4 g phosphorus) in the second phase of the optimization study.Two OSP doses (corresponding each to 0.4 g phosphorus) with a 12 hours’ time interval induced diarrhea in all animals and resulted in significantly increased serum phosphate concentrations with the highest levels  ,32 occurAdministration of two OSP doses (corresponding each to 0.4 g phosphorus or 1.2 g phosphate) with a 12 hours’ time interval resulted in transiently increased serum phosphate levels compared to control animals . Serum pSerum creatinine concentrations  significRenal calcium content  was signNaPi-2a was clearly localized to the apical membrane of proximal tubules in control animals. In animals receiving OSP, NaPi-2a staining was weaker along the apical membrane and appeared more intracellular .OSP administration induced diarrhea in all animals. The amount of insoluble bowel content of the entire colon and terminal 5 cm of the ileum (used as a measure of bowel cleansing) decreased from a median of 16.1% (range: 2.9–25.0%) in control animals to 4.6% (range: 2.1–12.5%) in animals receiving OSP .Neither phosphate binder treatment was able to attenuate the serological effects of OSP  when the amount of affected renal tubules is limited. ,29 As OSThe optimized OSP doses used in this study each contained 0.4 g phosphorus and, as such, correspond to approximately four times the normal daily phosphorus intake in rats (based on a diet containing 0.8% phosphorus and daily food intake of 25 g). Both OSP doses not only caused diarrhea, resulting from its osmotic effect and thus presenting evidence of efficient bowel cleansing, but also resulted in a nearly twofold increase in serum phosphate levels compared to baseline, which is comparable to the range reported in patients. ,32 MoreoThe phosphate binder doses used in this study, i.e. a 0.3x molar lanthanum/phosphate ratio and a 0.3x and 1x molar aluminum/phosphate ratio, did not attenuate the acute side-effects of OSP administration. In patients undergoing bowel cleansing, each OSP dose is equivalent to ∼6 g phosphorus (∼18 g phosphate).  When theInterestingly, both serum PTH and FGF-23 levels increased after OSP administration. Although well known for PTH and in the setting of hyperphosphatemia in chronic kidney disease (CKD), only scarce data are available on the effect of acute hyperphosphatemia on FGF-23 levels. While in patients with chronic renal failure serum FGF-23 levels have been shown to already increase at the early stages of CKD in the absence of any significant change of serum phosphate or PTH, ,45 in thBased on our rather unexpected findings showing no effect of both phosphate binders on the OSP-induced hyperphosphatemia, it was hypothesized that in untreated animals the first OSP dose would decrease NaPi-2b expression, resulting in less phosphate absorption from the second OSP dose as compared to animals receiving phosphate binder treatment. In these latter groups, an amount of phosphate of the first OSP dose would be bound in the intestine, resulting in less suppression of the NaPi-2b transporter and consequently more phosphate absorption from the second OSP dose. This hypothesis was examined by administration of the phosphate binder only with the second OSP dose, so that the first reaction of the intestine towards an increased phosphate load would be the same as in animals only receiving OSP. This strategy, however, also resulted in a twofold increase in serum phosphate levels as compared to baseline (data not shown).It was observed by others that in the duodenum an adaptive increase in NaPi-2b expression occurs in response to an acute switch from a low-to-high phosphate diet which is accompanied by decreased renal NaPi-2a expression and transient postprandial hyperphosphatemia. ,49 NaPi-A possible limitation of this study consists in the fact that no urinary parameters were measured. Urine sampling, however, was not feasible as these samples were contaminated with feces (diarrhea) during the housing of the animals in metabolic cages.In conclusion, a clinically relevant rat model of APN was developed. Animals showed increased serum phosphate and decreased serum calcium levels similar to those reported in humans and developed APN. Serum PTH and FGF-23 levels significantly increased. NaPi-2a expression in the apical membrane of proximal tubules was reduced, confirming the particular involvement of NaPi also in acute phosphate exposure. No evidence was found for an improved safety profile of OSP by using phosphate binders.


