While the experimental Alzheimer's drugs recently developed by pharmaceutical companies failed to stop the progression of Alzheimer's disease, clinicians strive to seek clues on how the patients would be when they visit back next year, based upon the patients' current clinical and neuropathologic diagnosis results. This is related to how to precisely identify the transitional patterns of Alzheimer's disease. Due to the complexities of the diagnosis of Alzheimer's disease, the condition of the disease is usually characterized by multiple clinical and neuropathologic measurements, including Clinical Dementia Rating (CDRGLOB), Mini-Mental State Examination (MMSE), a score derived from the clinician judgement on neuropsychological tests (COGSTAT), and Functional Activities Questionnaire (FAQ). In this research article, we investigate a class of novel joint random-effects transition models that are used to simultaneously analyze the transitional patterns of multiple primary measurements of Alzheimer's disease and, at the same time, account for the association between the measurements. The proposed methodology can avoid the bias introduced by ignoring the correlation between primary measurements and can predict subject-specific transitional patterns. Alzheimer's disease is the most common type of dementia with the loss of brain function, which affects mental processes including attention, memory, producing and understanding language, learning, reasoning, problem solving, and decision making. Patients with Alzheimer's disease often are 65 years old or older, but there have been cases of early onset Alzheimer's (diagnosed before the age of 65) In numerous clinical and epidemiologic studies on chronic diseases, the scientific interest lies in understanding the longitudinal transitions of primary disease measurements, and in identifying factors that govern transition probabilities. For Alzheimer's disease, the transition patterns contain important information on disease evolution and prognosis. Alzheimer's disease cannot be accurately diagnosed and described by a single measurement; clinicians need to synthesize information from various sources, including features of symptom onset and course, evaluation of mental status, and performance measurements from neurologic and neuropsychological examinations. Therefore, a major challenge in characterizing transitional patterns of Alzheimer's disease is that the disease status is represented by not one but multiple measurements. If the status of Alzheimer's disease could be ascertained by one clinical measurement, then the existing statistical methodologies for univariate transition models would be adequate for the present application. Various authors have proposed models for characterizing transition patterns with univariate longitudinal data: Zeger and Qaqish This research article proposes a class of innovative joint random-effects transition models for elucidating the transitional patterns of multiple longitudinal measurements that are closely related to Alzheimer's disease. Multivariate transition models had been discussed in three recent articles for binary longitudinal data. A generalized estimating equation method for joint transitional models of multivariate longitudinal binary data was proposed by Zeng and Cook The National Alzheimer's Coordinating Center is responsible for developing and maintaining a database of participant information collected from the 34 past and present Alzheimer's Disease Centers. The NIA organized the Alzheimer's Disease Centers Clinical Task Force and defined a standardized Uniform Data Set. Alzheimer's Disease Centers provide researchers a standard set of assessment procedures to characterize mild Alzheimer disease and mild cognitive impairment in comparison with nondemented controls. Our analysis is based on a data set concerning the status of Alzheimer's disease at five to six annual clinic visits for 746 subjects. The status of Alzheimer's disease for each subject was mainly characterized by four primary measurements: Clinical Dementia Rating, Mini-Mental State Examination, Composite Cognitive Score, and Functional Activities Questionnaire. At each visit, clinicians assessed the overall dementia level of the subject in term of Clinical Dementia Rating, a numeric scale used to quantify the severity of dementia Sloane et al. In this section, we initiate the discussion on joint random-effects transitional models by considering bivariate longitudinal data. General transitional models for multivariate longitudinal data (with three or more primary measurements) are discussed in the next section.Consider a longitudinal study in which We consider several scenarios. In the first scenario, it is assumed that the bivariate longitudinal response The random-effects transition model for the binary stochastic process To formulate a joint random-effects model for the Gaussian and binary mixed-type bivariate longitudinal process, we combine univariate models (2) and (3) through a joint multivariate mean-zero normal distribution for all random effects: In the second important scenario, the bivariate longitudinal outcome Generally, we consider a log-linear transition model for the count process A joint model for two binary stochastic processes When there are more than two longitudinal outcomes of different types :, joint models can be specified within the framework of generalized linear mixed models in a way similar to the case of two outcomes. As before, let In joint random-effects transition models for multivariate longitudinal data, statistical inference is challenging for several reasons. In (6) and (7), denote by Here, we construct a well-defined composite conditional likelihood function to overcome the difficulties in evaluating (8). A composite likelihood function is an inference function derived by multiplying a collection of weighted conditional or marginal likelihoods The composite conditional likelihood (9) focuses on the pairwise conditional likelihood, which avoids high-dimensional integration and specification of the distribution of the first Inference on the unknown parameters Remark 1:Under regularity conditions, the composite maximum likelihood estimator asA central limit theorem for the composite likelihood score statistic holds, which implies that whereis the sensitivity matrix,is the variability matrix, and The proof of Remark 1 is similar to the arguments of The joint modeling approach with the composite conditional likelihood is complicated, possibly involving mixed types of binary or multi-categorical outcomes. Although the composite likelihood asymptotic theories in Remark 1 ensure asymptotic validity, the finite sample performance of the proposed composite likelihood estimators still needs to be thoroughly examined, especially when the outcomes are binary or multi-categorical. We conducted a simulation study to investigate the finite sample performance of Two of the four primary measurements of Alzheimer's disease, MMSE and COGSTAT, are dichotomous and can be handled using model (3). The other two measurements, CDRGLOB and FAQ, are both on a five-level ordinal scale. To accommodate the ordinal nature of the latter two measurements, the following random-effects transition model is constructed. For a fixed A cautionary note on the usage of (10) is as follows. Investigators have to be very cautious about the specification of Our statistical analysis was based on the composite conditional likelihood derived in the Methods section. The SAS programs for this analysis are available upon request. The lower portion of ysis see , althougA new study suggests that the number of people diagnosed with Alzheimer's disease in the United States will triple over the next 40 years The joint random-effects transition models have complex structure with several components. There are important and challenging questions, such as how to check the key assumptions. First, statistical tests can be used to compare two nests models. This can help with checking the proportional odds assumption for ordinal responses. Molenberghs and Verbeke File S1Appendix.(PDF)Click here for additional data file.


Anisotropy is the directional dependence of the measurement of a property. As breast tissue structure and some breast diseases (DCIS) are anisotropic in structure, we aimed to establish the frequency, degree and diagnostic value of shear wave elastography anisotropy in solid breast lesions.t tests and chi-square tests were performed to establish statistical significance of the relationships.Ninety-eight solid breast lesions  were examined in the radial and anti-radial planes, with two mean stiffness measurements (in kPa) being taken in each plane and averaged. The difference between the radial and anti-radial measurements was squared to make all readings positive, and compared with the histological diagnosis. Paired Student P = 0.2). Anisotropy was greater in malignant lesions than benign lesions (P < 0.0001). Using a malignancy threshold value for the square of the difference in radial and anti-radial stiffness of 200, the sensitivity, specificity and diagnostic accuracy of the presence of this level of anisotropy were 72%, 87% and 77% respectively.Anisotropy was found in both benign and malignant lesions. However, the stiffness values were not related to the examination plane in either group of lesions (Stiffness of solid breast lesions on shear wave elastography is not directly related to the examination plane. Malignant lesions show more anisotropy than benign lesions. Therefore, adding anisotropy to other shear wave parameters has the potential to improve the ability of this modality to differentiate benign from malignant solid breast lesions.


