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Charting an organs’ biological atlas requires us to spatially resolve the entire single-cell transcriptome, and to relate such cellular features to the anatomical scale. Single-cell and single-nucleus RNA-seq (sc/snRNA-seq) can profile cells comprehensively, but lose spatial information. Spatial transcriptomics allows for spatial measurements, but at lower resolution and with limited sensitivity. Targeted in situ technologies solve both issues, but are limited in gene throughput. To overcome these limitations we present Tangram, a method that aligns sc/snRNA-seq data to various forms of spatial data collected from the same region, including MERFISH, STARmap, smFISH, Spatial Transcriptomics (Visium) and histological images. Tangram can map any type of sc/snRNA-seq data, including multimodal data such as those from SHARE-seq, which we used to reveal spatial patterns of chromatin accessibility. We demonstrate Tangram on healthy mouse brain tissue, by reconstructing a genome-wide anatomically integrated spatial map at single-cell resolution of the visual and somatomotor areas.

Gut decontamination could have some benefits in preventing infectious complications in acute pancreatitis (AP).To investigate whether the administration of rifaximin could have an impact on the outcomes of AP.We conducted a retrospective study on 373 patients with a median age of 50 years that were admitted to our Department of Gastroenterology in the years 2001-2016 with a diagnosis of AP. Patients were subclassified according to the revised Atlanta criteria: mild acute pancreatitis (MAP), moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP). Thereafter, all the patients were divided into 2 groups: in the 1st group (R0) with MSAP and SAP, patients did not receive rifaximin, and in the 2nd group (R1), in the cases of MSAP and SAP, rifaximin was administered to patients at a dose of 3 × 400 mg (for at least 5 days and up to 7 days). There was no other difference in the treatment between the groups. The median duration of hospital stay, the number of infectious complications and the mortality rate were recorded for both groups.A significant difference was observed between median durations of hospitalization between the groups with (R1) and without (R0) rifaximin treatment (14 days compared to 24 days, p = 0.001) and in the number of patients infected with pancreatic necrosis (7 compared to 1, p = 0.0487). However, there was no statistically significant difference between the R1 and R0 group in terms of mortality rate.The results indicate that rifaximin seems to be a promising novel therapeutic option in MSAP and SAP.

Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP), with incidence rates ranging between 2% and 16%. In addition to being experienced in endoscopic procedures and having knowledge of the patient qualification criteria, physicians should also be aware of the patient and procedure-related risk factors responsible for post-ERCP pancreatitis (PEP). Intrarectal administration of nonsteroidal anti-inflammatory drugs and pancreatic duct stenting were demonstrated to be efficient in high-risk patients. This review provides a broader summary of pharmacological methods and techniques aimed at reducing the risk of PEP.

The lysine acetyltransferases type 3 (KAT3) family members CBP and p300 are important transcriptional co-activators, but their specific functions in adult post-mitotic neurons remain unclear. Here, we show that the combined elimination of both proteins in forebrain excitatory neurons of adult mice resulted in a rapidly progressing neurological phenotype associated with severe ataxia, dendritic retraction and reduced electrical activity. At the molecular level, we observed the downregulation of neuronal genes, as well as decreased H3K27 acetylation and pro-neural transcription factor binding at the promoters and enhancers of canonical neuronal genes. The combined deletion of CBP and p300 in hippocampal neurons resulted in the rapid loss of neuronal molecular identity without de- or transdifferentiation. Restoring CBP expression or lysine acetylation rescued neuronal-specific transcription in cultured neurons. Together, these experiments show that KAT3 proteins maintain the excitatory neuron identity through the regulation of histone acetylation at cell type-specific promoter and enhancer regions., M.L. is recipient of a Santiago Grisolia fellowship given by the Generalitat Valenciana, J.M.C. is recipient of a fellowship from the Spanish Ministry of Education, Culture and Sport (MECD), J.F.-A. and C.M.N. are recipients of fellowships from the Spanish Ministry of Science and Innovation (MICINN). The ultrastructure research was supported by the Polish National Science Center Grant UMO-2014/15/N/NZ3/04468 and by the European Regional Development Fund POIG 01.01.02-00-008/08. J.P.L.-A. research is supported by Grants RYC-2015-18056 and RTI2018-102260-B-I00 from MICINN co-financed by ERDF. A.B. research is supported by Grants SAF2017-87928-R, PCIN-2015-192-C02-01, and SEV-2017-0723 from MICINN co-financed by ERDF, PROMETEO/2016/026 from the Generalitat Valenciana, and RGP0039/2017 from the Human Frontiers Science Program Organization (HFSPO). The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa”.