Even though forecasting future research can be risky, we still venture to predict that the future will see considerably more research projects drifting toward this ambitious aspiration. Computational Biology is powerful for abstracting signatures of disease, for predicting it, and for proposing medications. It is effective in figuring out disease mechanisms and forceful in bridging experimental disciplines to obtain testable predictions. However, perhaps its biggest challenges lie in putting together the available broad and disparate information, devising tools to efficiently and effectively carry out these tasks while sifting through noise and recognizing cell specificity, and most importantly coming up with sound, coherent, and testable schemes.Is Computational Biology increasingly—and steadily—progressing toward addressing the mammoth challenge of actually Among the examples of the complexity and the type of questions that we will increasingly face are the vast potential implications of findings that underscore the role of commensal microbiota in disease treatments. Further, the mechanisms which are involved—on the molecular level—are not understood and neither do we fully understand in detail how pathogens can modulate the host immune response and subvert it to their own advantage. We would like to identify—and understand—signatures of chronic inflammatory diseases; recurrent viral sequences in multiple patients and multiple cancers; we would like to map disease risks and to figure out what are the mechanisms for the distinct signaling of specific isoforms of oncogenic proteins in specific cancers. Analyses of cancer genomes points to driver mutations; however, we are baffled by the higher frequencies of specific mutations in certain tissues. We are also mystified by the complexity of the cellular network and its apparent redundancy which results in drug resistance. These are mere examples demonstrating the enormity of the questions which are facing us. Perhaps most tellingly is the fact that we are often even struggling to articulate specific objectives, to delineate the available knowledge and to evaluate apparent successes.Within the grand challenge to compute biology, efforts to compute human health fosters multidirectional and multidisciplinary integration of basic, patient-oriented, and population-based research at different levels and across scales. Diverse data accumulate at increasingly high rates and quantities. We do not have a crystal ball for the future of research; we expect, however, that human health is going to be at the center. Human health is complex and encompasses multiple areas; thus, focusing on human health does not necessarily imply a narrower direction. Indeed, we expect that it will drive expansion, algorithm and tool development, and integration, all merging with experiments. Tools involving pattern recognition in images may receive a boost as well as those geared toward diverse, high volume computing. And most of all is the hurdle of making sense of observations to obtain coherent stories that would lead to new questions and new developments.This shift toward computing human health has been in the making for some time. It reflects the huge accumulating data as well as the availability of increasingly powerful computing; it also reflects methodological advancements over a range of resolution scales. With new discoveries related to human health made almost every day and with these taken up by numerous labs, computational biology is faced with unprecedented challenges that we, as a community, must take up.ab initio protein folding, where the experimental structural repertoire is growing and techniques such as electron microscopy are increasingly able to churn out structures at higher resolution. At the same time, other areas are gaining momentum and fast growing, particularly those related to human health. We believe that PLOS Computational Biology should not only capture these emerging trends but also promote and foster them. As the premier journal in Computational Biology PLOS Computational Biology is poised to lead and drive; not follow.These are exciting times for Computational Biology. The field has expanded considerably; at the same time, its focus has been shifting. Areas once central to computational biology attract fewer investigators—often due to lack of sufficient funding as is the case with To be effective in continuing to lead the field requires an intense and well-planned coordinated effort, awareness and vigor. It requires familiarity with methodologies, types of data as they are becoming available, and initiatives to merge these together. It requires Focus Features, Perspectives and Reviews; it requires leadership and foresight in the increasingly diverse areas within these disciplines. We believe that to do this effectively, it requires a strong team at the helm. Doing it alone in addition to all the chores and travels may not achieve these aims at the level that we would like to see.PLOS Computational Biology is our first and top priority and we have recognized a real need to ensure that overall leadership of the journal is strong, robust and experienced, along with the support of our Editorial Team and the community, to guide the journal through the next period of time. Until this date, Sebastian Bonhoeffer, Jason Papin, and Olaf Sporns have combined their talents and expertise to serve the journal at a very senior level as Deputy Editors-in-Chief. Olaf Sporns has taken on the Editorship of a new journal and so is stepping away from his Deputy Editor-in-Chief role on PLOS Computational Biology. He will, however, remain a member of our Editorial Advisory Board. In light of this development, and especially combined with the expanded breadth of our field, we wish to announce a new structure for leadership of the journal.Following the successful model of other PLOS Community Journals and for the strength it will give to our journal, we are pleased to announce the appointment of Jason Papin as Co-Editor-in-Chief. We will share responsibility for the journal advancing it to meet the diverse emerging challenges. We are also very pleased to announce that Sebastian Bonhoeffer has agreed to assume the new position of Chair of the Editorial Advisory Board. In addition to continuing to serve as a