Barrett's esophagus (BE) is a disease with a rising prevalence in western countries probably due to the unhealthy lifestyle. In significant number of cases it develops to esophageal adenocarcinoma. Two decades ago, important gene regulators (microRNAs) were discovered and their attendance in the process of malignant transformation was demonstrated . Our aim was to select the patients with the increased risk of malignant transformation before the cancer develops.71 patients with BE disease were selected, slides from FFPE blocks were prepared, the lesions were microdissected and a qPCR relative expression analysis for selected microRNAs  was carried out.We demonstrated unequivocal statistically significant upregulation of two microRNAs  and downregulation of miR-203 and positive miR-196a correlation with progression from intestinal metaplasia to adenocarcinoma compared to normal individuals.We hypothetize that there do exist changes of selected microRNAs which can undoubtedly distinguish the patients with BE from normal healthy individuals. Barrett's esophagus (BE) is the gastrointestinal disorder termed after the physician Norman Barrett in the 1950s . SubjectBE can progress through dysplasia stages (low grade and high grade dysplasias) and even to the esophageal adenocarcinoma (EAC) . Thus, BCaenorrhabditis elegans. Successively, microRNAs were revealed across the plants and other animals including Homo sapiens. Nowadays, 1100 diverse microRNAs were identified in humans . All the qPCR reactions were performed in the LightCycler® 480 System .The total volume of the qPCR reaction mixture was 10 μl. The mixture consisted of 5 μl of the TaqMan® Stomach RNA  was used because BE is a glandular type of metaplasia. Normal glands are found in stomach which is simultaneously the examined area during the esophageal endoscopy. So, the efficiency of PCR reaction should be verified in the glandular tissue.For the efficiency of the qPCR reaction the FirstChoiceThe qPCR reaction for the chosen microRNA assay was adjusted for the 5 RNA template concentrations. The preamplification step was inserted as well. All the volumes were the same as for the regular qPCR reaction. After the reaction run, the efficiency was counted by the plotting the Cp value towards the log of the RNA concentration. The efficiency was presented by the slope of the axis.Each qPCR reaction was performed for 6 potential endogenous controls  according to the most cited reference genes in literature ,29. The p value formulation. In the regression relations (grading compared to other chosen parameters) the test of the coefficient significance in the regression model was used [The results of the study were processed by the biostatistician. The Kruskal-Wallis test with the multiple comparison was used for the was used .The results of the experiments are presented as the x-fold change. It is the ratio of the relative gene expressions . The relative gene expression is the expression of the target gene divided by the expression of the reference (housekeeping) gene. The number of the fold expresses how many times is the relative expression of the target gene higher or lower than the relative expression of the same gene in the calibrator. The x-fold is expressed by formula :cp = threshold pointE = efficiency of the qPCR reactionsample = Barrett's esophagus in any gradecalibrator = normal healthy esophageal epitheliumOn the basis of geNorm, reference genes RNU44 and U47 were used and all the x-fold changes are relativized to their geometrical mean.In the case of miR-21, no statistically significant differences between Barrett's esophagus and normal epithelia were acquired , miR-196a level can help distinguish between malignant and benign pancreatic tissue . Moreove7, miR-19In the case of miR-21, it was published, that six solid tumor tissues  where miR-21 is the only overexpressed microRNA do exist . Feber eDealing with the possibility of getting the tissue samples through all stages of BE progression in one individuality brings controversial situation. We succeed in obtaining of tissue samples from all stages of BE progression in one patient's case, however we have to point out that the NBI technique, which we are using in the endoscopic examination helps to vizualize the architecture of the BE lesion and gives us the most precise picture of the stage of potential dysplasia and if there are any indications of proliferation to higher stage of BE dysplasia, it is therapeutically intervened. Our aim is not to let the patient to escalate to HGD/EAC stage which is very difficult to cure.Most of the gene expression studies cited deal with relative expression data, but not all of them deal with the endogenous controls. Nonn et al.  use the In our study, we showed that there possibly do exist such combinations of microRNA expressions of which may be able to give us an information about the patient's status and possible disease progression. Expression of microRNA-196a was unequivocally confirmed as the Barrett's esophagus molecular marker with the rising trend through the disease progression. In combination with expression of microRNA-192 and microRNA-203 the patient could be independently diagnosed and his diagnosis could be confirmed in spite the fact that the BE diagnosis is not supported by the histological examination.AFI: autofluorescence; BE: Barrett's esophagus; cp: threshold point; DEPC: diethylpyrocarbamate; dNTPs: deoxynucleotide triphosphates; dTTP: deoxythymidine triphosphate; E: efficiency; EAC: esophageal adenocarcinoma; FFPE: formalin fixed paraffin embedded; GERD: gastroesophageal reflux disease; H-E: hematoxylin-eosin; IL: interleukin; LCM: laser capture microdissection; miR: microRNA; mRNA: mediator ribonucleic acid; NBI: narrow band imaging; nt: nucleotide; PAS: periodic acid Schiff; PCR: polymerase chain reaction; PET: polyethylene terephthalate; qPCR: quantitative polymerase chain reaction; RNA: ribonucleic acid; RT: reverse transcription; UV: ultravioletThe autors declare that they have no competing interests.PL: participated in the design of the study, carried out the molecular studies, carried out histological stainings, JG: performed the endoscopical examination of patients, collected tissue samples and patient's history, IU: carried out the molecular studies, LR: carried out the statistical and correlation analyses, VP: conceived the study and participated in its design, collected tissue samples and patient's history, JE: conceived the study and participated in its design, evaluated endoscopical biopsiesAll authors read and approved the final manuscript.


