Differential regulation of cytokine secretion in multiple sclerosis

Multiple sclerosis (MS) is the most common autoimmune inflammatory demyelinating disorder of the human nervous system affecting nearly 1 million people worldwide every year. Current treatments for first-line nontoxic therapy of the relapsing-remitting form of the disease are two forms of recombinant IFN(3, Ia and 1(3 andglatiramèr acetate. The pathogenesis of MS is highlighted by an inflammatory response and myelin destruction. Several recent studies have reported alterations in immune variables such as cytokine concentrations, immune-related molecules such as MHC and adhesion molecules and chemokines; which may contribute to an imbalance between Thi and Th2 T cellmediated immune response. The aims of the present study were to characterize the cytokinetic profile of MS patients through investigating the secretion of the main pro and anti-inflammatory cytokines from peripheral blood mononuclear cells of MS patients compared to controls, and to investigate cytokine receptor expression levels in T and NK cells. In addition, the induction of apoptosis and the involvement of adhesion molecules and metalloproteinases in oligodendrocyte destruction are examined. Finally, the effect of IFN(3 treatment on cytokine secretion levels as well as on the aforementioned immunoregulatory molecules was evaluated. The study population consisted of 60 MS patients (20 untreated, 20 treated with IFNf3-lcz and 20 treated with IFN(3-1(3) in parallel with 25 controls. Serumlplasma samples and peripheral blood mononuclear cells (PBMCs) were isolated from each participant. Using the enzyme linked immunospot (ELISPOT) assay the numbers of cytokine-secreting PBMCs were measured for the following cytokines: IFN-y, TNF-a, IL- 12, IL- 10 and IL-4. The expression levels of the cytokine receptors IL- 1 2R(3 1, IFN-y, IL- 1 OR, TNFaR were estimated in the surface of lymphocytes using flow cytometry and serum levels of soluble CD95, ICAM- 1, VCAM-1, metalloproteinase-9 (MMP-9) and the tissue inhibitor, metalloproteinase-1 (TIMP-1) were evaluated in all samples. The ELISPOT assay proved a very sensitive and valuable tool for characterisation of the cytokine profile of MS patients. Decreased numbers of PBMCs secreting IL-b 0 and IL-4, and increased numbers of PBMCs secreting TNF-a, IL-12 and IFN-y were observed in MS patients compared to healthy controls. Treatment with IFN(3 elevated IL-IO and IL-4 levels, and decreased TNF-a, IL-12 and IFN-y levels in these patients. IFN(3/lci was more efficient in decreasing IL-12 secreting cells and IFN(3/1(3 in decreasing IFN-y, and TNF-a secreting cells and elevating IL-4 and IL- 10 secreting cells Increased expression of IL-12Rj31 and TNF-aR was observed in NK cells and decreased expression of WN-7R and IL-I OR was shown in T cells of MS patients compared to controls. IFNf3 therapy reduced IL-12R(3l levels in I and NK cells (IFNf3-la was more effective), and TNF-uR levels in I cells (IFNj3- 1(3 was more effective), but it increased IFN-1R and IL-1OR in T and NK cells of MS patients. Increased levels of the soluble CD95 apoptosis marker were observed in serum of MS patients compared to controls, which further increased after IFN(3 treatment (IFN(3-10 was more efficient). Increased levels of soluble ICAM-1 and VCAM-1 were observed in serum of MS patients compared to controls, which were further increased after treatment with IFN(3 (IFN-1a was more efficient in increasing sICAM-1 and IFNI3-113 in increasing sVCAM- 1 levels) Increased levels of MMP-9, decreased levels of TIMP- 1, and increased MMP-9ITIMP- I ratio was found in serum of MS patients compared to controls, and treatment with IFN decreased MMP-9 levels, increased TIMP-1 levels and decreased MMP-9/TIMP-1 levels ITCXTII 1.. 4'P + tss i,p s a ,lvaS it"j*.. These results indicate an over expression of Thi type cytokines in MS accompanied by a concomitant suppression of Th2 type immune response as well as by alterations in the expression of cytokine receptors. A consequent activation of other immunoregulatory elements (sCD95, adhesion molecules, metalloproteinases) was also observed which was partly modified by IFNI3 treatment. This study provides important evidence on the role of cytokines and of other inflammatory molecules in MS pathogenesis and highlights possible mechanisms of action of IFNI3 treatment, offering new perspectives for novel, more efficient, diagnostic, and therapeutical approaches for the disease