Environmental factors and life experiences impinge on brain circuits triggering adaptive changes. Epigenetic regulators contribute to this neuroadaptation by enhancing or suppressing specific gene programs. The paralogous transcriptional coactivators and lysine acetyltransferases CREB binding protein (CBP) and p300 are involved in brain plasticity and stimulus-dependent transcription, but their specific roles in neuroadaptation are not fully understood. Here we investigated the impact of eliminating either CBP or p300 in excitatory neurons of the adult forebrain of mice from both sexes using inducible and cell type-restricted knock-out strains. The elimination of CBP, but not p300, reduced the expression and chromatin acetylation of plasticity genes, dampened activity-driven transcription, and caused memory deficits. The defects became more prominent in elderly mice and in paradigms that involved enduring changes in transcription, such as kindling and environmental enrichment, in which CBP loss interfered with the establishment of activity-induced transcriptional and epigenetic changes in response to stimulus or experience. These findings further strengthen the link between CBP deficiency in excitatory neurons and etiopathology in the nervous system., M.L. was the recipient of a Santiago Grisolia fellowship from Generalitat Valenciana. S.N. is the recipient of an FPI Pre-Doctoral Fellowship from the Spanish Ministry of Science and Innovation (MICINN). M.F.-R. is the recipient of an FPU-PhD Fellowship from the Spanish Ministry of Education. L.M.V. is the recipient of Miguel Servet II Contract CPII20/00025 from Instituto de Salud Carlos III (ISCIII) and the European Social Fund. A.B. research is supported by Grant 202003 from Fundación Tatiana Pérez de Guzmán el Bueno and Fundació la Marató de TV3; Grant PID2020-118169RB-100 from the Ministry of Science and Innovation cofinanced by the European Regional Development Fund (ERDF); Grant PROMETEO/2020/007 from the Generalitat Valenciana; and Grant RGP0039/2017 from the Human Frontiers Science Program Organization. L.M.V. research is supported by Grant PI19/00125 from Instituto de Salud Carlos III and the ERDF. J.P.L.-A. research is funded by grants from MICIU cofinanced by ERDF (Grant RTI2018-102260-B-I00), and Generalitat Valenciana (Grant PROMETEO/2020/007). The Instituto de Neurociencias is funded by “Centre of Excellence Severo Ochoa” Grant SEV-2017-0723.

In memory of Professor Witold Bartnik These guidelines constitute an update of the previous „Recommendations on the management of irritable bowel syndrome” issued in 2008. They have been developed by a Task Force organized by the Governing Board of the Polish Society of Gastroenterology. They discuss, with particular emphasis on new scientific data covering papers published since 2008: the etiology, epidemiology, clinical presentation, diagnostic principles and criteria for the diagnosis, and recommendations for the treatment of irritable bowel syndrome (IBS). The English-language acronym for the syndrome (IBS) has become popular in medical and popular scientific language, it is also widely recognized by patients who identify with this diagnosis. Therefore, in the discussed guidelines, this is what we will use.

This article describes the latest diagnostic and therapeutic recommendations in chronic pancreatitis, developed by the Working Group of the Polish Society of Gastroenterology and the Polish Pancreas Club. The recommendations refer to the diagnosis of chronic pancreatitis, autoimmune pancreatitis, conservative management, treatment of pain, and exocrine and endocrine pancreatic insufficiency, treatment of chronic pancreatitis by endoscopic and surgical methods, and oncological surveillance of chronic pancreatitis. This paper refers to the Polish recommendations published in 2011, which have been updated and supplemented. All recommendations were voted by experts of the Polish Society of Gastroenterology and the Polish Pancreas Club, who evaluated them each time on a five‑degree scale, where I meant full acceptance, II – acceptance with some reservation, III – acceptance with serious reservation, IV – rejection with some reservation and V – full rejection. The results of the voting, together with a brief commentary, have been included with each recommendation put to the vote. In addition, the expert group assessed the value of clinical studies on which the statements are based, on a scale where A means high (based on meta‑analyses and randomised clinical trials), B means medium (based on clinical trials and observational studies), and C means low (based mainly on expert opinion).