The bidirectional gene architecture has been studied in many organisms, and the conservation of bidirectional arrangement has received considerable attention. However, the explanation for the evolutionary conservation about this genomic structure is still insufficient. In this study the large scale identification and pathway enrichment analysis for bidirectional genes were performed in several eukaryotes and the comparative analysis of this arrangement between human and mouse were dissected for the purpose of discovering the driving force of the preservation of this genomic structure.We identified the bidirectional gene pairs in eight different species and found this structure to be prevalent in eukaryotes. The pathway enrichment analysis indicated the bidirectional genes at the genome level are conserved in certain pathways, such as the DNA repair and some other fundamental cellular pathways. The comparative analysis about the gene expression, function, between human and mouse bidirectional genes were also performed and we observed that the selective force of this architecture doesn't derive from the co-regulation between paired genes, but the functional bias of bidirectional genes at whole genome level is observed strengthened during evolution.Our result validated the coexpression of bidirectional genes; however failed to support their functional relevance. The conservation of bidirectional promoters seems not the result of functional connection between paired genes, but the functional bias at whole genome level, which imply that the genome-wide functional constraint is important for the conservation of bidirectional structure. The bidirectional promoters, as a special arrangement of neighbouring genes, have been discussed in many previous studies. The bidirectional gene pairs were defined as the divergent genes with the distance between their transcription start sites (TSS) less than 1 kb -4. Compaet al concluded that this genomic arrangement is ancient and conserved during the evolutionary process, where the function relevance of this structure was also reported in the literature [The co-regulation was believed to be the distinctive feature of bidirectional gene pairs, and the mechanism of the similarity of expression profiles may be the sharing of the regulatory elements . The preterature . Other cterature ,6, but tIn this study, we first performed the large-scale identification and pathway enrichment analysis of bidirectional gene pairs among several eukaryotes. Then we analyzed the general evolutionary tendency of this architecture. The functional preference of bidirectional genes at whole genome level was discovered and this preference was found to be conserved among species. The function relevance at the paired genes level as the driving force for the preservation of bidirectional promoters was excluded. The functional bias of bidirectional genes at the whole genome level is strengthened in human compared with mouse, which may imply the genuine origin of the conservation of bidirectional architecture.2 = 0.9578, p-value = 2.379E-05), however the correlation was not observed in the minor peak  of adjacent genes in opposite strands was detected in human genome, and the minor peak was considered as the peak of the distance between bidirectional gene pairs . The dis2 = 0.547, p-value = 0.036). Interestingly, the percentage of bidirectional genes falls sharply from invertebrates to vertebrates. This may be the consequence of the large-scale segmental duplications which was believed to increase gene numbers and genome size during the origin of vertebrates [The bidirectional promoters were then identified via employing the criteria of TSSs distance less than 1 kb in eight eukaryotic organisms. The number of recognized bidirectional promoters and the bidirectional genes are shown in Table tebrates .The prevalence of bidirectional promoters indicates this genomic architecture or the involved genes may have some special properties which make them preserved during the evolutionary history. We attempted to provide a potential explanation by the comparative analysis of bidirectional promoter among species, especially between human and mouse genome.It was examined that the sequence of bidirectional promoters can regulate both divergent genes . As a reHowever, there are two potential deficiencies in the former analyses. First, the tandem duplications, which may cause the co-regulation of paired gene as trivial reasons , must beet al [The neighbouring gene pairs in human genome were divided into three classes: 1) bidirectional gene pairs (BIP), which represent the adjacent gene pairs with TSSs distance less than 1 kb on the opposite strands; 2) remote head to head gene pairs (rH2H), the adjacent gene pairs on the opposite strands except the bidirectional gene pairs; 3) head to tail gene pairs (H2T), which represent the neighbouring gene pairs on the same strands. The tandem duplications were excluded from all these three architectures, and the randomly paired genes were chosen as the control. The Pearson correlation coefficient between gene expression profiles was computed employing the wide-distributed microarray data across 78 human cell types and 62 mouse cell types stemmed from a previous transcriptome analysis by Su et al . A signiet al's literature [The functional similarity of bidirectional gene pairs has been evaluated in a former study , and theterature , for theterature , and thiterature ,7. The DAs pointed out by Yanai and his co-worker, the similar gene expression profiles may not imply similar functions , so the It was reported that the genes involved in DNA-repair are more likely to be arranged in bidirectional manner ,7,18. ThThe more interesting finding is that the conserved bidirectional gene enriched pathways are more likely to involve the basic functions in cell. In order to confirm this observation, the tissue specificity of gene expression was then evaluated by the gene expression profiles. Large-scale gene expression variation has been used to select house-keeping genes in many former researches; the genes with lower expression variation among tissues are regarded as potential house-keeping genes ,20,21. TIn order to check the potential constraints for the conservation of bidirectional arrangements, we classified the human bidirectional genes into two categories: the conserved bidirectional genes whose mouse orthologous genes are still arranged in bidirectional architecture (human cBIP gene) and the human-specific bidirectional genes whose mouse orthologous genes are not regulated by bidirectional promoter (human sBIP gene). The human-mouse one to one orthologous gene pairs were extracted from Ensembl using Biomart . Only thIn this study, we found that the bidirectional gene pairs were prevalent in eukaryotes and the percentage of bidirectional genes declines along with the increasing of genome size. The increasing of genome size is much faster than that of gene number during evolution, which can be attributed to two reasons. First, the growing number and length of introns make the gene longer . Second,Only protein-coding gene was considered in this work, the non coding transcripts which are pervasive in many organisms were recently found enriched in the upstream of protein-coding genes and shared the same promoter with the adjacent genes ,25,26. BThe co-regulation of bidirectional gene pairs has been reported in many studies including the co-expression and function relevance ,5. Here The cross-species pathway enrichment analysis showed that the functions of bidirectional genes are greatly conserved in certain fundamental function classes like DNA-repair and transcription related pathways. And this function preference may increase along with the selection of bidirectional structure. The bidirectionality is the inherent feature of promoters , the < 1The chromosomal positions and sequences information of all the protein-coding genes were fetched from the Ensembl database  , while other gene pairs as the human specific bidirectional gene pairs (human sBIP pairs). Similarly, the mouse bidirectional gene pairs are also divided into mouse cBIP pairs and sBIP pairs using the human-mouse linkage. The 14024 one-to-one orthologous gene relationships between human and mouse were extracted from Ensembl database via the Biomart. As a result, 540 human conserved bidirectional promoters and 270 human unique bidirectional promoters were classified, while these numbers are 540 and 207 in mouse genome.The KEGG database  collecteThe calculations in the parentheses refer to the combinatorial calculation. Pathway was recognized as enriched with bidirectional genes if the p-value was lower than 0.05.et al. [The raw microarray data were obtained from Su et al. . For humet al.  with R aet al. . If a gewhere n represents the number of expression datasets, Emax as the maximum expression value of all across cell type expression values, Ei as gene expression value in each microarray experiment. In human and mouse genome, for the mapped head to head gene pairs, head to tail pairs and random-generated 20000 gene pairs, the gene coexpression level were then evaluated as the Pearson correlation coefficient between expression profiles of paired genes separately.The GO annotation for each gene was extracted from Gene Ontology database . For oneThe authors declare that they have no competing interests.CX carried out the computational analysis, CX, JC and BS participated in the design and drafted the manuscript. BS conceived and coordinated this study. All authors read and approved the final manuscript.Predicted peaks of distribution of distance between TSSs of head to head gene pairs using two mixed Gaussian distribution. The approximate positions of the minor and major peaks in the distance distributions were fitted in all the eight organisms. The average value for the minor peak and major peak were computed afterwards.Click here for fileDistribution of distance between genes and adjacent genes on opposite strand in human when including the non-coding transcripts. a). The distribution when only considering protein-coding genes. b). The distribution when including non-coding genes. The non-coding transcripts were defined as the genes labelled by 'lincRNA', 'miRNA', 'miscRNA', 'rRNA', 'snoRNA', 'snRNA', 'non-coding', 'processed_transcript' in biotype term in Ensembl Build 58.Click here for file


