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This paper presents a rewriting logic "interpreter" for networks of parametric timed automata with global variables (NPTAVs) in Real-Time Maude style. Since explicit-state analysis is not sound and complete for such dense-time systems, we explain how our real-time rewrite theory can be systematically transformed into a rewrite theory that is amenable to symbolic analysis using the integration of Maude with SMT solving. We show that symbolic reachability analysis using Maude-with-SMT of the resulting rewrite theory is sound and complete for the NPTAV reachability problem. We extend and optimize standard Maude-with-SMT reachability analysis with folding and merging of symbolic states, so that the analysis terminates when the symbolic state space of the NPTAV is finite. These procedures rely on a subsumption relation that requires eliminating existentially quantified SMT variables. We have therefore implemented the Fourier-Motzkin quantifier elimination algorithm, thereby making our rewrite theory executable with any SMT solver connected to Maude. We show how we can provide most reachability and parameter synthesis analysis methods provided by Imitator, a state-of-the-art tool for NPTAVs. We compare the performance of our analysis methods with those of Imitator on a wide range of benchmarks, with the expected outcome. The practical contributions are two-fold: providing new analysis methods for NPTAVs—e.g., allowing more general state properties and supporting reachability analysis combined with user-defined execution strategies—not supported by Imitator, and developing symbolic analysis methods for both real-time rewrite theories and rewrite theories in general. [ABSTRACT FROM AUTHOR]

The environmental problem generated by the poor used oil discard mechanisms at the present time in Colombia has enable the establishment of business focused on the proper collection and disposal of waste in some of Colombia's major cities; however, this mechanisms still do no guarantee that these companies provide full coverage. The city of Pereira has a high number of oil generating agents (such as Lubrication Centers, Service Centers, Repair shops, among others), which requires the creation of a proper oil waste recovery and disposal system in order to benefit the environment and the citizens. This paper presents the creation of a reverse logistics network associated with the proper used oil collection in the city of Pereira. To build the model it was necessary to identify the residue generators points, the distances between each of the nodes and the logistics variable costs evaluating two types of tanker trucks. The situation was modeled as a Capacited Vehicle Routing Problem (CVRP), which was solved by implementing the route-first cluster-second principle in vehicle routing, a two phase heuristic. The first phase is solved by using the Savings Algorithm, while the second phase is solved by using the Clustering Algorithm. Further on, both algorithms are programmed in MATLAB, where the solution determines the sub-routes integrating the reverse logistics network with the order in which each vehicle should visit the different used oil generating points. [ABSTRACT FROM AUTHOR]

The advances in authoring of interactive scores call for a thorough analysis of the written scores. A possible way to ensure correctness of an interactive score is through the use of formal techniques such as model checking. In this work, we present a visual model of the inter-media sequencer i-score and we propose a Timed Automata encoding to reason about the interactive scores written in this software. The verification of some properties of interactive scores is presented, along an evaluation of the performance of the model-checking process withuppaal. [ABSTRACT FROM AUTHOR]

This article presents the results of a research conducted in the field, where the conditions in the mobility of people with physical-motor disabilities in the metropolitan area of Bucaramanga, Colombia are analyzed. The methodology was based on the identification and classification of public transport systems (conventional bus, taxis and Metrolínea), the assessment of the appropriate infrastructure for the mobility of the population under study and the processing of data obtained through a stated preference survey applied to 100 people with physical limitations in the city. It is concluded that there is not any transportation system that unifies all the advantages when mobilising: comfort, coverage, economy and ease of access; situation that might allow some improvement in the quality of life of such a population. [ABSTRACT FROM AUTHOR]