During development, chromatin-modifying enzymes regulate both the timely establishment of cell-type-specific gene programs and the coordinated repression of alternative cell fates. To dissect the role of one such enzyme, the intellectual-disability-linked lysine demethylase 5C (Kdm5c), in the developing and adult brain, we conducted parallel behavioral, transcriptomic, and epigenomic studies in Kdm5c-null and forebrain-restricted inducible knockout mice. Together, genomic analyses and functional assays demonstrate that Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation. Although the importance of these functions declines after birth, Kdm5c retains an important genome surveillance role preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons., M.S. and A.M.-F. are recipients of “Formación de Personal Investigador” fellowships, and B.d.B. is the recipient of a “Juan de la Cierva – Incorporación” contract (all from the Spanish Ministry of Economy and Competitivity [MINECO]). J.P.L.-A.’s research is supported by a “Ramón y Cajal” contract and by grant SAF2014-60233-JIN from MINECO (co-financed by the European Regional Development Fund [ERDF]). A.B.’s research is supported by grants SAF2014-56197-R, PCIN-2015-192-C02-01 (part of the coordinated project ERA-Net NEURON8-2015), and SEV-2013-0317 from MINECO (co-financed by ERDF), grant PROMETEO/2016/006 from the Generalitat Valenciana, a NARSAD Independent Investigator grant (no. 21941) from the Brain & Behavior Research Foundation, and a grant from the Alicia Koplowitz Foundation. S.I.’s research is supported by NIH grant NS089896 and the Farrehi Family Foundation. KDM5C research in the Y.S. lab is supported by NIH grant MH096066. Y.S. is an American Cancer Society Research Professor. The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa.”

This paper presents the updated Polish Neuroendocrine Tumour Network expert panel recommendations on the management of neuroendocrine neoplasms (NENs) of the stomach and duodenum, including gastrinoma. The recommendations discuss the epidemiology, pathogenesis, and clinical presentation of these tumours as well as their diagnosis, including biochemical, histopathological, and localisation diagnoses. The principles of treatment are discussed, including endoscopic, surgical, pharmacological, and radionuclide treatments. Finally, there are also recommendations on patient monitoring.

This study presents the revised Polish guidelines regarding the management of patients suffering from neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common location for these neoplasms. Most are well differentiated and slow growing. Their symptoms may be atypical, which can result in delayed or accidental diagnosis. Appendicitis is usually the first manifestation of NEN in this location. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of patients suffering from small intestinal NENs with distant metastases. The main cause of death in patients with carcinoid syndrome is carcinoid heart disease. The most useful laboratory test is the determination of chromogranin A, while concentration of 5-hydroxyindoleacetic acid is helpful in the diagnostics of carcinoid syndrome. For visualisation, ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, double-balloon enteroscopy, and somatostatin receptor scintigraphy may be used. A detailed his-tological report is crucial for the proper diagnostics and therapy of NENs of the small intestine and appendix. The treatment of choice is surgical management, either radical or palliative. The pharmacological treatment of the hormonally active and non-active small intestinal NENs as well as NENs of the appendix is based on long-acting somatostatin analogues. In patients with generalised NENs of the small intestine in progress during the SSA treatment, with good expression of somatostatin receptors, the first-line treatment should be radio-isotope therapy, while targeted therapies, such as everolimus, should be considered afterwards. When the above therapies are exhausted, in certain cases chemotherapy may be considered.

Neuroendocrine neoplasms/tumours (NENs/NETs) of the large intestine are detected increasingly often, especially rectal tumours, which is probably associated with the widespread use of screening colonoscopy. There is a growing body of evidence supporting the thesis that the NENs of the rectum and the NENs of the colon are two different diseases. Rectal NENs are usually small lesions, of low to moderate histological malignancy, associated with good prognosis, and most may be treated endoscopically. NENs of the colon, however, are often aggressive, poorly differentiated, associated with a poor or uncer-tain prognosis, and require surgical treatment. The management guidelines regarding these groups of patients are constantly changing. On the basis of the recent literature data and conclusions reached by the working meeting of the Polish Network of Neuroendocrine Tumours (December 2016), this study completes and updates the data and management guidelines regarding colorectal NENs published in Endokrynologia Polska 2013; 64: 358-368.

Background Soluble urokinase-type plasminogen activator receptor (suPAR) is a glycoprotein secreted during inflammation and infections. Moreover, increased levels of suPAR are observed after hypoxia and ischaemia. The aim of the study was to assess whether suPAR could represent a useful marker of acute pancreatitis (AP) severity. Patients and methods We have observed a cohort of 126 prospectively enrolled patients. Based on the presence of persistent organ failure (more than 48 h) and local complications (diagnosis of moderate AP [MSAP]), patients were classified into three groups: mild AP (MAP), moderate and severe AP (SAP). The blood samples were taken on admission for detecting suPAR concentrations. Results AP was considered severe in 33 patients (26.2%), MSAP was found in 37 patients (29.4%), and MAP was found in 56 patients (44,4%). The AUC for SAP predicted by suPAR was 0.993. The calculated cut-off point for prognosis SAP is 4.75 ng/mL. The BISAP score of ≥3 for detection of SAP had sensitivity and specificity of 94.6% and 63.6%, respectively. The AUC for severity predicted by BISAP amounted to 0.916. Additionally, suPAR turned out to be a good predictor of fatal AP: for the cut-off point 7.05 ng/mL, the AUC was 0.917. The AUC for death prediction in AP patients based on the BISAP score ≥3 was 0.894. Conclusions suPAR concentration is a promising new diagnostic and prognostic indicator in SAP obtainable in the early stage of disease. Larger studies are recommended to evaluate this role further.