senior level editor, Sebastian will begin to work closely with the Editorial Advisory Board with the aim to re-enliven our communications with this august group of experts. Closer interaction with and involvement of the Editorial Advisors can only benefit the journal and our efforts to keep it at the forefront of the computational biology community, and so we are excited about this new dimension to the journal in the months and years ahead. Finally, we are very pleased to say that Phil Bourne will continue to support the journal in an advisory capacity as Founding Editor-in-Chief—for which we are grateful.PLOS Computational Biology will provide the leadership and inspiration to make real progress. We cherish the support of the Computational Biology and broader community and will be grateful for any comments that they may have. Our mutual aim is to advance and drive exciting, productive and fruitful science.Together, we will face the new era of Computing Biology. We will retain the open and receptive environment for all computational work which is of exceptional quality and adheres to our guidelines and principles. We hope that


Bactrocera zonata, established in Egypt” by Emtithal M. Abd-El-Samie, Zaki A. El Fiky“Molecular phylogeny and identification of the peach fruit fly, http://dx.doi.org/10.1673/031.011.17701DOI:Bactrocera zonata shows a lack of sequence similarity. In addition, phylogenetic analyses presented in the paper were not appropriate. Furthermore, the paper does not specify that voucher specimens were deposited, and therefore it is not possible to confirm the identification of the Egyptian specimen as B. zonata.The Journal of Insect Science was notified of concerns about the nucleotide sequence of a gene reported in this paper. Upon further investigation by the Journal, it was determined that the sequence does not translate to a protein and that comparison to other COI gene isolates of The journal has no evidence of intentional author misconduct in sequencing the gene that was isolated. However, based on the issues with the gene sequence and phylogenetic analysis, the Journal of Insect Science believes this paper to be sufficiently flawed that its conclusions cannot be relied upon. Therefore, the journal is retracting this paper.


This study was undertaken to investigate the immediate effect of static stretching on normal Achilles tendon morphology and stiffness, and the different effect on dominant and non-dominant legs; and to evaluate inter-operator and intra-operator reliability of using shear-wave elastography in measuring Achilles tendon stiffness.20 healthy subjects  were included in the study. Thickness, cross-sectional area and stiffness of Achilles tendons in both legs were measured before and after 5-min static stretching using grey-scale ultrasound and shear-wave elastography. Inter-operator and intra-operator reliability of tendon stiffness measurements of six operators were evaluated.Result showed that there was no significant change in the thickness and cross-sectional area of Achilles tendon after static stretching in both dominant and non-dominant legs (p > 0.05). Tendon stiffness showed a significant increase in non-dominant leg (p < 0.05) but not in dominant leg (p > 0.05). The inter-operator reliability of shear-wave elastography measurements was 0.749 and the intra-operator reliability ranged from 0.751 to 0.941.Shear-wave elastography is a useful and non-invasive imaging tool to assess the immediate stiffness change of Achilles tendon in response to static stretching with high intra-operator and inter-operator reliability. The intra-operator reliability of AT thickness and CSA measurements was 0.991 and 0.962 respectively.In the present study, the CSA and thickness of AT did not show significant change immediately after static stretching. These findings were consistent with previous studies adopting the same stretching protocol with the present study ,10. ResuThe AT stiffness in non-dominant legs was significantly increased after static stretching whereas there was no significant changes in AT stiffness in dominant legs after static stretching. The substantial stretching effect in non-dominant legs may be due to the significant difference in the pre-stretch stiffness of the tendon between dominant and non-dominant legs. It has been reported that strain magnitude applied to Achilles tendon must exceed a particular threshold in order to trigger adaptation effects on the mechanical properties of the tendon. The strains must be high enough to produce sufficient stimulus that beyond the strains triggered by the mechanical load applied during daily activities to trigger adaptation effects on the Achilles tendon . Since tCompared with the fair inter-operator reliability of SWE measurement of AT stiffness in Aubry’s study (inter-operator reliability is 0.46) , the intThe present study demonstrated the asymmetry of stiffness change of dominant and non-dominant AT where non-dominant AT had significant increase in stiffness after static stretching. This finding is useful in the design of stretching protocol in which it should consider the difference in the AT stiffness between the dominant and non-dominant legs.There are limitations in the present study. The sample size of the study was small and only young subjects were recruited. Different static stretching parameters including loading, dose, magnitude, torque, and number of stretching cycle and duration of stretching had been reported to have influence on tendon stiffness ,12,13,14In conclusion, SWE is a useful and reliable imaging tool for the assessment of immediate stiffness change of AT upon static stretching. Dominant leg AT has a higher baseline stiffness than non-dominant leg AT. A 5-minute static stretching with 30 degree dorsiflexion can lead to significant increase in non-dominant AT stiffness which may help enhance performance of manipulative activities. Asymmetry of stiffness change of bilateral AT provides scientific ground for supporting static stretching as a means to even out the inherent bilateral AT stiffness difference and provides insight for future studies to manipulate various stretching parameters in order to optimize athletes’ performance.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(DOCX)Click here for additional data file.