A process for obtaining planar anode-supported solid oxide fuel cells was developed. Aqueous-based slurries were prepared and sequentially deposited via tape casting to form half cell tapes consisting of the electrolyte, functional, and structural anode. Sintering of the three-layered tapes was done in two stages: presintering circular samples of 25 mm diameter in free conditions first, and then sintering them using zirconium disks as light loads (90 Pa), to obtain half cells having 20 mm and 3.8 m−1 in diameter and curvature, respectively. Active materials for the electrolyte, anode, and cathode were partially stabilized zirconia ( PSZ), Ni and LSM, respectively. Finally, thicknesses of complete cells were 400, 30, 30, and 80 μm for the structural anode, functional anode, electrolyte, and cathode, respectively. The cells were tested in a no-chamber (direct-flame) setup evaluating electrochemical performance and shock thermal resistance. Open circuit voltage was 830 mV at 560°C using methanol as fuel in a burner with porous media to modify the shape of the flame. Cells were also strong enough to resist the rapid temperature changes during several no-chamber tests. [ABSTRACT FROM AUTHOR]

In this paper different kinds of Solid Oxide Fuel Cells (SOFC) and their operating principles are presented. In terms of internal structure, SOFC can be classified into three categories: dual-chamber, single-chamber and no-chamber cells. Electrochemical performance is compared based on information available in the literature and advantages and disadvantages are established. Typical values of maximum power density (Pmax) and current density at Pmax are respectively: ∼ 1000 mW/cm²and ∼ 2000 mA/cm² for dual-chamber cells, ∼ 336 mW/cm² and ∼ 770 mA/cm² for singlechamber cells, and ∼ 210 mW/cm² and ∼ 440 mA/cm² for no-chamber cells. Although the electrochemical performance of the single- and no-chamber cells is lower than the dual-chamber cells, the operating advantages given are enough to consider them as viable alternative designs. Finally, are presented preliminary results of a new design of a no-chamber cell with a burner of porous media coupled with the fuel cell. [ABSTRACT FROM AUTHOR]

Today, thanks to global positioning systems technologies and mobile devices equipped with tracking sensors, and a lot of data about moving objects can be collected, e.g., spatio-temporal data related to the movement followed by objects. On the other hand, data warehouses, usually modeled using a multidimensional view of data, are specialized databases to support the decision-making process. Unfortunately, conventional data warehouses are mainly oriented to manage alphanumeric data. In this article, we incorporate temporal elements to a conceptual spatial multidimensional model resulting in a spatio-temporal multidimensional model. We illustrate our proposal with a case study related to animal migration. [ABSTRACT FROM AUTHOR]

Global support radial base functions are effective in eliminating impulsive noise in non-linear processing. This paper introduces an interpolation technique which efficiently reduces image impulsive noise by means of an interpolant obtained through radial base functions. These functions have been used in a research project designed to develop a system for the recovery of images of Amazonian aquatic resources. This technique starts with the tagging by interpolation of noisy image pixels. Thus, a value of reconstruction for the noisy pixels is generated using neighboring pixels. The results obtained with this technique have proved comparable and often better than those obtained with previously known techniques. According to results analysis, this technique can be successfully applied on images with high noise levels. The results are low error in noisy pixel reconstruction and better visual quality. [ABSTRACT FROM AUTHOR]

In Information Retrieval Systems, Image Retrieval Systems are located; they allow generating searching and storing processes of resources through coincidences by key words or other real-time methods. This type of systems can use visual content of images (color, texture, and brightness) as indices. In addition, these systems combine different attributes to improve the processes of classification and relevance of the searching process results known as "Information Quality." This paper presents the modeling of a Image Retrieval System which combines attributes of the contentbased retrieval such as color, texture, and shape, with the Information Quality-based retrieval as updating portability and relevance frequency in the context of Digital Image Collection of Aquatic Amazon Ecosystems of Universidad del Amazonia CAPREA Research Group. [ABSTRACT FROM AUTHOR]

The article focuses on a study that demonstrates that Ewing tumor cell lines and patient samples express high levels of both granulocyte-colony-stimulating factor (G-CSF) and its receptor (G-CSFR). It notes that G-CSF is a cytokine known to stimulate bone marrow (BM) stem cell production and angiogenesis and is routinely administered to ES patients after chemotherapy. It suggests that the potential consequences of G-CSF administration should be investigated further.