Acute and chronic pancreatitis result in considerable morbidity, are increasing in incidence, and have a high mortality rate. Due to the inaccessibility of the pancreas to study, our understanding of the pathophysiology of pancreatitis remains limited. Our current knowledge of the evolution of pancreatitis can be described as a progression from an initial injury to both the acinar and ductal components of the exocrine pancreas to local and systemic inflammatory responses . If resoToll-like receptors (TLR) belong to the superfamily of interleukin-1 receptors and enable the innate immune system to recognize different groups of pathogens, while initiating appropriate and distinct immunological responses. TLR4 proteins, expressed on the cell surface, are receptors for the Gram-negative bacteria cell membrane component, lipopolysaccharide . The heat shock protein HSP60 may play an important role in the protection of the pancreas against damage and against early zymogen activation in acute pancreatitis. J. Bonior et al. report a series of experiments investigating the effects of endotoxemia induced in newborn rats on TLR4, HSP60 and proapoptotic Bax, caspase-9 and -3, or antiapoptotic Bcl-2 protein expression in the pancreatic acinar cells of adult animals. Their results indicate that exposure of the infant rats to LPS promote the induction of HSP60 via TLR4 in their adult life and, in turn, activated Bax/Bcl-2 and caspase-9 and -3. It is likely that this process could play a part in the LPS-induced protection of the pancreatic tissue against acute damage in this experimental model.Melatonin, a product of the pineal gland, is released from the gut mucosa in response to food ingestion and specific receptors for melatonin have been detected in many gastrointestinal tissues including the pancreas. Melatonin has been shown to attenuate the severity of acute pancreatitis. J. Jaworek et al. review the protective effects of melatonin on acute pancreatitis, reported in many experimental studies and supported by clinical observations. They conclude that the beneficial effects of melatonin are sufficient to warrant clinical evaluation as a supportive therapy in acute pancreatitis.The causal relationship between tissue injury and pancreatitis and the mechanisms whereby tissue injury induces pancreatic inflammation is examined in a series of experiments reported by Nakumura et al. Although DNA has historically been believed to be immunologically inert, it is now appreciated that DNA can be released into the systemic circulation when cells undergo necrosis/apoptosis and recognized by the immune system. These authors hypothesised that cytosolic double-stranded DNA released by injured host cells may act as a “danger signal,” which affects pancreatic stellate cells by increasing the expression of several inflammatory genes in the rat.Research into the pathogenesis of pancreatitis is hampered by the inaccessibility and hazards of pancreatic tissue sampling during the course of the disease as well as by the ethical constraint that pancreatic tissue sampling is not a routine part of disease management. Infected pancreatic necrosis (and some cases of sterile necrosis) is an indication for intervention and I. Kovalska et al. have put together a remarkable series of 224 operative and postmortem specimens subjected to histological analysis. This study underlines the importance of early pancreatic microcirculation and local coagulation disorders in the pathogenesis of acute necrotising pancreatitis and that, despite aggressive surrounding necrosis, the islets of Langerhans are preserved in 74.1% of cases, most probably due to fibrin capsule formation. This emphasises the importance of the movement in modern surgery to undertake removal of necrotic pancreas using minimally invasive and organ-preserving approaches [Bridging the gap from bench to bedside, the editors of this special issue review the pro- and anti-inflammatory mediators that drive acute pancreatitis. This review examines the prospects for inflammatory mediators being identified as successful therapeutic targets. We explore the role of immunomodulation, monitoring the state of immune dysfunction by monocyte HLA-DR, signalling pathways of circulating leukocytes, and the narrow therapeutic window for intervention in acute pancreatitis.The search for a specific therapy to treat pancreatitis remains the paramount goal of research in this field. Despite extensive efforts so far, no agent has proved successful. Further efforts to mount a therapeutic damage control strategy to contain an inappropriate inflammatory response are justified and remain ongoing. The APCAP (activated protein C in acute pancreatitis) trial randomised 32 patients with severe acute pancreatitis to receive either recombinant activated protein C  or placebo for 96 hours [With an increasing elderly population in many parts of the world, the effect of ageing on systemic inflammation, focusing on that induced by acute pancreatitis, has become more important than ever. Several reports have related an increased susceptibility to a proinflammatory status called inflammaging, which decreases the capacity of the immunological system to respond to antigens. M.C.C. Machado et al. review the effects of aging on the systemic inflammation in pancreatitis. They discuss the effects of cellular senescence and how this probably contributes to the chronic inflammatory state related to ageing.State-of-the-art imaging remains a cornerstone of current management in acute pancreatitis. Early diagnosis and staging of complications are important clinical objectives. In this special issue, the method by which perfusion to an organ is measured by CT, and its clinical utility is reviewed by Y. Tsuji et al. They make the case that perfusion CT is a promising technique for diagnosis of local and systemic complications of severe acute pancreatitis at an early stage. Discriminating between focal chronic pancreatitis and pancreatic cancer remains challenging. Contrast-enhanced endoscopic ultrasound using Doppler techniques can reveal different vascularisation patterns in pancreatic tissue altered by chronic inflammatory processes and pancreatic cancer. M. Hocke et al. review the basics of contrast-enhanced high and low mechanical index endoscopic ultrasound and explain the pathophysiological differences behind the vascularisation of chronic pancreatitis and pancreatic carcinoma and how to use these techniques in daily clinical practice.Pancreatic pseudocyst is a complication that develops in both acute and chronic pancreatitis. It may remain asymptomatic or develop life-threatening complications. A. K. Khanna et al. address the therapeutic dilemma of whether or not to treat a patient with a pancreatic pseudocyst, as well as when and with which technique.  (Alexander III of Macedon (20/21 July 356–10/11 June 323 BCE)). Alexander ascended to the throne and was to become the most successful of Greek generals, extending Hellenic influence throughout the known world. However, a case for acute pancreatitis being retrospectively applied to Alexander's death certificate can be made: a rich meal and heavy alcohol consumption preceded the onset of the disease and were probably the precipitating factors; the course of the disease is typical of acute pancreatitis in its onset, severity and irreversibility; fever and the subsequent systemic effects point towards acute necrotising pancreatitis with sepsis and multiple-organ failure [An early account of acute pancreatitis may have been furnished by the death of Alexander the Great failure . If the We hope, however, that ongoing research, such as that contained within this special issue of the International Journal of Inflammation, provides the insight and inspiration necessary to make progress in our endeavours to obtain sufficient understanding to discover an effective treatment for this disease.


Metastasis of breast cancer is a multistep process that requires cancer cells to invade stroma at the primary site, gain access to vasculature, survive in the circulation, extravasate into the parenchyma of the secondary site, and survive and proliferate at the secondary site. During each of these steps, the microenvironment surrounding the cancer cells is believed to be an active participant. The cancer microenvironment also varies during the metastatic process. At the primary tumor in the breast, invasive cancer cells are surrounded by fibroblasts, extracellular matrix (ECM), cellular constituents of the vasculature, inflammatory/immune cells, and adipose tissue. Metastasizing cancer cells are exposed to a completely different microenvironment within the circulatory system. The cancer microenvironment at the secondary site is, again, very different from the microenvironment of the breast and varies depending on the sites of metastasis. At the primary and metastatic sites, the interaction between tumor cells and their surrounding milieu is reciprocal; the tumor cells influence the stroma and vice versa, ultimately fueling tumor progression. The papers in this issue discuss the dynamics of the interactions of tumor cells and their microenvironment, detailing how tumor cells manipulate their milieu and, conversely, how the reactive tumor microenvironment influences tumor cell plasticity, invasion, metastasis, and cancer therapy.