Differential Regulation of Cytokine Secretion in Multiple Sclerosis

Multiple sclerosis (MS) is the most common autoimmune inflammatory demyelinating disorder of the human nervous system affecting nearly 1 million people worldwide every year. Current treatments for first-line nontoxic therapy of the relapsing-remitting form of the disease are two forms of recombinant IFNp, la and lP and glatiramer acetate. The pathogenesis of MS is highlighted by an inflammatory response and myelin destruction. Several recent studies have reported alterations in immune variables such as cytokine concentrations, immune-related molecules such as MHC and adhesion molecules and chemokines; which may contribute to an imbalance between Thl and Th2 T ceIlmediated immune response. The aims of the present study were to characterize the cytokinetic profile of MS patients through investigating the secretion of the main pro- and anti-inflammatory cytokines from peripheral blood mononuclear ceIls of MS patients compared to controls, and to investigate cytokine receptor expression levels in T and NK ceIls. In addition, the induction of apoptosis and the involvement of adhesion molecules and metalloproteinases in oligodendrocyte destruction are examined. Finally, the effect of IFNp treatment on cytokine secretion levels as well as on the aforementioned immunoregulatory molecules was evaluated. The study population consisted of 60 MS patients (20 untreated, 20 treated with IFNP-l a and 20 treated with IFNP-l P) in paraIlel with 25 controls. Serum/plasma samples and peripheral blood mononuclear ceIls (PBMCs) were isolated from each participant. Using the enzyme linked immunospot (ELISPOT) assay the numbers of cytokine-secreting PBMCs were measured for the following cytokines: IFN-y, TNF-a, IL-12, IL-IO and IL-4. The expression levels of the cytokine receptors IL-12RPl, IFN-y, IL-IOR, TNFaR were estimated in the surface of lymphocytes using flow cytometry and serum levels of soluble CD95, ICAM-l, VCAM-l, metaIloproteinase-9 (MMP-9) and the tissue inhibitor, metalloproteinase-l (TIMP-l) were evaluated in all samples. The ELISPOT assay proved a very sensitive and valuable tool for characterisation of the cytokine profile ofMS patients. Decreased numbers ofPBMCs secreting IL-l 0 and IL-4, and increased numbers ofPBMCs secreting TNF-a, IL-12 and IFN-y were observed in MS patients compared to healthy controls. Treatment with IFNp elevated IL-IO and IL-4 levels, and decreased TNF-a, IL-12 and IFN-y levels in these patients. IFNp/la was more efficient in decreasing IL-12 secreting cells and IFNp/lP in decreasing IFN-y, and TNF-a secreting cells and elevating IL-4 and IL-l 0 secreting cells Increased expression ofIL-12RPl and TNF-aR was observed in NK cells and decreased expression of IFN-yR and IL-IOR was shown in T cells of MS patients compared to controls. IFNp therapy reduced IL-12RP i levels in T and NK cells (IFNP-l a. was more effective), and TNF-aR levels in T cells (IFNP- lP was more effective), but it increased IFN-yR and IL-IOR in T and NK cells ofMS patients. Increased levels of the soluble CD95 apoptosis marker were observed in serum of MS patients compared to controls, which further increased after IFNp treatment (IFNP-l P was more efficient). Increased levels of soluble ICAM-l and VCAM-l were observed in serum of MS patients compared to controls, which were further increased after treatment with IFNp (lFNP-l a was more efficient in increasing sICAM-1 and IFNP-I P in increasing sVCAMI levels) Increased levels of MMP-9, decreased levels of TIMP-l, and increased MMP-9/TIMP-l ratio was found in serum of MS patients compared to controls, and treatment with IFNp decreased MMP-9 levels, increased TIMP-l levels and decreased MMP-9/TIMP-l levels (lFNp-la was more effective). These results indicate an over expression ofThl type cytokines in MS accompanied by a concomitant suppression of Th2 type immune response as well as by alterations in the expression of cytokine receptors. A consequent activation of other immunoregulatory elements (sCD95, adhesion molecules, metalloproteinases) was also observed which was partly modified by IFNp treatment. This study provides important evidence on the role of cytokines and of other inflammatory molecules in MS pathogenesis and highlights possible mechanisms of action of IFNp treatment, offering new perspectives for novel, more efficient, diagnostic, and therapeutical approaches for the disease.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The exception handling riddle: An empirical study on the Android API