Introduction : Early prediction of severity of acute pancreatitis (AP) by a simple parameter that positively correlates with the activation stage of the immune system would be very helpful because it could influence the management and improve the outcome. Tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1) play a critical role in the pathogenesis systemic inflammatory response syndrome (SIRS) and severity of AP. One of the effects of IL-1 and TNF-α is an increase in the number of immature granulocytes (IGs) in the peripheral blood. Aim : To assess whether the IGs% in plasma could be an independent marker of AP severity. Material and methods : A cohort of 77 patients with AP were prospectively enrolled in the study. The IGs were measured from whole blood samples obtained from the first day of hospitalization using an automated analyser. Results : We observed 44 (57%) patients with mild AP, 21 (27%) patients with moderate severe AP (SAP) and 12 (16%) patients with SAP. The cut-off value of IGs was 0.6%. The IGs > 0.6% had a sensitivity, specificity, and positive and negative predictive value of 100%, 96%, 85.7%, and 100%, respectively (area under the curve (AUC) = 0.98). On admission, SIRS was present in 25 (32%) patients. We found that in patients who fulfilled at least two criteria for SIRS, SAP could be predicted with 75% sensitivity and 75.4% specificity, positive predictive value 36%, negative predictive value 94.2%. Conclusions : The IGs% as a routinely obtained marker appears to be a promising, independent biomarker and a better predictor of early prognosis in SAP than SIRS and white blood cell.

Very little is known about the mechanisms responsible for maintaining cell identity in mature tissues. The paralogous type 3 lysine acetyltransferases (KAT3) CBP and p300 are both essential during development, but their specific functions in nondividing differentiated cells remains unclear. Here, we show that when both proteins are simultaneously knocked-out in excitatory neurons of the adult brain, the mice express a rapidly progressing neurological phenotype associated with reduced dendritic complexity and electrical activity, the transcriptional shutdown of neuronal genes, and a dramatic loss of H3K27 acetylation and pro-neural transcription factor binding at neuronal enhancers. The neurons lacking both KAT3 rapidly acquire a molecularly undefined fate with no sign of dedifferentiation, transdifferentiation or death. Restoring CBP expression or lysine acetylation reestablished neuronal-specific transcription. Our experiments demonstrate that KAT3 proteins act as fate-keepers in excitatory neurons and other cell types by jointly safeguarding chromatin acetylation levels at cell type-specific enhancers throughout life.

SummaryActivity-driven transcription plays an important role in many brain processes, including those underlying memory and epilepsy. Here, we combine the genetic tagging of neuronal nuclei and ribosomes with various sequencing-based techniques to investigate the transcriptional and chromatin changes occurring at hippocampal excitatory neurons upon synchronous activation during status epilepticus and sparse activation during novel context exploration. The transcriptional burst, which affects both nucleus-resident non-coding RNAs and numerous protein-coding genes involved in neuroplasticity, is associated with a dramatic increase in chromatin accessibility of activity-regulated genes and enhancers,de novobinding of activity-regulated transcription factors, augmented promoter-enhancer interactions, and the formation of gene loops that bring together the TSS and TTS of strongly induced genes to sustain the fast re-loading of RNAPII complexes. Remarkably, some chromatin occupancy changes and interactions remain long after neuronal activation and may underlie the changes in neuronal responsiveness and circuit connectivity observed in these neuroplasticity paradigms.