“Active roles of tumor stroma in breast cancer metastasis.” The authors discuss research findings related to the contribution of various constituents of the tumor microenvironment, including inflammatory cells, fibroblasts, extracellular matrix, and blood vessels, in the metastatic process. They also include a discussion of the signaling pathways utilized by cancer cells to modify the stroma and ECM. This review serves as an excellent overview for this issue.Z. I. Khamis et al. provide a thorough summary of the roles of the tumor stroma and tumor microenvironment in the various steps involved in the metastatic process, as well as in the development of breast cancer in their paper “The role of cancer stem cells in the organ tropism of breast cancer metastasis: a mechanistic balance between the “seed” and the “soil?”” have exhaustively summarized the role of the cancer stem cells in determining the organ tropism exhibited by breast cancer cells. Given the fact that metastasis is an inefficient process, the authors make a compelling case for cancer stem cells to be the rare population that is equipped with the necessary armamentarium of traits to successfully metastasize. The paper summarizes the hierarchical role of cancer stem cells within the various subtypes of breast cancer and the phenotypic and functional signatures of breast cancer stem cells. It also puts into perspective the origin of cancer stem cells and their role in conditioning the premetastatic niche. The authors also provide a detailed analysis of the microenvironment of the various metastatic niches encountered by metastatic breast cancer cells, specifically the bone, brain, lungs, liver, and lymph nodes. The paper concludes with a stimulating discussion on the contribution of cancer stem cells to therapeutic resistance taking into account the interactions of the cancer stem cells with the microenvironment.Two papers in this issue discuss the cancer cells themselves and how characteristics or functions of the cancer cells influence the tumor microenvironment. Just as the microenvironment signals to the cancer cells, the cancer cells alter the microenvironment to promote tumor progression and metastasis. J. E. Chu and A. L. Allan in their paper Bromodomain-containing protein 4: a dynamic regulator of breast cancer metastasis through modulation of the extracellular matrix”, is focused on the activity of bromodomain-containing protein 4 (BRD4) in breast cancer cells. BRD4 functions as an inherited susceptibility gene for breast cancer progression and metastasis and regulates the transcription of select genes through epigenetic mechanisms. Multiple ECM genes are regulated by BRD4 that may lead to changes in the overall structure of the surrounding environment or alter the cell-matrix interactions to promote breast cancer invasion and metastasis. The review by J. Alsarraj and K. W. Hunter, “Role of estrogen receptor signaling in breast cancer metastasis”. They emphasize the importance of ER-coregulatory proteins and their misexpression in promoting metastasis of ER-positive breast cancer cells. They have discussed possible therapeutic targets to block ER-driven metastasis. Most significantly, this paper brings to notice the importance of defining alternative signaling pathways. Specifically, multiple signaling pathways in addition to estrogen signaling are involved in activating ERs. Hence, combination therapies using both endocrine and nonendocrine agents that block these different pathways may have better therapeutic effects and may delay metastasis. The roles of estrogen receptor (ER) signaling and signaling through Toll-like receptors (TLR) in the crosstalk and interactions of breast cancer cells with the tumor microenvironment are the topics of another two papers in this issue. Hormones play a critical role in directing breast cancer progression. Specifically, ER signaling is one of the critical and complex determinants of breast cancer metastasis. S. S. Roy and R. K. Vadlamudi have provided an integrated picture of this specific signaling in the paper ““Expression of Toll-like receptors on breast tumors: taking a Toll on tumor microenvironment.” The immune system is intricately involved in the process of tumor progression and metastasis and can play key roles in both tumor promotion and tumor suppression. TLRs are critical for innate and adaptive immunity and are expressed on inflammatory cells surrounding the tumor. Recent studies have identified many TLRs expressed by tumor cells that may promote growth and immune evasion. This has led to the emergence of TLR signaling as a potential target for the treatment of various tumors. D. Bhattacharya and N. Yusuf discuss the data regarding TLR expression in breast cancer and its role in inflammation and cell survival in the tumor microenvironment in “The microenvironmental effect in the progression, metastasis, and dormancy of breast cancer: a model system within bone marrow.” The heterogeneous composition of the bone microenvironment not only facilitates the growth of breast cancer cells but also supports and protects the tumor cells. There is a bidirectional crosstalk between the cells comprising the bone microenvironment and the metastatic breast cancer cells. While modulation of macrophage function can cause immune suppression, the release of inflammatory cytokines by adipocytes can stimulate tumor cell invasion, and the expression of SDF-1 by the myofibroblasts accelerates tumor cell growth. The contribution of mechanical stress in impacting tumor cell survival, elicitation of angiogenesis, and influencing drug delivery is elegantly summarized. This paper also discusses the role of microenvironment-derived cytokines, chemokines, and miRNA in inducing epithelial-mesenchymal changes and influencing cancer cell quiescence.One of the most common sites for the metastasis of breast cancer is to bone. In accordance with this, four papers focus on breast cancer metastasis to bone. B. Y. Reddy et al. put into perspective the role of the microenvironment of the bone in breast cancer metastasis in “Changes in cytokines of the bone microenvironment during breast cancer metastasis.” Using a xenograft model of breast cancer metastases to bone, they demonstrate that the presence of the breast cancer cells in bone changes the normal levels of specific cytokines. Cytokines are important for bone remodeling, hematopoietic processes, and homeostatic balance in the bone. Therefore, by altering cytokine levels in the bone, metastatic breast cancer manipulates the bone microenvironment. D. M. Sosnoski et al. present their findings on the influence of metastases on the levels of a variety of cytokines and growth factors in the bone in their research article “RKIP suppresses breast cancer metastasis to the bone by regulating stroma-associated genes.” This focuses on the metastasis suppressor, Raf Kinase Inhibitory Protein (RKIP), and its ability to influence the tumor microenvironment in the bone. RKIP inhibits breast cancer invasion, intravasation, and bone metastasis via the induction of miRNA let-7, resulting in suppression of the chromatin-remodeling factor HMGA2 and modulation of epithelial to mesenchymal plasticity. The use of a savvy, interdisciplinary approach involving expression arrays from breast cancer patients yielded a deeper understanding of key regulators of genes that form the bone metastasis signature of cancer cells, putting the spotlight on RKIP as a critical regulator of the tumor milieu and impacting the ability of tumor cells to establish bone metastases. A complementary perspective on the dynamic dialogue between the stroma and the tumor cells, which impacts metastasis of tumor cells to bone, is provided by E. Bevilacqua et al. in “The hedgehog pathway conditions the bone microenvironment for osteolytic metastasis of breast cancer,” S. Das et al. discuss our current understanding of how the hedgehog signaling pathway alters the bone microenvironment to promote metastatic breast cancer growth. Hedgehog inhibitors may be a viable option for the treatment and/or prevention of breast cancer metastasis to bone. The bone microenvironment is a fertile soil for metastasis with multiple regulatory molecules affecting growth. Accumulating evidence supports the notion that hedgehog signaling plays a role in breast cancer metastasis to bone. In “Current operative management of breast cancer: an age of smaller resections and bigger cures.” Consideration of the tumor microenvironment is an emerging frontier in the treatment of breast cancer. The surgeon's primary focus with breast-conserving surgery is obtaining tumor-free surgical margins, but there is a question as to whether residual stromal changes in the breast may affect local recurrence. The authors emphasize that surgical intervention is currently the best hope for definitive cure of breast cancer; however, advances in the treatment of breast cancer as a systemic disease are needed to facilitate long-term cures. Patient-specific molecular diagnosis and the development of targeted chemotherapeutic agents are future hopes for improved survival and will offer the surgeon an opportunity to be more focused and allow easier management of the disease.Finally, J. W. Rostas and D. L. Dyess have provided the surgeon's perspective of current surgical management of breast cancer in Andra R. FrostAndra R. FrostDouglas R. HurstDouglas R. HurstLalita A. ShevdeLalita A. ShevdeRajeev S. SamantRajeev S. Samant


The petrous apex is a pyramid-shaped structure, located medial to the inner ear and the intrapetrous segment of the internal carotid artery. Lesions of the petrous apex can be surgically treated through different surgical routes. Because of the important neurovascular structures located inside the temporal bone, anatomical 3D knowledge is paramount. For this reason, image-guided surgery could represent a useful tool. We report the case of a young woman who came to our observation for a trigeminal neuralgia due to a petrous apex cholesterol granuloma. The lesion was treated through the placement of a drainage tube via an infracochlear approach, with the aid of neuronavigation and intraoperative MRI. Preoperative CT scan images and intraoperative MRI images were fused for surgical planning. The accuracy of the neuronavigation system has proved to be good, and the safety of the procedure was enhanced. Therefore, neuronavigation and intraoperative MRI, though not available in all neurootological centres, should be considered useful tools in these challenging procedures. The petrous apex is a pyramid-shaped structure that represents the most medial part of the temporal bone , 2. It iA 36-year-old woman came to our observation because of a three-month history of left trigeminal neuralgia with pain distributed along the ophthalmic division of the fifth cranial nerve. The neurological examination revealed the absence of neurological deficits. MRI with gadolinium showed a hyperintense lesion on both T1- and T2-weighted images, with no postcontrast enhancement Figures . At the The petrous apex can be anatomically described as a pyramid-shaped structure that can be divided in a posterior and an anterior part by a line passing in the coronal plane through the internal auditory canal . The basIn conclusion, this report outlines the usefulness of intraoperative image guidance for transtemporal approaches to the petrous apex, especially in patients with serviceable hearing and no preoperative cranial nerve deficits. The absence of brain shifting and the advancements in neuroimaging techniques make it highly accurate, without increasing surgical time. Moreover, our personal experience emphasizes the advantage of matching preoperative CT and intraoperative MRI scans, since the different type of information provided by these two studies enhance the accuracy of the 3D representation of the temporal bone anatomy, allowing a safer drilling of the petrous bone.