We examine the use of the Java exception types in the Android platform’s Application Programming Interface (API) reference documentation and their impact on the stability of Android applications. We develop a method that automatically assesses an API’s quality regarding the exceptions listed in the API’s documentation. We statically analyze ten versions of the Android platform’s API (14–23) and 3539 Android applications to determine inconsistencies between exceptions that analysis can find in the source code and exceptions that are documented. We cross-check the analysis of the Android platform’s API and applications with crash data from 901,274 application execution failures (crashes). We discover that almost 10% of the undocumented exceptions that static analysis can find in the Android platform’s API source code manifest themselves in crashes. Additionally, we observe that 38% of the undocumented exceptions that developers use in their client applications to handle API methods also manifest themselves in crashes. These findings argue for documenting known might-thrown exceptions that lead to execution failures. However, a randomized controlled trial we run shows that relevant documentation improvements are ineffective and that making such exceptions checked is a more effective way for improving applications’ stability

Can Adult Education Boost Sustainability Transitions? Some Evidence from Farmers and Teachers

Sustainability transitions are long-term processes that involve interactions among societal groups and promote co-evolutionary socio-technical transformations aimed at addressing crucial sustainability challenges. Although the focus of relevant work is often on groups, sustainability transitions also require personal transformations. Can adult education be a vehicle for promoting such transformations? In the present study, we attempted to answer this question by examining whether participation in sustainability-related adult education programs (AEPs) leads to the development of sustainability awareness, formation of sustainability-related values, construction of sustainability empathy, and initiation of pro-sustainability action among individuals. Following a quantitative research design and drawing upon data from farmers and teachers, we compared attendees and non-attendees of AEPs on the above-mentioned constructs. The analysis revealed that attendees scored significantly higher than non-attendees in awareness, values, empathy, and action. A series of hierarchical regressions confirmed the association between participation and the outcome variables, also showing no effects of demographic factors on the models. These results underscore the potential contribution of sustainability-related adult education to individual transformation, thus suggesting that targeted adult education interventions can facilitate sustainability transitions

Can Adult Education Boost Sustainability Transitions? Some Evidence from Farmers and Teachers

Sustainability transitions are long-term processes that involve interactions among societal groups and promote co-evolutionary socio-technical transformations aimed at addressing crucial sustainability challenges. Although the focus of relevant work is often on groups, sustainability transitions also require personal transformations. Can adult education be a vehicle for promoting such transformations? In the present study, we attempted to answer this question by examining whether participation in sustainability-related adult education programs (AEPs) leads to the development of sustainability awareness, formation of sustainability-related values, construction of sustainability empathy, and initiation of pro-sustainability action among individuals. Following a quantitative research design and drawing upon data from farmers and teachers, we compared attendees and non-attendees of AEPs on the above-mentioned constructs. The analysis revealed that attendees scored significantly higher than non-attendees in awareness, values, empathy, and action. A series of hierarchical regressions confirmed the association between participation and the outcome variables, also showing no effects of demographic factors on the models. These results underscore the potential contribution of sustainability-related adult education to individual transformation, thus suggesting that targeted adult education interventions can facilitate sustainability transitions

Metaheuristic Procedures for the Determination of a Bank of Switching Observers toward Soft Sensor Design with Application to an Alcoholic Fermentation Process

The present work focused on the development of soft sensors for single-input single-output (SISO) nonlinear dynamic systems with unknown physical parameters using a switching observer design. Toward the development of more accurate soft sensors, as compared with hard sensors, an extended design methodology for the determination of a bank of operating points satisfying the dense web principle was proposed, where for the determination of the bank of operating points and the observer parameters, a metaheuristic procedure was developed. To validate the results of the metaheuristic algorithm, the case of an alcoholic fermentation process was studied as a special case of the present approach. For the nonlinear model of the process, an observer-based soft sensor was developed using the metaheuristic procedure. First, the accuracy of the linear approximant of the process with respect to the original nonlinear model was investigated. Second, the I/O reconstructability of the linear approximant was verified. Third, based on the linear approximant, an observer was designed for the estimation of the non-measurable variable. Fourth, considering that the observer is designed upon the linear approximant, the linear approximant model parameters are derived through identification, for different operating points, upon the nonlinear model. Fifth, the observers corresponding to the different operating points, constitute a bank of observers. The design was completed using a data-driven rule-based system, performing stepwise switching between the observers of the bank. The efficiency of the proposed metaheuristic algorithm and the performance of the switching scheme were demonstrated through a series of computational experiments, where it was observed that the herein-proposed approach was more than two orders of magnitude more accurate than traditional single-step approaches of transition from one operating point to another