Objective. The aim of this study was to evaluate the effect of incorporation of glass fiber, zirconia, and nano-zirconia on the transverse strength of repaired denture base. Materials and Methods. Eighty specimens of heat polymerized acrylic resin were prepared and randomly divided into eight groups (n = 10): one intact group (control) and seven repaired groups. One group was repaired with autopolymerized resin while the other six groups were repaired using autopolymerized resin reinforced with 2 wt% or 5 wt% glass fiber, zirconia, or nano-zirconia particles. A three-point bending test was used to measure the transverse strength. The results were analyzed using SPSS and repeated measure ANOVA and post hoc least significance (LSD) test (P ≤ 0.05). Results. Among repaired groups it was found that autopolymerized resin reinforced with 2 or 5 wt% nano-zirconia showed the highest transverse strength (P ≤ 0.05). Repairs with autopolymerized acrylic resin reinforced with 5 wt% zirconia showed the lowest transverse strength value. There was no significant difference between the groups repaired with repair resin without reinforcement, 2 wt% zirconia, and glass fiber reinforced resin. Conclusion. Reinforcing of repair material with nano-zirconia may significantly improve the transverse strength of some fractured denture base polymers. Denture fracture is a common problem in prosthodontic practice that troubles both patients and prosthodontists. Inordinate masticatory forces or denture deformation during use can result in bending forces that contribute to fatigue of the material and subsequent fracture . A new dGlass fiber is one of the most common reinforcement materials and many investigations of its effect on repaired denture base have been performed. Addition of glass fiber to repair material improves the strength of a denture base repair and may decrease the occurrence of future fracture , 14, 15.2) is a metal oxide and may be used as a reinforcement material to improve the transverse strength of denture base resin [Zirconia  for 15 minutes. After curing, the specimens were removed from the mold, finished, polished, and then put into distilled water and incubated at 37°C for 48 hours and then tested [W is the fracture load (N), L is the distance between the two supports, b is the specimen width, and d is the specimen thickness [In accordance with ANSI/ADA specification number 12, eighty rectangular specimens of heat polymerized acrylic resin with dimensions (65 × 10 × 2.5 mm ± 0.1) were prepared using customized molds . Molds wn tested . To detehickness , 25.P value ≤0.05 was considered statistically significant result.Data analysis was performed by using SPSS-20.0, IBM software, Chicago (USA). The results were presented as mean and standard deviations. Repeated measure ANOVA was applied to see the statistical significance of the variables in comparison with control group and AP. Post hoc least significance (LSD) test was used to see the pairwise comparison of the variables. P ≤ 0.05). The higher transverse strength values were in groups 5NZR, 2NZR, and 2GF, respectively. Meanwhile 5ZR showed a significant decrease in transverse strength value. There was no significant difference in transverse strength between 2ZR and 5GF with AP.The mean value and standard deviation of transverse strength are summarized in  in vitro study was carried out to evaluate the reinforcing effect of different concentrations of glass fiber, zirconia, and nano-zirconia on the transverse strength of a repaired denture base. Results revealed that the HC group had the highest transverse strength values amongst all groups, which is in agreement with the results of a previous study [2 crystals occurs and places the crack under a state of compressive stress and arresting the crack propagation [Thisus study . Some reus study , 27, 28.us study –31 (Figuus study . Findingus study . This inus study . 5GF shous study . This cous study . The respagation . The respagation , 37. In pagation . Resultspagation . This inpagation . It was pagation , 39, andpagation , 40. Cli in vitro study, it could be concluded that nano-zirconia may be considered as a new approach for denture base repair. The repairs resulted in significantly higher transverse strength as compared to unreinforced repaired resin.According to the results and limitations of this