Dear Editor,With introduction of concept like nephron-sparing surgery, partial nephrectomy using surgicel as a haemostatic agent is now being recommended as a procedure of choice for an increasing number of pediatric urology disorders. Although surgicel is considered a safe haemostat, it still has been found to be associated with unusual complications.–4 Thus, A 1.2-year-old female baby with features of left hemihypertrophy associated with complex cystic mass in upper pole of left kidney underwent partial nephrectomy. During partial nephrectomy hemostasis was achieved by ligation of vessels and surgicel was applied in multiple layers after application of Glubran 2 tissue glue. In postoperative period, an increase in drainage in the form of yellowish thick fluid approximately 5-10 ml in 24 hours was observed from fourth postoperative day. The biochemical analysis of fluid in form of creatinine and sodium values done twice on the fifth and eighth postoperative day, corresponded to serum values, thus confirming absence of urine leak. The microbiological analysis showed absence of inflammatory pathology. Thus, presence of thick yellowish sterile fluid was attributed to biodegradation of thick layer of surgicel and the correlation of drain output with ultrasonic thickness of surgicel showed progressive decrease in drainage by the end of second week, which coincided with decrease in ultrasonic thickness of surgicel. Thus, the serum values of fluid and the correlation of ultrasonic thickness with drain output provided evidence that excessive use of surgicel may be a contributing factor for prolonged drainage. The patient recovered well and is asymptomatic on follow-up for the last three months.Since the use of oxidized cellulose by Frantz, sugicel has been used successfully as the biodegradable hemostatic agent.2 Althoug113


The TELEKAT project  has developed a telerehabilitation programme enabling patients with chronic obstructive pulmonary disease (COPD) to perform preventive home monitoring across sectors. The goal of the project is to help patients avoid readmission to hospital, perform self-monitoring and to maintain rehabilitation activities in their homes. The study includes COPD patients with severe and very severe COPD (n=111). Nurses and doctors at a hospital, GPs, district nurses and nurses from a healthcare center have monitored COPD patients in the programme.The aim of this paper is to discuss how telerehabilitation technology affects interaction between healthcare professionals in the Telekat network.Inter-organisational theory and learning theory.The case study approach was applied using a triangulation of data collection techniques. The data included documents, participant-observation (163 hours) and qualitative interviews with nurses and doctors at a hospital, GPs, district nurses, nurses and physiotherapists at a healthcare centre (n=40). All the interviews were transcribed and data were coded using Nvivo 8.0 software, as inspired by Kvale (2009).The healthcare professionals expressed the view that during the process of creating and testing the programme for telerehabilitation, they have created new roles in the cooperation between district nurses, GPs, nurses and doctors at hospital and healthcare centre. The roles have changed concerning counseling on rehabilitation issues. Through the process of developing the programme of telerehabilitation, mutual trust has emerged between the healthcare professionals, enhancing collaboration and coordination activities related to telerehabilitation of COPD patients across sectors. Video conferences between the healthcare professionals have facilitated knowledge-sharing and reflections on professionals’ issues between experts and generalists. Finally, the healthcare professionals expressed the view that participation and interaction via the technology allows them to feel part of a community of telerehabilitation.The telerehabilitation technology facilitates participation and interaction between the healthcare professionals across sectors, giving them a feeling of belonging to a part of a community of telerehabilitation.


Currently the major barrier in biomass utilization is the lack of an effective pretreatment of plant cell wall so that the carbohydrates can subsequently be hydrolyzed into sugars for fermentation into fuel or chemical molecules. Termites are highly effective in degrading lignocellulosics and thus can be used as model biological systems for studying plant cell wall degradation.Coptotermes formosanus, which are critical for efficient cell wall digestion. Comparative studies on the termite-chewed and native (control) softwood tissues at the same size were conducted with the aid of advanced analytical techniques such as pyrolysis gas chromatography mass spectrometry, attenuated total reflectance Fourier transform infrared spectroscopy and thermogravimetry. The results strongly suggest a significant increase in the softwood cellulose enzymatic digestibility after termite chewing, accompanied with utilization of holocellulosic counterparts and an increase in the hydrolysable capacity of lignin collectively. In other words, the termite mechanical chewing process combines with specific biological pretreatment on the lignin counterpart in the plant cell wall, resulting in increased enzymatic cellulose digestibility in vitro. The specific lignin unlocking mechanism at this chewing stage comprises mainly of the cleavage of specific bonds from the lignin network and the modification and redistribution of functional groups in the resulting chewed plant tissue, which better expose the carbohydrate within the plant cell wall. Moreover, cleavage of the bond between the holocellulosic network and lignin molecule during the chewing process results in much better exposure of the biomass carbohydrate.We discovered a combination of specific structural and compositional modification of the lignin framework and partial degradation of carbohydrates that occurs in softwood with physical chewing by the termite, C. formosanus, resulting in an efficient pretreatment of biomass through a combination of mechanical and enzymatic processes. This pretreatment could be mimicked for industrial biomass conversion.Collectively, these data indicate the participation of lignin-related enzyme(s) or polypeptide(s) and/or esterase(s), along with involvement of cellulases and hemicellulases in the chewing process of  Transformational scientific knowledge on bioprocessing is required for developing enabling technologies toward converting renewable biomass to targeted biofuels or biochemicals. A major barrier in biomass utilization is the lack of an effective pretreatment of plant cell wall (PCW) so that the carbohydrates can subsequently be hydrolyzed into sugars to be fermented into fuel or chemicals. Existing technologies typically employ thermochemical processes for biomass pretreatment to break down the barriers formed by lignin and lignin-hemicellulose association. Although effective, these processes are energy intensive, environmentally unfavorable and associated with the production of inhibitors that compromise the performance of downstream fermentation. The fact that there is still no successfully demonstrated commercial system in the world for producing biofuels and biochemicals from lignocellulosic biomass underscores the magnitude of the related technical challenges. There is an urgent need for new systems that are more efficient, cost-effective and environmentally-friendly for deconstructing PCW for sugar release.Nature, through millions of years' evolution, has developed highly efficient biological systems. Wood-feeding termites  are among the most effective lignocellulose-recycling invertebrates in terms of the rate and extent of cellulose utilization . Termiteet al.  versus 1/T results in a straight line with a slope of -E/R and a y intercept of ln[(AR)/(βE)], providing the values of E and A.Plotting ln[g(α)/TThe authors declare that they have no competing interests.JK and DL conceived and designed the experiments. JK and DG performed the experiments. JK and DL analyzed the data. SC contributed reagents, materials and analysis tools. JK and DL wrote the paper. SC mentored and revised the paper. All authors read and approved the final manuscript.Pyrogram. Py-GC/MS spectrum of the whole guts of two termites starved for 40 hours. The appeared peaks represent CO2 and fatty acids, respectively. Non-existence of pyrolysate from lignin, cellulose or hemicellulose suggested complete evacuation of the gut contents.Click here for file