Activity-driven transcription plays an important role in many brain processes, including those underlying memory and epilepsy. Here we combine genetic tagging of nuclei and ribosomes with RNA sequencing, chromatin immunoprecipitation with sequencing, assay for transposase-accessible chromatin using sequencing and Hi-C to investigate transcriptional and chromatin changes occurring in mouse hippocampal excitatory neurons at different time points after synchronous activation during seizure and sparse activation by novel context exploration. The transcriptional burst is associated with an increase in chromatin accessibility of activity-regulated genes and enhancers, de novo binding of activity-regulated transcription factors, augmented promoter–enhancer interactions and the formation of gene loops that bring together the transcription start site and transcription termination site of induced genes and may sustain the fast reloading of RNA polymerase complexes. Some chromatin occupancy changes and interactions, particularly those driven by AP1, remain long after neuronal activation and could underlie the changes in neuronal responsiveness and circuit connectivity observed in these neuroplasticity paradigms, perhaps thereby contributing to metaplasticity in the adult brain., J.F.-A. and M.T.L.-C. are recipients of fellowships from the Spanish Ministry of Science and Innovation (MICINN, SVP-2014-068387 and BES-2017-081298, respectively). The research of A.B. is supported by grants SAF2017-87928-R and SEV-2017-0723 from the MICINN co-financed by the ERDF, PROMETEO/2016/026 from the Generalitat Valenciana and RGP0039/2017 from the Human Frontiers Science Program Organization (HFSPO). M.J.R. is supported by the National Institutes of Health (NIH) Pathway to Independence Award K99/R00 GM127671. The research of V.G.C. is supported by the US Public Health Service Award (R01) GM035463 from the NIH. The content of the article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa”.

The presented recommendations concern the current management of acute pancreatitis. The recommendations relate to the diagnostics and treatment of early and late phases of acute pancreatitis and complications of the disease taking into consideration surgical and endoscopic methods. All the recommendations were subjected to voting by the members of the Working Group of the Polish Pancreatic Club, who evaluated them every single time on a five-point scale, where A means full acceptance, B means acceptance with a certain reservation, C means acceptance with a serious reservation, D means rejection with a certain reservation and E means full rejection. The results of the vote, together with commentary, are provided for each recommendation.

The paralogous transcriptional co-activators CBP and p300 (aka KAT3A and KAT3B, respectively) contain a characteristic and promiscuous lysine acetyltransferase (KAT) domain and multiple independent protein-binding domains that enable them to interact with hundreds of proteins, possibly promoting the acetylation of thousands of target lysine residues. Both proteins play critical roles during the development of the nervous system and may also regulate stimuli-driven transcription and plasticity in postmitotic neurons. The multiplicity of functions, substrates, and molecular partners, together with the redundancy and singularity of the two KAT3 paralogs, define a complex cat’s cradle of relationships. In this review, we discuss the role of the KAT3 proteins in neurons and integrate recent information regarding their function and mode of action., A.B. research is supported by grants SAF2017-87928-R, PCIN-2015-192-C02-01 (part of the ERA-NET NEURON JTC2015 project ChromISyn) and SEV-2017-0723 from Ministerio de Ciencia, Innovación y Universidades (MICINN) co-financed by European Regional Development Fund (ERDF), PROMETEO/2016/026 from the Generalitat Valenciana, and RGP0039/2017 from the Human Frontiers Science Program Organization (HFSPO). The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa”.

The development of addiction is associated with a dysregulation of glutamatergic transmission in the brain reward circuit. α isoform of calcium/calmodulin-dependent kinase II (αCaMKII) is one of the key proteins that regulates structural and functional plasticity of glutamatergic synapses. αCaMKII activity can be controlled by the autophosphorylation of threonine 286. The role of this autophosphorylation in the regulation of addiction-related behaviors has been proposed but is still poorly understood. Here, using αCaMKII autophosphorylation-deficient mutant mice (T286A), we show that, in comparison with wild-type animals, they are less resistant to high doses of alcohol and do not show psychostimulant response neither to alcohol injections nor during voluntary alcohol drinking. T286A mutants are also less prone to develop alcohol addiction-related behaviors including an increased motivation for alcohol, persistent alcohol seeking during withdrawal and alcohol consumption on relapse. Finally, we demonstrate that αCaMKII autophosphorylation regulates also alcohol-induced remodeling of glutamatergic synapses in the hippocampus and amygdala. In conclusion, our data suggest that αCaMKII autophosphorylation-dependent remodeling of glutamatergic synapses is a plausible mechanism for the regulation of the alcohol addiction-related behaviors.