This article presents a compilation of the researches carried on the image recovery from web digital collections, based upon their contents and data quality management. Using this state-of-the-art study as a support, the article presents a methodological proposal to design and implement a system prototype in image recovery that uses these two search techniques; and finally the article presents the progress achieved in developing this proposal. [ABSTRACT FROM AUTHOR]

Abstract: Supermarkets are great energy users in many countries. The potential for increased energy efficiency is large. One option is to utilize heat recovery (or heat reclaim) from condensers to heat the premises. Obviously this option is only interesting in relatively cold areas such as northern Europe, Canada, etc. An alternative to heat recovery is floating condensing pressure, which improves the coefficient of performance and decreases the energy consumption of the refrigeration system at lower outdoor temperature. Both heat recovery and floating condensing pressure can be utilized interchangeably depending on the heat requirements of the premises. A computer model that calculates the energy consumption in a supermarket with the possibility to simulate different system solutions for the refrigeration system has been developed at the Royal Institute of Technology, Department of Energy Technology. The software “CyberMart” is used in the present study to compare the potential of heat recovery and floating condensing in Swedish supermarkets. Measurements of different parameters such as temperatures, relative humidity and compressor power have been carried out in different supermarkets with heat recovery to validate the theoretical calculations. The present study shows that heating requirements can be covered completely by heat reclaim from the condenser. However, practical experiences show that installations are less efficient due to poor system solutions and/or control strategies. According to the results from CyberMart, the highest potential of energy saving is obtained from using a systems solution with both heat recovery and floating condensing. [Copyright &y& Elsevier]

In this paper we present a method that permits the reduction of redundant information in range images using radial base functions and we indicate how these functions permit a continuous surface without holes or superposition when the images are integrated in a common system of coordinates. [ABSTRACT FROM AUTHOR]

Abstract: A series of palladium thiolate complexes of the [Pd(Ph2PC6H4-2-(CH2NMe2))(SRF)2] type have been synthesized in good yields by metathetical reactions of [Pd(Ph2PC6H4-2-(CH2NMe2))Cl2] (1) with [Pb(SRF)2], (SRF = C6F5, C6F4-4-H, C6H4-2-CF3, C6H4-4-F, C6H4-2-F) and their crystal structures determined. Heck coupling reactions were carried out using [Pd(Ph2PC6H4-2-(CH2NMe2))(SRF)2], SRF = C6F5 (2), C6F4-4-H (3), C6H4-2-CF3 (4), C6H4-4-F (5), C6H4-2-F (6) complexes as catalysts in order to examine the effect of the thiolates in the reaction of bromobenzene and styrene. The results obtained indicate that the less electron-withdrawing substituents on the thiolate moiety may favor higher yields in the Pd catalyzed Heck reaction using [Pd(Ph2PC6H4-2-(CH2NMe2))(SRF)2] as catalysts. [Copyright &y& Elsevier]

A steady-state equilibrium-stage model based on normalized MESH equations is proposed to simulate saline extractive distillation columns and applied to the production of absolute ethanol, using CaCl2 to break the ethanol–water azeotrope. Among the activity coefficient models available for mixed solvent/salt systems, the NRTL-E model (with refitted parameters), is shown to be the most accurate to correlate the experimental vapor–liquid equilibrium (VLE) data available for the ethanol/water/CaCl2 system. A model is proposed and implemented to calculate the salt contribution to the liquid phase enthalpy by combining calorimetric quantities of the solute such as its relative apparent enthalpy and the infinite dilution values of its integral heat of solution and partial isobaric heat capacity. The column model is solved by use of the Newton–Raphson method with a damping factor found by minimizing the Euclidean norm of the vector of discrepancy functions associated with the MESH equations. [Copyright &y& Elsevier]

Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence in humans remains scarce, requiring improved non-invasive techniques and integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators and incorporating resting-state functional MRI, amyloid-β (Aβ) and tau-PET from 132 individuals in the AD spectrum to evaluate the direct impact of toxic protein deposition on neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) and grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show the hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aβ-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental activation phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions. Personalized brain activity models in Alzheimer's disease detect synergistic amyloid-β and tau impacts on neuronal excitability values, which significantly predict brain atrophy, p-tau217 plasma concentrations, and cognitive deterioration. [ABSTRACT FROM AUTHOR]

