Citrullination Licenses Calpain to Decondense Nuclei in Neutrophil Extracellular Trap Formation

Neutrophils respond to various stimuli by decondensing and releasing nuclear chromatin characterized by citrullinated histones as neutrophil extracellular traps (NETs). This achieves pathogen immobilization or initiation of thrombosis, yet the molecular mechanisms of NET formation remain elusive. Peptidyl arginine deiminase-4 (PAD4) achieves protein citrullination and has been intricately linked to NET formation. Here we show that citrullination represents a major regulator of proteolysis in the course of NET formation. Elevated cytosolic calcium levels trigger both peptidylarginine deiminase-4 (PAD4) and calpain activity in neutrophils resulting in nuclear decondensation typical of NETs. Interestingly, PAD4 relies on proteolysis by calpain to achieve efficient nuclear lamina breakdown and chromatin decondensation. Pharmacological or genetic inhibition of PAD4 and calpain strongly inhibit chromatin decondensation of human and murine neutrophils in response to calcium ionophores as well as the proteolysis of nuclear proteins like lamin B1 and high mobility group box protein 1 (HMGB1). Taken together, the concerted action of PAD4 and calpain induces nuclear decondensation in the course of calcium-mediated NET formation

Psychometric properties of a German version of the neck pain and disability scale

The aim of this study is to evaluate the validity and the psychometric properties of a German version of the 20-item neck pain and disability scale (NPAD) for use in primary care settings. Four hundred and forty-eight participants from 15 general practices in the area of Göttingen Germany completed a multidimensional questionnaire including a newly developed German version of the NPAD (NPAD-d) and self-reported demographic and clinical information. Reliability was tested using Cronbach’s alpha. Item-to-total score correlations were analysed. Factor structure was explored by using unrestricted principal factor analysis. Construct validity of the NPAD-d was evaluated by simple correlation analyses (Pearson’s rho) with social and clinical characteristics. The discriminative abilities of the NPAD-d were examined by comparing differences between subgroups stratified on non-NPAD-d pain related characteristics using t tests for mean scores. Cronbach’s alpha of NPAD-d was 0.94. Item-to-total scale correlations ranged between 0.414 and 0.829. Exploratory principal factor analysis indicated that the NPAD-d covers one factor with an explained variance of 48%. Correlation analysis showed high correlations with criterion variables. The NAPD-d scores of subgroups of patients were significantly different showing good discriminative validity of the scale. The NPAD-d demonstrated good validity and reliability in this general practice setting. The NPAD-d may be useful in the clinical assessment process and the management of neck pain

Bacterial porin disrupts mitochondrial membrane potential and sensitizes host cells to apoptosis

The bacterial PorB porin, an ATP-binding beta-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (delta psi m). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of beta-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of delta psi m. The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce delta psi m loss and apoptosis, demonstrating that dissipation of delta psi m is a requirement for cell death caused by neisserial infection

Sensitivity to change of the Neck Pain and Disability Scale

The Neck Pain and Disability Scale (NPAD) is a 20-item instrument to measure neck pain and related disability. The aim of this study was to assess sensitivity to change of the NPAD. A total of 411 participants from 15 general practices in the middle of Germany completed a multidimensional questionnaire including the German version of the NPAD and self-reported demographic and clinical information. Sensitivity to change was analysed by linear regression analysis of the NPAD at follow-up and educational level, age class, depression, anxiety, and deficits in social support, respectively, and by Pearson’s correlation analyses between mean change in NPAD at follow-up and mean change in prognostic markers. Those having more than basic education (regression coefficient −7.2, p < 0.001) and/or being in a younger age class (−2.9, p = 0.020) consistently reported significantly lower average NPAD scores at follow-up compared to those with basic education and/or a older age class. In contrast, those who were classified to be depressed (regression coefficient 2.1, p < 0.001), anxious (1.9, p < 0.001), or having deficits in social support (5.5, p = 0.004) reported significantly higher NPAD scores. Change in depression, anxiety, and social support scale between baseline and follow-up was significantly correlated with change in the NPAD score. Hence, these data are in the direction anticipated across all baseline factors investigated. In conclusion, the NPAD seems to be a sensitive measure for use in clinical practice and future studies of neck pain and related disability