Spontaneous enterobiliary fistulae are a complication of biliary disease or a disease of adjacent structures. Cholecystocolic fistulae are rare in relation to gallbladder carcinoma (GBC). Previous reports have presented images showing subtle findings suggestive of cholecystocolic fistula. We report the unusual spread and rare images of a case of cholecystocolicfistula,to highlight the aggressive nature of GBC and findings of gross transmural invasion of the colonic wall. The images acquired in all three planes define the anatomical and pathological extent conclusively. There are a higher number of GBC cases across the geographic belt of North India compared to the West. In this case, the patient’s pathology was extensive and unresectable, and therefore palliative and supportive care wasadvised. The cholecystocolonic fistula is an uncommon but pertinent complication of gallbladder disease, occurring in 0.06 to 0.14% of patients with biliary disease . Among tWe discuss the case of a 48-year-old woman who presented with right hypochondrial pain, jaundice and melena. On examination there was severe jaundice and a lump in the right hypochondrium. The patient underwent an abdominal ultrasonography which showed gallbladder fossa mass infiltrating the portahepatis with proximal biliary dilatation. Fine needle aspiration cytology (FNAC) was undertaken and revealed high grade adenocarcinoma. The patient was advised MDCT evaluation. Contrast enhanced multiplanar CT  with IV and oral contrast was performed.Axial sections showedan ill-defined, hypoattenuating infiltrative soft tissue mass lesion in the gallbladder fossa. The lesion showed frank transmural invasion of the colonic wall with a discernible fistulous tract. Multiple air loculi were visible within the mass lesion. Contiguous axial sections demonstrated the fistulous tract and relation of the transverse colon and ascending colon Figure A-C. The Spontaneous enterobiliary fistulae are a complication of biliary disease or a disease of adjacent structures. They are usually associated with gallstones; however, peptic ulcer disease, abdominal trauma, Crohn’s disease, and malignancies of the biliary tract, bowel and head of pancreas, have also been implicated as causes -3. The oGBC has been notorious to have a poor prognosis, with an overall 5-year survival rate reported to be 4% . It is rThe endemic zone of North India comes across aggressive behavior of GBC. Imaging can be definitive and conclusive, and can obviate surgical exploration in appropriately selected cases. A combined approach using noninvasive diagnostic methods and percutaneous aspiration biopsies may reduce the number of explorative laparotomies in advanced cases of GBC. Multidetector scanners are a powerful modality to define the extent, anatomical information and associated complications of GBC.Written informed consent was obtained from the patient for publication of this Case Report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.CT: Computed tomography; FNAC: Fine needle aspiration cytology; GBC: Gallbladder carcinoma; MDCT: Multidetector computerized tomography.The authors declare that they have no competing interests.ANDD: Conceived and designed the study. Drafted the manuscript and contributed to the intellectual content and given final approval of the version to be published. SK: Involved in data acquisition and data interpretation and has participated in design of study and intellectual content. SR: Has helped in data acquisition and image analysis and helped in drafting and revising the manuscript. BNM: Participated in data acquisition and data analysis and participated in its design. All authors read and approved the final manuscript.


Status Epilepticus induced by pilocarpine and control rats were used to evaluate whether morphological differences alone between these cells have an impact on their electrophysiological behavior. The cell models were constructed using morphological information from tridimensional reconstructions with Neurolucida software. To evaluate the effect of morphology differences alone, ion channel conductances, densities and distributions over the dendritic trees of dentate gyrus granule cells were the same for all models. External simulated currents were injected in randomly chosen dendrites belonging to one of three different areas of dentate gyrus granule cell molecular layer: inner molecular layer, medial molecular layer and outer molecular layer. Somatic membrane potentials were recorded to determine firing frequencies and inter-spike intervals. The results show that morphologically altered granule cells from pilocarpine-induced epileptic rats are less excitable than control cells, especially when they are stimulated in the inner molecular layer, which is the target area for mossy fibers that sprout after pilocarpine-induced cell degeneration. This suggests that morphological alterations may act as a protective mechanism to allow dentate gyrus granule cells to cope with the increase of stimulation caused by mossy fiber sprouting.Computer simulations of external current stimulations of dentate gyrus granule cells of rats with  Status Epilepticus (SE) on neurogenesis of the dentate gyrus (DG) granule cells (GCs) have been widely described The effects of These cells also present differences in the number of dendritic spines on the basal dendrites Regarding the electrophysiological behavior of GCs in SE rats, there are conflicting results. Some studies The way in which changes in the morphology of DG GCs are integrated into the DG and how they can eventually affect the spontaneous emergence of seizures is still unknown. A possible effect of the morphological changes would be that they, combined with reduced inhibition, contribute to turn the cells more excitable Therefore, new approaches are necessary to elucidate the consequences of morphological alterations and their associated mechanisms. In this context, computational modeling presents a quite good alternative to generate hypotheses and guide future research. Different biologically detailed models of DG GCs have been constructed, from single cell models in normal conditions These computational studies For this reason, in the present study we constructed computational models of morphologically reconstructed newborn DG GCs from rats that had SE induced by PILO and from control rats to compare their firing responses when stimulated by simulated current injections in their dendritic trees. The source of our morphological data was a set of Neurolucida-based tridimensional reconstructions of rat newly born doublecortin-positive DG GCs To construct our cell models, we assumed that the ionic channels, their maximal conductance densities and their distributions over the different areas of the DG GC dendritic tree are the same for all cells. This would allow us to predict possible effects that changes in dendritic arborization alone can have on the electrical behavior of the cells.Our results show that newborn DG GCs from rats with SE induced by PILO are less excitable than newborn DG GCs from control rats. Based on this finding we predict that morphological alterations in newborn DG GCs caused by SE induced by PILO can provoke changes in the firing behavior of these cells. Moreover, these changes tend to cause opposite effects on the activity of newborn DG GCs than the ones caused by PILO.In general the compartmental cell models reproduced the responses of actual DG GCs to current step injection with a sequence of spikes with adaptation and no burst The cell models in the PILO groups show smaller firing frequencies and higher inter-spike intervals than control cells. This pattern was observed in all groups of cell models , with minor differences depending on the number of electrodes or the layer in which the cell was stimulated see  and 3.Most of the significant differences in the number of spikes in the F–I curves occur for the pruned models, and they are concentrated mainly in the stimulations made in the IML regardless of the number of electrodes see . In partThe inter-spike intervals show a similar pattern to the F–I curves, with differences between PILO and control cells occurring mostly for current injections in the IML regardless of the number of electrodes see  and 3E–F3 = 8 different samples of cell models: PILO-pruned-distance 1, PILO-pruned-distance 2, PILO-shrank-distance 1, PILO-shrank distance 2, Control-pruned-distance 1, Control-pruned-distance 2, Control-shrank-distance 1 and Control-shrank-distance 2.This study investigated the effect that morphology differences alone can have on the spiking behavior of biophysically realistic multicompartmental models Our simulation results allow a prediction of what could be found in electrophysiological studies with newly born DG GCs following SE induced by PILO. The prediction is that these cells are less excitable than the control ones. Moreover, this decrease in cell excitability can be a consequence of the morphological differences between PILO and control cells alone, because in both groups we placed the same ion channel conductances, densities and distributions.Although in our simulations the average values of the input resistances of PILO and Control cell models were not significantly different, the average value