Dates such as this are particularly significant, given that they lead us to reflect on many of the aspects related to the existence of the BJP: its history; its current relevance; and its prospects.This is a special year for the Brazilian Journal of Pulmonology (BJP); in October, the BJP will turn 40. Dates sThe BJP was founded in 1975, and the fact that it continues its journey today is undoubtedly due to the continuous efforts of numerous colleagues who, directly or indirectly, have sought to make the Journal function as a great common denominator linking all members of the respiratory medicine community. This process has been spearheaded by a group of brave editors whose efforts have led the BJP to great achievements: Manoel Lopes dos Santos (1975-6); Bruno Carlos Palombini (1976-8); Carlos Frazzatto Junior (1978-82); José Roberto de Brito Jardim (1982-6); Miguel Bogossian (1986-90); Nelson Morrone (1990-4); Carlos Alberto de Castro Pereira (1994-8); Thais Helena Abrahão Tomaz Queluz (1998-2002); Geraldo Lorenzi Filho (2002-4); José Antônio Baddini Martinez (2004-10); and, most recently, Carlos Roberto Ribeiro Carvalho (2010-4), all of whom have contributed to making the BJP the most important scientific journal in the respiratory field in Latin America and one of the most important scientific journals in Brazil. Such a feat gives us a measure of the responsibility we all have to our Journal henceforward. We have recently been penalized by having our impact factor temporarily suspended, a fact that will affect us in the next evaluation. However, we have to bear in mind that this metric associated with scientific publication should be understood within its surrounding context rather than as a single number. In particular, the BJP has two very clear functions: to be a publication of quality, providing a vehicle for scientific production in the field of respiratory medicine, especially in Brazil but also worldwide, and to be the major instrument for the continuing education of pulmonologists in Brazil. For the latter mission, the commitment is to reach into the daily lives of its readers through review articles that reflect the necessities of daily clinical practice in the respiratory field. It is for the dissemination of scientific production that we will use common editorial metrics, such as the impact factor. Such metrics, despite their limitations, allow editorial policy planning, with course changes when necessary, in order to increase the national and international visibility of the Journal, thereby attracting the very best science in the field. To that end, several steps have been taken with a view toward increasing the international exposure of the BJP, among which is the fact that, since 2014, the Journal has been available on PubMed Central, an open archive of the U.S. National Institutes of Health National Library of Medicine, making it possible to access the full-text articles published by the BJP (in English) directly via the PubMed search function.In recent decades, the BJP was indexed for SciELO 2002) and, subsequently, for PubMed/MEDLINE (2006), which has greatly increased the visibility of the Journal and therefore the number of articles submitted, particularly after it was indexed for the Thomson Reuters Institute for Scientific Information Web of Science and its first impact factor appeared in Journal Citation Reports.002 and, luation. HoweverWe will now make all articles accepted by the BJP available online ahead of print, in order to maximize the exposure time of our publications. In parallel, all BJP content will be screened for plagiarism with the same tools used by the major scientific journals in the medical field. With this screening, along with the exposure, the trustworthiness of the content of the BJP will also increase significantly.Although the responsibility of managing the BJP is huge, standing on the shoulders of those who have made the Journal so solid makes the path much smoother. The aforementioned changes are aimed at preparing us for further growth. In addition, another very important change deserves special mention. The board of associate editors of the BJP has grown significantly. In advance, I thank all the editors who have embarked on the project for the next four-year term of editorship of the BJP, which begins now. The participation of such a significant body of researchers in the editorship of the Journal undoubtedly allows a closer relationship between the BJP and major research groups, in Brazil and around the world. It also allows the BJP to play its aforementioned role in the continuing education of respiratory medicine professionals working in Brazil, particularly those who are not affiliated with educational institutions. The selection of the topics of greatest interest to all kinds of readers will come to be shared by a group that is representative of the various fields of study in respiratory medicine, potentially enhancing the scope of the Journal.The ultimate goal for the next four years is to increase the representativeness of the BJP, not only via its role of disseminating scientific knowledge, which is to be measured by various existing metrics, but also via the role it plays in the education of health professionals in Brazil, which is to be measured by the interest in the different areas of the Journal, on the basis of the number of logins/downloads and requested reprints. Let us hope that the celebrations of and reflections on the last 40 years of BJP history will lead us steadily toward a 2015 full of achievements.


Usually inaugural editorials are written by the Editor-in-Chief to describe the scope and vision for the journal to potential authors and readers. This editorial is written by the Editor-in-Chief, the Deputy Editors and the Associate Editors collaboratively as a clear signal that this is a unique and different journal. We will build this journal on a set of principles which are fundamental to improving the outcomes of patients with kidney disease. To that end, we aim to be supportive, to collaborate, to integrate multiple perspectives and to be open to possibilities. Canadian Journal of Kidney Health and Disease – the official journal of the Canadian Society of Nephrology launches now following Kidney Month in Canada, as well as World Kidney Day, March 13th 2014, in recognition of our commitment to international perspectives. We have a vision of a high-quality journal publishing basic, translational, clinical, and health-services research in the field of kidney disease, dialysis, and kidney transplantation, with the mandate to promote and advocate for kidney health as it affects Canadians and people worldwide. The Journal has, and will continue to develop, an explicit culture of enquiry, sharing and knowledge dissemination for nephrologists and others involved in the care and prevention of kidney disease in Canada and the world.This inaugural virtual edition of the Supportive review. Our explicit and unique policy is to address our authors as our colleagues, and to aim to improve the work submitted, regardless of our decision to publish. We will be no less scientifically and constructively critical, but we will write to authors as we would wish to be written to ourselves.Clear review. Our associate editors will clearly indicate the major obstacles to publication. We expect authors will respond with openness to feedback, integrity, and clarity, so that most publications will require a single round of scientific revision.Timely review. We will provide authors with a review within 2 weeks of receiving a manuscript, or notify authors of the delay and the proposed timeline if we cannot.Easy formatting. We recognise the irritation and waste of time involved in formatting a paper differently for each journal and we know that many manuscripts are seen by more than one journal before publication. We will not ask authors to waste time on reformatting for our needs before scientific acceptance. We would like a structured abstract, but can work on that with authors before publication. We ask only that authors limit the abstract to 450 words, main text to 3000 words, and use one of the standard numbered citation formats for references.Timely publication. Delay in author submission of revisions is one of the major obstacles to timely publication. When authors receive supportive feedback within 2 weeks of submission, we anticipate that it will be cognitively easier for them to respond: immediately in many cases. If additional experimental work or complex re-analyses are necessary, there will be an inevitable lapse of time, but we encourage all authors to respond as soon as they are able. Once accepted, work can be published in PDF within 2 to 3 weeks.Recognition of limitations. All scientific work is limited. We challenge authors to explicitly recognise the limitations of their own work without fear that it will reduce the likelihood of publication. We will acknowledge limitations in full text and abstracts, and will work with authors to highlight the importance of their findings without overstating them.Openness to creativity and innovation. We would like to hear from you what you would like to read or to write.Open access publication. This translates into work being available, in full text, to anyone with internet access worldwide. This is critical to the dissemination of findings to inform kidney care and research internationally, and particularly important for those working in resource-limited environments. Authors retain the copyright to their published content enabling full rights to reproduce and reuse provided correct attribution is given [is given .Dissemination. We will push monthly summaries of content, with hypertext links to full text, to all members of the Canadian Society of Nephrology and to all registrants at our website. We have an active publicity campaign reaching out through meetings of societies of nephrology, dialysis, hypertension, and transplantation worldwide that will rapidly increase the prominence and readership of the journal. Those who wish can additionally subscribe to RSS feeds that will push each article as published.All journals strive for quality in their publications. To attract those publications, our journal is distinguished by:The Journal logo, a variation on the tree of knowledge and of life, is symbolic of the ethos of the journal. Through a philosophy of thoughtful and timely reviews of publications, we hope to foster the growth in knowledge, and thus in wellness of patients living with kidney disease.While many Canadian kidney researchers are well celebrated and have excellent track records in high impact journals, the importance of their work is often not fully appreciated in Canada. This Journal will afford that opportunity. Furthermore, the Journal will help with knowledge translation of research findings by giving Canadians a voice that can be heard clearly by Canadian health care administrators and policy makers – and therefore, lead to meaningful and necessary changes in health care delivery. Regular high-value features or reviews by Canadians and for Canadians also may be powerful tools for impacting change. In addition, Canadian practitioners and administrators may not always have access to information about important and relevant research and programs outside Canada. Thus, we hope that our emphasis on quality in our publications, our timely, thoughtful and collaborative approach to reviewing, and the open-access publication of their work will attract high-quality submissions from the international kidney community.The editor-in-chief’s commitment to showcasing excellence in Canadian research, recognition of the importance of the voice of Canadian research contextualized within the Canadian health care environment, and determination to impact policy and practice at home with research by and for Canadians, are critical to her role in this inaugural position. Her international roles and relationships through the International Society of Nephrology, positions the journal uniquely to fulfilling a broader mandate and informing health research and care around the world. The deputy editors and associate editors also have diverse perspectives and spheres of influence: they represent adult and paediatric nephrologists, basic and clinical researchers, administrators, and nurses, hail from across Canada. There is equal representation of both genders on the editorial team. Our managing editor, Elizabeth Dicks, is a PhD Nurse Scientist, with an established career in nephrology research.Thus, as the official journal of the Canadian Society of Nephrology, we start life with a core of Canadian associate editors encompassing junior, middle and senior investigators. Over time, we will include scientists from other countries. The larger Editorial Board is a diverse and international group, including health policy experts, administrators, health economists, and academics from diverse disciplines, and is representative of the general nephrology community. As a unique endeavor, we have also included on this Editorial Board , the traThe timing is right for a Canadian nephrology journal. Canadian nephrology administrators and researchers are highly prominent internationally and there is an unprecedented sense of internal and external collaboration in the Canadian kidney community presently. Canadian nephrologists chairing global kidney disease guidelines committees, funding of the Canadian Kidney Knowledge Translation and Generation Network by the Canadian Institutes for Health Research (CIHR), and co-funding of the KRESCENT program by CIHR, Canadian Society of Nephrology and the Kidney Foundation of Canada (KFoC) attest to this. We recognize that there is international competition between journals for impact factor and citations. We believe that established Canadian and international investigators, motivated by a sense of congruence with our mandate and ethos, will publish with us. In addition to this motivation, newer investigators will particularly value the constructive, collaborative and timely nature of our reviewing process.The goal is to develop a journal that complements existing journals by offering something unique. In addition to reports of completed basic, translational, clinical, economic and policy research, you can expect to read about knowledge translation activities, reports on research team development and outputs, descriptions of provincial structures for renal services, progress in clinical trials being conducted in Canada  and high-quality work by fellow, resident and student researchers. Articles describing challenges in health care delivery, and perspectives from different provinces or jurisdictions will be of value to the nephrology community. Work on disadvantaged populations (within and outside of Canada) will bring our collective social conscience into focus and make kidney care relevant for all. Clinical practice guidelines, their rationale, methods, and applicability will clearly differentiate what is evidence-based and what is clinical judgment. Our open-access structure means that we can reasonably consider our readership to include other disciplines and specialties and, in particular we wish to include work that is relevant to allied health, primary care, and non-academics worldwide. Special issues will focus on educational features in both adult and pediatric nephrology, as well as basic and clinical science challenges. We will maintain close linkages with the Canadian Society of Nephrology Education Committee, showcasing the output from our national meetings both by established researchers and by trainees.We will ensure that the Journal truly reflects the needs of the Canadian Society of Nephrology membership, the Canadian health care system and patients and practitioners within it. We will be sensitive to the international applications and implications of our publications. Through striving for excellence in the quality and relevance of published articles we aim to become a leading national and international nephrology journal. We consider it a privilege to be able to disseminate high quality work, to contribute as a community to that work, and ultimately to improve the lives of those living with kidney disease.To achieve these aims, we solicit submissions and will do our best to provide thoughtful, constructive and timely review. And above all, we solicit your interest and readership as we set out on this journey.