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies. Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny

A Multi-Variant, Viral Dynamic Model of Genotype 1 HCV to Assess the in vivo Evolution of Protease-Inhibitor Resistant Variants

Variants resistant to compounds specifically targeting HCV are observed in clinical trials. A multi-variant viral dynamic model was developed to quantify the evolution and in vivo fitness of variants in subjects dosed with monotherapy of an HCV protease inhibitor, telaprevir. Variant fitness was estimated using a model in which variants were selected by competition for shared limited replication space. Fitness was represented in the absence of telaprevir by different variant production rate constants and in the presence of telaprevir by additional antiviral blockage by telaprevir. Model parameters, including rate constants for viral production, clearance, and effective telaprevir concentration, were estimated from 1) plasma HCV RNA levels of subjects before, during, and after dosing, 2) post-dosing prevalence of plasma variants from subjects, and 3) sensitivity of variants to telaprevir in the HCV replicon. The model provided a good fit to plasma HCV RNA levels observed both during and after telaprevir dosing, as well as to variant prevalence observed after telaprevir dosing. After an initial sharp decline in HCV RNA levels during dosing with telaprevir, HCV RNA levels increased in some subjects. The model predicted this increase to be caused by pre-existing variants with sufficient fitness to expand once available replication space increased due to rapid clearance of wild-type (WT) virus. The average replicative fitness estimates in the absence of telaprevir ranged from 1% to 68% of WT fitness. Compared to the relative fitness method, the in vivo estimates from the viral dynamic model corresponded more closely to in vitro replicon data, as well as to qualitative behaviors observed in both on-dosing and long-term post-dosing clinical data. The modeling fitness estimates were robust in sensitivity analyses in which the restoration dynamics of replication space and assumptions of HCV mutation rates were varied

An APRI+ALBI Based Multivariable Model as Preoperative Predictor for Posthepatectomy Liver Failure.

OBJECTIVE AND BACKGROUND Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an APRI+ALBI, aspartate aminotransferase to platelet ratio (APRI) combined with albumin-bilirubin grade (ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). METHODS 12,056 patients from the National Surgical Quality Improvement Program (NSQIP) database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. Performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2,525 patients. In 620 patients, the APRI+ALBI MVM, trained in the NSQIP cohort, was compared with MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). RESULTS A MVM including APRI+ALBI, age, sex, tumor type and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for calculation of the APRI+ALBI MVM was designed. CONCLUSION Risk assessment via the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents an universally available and cost-effective risk assessment prior to hepatectomy, facilitated by a freely available smartphone app

Soluble Serum CD81 Is Elevated in Patients with Chronic Hepatitis C and Correlates with Alanine Aminotransferase Serum Activity

Aim: Cellular CD81 is a well characterized hepatitis C virus (HCV) entry factor, while the relevance of soluble exosomal CD81 in HCV pathogenesis is poorly defined. We performed a case-control study to investigate whether soluble CD81 in the exosomal serum fraction is associated with HCV replication and inflammatory activity. Patients and Methods: Four cohorts were investigated, patients with chronic hepatitis C (n = 37), patients with chronic HCV infection and persistently normal ALT levels (n = 24), patients with long term sustained virologic response (SVR, n = 7), and healthy volunteers (n = 23). Concentration of soluble CD81 was assessed semi-quantitatively after differential centrifugation ranging from 200 g to 100,000 g in the fifth centrifugation fraction by immunoblotting and densitometry. Results: Soluble CD81 was increased in patients with chronic hepatitis C compared to healthy subjects (p = 0.03) and cured patients (p = 0.017). Patients with chronic HCV infection and persistently normal ALT levels and patients with long term SVR had similar soluble CD81 levels as healthy controls (p>0.2). Overall, soluble CD81 levels were associated with ALT levels (r = 0.334, p = 0.016) and severe liver fibrosis (p = 0.027). Conclusion: CD81 is increased in the exosomal serum fraction in patients with chronic hepatitis C and appears to be associated with inflammatory activity and severity of fibrosis