Females are disproportionately affected by dementia due to Alzheimer's disease. Despite a similar amyloid-β (Aβ) load, a higher load of neurofibrillary tangles (NFTs) is seen in females than males. Previous literature has proposed that Aβ and phosphorylated-tau (p-tau) synergism accelerates tau tangle formation, yet the effect of biological sex in this process has been overlooked. In this observational study, we examined longitudinal neuroimaging data from the TRIAD and ADNI cohorts from Canada and USA, respectively. We assessed 457 participants across the clinical spectrum of Alzheimer's disease. All participants underwent baseline multimodal imaging assessment, including MRI and PET, with radioligands targeting Aβ plaques and tau tangles, respectively. CSF data were also collected. Follow-up imaging assessments were conducted at 1- and 2-year intervals for the TRIAD cohort and 1-, 2- and 4-year intervals for the ADNI cohort. The upstream pathological events contributing to faster tau progression in females were investigated—specifically, whether the contribution of Aβ and p-tau synergism to accelerated tau tangle formation is modulated by biological sex. We hypothesized that cortical Aβ predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings revealed that Aβ-positive females presented higher CSF p-tau181 concentrations compared with Aβ-positive males in both the TRIAD (P = 0.04, Cohen's d = 0.51) and ADNI (P = 0.027, Cohen's d = 0.41) cohorts. In addition, Aβ-positive females presented faster NFT accumulation compared with their male counterparts (TRIAD: P = 0.026, Cohen's d = 0.52; ADNI: P = 0.049, Cohen's d = 1.14). Finally, the triple interaction between female sex, Aβ and CSF p-tau181 was revealed as a significant predictor of accelerated tau accumulation at the 2-year follow-up visit (Braak I: P = 0.0067, t = 2.81; Braak III: P = 0.017, t = 2.45; Braak IV: P = 0.002, t = 3.17; Braak V: P = 0.006, t = 2.88; Braak VI: P = 0.0049, t = 2.93). Overall, we report sex-specific modulation of cortical Aβ in tau phosphorylation, consequently facilitating faster NFT progression in female individuals over time. This presents important clinical implications and suggests that early intervention that targets Aβ plaques and tau phosphorylation may be a promising therapeutic strategy in females to prevent the further accumulation and spread of tau aggregates. [ABSTRACT FROM AUTHOR]

The editorial analyzes the research on Portal hypertension in patients with chronic liver diseases, characterized by an increase in portal pressure and the development of portal-systematic collateral circulation. An overview of the research done by Chan et. al, and its correlation with other studies is narrated. Information on trophic properties and significance of the portal-systematic collateral circulation is presented to highlight the pathophysiology of portal hypertension.

Background and objective. Complications related to implant-based breast surgery are a potential safety issue due to its high incidence. Implant displacement is one of these complications that has been associated to frequent revision surgery. However, there is a lack of information about the characteristics and epidemiology of this condition. The aim of this study is to research in the scientific literature and propose a displacement classification. Methods. A literature review was done by using the keywords: Implant displacement, complications and breast implants, looking for publications about complications in breast surgery including implant displacement and the associated factors. Results. We found 186 publications of which 8 were included, with a total of 29.917 patients, age ranged from 14 to 77 and a follow up time from 0.1 to 34 years; 97.55% were silicone implants, 1% saline and 1% with no information. The smooth surface was used in 19.01% and textured in 79.63%. Subglandular approach was used from 5.7% to 73.3% of the cases, subpectoral from 5.4% to 80%, subfascial plane was used in 725 subjects in 1 study, and dual plane was used in 2 studies with 16.7% and 56.6%. Implant size was reported from 50 up to 800 cc. The reported displacement was between 0.3 up to 16.6% with a mean of 5.26% Conclusions. There is heterogeneity in the diagnosis and the reported outcomes, and a lack of a standard definition and diagnosis of the displacement. Implant displacement has been accused of being one of the first causes for revision in breast surgery, however, there is a lack of clinical studies that estimate the frequency of presentation and the related factors. A classification tool to assess the displacement is critical to standardize the outcomes and improve the quality of the studies. [ABSTRACT FROM AUTHOR]