A multilayered complexity of epigenetic and transcriptional regulatory mechanisms underlies neuronal activity-dependent gene transcription. The regulation of RNA Pol II progression along the transcription cycle, from promoter-proximal poising (with RNA Pol II paused at promoter-proximal regions, characterized by a Ser5P+-rich and Ser2P+-poor RPB1 CTD) to active elongation, has emerged as a major step in transcriptional regulation across several organisms, tissues, and developmental stages, including the nervous system. However, it is not known whether this mechanism is modulated by experience. We investigated the impact of learning a motor skill on RNA Pol II phosphorylation dynamics in the adult mouse striatum. We uncovered that learning modulates thein vivostriatal phosphorylation dynamics of the CTD of the RNA Pol II RPB1 subunit, leading to an increased poising index in trained mice. We found that this modulation occurs at immediate early genes (IEGs), with increased poising of RNA Pol II at bothArcandFosgenes but not at constitutively expressed genes. Furthermore, we confirmed that this was learning dependent, and not just regulated by context or motor activity. These experiments demonstrate a novel phenomenon of learning induced transcriptional modulation in adult brain, which may have implications for our understanding of learning, memory allocation, and consolidation.

Progress in the diagnostics and therapy of gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NEN), the published results of new randomised clinical trials, and the new guidelines issued by the European Neuroendocrine Tumour Society (ENETS) have led the Polish Network of Neuroendocrine Tumours to update the 2013 guidelines regarding management of these neoplasms. We present the general recommendations for the management of NENs, developed by experts during the Third Round Table Conference - Diagnostics and therapy of gastro-entero-pancreatic neuroendocrine neoplasms: Polish recommendations in view of current European recommenda-tions, which took place in December 2016 in Żelechow near Warsaw. Drawing from the extensive experience of centres dealing with this type of neoplasms, we hope that we have managed to develop the optimal management system, applying the most recent achievements in the field of medicine, for these patients, and that it can be implemented effectively in Poland. These management guidelines have been arranged in the following order: gastric and duodenal NENs (including gastrinoma); pancreatic NENs; NENs of the small intestine and appendix, and colorectal NENs.

This article presents updated diagnostic and therapeutic guidelines for the management of pancreatic neuroendocrine tumours (PNEN), proposed by the Polish Network of Neuroendocrine Tumours. The guidelines contain new data received in the years 2013-2016, which confirm previous recommendations, and have led to modification of previous guidelines or have resulted in the formulation of new guidelines. Biochemical and imaging (anatomical and functional) tests are of great importance in diagnostics, as well as histopathological diagnosis to determine the management of PNEN patients, but they must be confirmed by an immunohistochemical examination. PNEN therapy requires collaboration among the members a multidisciplinary team of specialists experienced in the management of these neoplasms. Surgery is the basic form of treatment in many cases. Further therapy requires a multidirectional procedure; therefore, the rules of biotherapy, peptide receptor radionuclide therapy, molecular targeted therapy, and chemotherapy are discussed.

Biosimilars in Gastroenterology- An Important Moment in the Treatment of Inflammatory Bowel Diseases

Aim The aim of the study was to evaluate the significance of serum creatinine level (SCL) and estimated glomerular filtration rate (eGFR) measured in an early phase of acute pancreatitis (AP) for prediction of pancreatic necrosis (PNec) and mortality. Methods One hundred and forty-seven patients with AP were retrospectively reviewed in the study. Serum creatinine level and estimated glomerular filtration rate (calculated using the abbreviated Modification of Diet in Renal Disease equation) on admission and 48 h thereafter were analyzed for each patient. These parameters were compared with contrast-enhanced computed tomography images performed within 96 h from admission ( n = 103). Usefulness of SCL and eGFR for prediction of PNec and fatal outcome of AP was evaluated using a receiver operator characteristic curve analysis and comparison of average parameter values. Results We confirmed pancreatic necrosis in 41 (39.8%) of 103 patients using computed tomography examination. Both creatinine and estimated glomerular filtration rate measured on admission ( p p p = 0.001, p Moreover, serum creatinine level and eGFR measured on the 1st day proved to be a good predictor of fatal outcome. Both, mortality and presence of pancreatic necrosis were significantly higher in the group with elevated serum creatinine level and low eGFR values. Conclusions SCL and eGFR on admission are useful indicators of PNec and mortality.

Acute pancreatitis (AP) is a systemic disease involving acute inflammation of the pancreatic gland due to premature activation of pancreatic proenzymes and different degree of damage to the adjacent tissues and sometimes more distant organs. An increasing trend is observed with the incidence of AP approximately 72 cases/100,000 inhabitants per year (1).