Flow shop rescheduling under different types of disruption

This is an Accepted Manuscript of an article published by Taylor & Francis in International Journal of Production Research on 2013, available online:http://www.tandfonline.com/10.1080/00207543.2012.666856Almost all manufacturing facilities need to use production planning and scheduling systems to increase productivity and to reduce production costs. Real-life production operations are subject to a large number of unexpected disruptions that may invalidate the original schedules. In these cases, rescheduling is essential to minimise the impact on the performance of the system. In this work we consider flow shop layouts that have seldom been studied in the rescheduling literature. We generate and employ three types of disruption that interrupt the original schedules simultaneously. We develop rescheduling algorithms to finally accomplish the twofold objective of establishing a standard framework on the one hand, and proposing rescheduling methods that seek a good trade-off between schedule quality and stability on the other.The authors would like to thank the anonymous referees for their careful and detailed comments that helped to improve the paper considerably. This work is partially financed by the Small and Medium Industry of the Generalitat Valenciana (IMPIVA) and by the European Union through the European Regional Development Fund (FEDER) inside the R + D program "Ayudas dirigidas a Institutos tecnologicos de la Red IMPIVA" during the year 2011, with project number IMDEEA/2011/142.Katragjini Prifti, K.; Vallada Regalado, E.; Ruiz García, R. (2013). Flow shop rescheduling under different types of disruption. International Journal of Production Research. 51(3):780-797. https://doi.org/10.1080/00207543.2012.666856S780797513Abumaizar, R. J., & Svestka, J. A. (1997). Rescheduling job shops under random disruptions. International Journal of Production Research, 35(7), 2065-2082. doi:10.1080/002075497195074Adiri, I., Frostig, E., & Kan, A. H. G. R. (1991). Scheduling on a single machine with a single breakdown to minimize stochastically the number of tardy jobs. Naval Research Logistics, 38(2), 261-271. doi:10.1002/1520-6750(199104)38:23.0.co;2-iAkturk, M. S., & Gorgulu, E. (1999). Match-up scheduling under a machine breakdown. European Journal of Operational Research, 112(1), 81-97. doi:10.1016/s0377-2217(97)00396-2Allahverdi, A. (1996). Two-machine proportionate flowshop scheduling with breakdowns to minimize maximum lateness. Computers & Operations Research, 23(10), 909-916. doi:10.1016/0305-0548(96)00012-3Arnaout, J. P., & Rabadi, G. (2008). Rescheduling of unrelated parallel machines under machine breakdowns. International Journal of Applied Management Science, 1(1), 75. doi:10.1504/ijams.2008.020040Artigues, C., Billaut, J.-C., & Esswein, C. (2005). Maximization of solution flexibility for robust shop scheduling. European Journal of Operational Research, 165(2), 314-328. doi:10.1016/j.ejor.2004.04.004Azizoglu, M., & Alagöz, O. (2005). Parallel-machine rescheduling with machine disruptions. IIE Transactions, 37(12), 1113-1118. doi:10.1080/07408170500288133Bean, J. C., Birge, J. R., Mittenthal, J., & Noon, C. E. (1991). Matchup Scheduling with Multiple Resources, Release Dates and Disruptions. Operations Research, 39(3), 470-483. doi:10.1287/opre.39.3.470Caricato, P., & Grieco, A. (2008). An online approach to dynamic rescheduling for production planning applications. International Journal of Production Research, 46(16), 4597-4617. doi:10.1080/00207540601136225CHURCH, L. K., & UZSOY, R. (1992). Analysis of periodic and event-driven rescheduling policies in dynamic shops. International Journal of Computer Integrated Manufacturing, 5(3), 153-163. doi:10.1080/09511929208944524Cowling, P., & Johansson, M. (2002). Using real time information for effective dynamic