Introduction: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. Methods: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ( ζ / δ ) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. Results: 14-3-3 ζ / δ was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 ζ / δ correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. Conclusions: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation. [ABSTRACT FROM AUTHOR]

Patients with cold agglutinin disease (CAD) experience fatigue and poor quality of life. However, previous CAD-related studies have not explored patient-reported outcomes such as the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Sutimlimab, a C1s complement inhibitor, has been shown to halt haemolysis in CAD. Here, we present 26-weeks' patient-reported data from CARDINAL Part A (ClinicalTrials.gov, NCT03347396), which assessed efficacy and safety of sutimlimab in patients with CAD and recent history of transfusion. Aside from measuring changes in haemolytic markers, FACIT-Fatigue was measured at the treatment assessment timepoint (TAT; average of weeks 23, 25, and 26). Exploratory endpoints included the change in EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) and the 12-Item Short Form Health Survey (SF-12) at TAT, and Patient Global Impression of Change (PGIC), and Patient Global Impression of (fatigue) Severity (PGIS) at week 26. Mean (range) FACIT-Fatigue scores increased from 32.5 (14.0-47.0) at baseline (a score indicative of severe fatigue) to 44.3 (28.0-51.0) at TAT. Considerable improvements were reported for EQ-5D-5L at TAT, SF-12 scores at TAT, and PGIC and PGIS scores at week 26. Sutimlimab treatment resulted in sustained improvements in symptoms of fatigue and overall quality of life in patients with CAD. NCT03347396. Registered 20 November, 2017. [ABSTRACT FROM AUTHOR]

Background and purpose: Abnormal mitochondrial metabolism has been described in the Alzheimer's disease (AD) brain. However, the relationship between AD pathophysiology and key mitochondrial processes remains elusive. The purpose of this study was to investigate whether mitochondrial complex I dysfunction is associated with amyloid aggregation or glucose metabolism and brain atrophy in patients with mild AD using positron emission tomography (PET). Methods: Amyloid‐ and tau‐positive symptomatic AD patients with clinical dementia rating 0.5 or 1 (N = 30; mean age ± standard deviation: 71.8 ± 7.6 years) underwent magnetic resonance imaging and PET scans with [18F]2‐tert‐butyl‐4‐chloro‐5–2H‐pyridazin‐3‐one (BCPP‐EF), [11C]Pittsburgh Compound‐B (PiB) and [18F]fluorodeoxyglucose (FDG) to assess brain atrophy, mitochondrial complex I dysfunction, amyloid deposition, and glucose metabolism, respectively. Local cortical associations among these biomarkers and gray matter volume were evaluated with voxel‐based regressions models. Results: [18F]BCPP‐EF standardized uptake value ratio (SUVR) was positively correlated with [18F]FDG SUVR in the widespread brain area, while its associations with gray matter volume were restricted to the parahippocampal gyrus. Reductions in [18F]BCPP‐EF SUVR were associated with domain‐specific cognitive performance. We did not observe regional associations between mitochondrial dysfunction and amyloid burden. Conclusions: In symptomatic cases, although mitochondrial complex I reduction is linked to a wide range of downstream neurodegenerative processes such as hypometabolism, atrophy, and cognitive decline, a link to amyloid was not observable. The data presented here support [18F]BCPP‐EF as an excellent imaging tool to investigate mitochondrial dysfunction in AD. [ABSTRACT FROM AUTHOR]