48 Pags.- 7 Figs. The definitive version, with suppl. Figs. and Supp. Tabls., is available at: http://www.nature.com/ncomms/index.html, The interior of the neuronal cell nucleus is a highly organized three-dimensional (3D) structure where regions of the genome that are linearly millions of bases apart establish sub-structures with specialized functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice expressing GFP-tagged histone H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons caused chromocenter declustering and disrupted the association of heterochromatin with the nuclear lamina. The loss of these structures did not affect neuronal viability but was associated with specific transcriptional and behavioural deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D organization of chromatin within neuronal cells provides an additional level of epigenetic regulation of gene expression that critically impacts neuronal function. This in turn suggests that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture., S.J. held a Juan de la Cierva contract from the Spanish Ministry of Economy and Competitiveness (MJNECO). J.L.A. held a postdoctoral contract (JAE DOC) from the Program Junta para la Ampliacion de Estudios’ co funded by the Fondo Social Europeo (FSE). AM. is supported by a posdoctoral fellowship from EU FP7 Project GA, N° 264173 (Bio Jmage). Research at ABs lab is supported by grants from MJNECO (SAF2O11 22855) and the Generalitat Valenciana (Prometeo/2012/005). Research at E.G.’s lab is supported by the grant BFU2O11 27326 and research at R.L.’s lab is supported by the CONSOLJDER grant C5D2008 00005 both given by MJNECO. Research at G.W.’s lab is supported by the grant POJG 01.01.02 00 008/08 from the European Regional Development Fund.

The aim of the study was to evaluate the significance of serum creatinine level (SCL) and estimated glomerular filtration rate (eGFR) measured in an early phase of acute pancreatitis (AP) for prediction of pancreatic necrosis (PNec) and mortality.One hundred and forty-seven patients with AP were retrospectively reviewed in the study. Serum creatinine level and estimated glomerular filtration rate (calculated using the abbreviated Modification of Diet in Renal Disease equation) on admission and 48 h thereafter were analyzed for each patient. These parameters were compared with contrast-enhanced computed tomography images performed within 96 h from admission (n = 103). Usefulness of SCL and eGFR for prediction of PNec and fatal outcome of AP was evaluated using a receiver operator characteristic curve analysis and comparison of average parameter values.We confirmed pancreatic necrosis in 41 (39.8%) of 103 patients using computed tomography examination. Both creatinine and estimated glomerular filtration rate measured on admission (p 0.001, p 0.001 respectively) and 48 h later (p = 0.001, p 0.001 respectively) were significantly associated with the presence of pancreatic necrosis. Moreover, serum creatinine level and eGFR measured on the 1st day proved to be a good predictor of fatal outcome. Both, mortality and presence of pancreatic necrosis were significantly higher in the group with elevated serum creatinine level and low eGFR values.SCL and eGFR on admission are useful indicators of PNec and mortality.

Long-term memory (LTM) formation has been linked with functional strengthening of existing synapses and other processes including de novo synaptogenesis. However, it is unclear whether synaptogenesis can contribute to LTM formation. Here, using α-calcium/calmodulin kinase II autophosphorylation-deficient (T286A) mutants, we demonstrate that when functional strengthening is severely impaired, contextual LTM formation is linked with training-induced PSD95 up-regulation followed by persistent generation of multiinnervated spines, a type of synapse that is characterized by several presynaptic terminals contacting the same postsynaptic spine. Both PSD95 up-regulation and contextual LTM formation in T286A mutants required signaling by the mammalian target of rapamycin (mTOR). Furthermore, we show that contextual LTM resists destabilization in T286A mutants, indicating that LTM is less flexible when synaptic strengthening is impaired. Taken together, we suggest that activation of mTOR signaling, followed by overexpression of PSD95 protein and synaptogenesis, contributes to formation of invariant LTM when functional strengthening is impaired.