scheduling. European Journal of Operational Research, 139(2), 230-244. doi:10.1016/s0377-2217(01)00355-1Curry, J., & Peters *, B. (2005). Rescheduling parallel machines with stepwise increasing tardiness and machine assignment stability objectives. International Journal of Production Research, 43(15), 3231-3246. doi:10.1080/00207540500103953DUTTA, A. (1990). Reacting to Scheduling Exceptions in FMS Environments. IIE Transactions, 22(4), 300-314. doi:10.1080/07408179008964185Ghezail, F., Pierreval, H., & Hajri-Gabouj, S. (2010). Analysis of robustness in proactive scheduling: A graphical approach. Computers & Industrial Engineering, 58(2), 193-198. doi:10.1016/j.cie.2009.03.004Goren, S., & Sabuncuoglu, I. (2008). Robustness and stability measures for scheduling: single-machine environment. IIE Transactions, 40(1), 66-83. doi:10.1080/07408170701283198Hall, N. G., & Potts, C. N. (2004). Rescheduling for New Orders. Operations Research, 52(3), 440-453. doi:10.1287/opre.1030.0101Herrmann, J. W., Lee, C.-Y., & Snowdon, J. L. (1993). A Classification of Static Scheduling Problems. Complexity in Numerical Optimization, 203-253. doi:10.1142/9789814354363_0011Herroelen, W., & Leus, R. (2005). Project scheduling under uncertainty: Survey and research potentials. European Journal of Operational Research, 165(2), 289-306. doi:10.1016/j.ejor.2004.04.002Hozak, K., & Hill, J. A. (2009). Issues and opportunities regarding replanning and rescheduling frequencies. International Journal of Production Research, 47(18), 4955-4970. doi:10.1080/00207540802047106Huaccho Huatuco, L., Efstathiou, J., Calinescu, A., Sivadasan, S., & Kariuki, S. (2009). Comparing the impact of different rescheduling strategies on the entropic-related complexity of manufacturing systems. International Journal of Production Research, 47(15), 4305-4325. doi:10.1080/00207540701871036Jensen, M. T. (2003). Generating robust and flexible job shop schedules using genetic algorithms. IEEE Transactions on Evolutionary Computation, 7(3), 275-288. doi:10.1109/tevc.2003.810067King, J. R. (1976). The theory-practice gap in job-shop scheduling. Production Engineer, 55(3), 137. doi:10.1049/tpe.1976.0044Kopanos, G. M., Capón-García, E., Espuña,, A., & Puigjaner, L. (2008). Costs for Rescheduling Actions: A Critical Issue for Reducing the Gap between Scheduling Theory and Practice. Industrial & Engineering Chemistry Research, 47(22), 8785-8795. doi:10.1021/ie8005676Lee, C.-Y., Leung, J. Y.-T., & Yu, G. (2006). Two Machine Scheduling under Disruptions with Transportation Considerations. Journal of Scheduling, 9(1), 35-48. doi:10.1007/s10951-006-5592-7Li, Z., & Ierapetritou, M. (2008). Process scheduling under uncertainty: Review and challenges. Computers & Chemical Engineering, 32(4-5), 715-727. doi:10.1016/j.compchemeng.2007.03.001Liao, C. J., & Chen, W. J. (2004). Scheduling under machine breakdown in a continuous process industry. Computers & Operations Research, 31(3), 415-428. doi:10.1016/s0305-0548(02)00224-1Mehta, S. V. (1999). Predictable scheduling of a single machine subject to breakdowns. International Journal of Computer Integrated Manufacturing, 12(1), 15-38. doi:10.1080/095119299130443MUHLEMANN, A. P., LOCKETT, A. G., & FARN, C.-K. (1982). Job shop scheduling heuristics and frequency of scheduling. International Journal of Production Research, 20(2), 227-241. doi:10.1080/00207548208947763Nawaz, M., Enscore, E. E., & Ham, I. (1983). A heuristic algorithm for the m-machine, n-job flow-shop sequencing problem. Omega, 11(1), 91-95. doi:10.1016/0305-0483(83)90088-9O’Donovan, R., Uzsoy, R., & McKay, K. N. (1999). Predictable scheduling of a single machine with breakdowns and sensitive jobs. International Journal of Production Research, 37(18), 4217-4233. doi:10.1080/002075499189745Özlen, M., & Azizoğlu, M. (2009). Generating all efficient solutions of a rescheduling problem on unrelated parallel machines. International Journal of Production Research, 47(19), 5245-5270. doi:10.1080/00207540802043998Pfeiffer, A., Kádár, B., & Monostori, L. (2007). Stability-oriented evaluation of rescheduling strategies, by using simulation. Computers in Industry, 58(7), 630-643. doi:10.1016/j.compind.2007.05.009Pierreval, H., & Durieux-Paris, S. (2007). Robust simulation with a base environmental scenario. European Journal of Operational Research, 182(2), 783-793. doi:10.1016/j.ejor.2006.07.045Damodaran, P., Hirani, N. S., & Gallego, M. C. V. (2009). Scheduling identical parallel batch processing machines to minimise makespan using genetic algorithms. European J. of Industrial Engineering, 3(2), 187. doi:10.1504/ejie.2009.023605Qi, X., Bard, J. F., & Yu, G. (2006). Disruption management for machine scheduling: The case of SPT schedules. International Journal of Production Economics, 103(1), 166-184. doi:10.1016/j.ijpe.2005.05.021Rangsaritratsamee, R., Ferrell, W. G., & Kurz, M. B. (2004). Dynamic rescheduling that simultaneously considers efficiency and stability. Computers & Industrial Engineering, 46(1), 1-15. doi:10.1016/j.cie.2003.09.007Ruiz, R., & Stützle, T. (2007). A simple and effective iterated greedy algorithm for the permutation flowshop scheduling problem. European Journal of Operational Research, 177(3), 2033-2049. doi:10.1016/j.ejor.2005.12.009Sabuncuoglu, I., & Goren, S. (2009). Hedging production schedules against uncertainty in manufacturing environment with a review of robustness and stability research. International Journal of Computer Integrated Manufacturing, 22(2), 138-157. doi:10.1080/09511920802209033Sabuncuoglu, I., & Kizilisik, O. B. (2003). Reactive scheduling in a dynamic and stochastic FMS environment. International Journal of Production Research, 41(17), 4211-4231. doi:10.1080/0020754031000149202Salveson, M. E. (1952). On a Quantitative Method in Production Planning and Scheduling. Econometrica, 20(4), 554. doi:10.2307/1907643Samarghandi, H., & ElMekkawy, T. Y. (2011). An efficient hybrid algorithm for the two-machine no-wait flow shop problem with separable setup times and single server. European J. of Industrial Engineering, 5(2), 111. doi:10.1504/ejie.2011.039869Subramaniam *, V., Raheja, A. S., & Rama Bhupal Reddy, K. (2005). Reactive repair tool for job shop schedules. International Journal of Production Research, 43(1), 1-23. doi:10.1080/0020754042000270412Taillard, E. (1990). Some efficient heuristic methods for the flow shop sequencing problem. European Journal of Operational Research, 47(1), 65-74. doi:10.1016/0377-2217(90)90090-xTaillard, E. (1993). Benchmarks for basic scheduling problems. European Journal of Operational Research, 64(2), 278-285. doi:10.1016/0377-2217(93)90182-mValente, J. M. S., & Schaller, J. E. (2010). Improved heuristics for the single machine scheduling problem with linear early and quadratic tardy penalties. European J. of Industrial Engineering, 4(1), 99. doi:10.1504/ejie.2010.029572Vallada, E., & Ruiz, R. (2010). Genetic algorithms with path relinking for the minimum tardiness permutation flowshop problem☆. Omega, 38(1-2), 57-67. doi:10.1016/j.omega.2009.04.002Vieira, G. E., Herrmann, J. W., & Lin, E. (2000). Predicting the performance of rescheduling strategies for parallel machine systems. Journal of Manufacturing Systems, 19(4), 256-266. doi:10.1016/s0278-6125(01)80005-4Vieira, G. E., Herrmann, J. W., & Lin, E. (2003). Journal of Scheduling, 6(1), 39-62. doi:10.1023/a:1022235519958Yang, J., & Yu, G. (2002). Journal of Combinatorial Optimization, 6(1), 17-33. doi:10.1023/a:1013333232691Zandieh, M., & Gholami, M. (2009). An immune algorithm for scheduling a hybrid flow shop with sequence-dependent setup times and machines with random breakdowns. International Journal of Production Research, 47(24), 6999-7027. doi:10.1080/0020754080240063