for PILO cells was slightly smaller than the one for Control cells, and this is also consistent with the prediction of smaller excitability of PILO cells.The strategy of using different numbers of electrodes placed randomly in different dendritic regions makes it possible to evaluate the effects of the morphological differences in a more accurate way. With this strategy we evaluate how the same stimulus intensity can provoke different patterns of response depending on its distributions in the dendritic tree. Our finding that there are differences in cell response depending on both the number of electrodes and the local of stimulation confirms previous studies The major contribution of the current study is that it is possible to discriminate the level of excitability between control and PILO cells based on morphology alone. We found that depending on the dendritic region where the stimuli (electrodes) are placed, the response (firing frequency) of PILO cells is smaller than the one of control cells. This result is significant for pruned-distance 2 cell models stimulated in the IML. This result is important because it suggests that the excitability of PILO cells is highly dependent on the specific area of their dendritic trees which serve as target for synaptic input. For example, from Arisi and Garcia-Cairasco It is important to mention that even though we used the same distributions of maximum ionic conductance densities and passive electrophysiological properties across dendritic segments in our cell models, because of the differences in dendritic lengths between control and PILO cells the actual dendritic surface areas reached by currents injected in the three molecular layers  were different for the two cell groups. This implies that, effectively, the number of ionic channels activated by current injection in the same molecular layer, e.g. IML, was different from control to PILO cells . Moreover, this difference also depends on the segmentation criterion used, and this is why the excitability reduction was more pronounced in pruned models than in shrank models.SE induced by PILO may be accompanied by changes in these densities (from the point of view of the mossy fibers that innervate the IML). We propose that these changes are partly responsible for the excitability reduction in PILO cells observed in our study.Therefore, even in the absence of explicit changes in the maximal ionic conductance densities, morphological alterations caused by SE may also have explicit changes in the ionic channels and their density distributions Newborn DG GCs after It is interesting that despite the differences observed between cells built with distance 1 and distance 2 criteria, both groups of PILO cell models showed less excitability than control groups. This finding suggests two possible scenarios in which the effects of the morphological differences can be mitigated or accentuated depending on the way in which the ionic conductances and densities are distributed. In the first, using the distance 1 criterion, for which the distribution of ionic conductances and densities did not take into consideration the dendrite length and considered only its beginning position, the excitability reduction is moderate. In the second, using the distance 2 criterion for which the distribution of biophysical properties considered the length of the dendrite there is an accentuated reduction in the cell excitability. This suggests that longer dendrites may have a more important role in the decrease of excitability than short dendrites that grow close to soma, because the differences between distance 1 and distance 2 models are concentrated in longer dendrites, which have different distance 1 and distance 2 values and, therefore, different distributions of biophysical properties.Also, the pruning and shrinking criteria offer two possible scenarios for the effects of the morphological differences: in the first one the shorter dendrites of the PILO cells may be a product of pruning, while in the second one these dendrites may be a product of shrinking. In our simulations the pruning criterion showed more differences between control and PILO cells than the shrinking criterion. Therefore, the morphological pattern of pruned DD dendrites in PILO cell models produces decreased excitability, which could be tested in the lab using, for example, techniques of neuronal growth cone identification A receptors in dentate GCs in epilepsy animal models, which enhances the inhibitory effects upon these cells. In the same direction Santos et al. A final commentary can be made on the potential causes of decreased excitation of the GCs in an epileptogenic circuit or network. Jakubs et al. Although our computational modeling is based upon single neuron morphologies, it is clear that network modeling is needed in order to better understand the role of the newly generated cells in an environment, as close as possible to physiology. In this direction, elegant examples such as the DG network model developed by Santhakumar et al. Summarizing, our results predict a decrease in the excitability in PILO cells that emerge after SE. But how do we explain this kind of prediction? Why do these cells need more stimulation to reach the same response? A possible hypothesis is that this reduction in excitability due to morphological alterations is a protective mechanism that, in addition with the increase of inhibition In this context, changes in the morphology – such as the fiber sprouting, which increases the stimulation © (MBF Bioscience). They are available at NeuroMorpho.org We used a sample of 40 tridimensional reconstructions of newly born doublecortin-positive DG GCs, including 20 from rats that underwent SE after treatment with PILO  and 20 from control rats  , medial molecular layer (MML) and outer molecular layer (OML) The cell models were constructed according to Rall’s compartmental approach with membrane properties and ionic channels modeled according to the Hodgkin-Huxley formalism Each cell in our sample had its dendritic arbor divided into segments following the canonical representation suggested by Aradi and Holmes We used the average maximum values of the distance measures for the control and PILO cells to classify the dendrites into two additional patterns: in the first we used only the average maximum values of the control cells to classify control and PILO dendrites, and called this set of models the “pruned models” see . The reaA total of 160 cell models were built, combining pruning-shrinking and distance 1-distance 2 criteria. Forty of them were pruned models classified using distance 1 criterion, 40 were pruned models classified using distance 2 criterion, 40 were shrank models classified using distance 1 criterion and 40 were shrank models classified using distance 2 criterion.Na), fast and slow delayed rectifier potassium currents (IfKDR and IsKDR), A-type potassium current (IKA), T, N, and L calcium current types, and BK- and SK-type calcium-activated potassium channels. Aradi and Holmes Aradi and Holmes In the current study we adopted the criterion of keeping the same nine currents (with the same kinetic parameters) used by Aradi and Holmes The 160 computational models were divided into 8 groups of 20 cells each: PILO-pruned-distance 1, PILO-pruned-distance 2, PILO-shrank-distance 1, PILO-shrank distance 2, Control-pruned-distance 1, Control-pruned-distance 2, Control-shrank-distance 1 and Control-shrank-distance 2. To characterize the cells, we worked with random samples of 10 cells taken from each one of the eight groups. Each cell model from each sample was submitted to simulated voltage clamp with 14 current values ranging from 0.005 nanoamperes (na) to 0.075 na in steps of 0.005 na. All current clamp values were injected in a consecutive way with intervals of 500 milliseconds (ms) between the end of a current injection and the start of the next.The experimental protocol of submitting cell models to sequences of 14 current clamps was repeated three times for each cell model. In each one of them currents were applied to dendrites belonging to a different area of the DG molecular layer: IML, MML and OML see . These tversus time and frequency of spikes versus current (F-I curves), and also estimated the inter-spike intervals. These measurements were made for each region  of stimulation and for each number (1–5) of electrodes.The currents were injected using different numbers of electrodes connected randomly to one up to five dendrites in a given layer see . Each cuin) of the GC models from the slope of the steady-state current–voltage (I–V) relation from voltage responses to an injected current of −0.01 na.In addition, we calculated the input resistance (Rt-test for independent samples, with an alpha of 0.05 in all cases.The values of input resistance, number of spikes and inter-spike intervals for control and PILO groups were compared using a Student