Background: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia mediated by immunoglobulin M autoantibodies that bind to the "I" antigen on erythrocytes. IgM binding results in either agglutination at ≤37°C, activation of the classical complement pathway, or both. Patients with CAD can have transient agglutination‐mediated circulatory symptoms triggered by exposure to cold conditions. Separately, patients with CAD can experience complement‐mediated symptoms such as anemia, hemolysis, and fatigue, but the effect of the season on these complement‐mediated manifestations of CAD and clinical outcomes is not well understood. Methods: Using data from the Optum® de‐identified Electronic Health Record dataset, we compared hemoglobin, markers of hemolysis (bilirubin and lactate dehydrogenase [LDH]), and healthcare resource utilization (HRU) between seasons for 594 patients (62% female; 66% aged ≥65 years) with CAD (defined as having CAD‐related terms in their clinical notes on ≥3 separate occasions between December 2008 and May 2016). Laboratory parameters and HRU were compared between seasons using multivariate regression models. Results: Estimated median hemoglobin (9.87 g/dL in summer and 9.86 g/dL in winter; P = 0.944) and bilirubin (1.04 mg/dL in summer and 1.09 mg/dL in winter; P = 0.257) were similar in winter versus summer. While LDH was statistically significantly higher in winter compared with summer (P < 0.001), the estimated median value was above normal for both seasons (309 U/L in summer and 367 U/L in winter). HRU measures and transfusion and thromboembolism rates were similar across seasons. Conclusions: Patients with CAD had evidence of persistent chronic hemolysis, HRU, and thromboembolism risk year round. See article on page 2–10, in this issue [ABSTRACT FROM AUTHOR]

Portal hypertension is a major complication of cirrhosis that frequently leads to a neuropsychiatric disorder that affects cognition. The present study was undertaken in order to compare the performance of sham-operated rats (SHAM) and portal hypertension rats (PH) in reference memory tasks in the Morris water maze (MWM). Two groups of animals were used: SHAM group ( n = 12) was used as a control group and PH group ( n = 12) by the triple portal vein ligation method was used as an animal model of early evolutive phase of PH. The portal pressure was measured in the splenic parenchyma. Our work shows that spatial learning in the MWM is not impaired in PH group although this group showed a one-day delay in the task acquisition compared to the SHAM group. We assessed the brain metabolic activity of the animals by means of cytochrome c-oxidase (COx) histochemistry. Significant changes were found in the CA3, dentate gyrus, basolateral, medial, lateral and central amygdala, showing lower COx activity in the PH group as compared to the SHAM group in all cases. We found no changes in metabolic activity in prefrontal cortex and CA1 area between groups. In fact, different neural networks were shown according to the execution level of the subjects. The early PH evolution induced changes in brain metabolic activity without biggest alterations in spatial memory. [ABSTRACT FROM AUTHOR]

Today, thanks to global positioning systems and mobile devices equipped with sensors, it is possible to capture information about the trajectory followed by moving objects such as persons, animals, and vehicles, among others. In this paper we analyze, in particular, the trajectories followed by moving objects on a predefined route, as in the case of a public transport system, in which vehicles should travel by a predetermined route. We present a case study where this type of trajectories are incorporated as a subject of analysis in a data warehouse. [ABSTRACT FROM AUTHOR]

Tetrapyrrole molecules are distributed in virtually all living organisms on Earth. In mammals, tetrapyrrole end products are closely linked to oxygen metabolism. Since increasingly complex trophic functional systems for using oxygen are considered in the post-traumatic inflammatory response, it can be suggested that tetrapyrrole molecules and, particularly their derived pigments, play a key role in modulating inflammation. In this way, the diverse colorfulness that the inflammatory response triggers during its evolution would reflect the major pathophysiological importance of these pigments in each one of its phases. Therefore, the need of exploiting this color resource could be considered for both the diagnosis and treatment of the inflammation. [ABSTRACT FROM AUTHOR]