Under a set of reasonable assumptions, it is shown that all manuscripts submitted to any journal will ultimately be published, either by the first journal or by one of the following journals to which a manuscript is resubmitted. This suggests that low quality manuscripts may also be published, which further suggests that there may be too many journals. During a recent panel of scientific journal editors, all participating editors proudly announced that their journals maintained high quality standards.To analyse this question, we start with a base model of the cumulative acceptance or cumulative rejection of a single scientific manuscript, which is as simple as possible. Hence, in first instance, we do away with most complications that arise in reality, and introduce more realistic assumptions later on.a, and rejected with a probability r, with no third option: thus a + r = 1. Assume further that this article, when rejected, is resubmitted endlessly, unless it is accepted. This last assumption obviously cannot be true, but reality comes close.ra. In the third round it will be r2a. In the fourth round it will be r3a, and so on. The question then is whether the sum of this series converges to 1 or not, that is, whether the article ultimately will be published or not. The answer is that it will, as the ultimate acceptance rate equalsr, as long as that rejection rate does not increase with the number of resubmissions. This raises the side question, whether there is a type of increase in r that would prevent the ultimate acceptance of this article.Assume a single journal, with a single editor, who has no memory, and a single manuscript that is accepted with a probability r is the speed of convergence, i.e., after how many rounds the cumulative acceptance rate will reach which values. Table The only thing that does depend on Note that our wording has changed from a single article to a population of identical articles facing identical rejection rates in each (re)submission round. Obviously, this minor generalisation does not change , nor theJ journals, instead of only one, and assume that each journal has its own rejection rate rj, rank-ordered in a column vector r or a diagonal matrix r on its main diagonal. Again assume that there is no third option. Then the sum of each journal´s acceptance rate, a + r = i. Since, in this second model, there are more journals, there is no more need of the unrealistic assumption of a single editor without memory.Therefore, next, assume, without loss of generality, that we have i will be resubmitted to a different journal j with a transfer probability pii = 0. We, however, maintain the assumption that each rejected article is resubmitted, i.e., that authors do not withdraw their articles from the publication process. This implies that the matrix with the transfer probabilities has row sums that are equal to one, that is, Instead, we assume that a manuscript that is rejected by journal ultimate acceptance rate of a manuscript that was originally submitted to journal i, as follows:−1 = the inverse of the matrix , for which holds that −1  = I.With these new, more realistic and more general assumptions, Eq.  changes ui in submission rounds.Besides, in part to counteract the possible increase in the likelihood of a next rejection, authors usually react by choosing a new journal with a lower rejection rate, reflecting a lower status in the quality hierarchy of journals of which most authors are usually well aware. This implies that, besides rsion of  with varu reaches unity before or after the maximum number of (re)submission rounds J is reached. The answer can no longer be given analytically, but needs to be based on empirical values of Pj.The question now becomes whether In summary, we developed three, increasingly realistic theoretical models that all show that the dissenting editor of the panel, mentioned in the introduction, is right on both counts. High rejection rates may well go together with the ultimate acceptance of at least the majority of the initially submitted articles, while a large number of journals increases the probability of ultimate acceptance.Adding an empirical foundation to our third and last theoretical model requires information on the rejection rates of journals and the resubmission behaviour of authors. The average rejection rates by journal are readily available, but how rejection rates change with resubmissions is difficult to establish, as editors mostly have no information about how many other journals, if any, rejected the article earlier, i.e., before it reaches their own desk. Further, information about the resubmission behaviour of authors is practically absent. A survey done via the editors of scientific journals probably leads to strategic and thus false answers.The New England Journal of Medicine and the Journal of Clinical Investigation, which have high own rejection rates of, respectively, 85 and 70 %.Anyhow, a conclusive empirical proof of the validity of the above three models, will need time to develop, as the data needed for such a proof are not readily available. Still, Kochar  found twOur conclusion that most manuscripts will ultimately be accepted, therefore, not only has the theoretical backing given in this short article, but also has some initial empirical backing. This conclusion not necessarily, but most likely implies that too many manuscripts do get published in the end. The adjective “too” is justified because our conclusion implies that manuscripts of low quality also get published, unless one believes that the repeated refereeing process increases the quality of each manuscript sufficiently to warrant its ultimate publication.