AIM: To investigate whether administration of Ringer’s solution (RL) could have an impact on the outcome of acute pancreatitis (AP). METHODS: We conducted a retrospective study on 103 patients [68 men and 35 women, mean age 51.2 years (range, 19-92 years)] hospitalized between 2011 and 2012. All patients admitted to the Department of Gastroenterology of the Central Clinical Hospital of the Ministry of Interior (Poland) with a diagnosis of AP who had disease onset within 48 h of presentation were included in this study. Based on the presence of persistent organ failure (longer than 48 h) as a criterion for the diagnosis of severe AP (SAP) and the presence of local complications [diagnosis of moderately severe AP (MSAP)], patients were classified into 3 groups: mild AP (MAP), MSAP and SAP. Data were compared between the groups in terms of severity (using the revised Atlanta criteria) and outcome. Patients were stratified into 2 groups based on the type of fluid resuscitation: the 1-RL group who underwent standard fluid resuscitation with a RL 1000 mL solution or the 2-NS group who underwent standard fluid resuscitation with 1000 mL normal saline (NS). All patients from both groups received an additional 5% glucose solution (1000-1500 mL) and a multi-electrolyte solution (500-1000 mL). RESULTS: We observed 64 (62.1%) patients with MAP, 26 (25.24%) patients with MSAP and 13 (12.62%) patients with SAP. No significant difference in the distribution of AP severity between the two groups was found. In the 1-RL group, we identified 22 (55.5%) MAP, 10 (25.5%) MSAP and 8 (20.0%) SAP patients, compared with 42 (66.7%) MAP, 16 (24.4%) MSAP and 5 (7.9%) SAP cases in the 2-NS group (P = 0.187). The volumes of fluid administered during the initial 72-h period of hospitalization were similar among the patients from both the 1-RL and 2-NS groups (mean 3400 mL vs 3000 mL, respectively). No significant differences between the 1-RL and 2-NS groups were found in confirmed pancreatic necrosis [10 patients (25%) vs 12 patients (19%), respectively, P = 0.637]. There were no statistically significant differences between the 1-RL and 2-NS groups in the percentage of patients who required enteral nutrition (23 patients vs 17 patients, respectively, P = 0.534). Logistic regression analysis confirmed these findings (OR = 1.344, 95%CI: 0.595-3.035, P = 0.477). There were no significant differences between the 1-RL and 2-NS groups in mortality and the duration of hospital stay (median of 9 d for both groups, P = 0.776). CONCLUSION: Our study failed to find any evidence that the administration of RL in the first days of AP leads to improved clinical outcomes.

Introduction: Early prediction of severity of acute pancreatitis (AP) by a simple system which includes clinical features would be very helpful as it may direct management and improve outcome. Certain components of different scores reflecting severe intravascular volume depletion can play an important role in accuracy of the method (but sensitivity and specificity of these scores are not at the desired level yet). Low eGFR (estimated glomerular filtration rate) is already known to be unfavorable prognostic parameter in AP, however it was never assessed as an element of multifactor score. Aim: The aim of this study is to determine whether replacing urea nitrogen (BUN) in bedside index of severity in acute pancreatitis (BISAP) score by eGFR (BISAP-eGFR score) improves prediction of severity and mortality in patients with AP. Methods: Cohort of 100 patients with AP were prospectively enrolled in the study. The BISAP and eGFR (abbreviated Modification of Diet in Renal Disease equation) were calculated using data from the first 24 h from admission. Severe AP was defined as the persistence of organ failure exceeding 48 hours. The predictive accuracy of the BISAP and BISAP-eGFR score was measured as the area under the receiver operating characteristic curve (AUC). Results: We evaluated a total of 100 consecutive patients with AP. Twenty of the 100 patients (20%) were considered severe AP. The best cutoff value of eGFR was 80 ml/min/1,73 m2. All 20 patients with severe pancreatitis had eGFR 25 mg/dL (BISAP score cut-off for BUN). Overall, 16% of the 100 evaluated patients had a BISAP score ≥3 while BISAP-eGFR score ≥ 3 was reported for 23% patients. A BISAP score ≥ 3 had a sensitivity, specificity, positive and negative predictive value of 65%, 96.1%, 81.2% and 91.3% respectively, with an accuracy of 87% comparing to 95.2%, 96.2%, 86.9% and 98.7% respectively for BISAP-eGFR score with an accuracy of 96%. The AUC for severity predicted by BISAP was 0.762 and by BISAP-eGFR score was 0.942. There were statistically significant trends for increasing severity (P

OBJECTIVES In reference to our earlier publication, laboratory tests that reflect severe intravascular volume depletion can be used for predicting the severity of acute pancreatitis (AP). The aim of the study was to assess whether urinary level of neutrophil gelatinase-associated lipocalin (NGAL) could represent a useful marker of AP severity. METHODS We observed a cohort of 104 prospectively enrolled patients. The patients were classified into 3 groups: mild AP, moderately severe AP, and severe AP. Urine samples were collected on admission (NGAL-as) and during the first 24 hours (NGAL-first day) for examination of urinary level of NGAL concentrations from the first day. RESULTS Acute pancreatitis was considered severe in 16 (15%) patients, moderately severe in 25 (24%) patients, and mild in 63 (61%) patients.There were statistically significant trends for an increase in severity (P = 0.04, P = 0.003) and mortality (P < 0.031, P = 0.01) with raising NGAL-as and NGAL-first day concentrations, respectively. The areas under the curve for severity predicted by NGAL-as and NGAL-first day were 0.75 and 0.93, respectively. The areas under the curve for mortality prediction by NGAL-as and NGAL-first day were 0.980 and 0.92, respectively. CONCLUSIONS The urinary level of NGAL is a promising new diagnostic and prognostic factor for severe AP in an early stage of the disease.