Modular Supervisory Control for the Coordination of a Manufacturing Cell with Observable Faults

In the present paper, a manufacturing cell in the presence of faults, coming from the devices of the process, is considered. The modular modeling of the subsystems of the cell is accomplished using of appropriate finite deterministic automata. The desired functionality of the cell as well as appropriate safety specifications are formulated as eleven desired languages. The desired languages are expressed as regular expressions in analytic forms. The languages are realized in the form of appropriate general type supervisor forms. Using these forms, a modular supervisory design scheme is accomplished providing satisfactory performance in the presence of faults as well guaranteeing the safety requirements. The aim of the present supervisor control scheme is to achieve tolerance of basic characteristics of the process coordination to upper-level faults, despite the presence of low-level faults in the devices of the process. The complexity of the supervisor scheme is computed

Clonos: Consistent Causal Recovery for Highly-Available Streaming Dataflows

Stream processing lies in the backbone of modern businesses, being employed for mission critical applications such as real-time fraud detection, car-trip fare calculations, traffic management, and stock trading. Large-scale applications are executed by scale-out stream processing systems on thousands of long-lived operators, which are subject to failures. Recovering from failures fast and consistently are both top priorities, yet they are only partly satisfied by existing fault tolerance methods due to the strong assumptions these make. In particular, prior solutions fail to address consistency in the presence of nondeterminism, such as calls to external services, asynchronous timers and processing-time windows. This paper describes Clonos, a fault tolerance approach that achieves fast, local operator recovery with exactly-once guarantees and high availability by instantly switching to passive standby operators. Clonos enforces causally consistent recovery, including output deduplication, by tracking nondeterminism within the system through causal logging. To implement Clonos we re-engineered many of the internal subsystems of a state of the art stream processor. We evaluate Clonos' overhead and recovery on the Nexmark benchmark against Apache Flink. Clonos achieves instant recovery with negligible overhead and, unlike previous work, does not make assumptions on the deterministic nature of operators.Web Information SystemsSoftware Engineerin

Validity and reliability of the Greek version of the neurogenic bladder symptom score (NBSS) questionnaire in a sample of Greek patients with multiple sclerosis

Background and objectives: There is no data regarding validity and reliability of the Greek version of Neurogenic Bladder Symptom Score (NBSS) questionnaire. In this study we investigated these parameters using a sample of Greek patients with multiple sclerosis (MS). Materials and methods: Patients with different types and severity of multiple sclerosis were recruited from a single center in Greece prospectively. All patients completed the MusiQoL and NBSS questionnaires at baseline and 20 days later, without receiving any new treatment. Construct validity, internal consistency and test–retest reliability were tested. Internal consistency was investigated using Cronbach’s alpha coefficient, while test–retest reliability using Intraclass Correlation Coefficient (ICC). Construct validity was assessed by comparing NBSS quality of life question 24 with MusiQoL questionnaire. Results: A total of 91 patients were evaluated. The dimensions of NBSS exhibited high internal consistency, both for overall questionnaire score (Cronbach’s alpha coefficient of 0.91) and for every subdomain separately (Cronbach’s alpha coefficient of 0.95 for incontinence, 0.88 for storage symptoms and 0.74 for consequences). Test–retest reliability was satisfactory both for overall score [ICC of 0.85, (0.35–0.94), p < 0.001] and for every subdomain separately (ICC of 0.90 for incontinence, 0.83 for storage symptoms and 0.90 for consequences). Pearson’s correlation coefficient of question number 24 of the NBSS questionnaire regarding quality of life with the MusiQoL questionnaire revealed a moderate correlation [r = 0.64, (0.48–0.80), p < 0.0001]. Conclusions: The Greek version of NBSS appears to be a valid and reliable instrument for assessing neurogenic bladder symptoms in Greek population suffering from multiple sclerosis. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature