Acute pancreatitis (AP) is a common but potentially devastating disease characterized at onset pathophysiologically by premature activation of digestive enzymes within the pancreas. Despite an abundance of preclinical research and, until recently, a series of disappointing clinical trials, no specific disease modifying pharmacological treatment has yet been approved for this condition. Recent novel approaches to understanding the molecular pathogenesis of AP provide us with renewed optimism for translational drug discovery. Although digestive enzyme activation is the hallmark of AP, a critical mechanism that initiates AP is intracellular calcium (Ca2+) overload in pancreatic parenchymal cells, which triggers mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and impairs autophagic flux. These processes are pivotal to the disease and present a range of drug targets, associated with the inflammatory responses that drive local and systemic inflammation in AP. Progress in translation has now been made, targeting the ORAI channel with the inhibitor zegocractin (Auxora) to reduce pancreatic injury and inflammatory responses in human AP. Herein we evaluated potential drug targets for the early treatment of AP, focused on intra-acinar mechanisms of injury central to the onset and severity of AP. Our analysis highlights the opportunities and progress in translating these molecular insights into clinical therapies.

Background: Pediatric pancreatitis is an underdiagnosed disease with variable etiology. In the past 10-15 years the incidence of pediatric pancreatitis has increased, it is now 3.6-13.3 cases per 100,000 children. Up-to-date evidence based management guidelines are lacking for the pediatric pancreatitis. The European Pancreatic Club, in collaboration with the Hungarian Pancreatic Study Group organized a consensus guideline meeting on the diagnosis and management of pancreatitis in the pediatric population. Methods: Pediatric Pancreatitis was divided into three main clinical categories: acute pancreatitis, acute recurrent pancreatitis and chronic pancreatitis. Fifteen relevant topics (acute pancreatitis: diagnosis; etiology; prognosis; imaging; complications; therapy; biliary tract management; acute recurrent pancreatitis: diagnosis; chronic pancreatitis: diagnosis, etiology, treatment, imaging, intervention, pain, complications; enzyme replacement) were defined. Ten experts from the USA and Europe reviewed and summarized the available literature. Evidence was classified according to the GRADE classification system. Results: Within fifteen topics, forty-seven relevant clinical questions were defined. The draft of the updated guideline was presented and discussed at the consensus meeting held during the 49th Meeting of European Pancreatic Club, in Budapest, on July 1, 2017. Conclusions: These evidence-based guidelines provides the current state of the art of the diagnosis and management of pediatric pancreatitis. (C) 2018 IAP and EPC. Published by Elsevier B.V.

BACKGROUND:Pancreatic cancer diagnosis and staging can be difficult in 10-20% of patients. Positron emission tomography (PET)/computed tomography (CT) adds precise anatomical localisation to functional data. The use of PET/CT may add further value to the diagnosis and staging of pancreatic cancer. OBJECTIVE:To determine the incremental diagnostic accuracy and impact of PET/CT in addition to standard diagnostic work-up in patients with suspected pancreatic cancer. DESIGN:A multicentre prospective diagnostic accuracy and clinical value study of PET/CT in suspected pancreatic malignancy. PARTICIPANTS:Patients with suspected pancreatic malignancy. INTERVENTIONS:All patients to undergo PET/CT following standard diagnostic work-up. MAIN OUTCOME MEASURES:The primary outcome was the incremental diagnostic value of PET/CT in addition to standard diagnostic work-up with multidetector computed tomography (MDCT). Secondary outcomes were (1) changes in patients' diagnosis, staging and management as a result of PET/CT; (2) changes in the costs and effectiveness of patient management as a result of PET/CT; (3) the incremental diagnostic value of PET/CT in chronic pancreatitis; (4) the identification of groups of patients who would benefit most from PET/CT; and (5) the incremental diagnostic value of PET/CT in other pancreatic tumours. RESULTS:Between 2011 and 2013, 589 patients with suspected pancreatic cancer underwent MDCT and PET/CT, with 550 patients having complete data and in-range PET/CT. Sensitivity and specificity for the diagnosis of pancreatic cancer were 88.5% and 70.6%, respectively, for MDCT and 92.7% and 75.8%, respectively, for PET/CT. The maximum standardised uptake value (SUVmax.) for a pancreatic cancer diagnosis was 7.5. PET/CT demonstrated a significant improvement in relative sensitivity (p = 0.01) and specificity (p = 0.023) compared with MDCT. Incremental likelihood ratios demonstrated that PET/CT significantly improved diagnostic accuracy in all scenarios (p < 0.0002). PET/CT correctly changed the staging of pancreatic cancer in 56 patients (p = 0.001). PET/CT influenced management in 250 (45%) patients. PET/CT stopped resection in 58 (20%) patients who were due to have surgery. The benefit of PET/CT was limited in patients with chronic pancreatitis or other pancreatic tumours. PET/CT was associated with a gain in quality-adjusted life-years of 0.0157 (95% confidence interval -0.0101 to 0.0430). In the base-case model PET/CT was seen to dominate MDCT alone and is thus highly likely to be cost-effective for the UK NHS. PET/CT was seen to be most cost-effective for the subgroup of patients with suspected pancreatic cancer who were thought to be resectable. CONCLUSION:PET/CT provided a significant incremental diagnostic benefit in the diagnosis of pancreatic cancer and significantly influenced the staging and management of patients. PET/CT had limited utility in chronic pancreatitis and other pancreatic tumours. PET/CT is likely to be cost-effective at current reimbursement rates for PET/CT to the UK NHS. This was not a randomised controlled trial and therefore we do not have any information from patients who would have undergone MDCT only for comparison. In addition, there were issues in estimating costs for PET/CT. Future work should evaluate the role of PET/CT in intraductal papillary mucinous neoplasm and prognosis and response to therapy in patients with pancreatic cancer. STUDY REGISTRATION:Current Controlled Trials ISRCTN73852054 and UKCRN 8166. FUNDING:The National Institute for Health Research Health Technology Assessment programme.

Background There are currently 2 Tumour-Node-Metastasis (TNM) staging systems for pancreatic neuroendocrine tumours (p-NETs) - European Neuroendocrine Tumour Society (ENETS) and American Joint Committee on Cancer (AJCC). P-NETs being heterogeneous, we investigated the prognostic value of the 2 systems in p-NETs, as a whole, and more interestingly in functional and non-functional sub-groups separately, with a view to ascertaining any potential clinical benefits of using one system over the other. Methods Data from patients with surgically resected p-NETs were retrospectively reviewed. Kaplan-Meier method and Cox Regression proportional hazards model were used to analyse overall survival (OS) and prognostic predictors respectively. Results In the whole group of 165 patients, both TNM systems successfully discriminated OS differences when comparing stages I and II with stages III and IV (P<0.05); ENETS stage III patients had a significantly better OS than those in stage IV (P=0.003). Patients with functional p-NETs in ENETS stage II showed a statistically better OS than those in stages III and IV (P<0.05). For non-functional tumours, the AJCC staging system could effectively discriminate between the OS differences of patients in stage I with stages III and IV, or stage II with III and IV (P<0.05). Along with surgical intent and World Health Organisation (WHO) 2010 grade, both ENETS and AJCC staging systems were effective predictors of OS for different function-status p-NETs. Conclusions The ENETS system might have potential advantages when applied to all p-NETs and to the functional sub-group, while the AJCC system might be clinically more practical for non-functional p-NETs.

To evaluate the therapeutic potential of I-BET-762, an inhibitor of the bromodomain and extra-terminal (BET) protein family, in experimental acute pancreatitis (AP).AP was induced by retrograde infusion of taurolithocholic acid sulphate into the biliopancreatic duct (TLCS-AP) or 2 intraperitoneal (i.p.) injections of ethanol and palmitoleic acid 1 h apart (FAEE-AP) or 12 hourly i.p. injections of caerulein (CER-AP). In all treatment groups, I-BET-762 (30 mg/kg, i.p.) was administered at the time of disease induction and again 12 h later. AP severity was assessed at 24 h by serum biochemistry, multiple cytokines and histopathology.TLCS-AP, FAEE-AP and CER-AP resulted in characteristic elevations in serum amylase and cytokine levels, increased pancreatic trypsin and myeloperoxidase activity, typical pancreatic histopathological changes and lung injury. Treatment with I-BET-762 significantly reduced biochemical, cytokine and histopathological responses in TLCS-AP and FAEE-AP, but not CER-AP.These results suggest that in different forms of AP there are significant differences in the epigenetic control of gene transcription contributing to the severity of disease responses. There is therapeutic potential in targeting bromodomains for the treatment of gallstone- and alcohol-related pancreatitis.

BACKGROUND/OBJECTIVES:Respiratory dysfunction and/or failure from acute lung injury (ALI) are common in acute pancreatitis (AP), but assessment of ALI in experimental AP has lacked standardisation.METHODS:A range of experimental AP models induced in C57BL/6 mice with corresponding controls (n = 6/group). Full double lung or right lung specimens were taken for histopathological assessment and slides analysed by a pre-set pipeline using Aperio Scanner (Leica), ImageJ software and CellProfiler software. Findings were compared to other routinely assessed parameters.RESULTS:Overall histopathological changes were similar between both lungs. Mean lung field occupancy was significantly different between moderate and severe CER-AP (21.9% v 27.5%, p < 0.05) and corresponded with lung MPO and local injury severity parameters and was mirrored for all models tested.CONCLUSION:We have developed a novel, simple method for assessment of ALI to improve measurement of systemic organ injury in experimental AP and contribute to preclinical drug development.

Background: The optimal management approach to pancreatic serous cystic neoplasms (SCNs) is still evolving. Methods: Consecutive patients with SCN managed at the Liverpool Pancreas Cancer Centre between 2000 and 2013 were retrospectively reviewed. Results: There were 64 patients consisting of 39 women (60.9%) and 25 men (39.1%). Forty-seven patients (73.4%) had surgical removal and 17 (26.6%) were observed. The possibility of a non-SCN malignancy was the predominant indication for resection in 27 (57.4%) patients. Postoperative morbidity occurred in 26 (55.3%) patients with 2 (4.3%) deaths. An increased risk of resection was associated with patient's age (p = 0.011), diagnosis before 2009 (p < 0.001), pain (p = 0.043), possibility of cancer (p = 0.009) and a solid SCN component on imaging (p = 0.002). Independent factors associated with resection were a diagnosis before 2009 (p = 0.005) and a solid SCN component (p < 0.001). Independent factors associated with shorter time to surgical resection were persistent pain (p = 0.003) and a solid SCN component (p = 0.007). Conclusion: There was a reduction in the proportion of resections with the application of an observe-only policy for asymptomatic patients with more definite features of SCN. Improved criteria are still required in the remainder of patients with uncertain features of SCN in deciding for intervention or surveillance.

STIM1 and ORAI1 constitute the core machinery of the ubiquitous store-operated calcium entry pathway and loss of function in these proteins is associated with severe immune and muscular disorders. Other isoforms—STIM1L, STIM2, ORAI2 and ORAI3 exhibit varied expression levels in different cell types along with several other interaction partners and thereby play different roles to facilitate, regulate and fine-tune the calcium entry. STIM proteins convey the Ca2+ store-depletion message to the PM and thereby participate in refilling of the ER by physically interacting with the Ca2+-selective ORAI channels at the PM. STIM and ORAI are exposed to oxidative modifications in the ER, the cytosol, and at the cell surface, and redox-mediated alterations in STIM/ORAI coupling might contribute to autoimmune disorders and cancer progression. This review discusses the redox reactivity of cysteine residues in STIM and ORAI isoforms, focusing on the oxidative modifications of STIM and ORAI proteins by which STIM-ORAI signaling can be modulated.

The stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR-4) axis plays an important role during stem cell recruitment. SDF-1 can also bind the more recently described CXCR-7 receptor, but effects of SDF-1/CXCR-7 signaling on stem cell migrating to ischemic brain injury area are little known. In the present study, we investigated the effect of CXCR-7 on bone marrow mesenchymal stem cell (BMSC) migration toward SDF-1α in the cerebral ischemia/reperfusion (I/R) rat hippocampus. We cultured BMSCs from rats and characterized them using flow cytometry, immunocytochemistry, western blotting, and immunofluorescence to detect SDF-1α, CXCR-4, and CXCR-7 expression in third passage BMSCs (P3-BMSCs). We also prepared the model of transient cerebral I/R by four-vessel occlusion (4-VO), and BMSCs were transplanted into I/R rat brain via lateral ventricle (LV) injection (20 μl, 1×106/ml). After that, we examined the effect of BMSCs migration in the cerebral I/R rat hippocampus through Transwell chamber assay. Our results show that SDF-1α, CXCR-4, and CXCR-7 were expressed in P3-BMSCs. Moreover, SDF-1α expression was increased in I/R hippocampus. At 48 h after transplant, green fluorescent BrdU-BMSCs were observed in transplant groups, but no green fluorescent BrdU-BMSCs were seen in medium group. Among BMSCs transplant groups, the number of BrdU-BMSCs positive cell was the highest in BMSC group. Treatment with AMD3100 and/or CXCR-7 neutralizing antibody decreased the number of BMSC migration. Collectively, these findings indicate that CXCR-4 and -7 receptors were co-expressed in BMSCs and synergistically promoted BMSC migration. The effect of CXCR-7 was stronger than that of CXCR-4. Moreover, BMSCs that migrated to hippocampus promoted the autocrine and paracrine signaling of SDF-1α.

Mahatma Gandhi National Rural Employment Guarantee Act (MGNREGA) is the world’s largest social welfare scheme in India for the poverty alleviation through rural employment generation. This paper aims to evaluate and rank the performance of the states in India under MGNREGA scheme. A non-parametric approach, Data Envelopment Analysis (DEA) is used to calculate the overall technical, pure technical, and scale efficiencies of states in India. The sample data is drawn from the annual official reports published by the Ministry of Rural Development, Government of India. Based on three selected input parameters (expenditure indicators) and five output parameters (employment generation indicators), I apply both input and output oriented DEA models to estimate how well the states utilize their resources and generate outputs during the financial year 2013–14. The relative performance evaluation has been made under the assumption of constant returns and also under variable returns to scale to assess the impact of scale on performance. The results indicate that the main source of inefficiency is both technical and managerial practices adopted. 11 states are overall technically efficient and operate at the optimum scale whereas 18 states are pure technical or managerially efficient. It has been found that for some states it necessary to alter scheme size to perform at par with the best performing states. For inefficient states optimal input and output targets along with the resource savings and output gains are calculated. Analysis shows that if all inefficient states operate at optimal input and output levels, on an average 17.89% of total expenditure and a total amount of $780million could have been saved in a single year. Most of the inefficient states perform poorly when it comes to the participation of women and disadvantaged sections (SC&ST) in the scheme. In order to catch up with the performance of best performing states, inefficient states on an average need to enhance women participation by 133%. In addition, the states are also ranked using the cross efficiency approach and results are analyzed. State of Tamil Nadu occupies the top position followed by Puducherry, Punjab, and Rajasthan in the ranking list. To the best of my knowledge, this is the first pan-India level study to evaluate and rank the performance of MGNREGA scheme quantitatively and so comprehensively.

Abstract Purpose: Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Serum protein profiles in patients with preclinical disease and at diagnosis were investigated. Experimental Design: Serum from cases up to 4 years prior to PDAC diagnosis and controls (UKCTOCS, n = 174) were studied, alongside samples from patients diagnosed with PDAC, chronic pancreatitis, benign biliary disease, type 2 diabetes mellitus, and healthy subjects (n = 298). Isobaric tags for relative and absolute quantification (iTRAQ) enabled comparisons of pooled serum from a test set (n = 150). Validation was undertaken using multiple reaction monitoring (MRM) and/or Western blotting in all 472 human samples and samples from a KPC mouse model. Results: iTRAQ identified thrombospondin-1 (TSP-1) as reduced preclinically and in diagnosed samples. MRM confirmed significant reduction in levels of TSP-1 up to 24 months prior to diagnosis. A combination of TSP-1 and CA19-9 gave an AUC of 0.86, significantly outperforming both markers alone (0.69 and 0.77, respectively; P < 0.01). TSP-1 was also decreased in PDAC patients compared with healthy controls (P < 0.05) and patients with benign biliary obstruction (P < 0.01). Low levels of TSP-1 correlated with poorer survival, preclinically (P < 0.05) and at clinical diagnosis (P < 0.02). In PDAC patients, reduced TSP-1 levels were more frequently observed in those with confirmed diabetes mellitus (P < 0.01). Significantly lower levels were also observed in PDAC patients with diabetes compared with individuals with type 2 diabetes mellitus (P = 0.01). Conclusions: Circulating TSP-1 levels decrease up to 24 months prior to diagnosis of PDAC and significantly enhance the diagnostic performance of CA19-9. The influence of diabetes mellitus on biomarker behavior should be considered in future studies. Clin Cancer Res; 22(7); 1734–43. ©2015 AACR.

There is little evidence on the prognostic influence of intravenous nitrates in patients with acute heart failure. Our purpose was to determine the influence of this treatment on early mortality and new visits.Prospective, multicenter cohort study of patients with acute heart failure in an emergency room during 2 periods (May 2009 and November-December 2011). Patients with systolic blood pressure > 110 mmHg were included, grouped according to whether they received intravenous nitroglycerin or not. Endpoints were mortality at 3, 7, 14, and 30 days and new visits at 30 days. The propensity score was estimated by logistic regression to determine the prognostic influence of the treatment.We included 3178 of 4897 individuals. A total of 308 (9.7%) had died within 30 days and 465 (17%) attended new visits. The mean (standard deviation) age was 79.5 (10.0) years, and 796 (25%) patients received intravenous nitrates. After matching, there were 685 individuals in each group. The hazard ratio for 30-day mortality with nitrates was 1.21 (95% confidence interval, 0.87-1.70) and was 0.93 for new visits (95% confidence interval, 0.71-1.22). The results were similar for mortality at 3, 7, and 14 days (hazard ratio = 1.05 [95% confidence interval, 0.56-1.96], hazard ratio = 1.20 [95% confidence interval, 0.74-1.94], and hazard ratio = 1.23 [95% confidence interval, 0.82-1.84], respectively). In the presence of hypertensive pulmonary edema, the nitrates group showed a hazard ratio of 0.88 (95% confidence interval, 0.47-1.63) for 30-day mortality.Intravenous nitrates do not influence early mortality or new visits in patients with acute heart failure.La evidencia sobre la influencia pronóstica de los nitratos intravenosos en pacientes con insuficiencia cardiaca aguda es escasa. El objetivo del estudio es determinar la influencia de este tratamiento en mortalidad precoz y reconsulta.Estudio de cohortes, multicéntrico, prospectivo de pacientes con insuficiencia cardiaca aguda en servicios de urgencias en 2 periodos (mayo de 2009 y noviembre-diciembre de 2011). Se incluyó pacientes con presión arterial sistólica > 110 mmHg agrupados en función de si recibieron nitroglicerina intravenosa o no. Las variables objetivo fueron mortalidad a 3, 7, 14 y 30 días y reconsulta a 30 días. Para determinar la influencia pronóstica del tratamiento se realizó un propensity score mediante regresión logística.De 4.897 individuos se incluyeron 3.178. Fallecieron a 30 días 308 (9,7%) y reconsultaron 465 (17%). La edad media era de 79,5 ± 10,0 años y 796 (25%) recibieron nitratos intravenosos. Tras emparejarlos quedaron 685 individuos en cada grupo. La hazard ratio de los nitratos para mortalidad a 30 días fue 1,21 (intervalo de confianza del 95%, 0,87-1,70) y para reconsulta 0,93 (intervalo de confianza del 95%, 0,71-1,22). Los resultados fueron similares para la mortalidad a 3, 7 y 14 días (hazard ratio = 1,05 [intervalo de confianza del 95%, 0,56-1,96], hazard ratio = 1,20 [intervalo de confianza del 95%, 0,74-1,94] y hazard ratio = 1,23 [intervalo de confianza del 95%, 0,82-1,84], respectivamente). En presencia de edema de pulmón hipertensivo, el grupo de nitratos mostró una hazard ratio de 0,88 (intervalo de confianza del 95%, 0,47-1,63) para mortalidad a 30 días.Los nitratos intravenosos no influyen en mortalidad precoz ni en reconsulta en pacientes con insuficiencia cardiaca aguda.

TiO2 nanotubes prepared by electrochemical anodization have received considerable attention in the biomedical field. In this work, different amounts of gold nanoparticles were immobilized onto TiO2 nanotubes using 3-aminopropyltrimethoxysilane as coupling agent. Field emission scanning electron microscopy and X-ray photoelectron spectroscopy were used to investigate the surface morphology and composition. Photoluminescence spectra and surface zeta potential were also measured. The obtained results indicate that the surface modified gold nanoparticles can significantly enhance the electron storage capability and reduce the surface zeta potential compared to pristine TiO2 nanotubes. Moreover, the surface modified gold nanoparticles can stimulate initial adhesion and spreading of rat bone mesenchymal stem cells as well as proliferation, while the osteogenous performance of TiO2 nanotubes will not be reduced. The gold-modified surface presents moderate antibacterial effect on both Staphylococcus aureus and Escherichia coli. It should be noted that the surface modified fewer gold nanoparticles has better antibacterial effect compared to the surface of substantial modification of gold nanoparticles. Our study illustrates a composite surface with favorable cytocompatibility and antibacterial effect and provides a promising candidate for orthopedic and dental implant.

The rheology of a highly filled thermoplastic paste employed in a novel continuous casting process was investigated across the melt-mushy zone temperature transition. The paste comprises of an ultrafine (or nano-particulate) zinc oxide powder (d1,0=85nm, 50 vol%) and a continuous phase consisting of a blend of organic waxes with an onset of solidification around 54∘C. Data were collected over nine decades of shear rate, using controlled strain and controlled stress devices, steady shear and oscillatory modes, rotational rheometry, and capillary rheometry using the multi-pass technique. The melt rheology could be described using a Carreau-type constitutive model, with strong evidence of a low shear rate viscosity plateau and a possible high shear rate viscosity plateau, with a transition between the two described by a highly shear-thinning power-law region. Nearer the solidification temperature the material exhibited strong pseudo-plastic behaviour, and capillary flow appears to be determined by pressure-dependent slip behaviour.

AIM: To conduct a meta-analysis comparing outcomes after pancreaticoduodenectomy (PD) with or without prophylactic drainage.METHODS: Relevant comparative randomized and non-randomized studies were systemically searched based on specific inclusion and exclusion criteria. Postoperative outcomes were compared between patients with and those without routine drainage. Pooled odds ratios (OR) with 95% CI were calculated using either fixed effects or random effects models.RESULTS: One randomized controlled trial and four non-randomized comparative studies recruiting 1728 patients were analyzed. Patients without prophylactic drainage after PD had significantly higher mortality (OR = 2.32, 95% CI: 1.11-4.85; P = 0.02), despite the fact that they were associated with fewer overall complications (OR = 0.62, 95% CI: 0.48-0.82; P = 0.00), major complications (OR = 0.75, 95% CI: 0.60-0.93; P = 0.01) and readmissions (OR = 0.77, 95% CI: 0.60-0.98; P = 0.04). There were no significant differences in the rates of pancreatic fistula, intra-abdominal abscesses, postpancreatectomy hemorrhage, biliary fistula, delayed gastric emptying, reoperation or radiologic-guided drains between the two groups.CONCLUSION: Indiscriminate abandonment of intra-abdominal drainage following PD is associated with greater mortality, but lower complication rates. Future randomized trials should compare routine vs selective drainage.

The purpose of this article is to describe the way of developing and assessing the meeting skills in the teaching of Business English at the Faculty of Informatics and Management in Hradec Kralove, Czech Republic. This form of communication supports and reveals not only studentś language abilities but also contributes to interdisciplinary relations because students can apply their theoretical knowledge of the core subjects (management or economics) and develop their skill of team work. The article firstly gives brief characteristics of Business English; secondly, it depicts the methods of assessments at the faculty as far as the teaching of English is concerned; and thirdly, it explains how the meeting skills are taught and assessed.