Background: Inflammation is increasingly recognized as an important component of tumorigenesis, although the mechanisms involved are not fully characterized. The invasive capacity of cancers is reflected in the classic metastatic cascade: tumor (T), node (N) and metastasis (M). However, this staging system for cancer would also have a tumoral biological significance. Presentation of the hypothesis: To integrate the mechanisms that control the inflammatory response in the actual staging system of cancer. It is considered that in both processes of inflammation and cancer, three successive phenotypes are presented that represent the expression of trophic functional systems of increasing metabolic complexity for using oxygen. Testing the hypothesis: While a malignant tumor develops it express phenotypes that also share the inflammatory response such as: an ischemic phenotype (anoxic-hypoxic), a leukocytic phenotype with anaerobic glycolysis and migration, and an angiogenic phenotype with hyperactivity of glycolytic enzymes, tumor proliferation and metastasis, and cachexia of the host. The increasing metabolic complexity of the tumor cell to use oxygen allows for it to be released, migrate and proliferate, thus creating structures of growing complexity. Implication of the hypothesis: One aim of cancer gene therapy could be the induction of oxidative phosphorylation, the last metabolic step required by inflammation in order to differentiate the tissue that it produces. [ABSTRACT FROM AUTHOR]

Portal hypertension is a clinical syndrome that is difficult to study in an isolated manner since it is always associated with a greater or lesser degree of liver functional impairment. The aim of this review is to integrate the complications related to chronic liver disease by using both, the array of mast cell functions and mediators, since they possibly are involved in the pathophysiological mechanisms of these complications. The portal vein ligated rat is the experimental model most widely used to study this syndrome and it has been considered that a systemic inflammatory response is produced. This response is mediated among other inflammatory cells by mast cells and it evolves in three linked pathological functional systems. The nervous functional system presents ischemia-reperfusion and edema (oxidative stress) and would be responsible for hyperdynamic circulation; the immune functional system causes tissue infiltration by inflammatory cells, particularly mast cells and bacteria (enzymatic stress) and the endocrine functional system presents endothelial proliferation (antioxidative and antienzymatic stress) and angiogenesis. Mast cells could develop a key role in the expression of these three phenotypes because their mediators have the ability to produce all the aforementioned alterations, both at the splanchnic level (portal hypertensive enteropathy, mesenteric adenitis, liver steatosis) and the systemic level (portal hypertensive encephalopathy). This hypothetical splanchnic and systemic inflammatory response would be aggravated during the progression of the chronic liver disease, since the antioxidant ability of the body decreases. Thus, a critical state is produced, in which the appearance of noxious factors would favor the development of a dedifferentiation process protagonized by the nervous functional system. This system rapidly induces an ischemia-reperfusion phenotype with hydration and salinization of the body (hepatorenal syndrome, ascites) which, in turn would reduce the metabolic needs of the body and facilitate its temporary survival. [ABSTRACT FROM AUTHOR]

Background: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway.Methods: We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol.Results: A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred.Conclusions: In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.). [ABSTRACT FROM AUTHOR]

Background: To investigate the association of plasma pTau181, assessed with a new immunoassay, with neurodegeneration of white matter and gray matter cross-sectionally and longitudinally, in aging and Alzheimer's disease. Methods: Observational data was obtained from the Alzheimer's Disease Neuroimaging Initiative, in which participants underwent plasma assessment and magnetic resonance imaging. Based on their clinical diagnosis, participants were classified as cognitively unimpaired and cognitively impaired. Linear regressions and linear mixed-effect models were used to test the cross-sectional and longitudinal associations between baseline plasma pTau181 and neurodegeneration using voxel-based morphometry. Results: We observed a negative correlation at baseline between plasma pTau181 and gray matter volume in cognitively unimpaired individuals. In cognitively impaired individuals, we observed a negative association between plasma pTau181 and both gray and white matter volume. In longitudinal analyses conducted in the cognitively unimpaired group, plasma pTau181 was negatively correlated with gray matter volume, starting 36 months after baseline assessments. Finally, in cognitively impaired individuals, plasma pTau181 concentrations were negatively correlated with both gray and white matter volume as early as 12 months after baseline, and neurodegeneration increased in an incremental manner until 48 months. Conclusions: Higher levels of plasma pTau181 correlate with neurodegeneration and predict further brain atrophy in aging and Alzheimer's disease. Plasma pTau181 may be useful in predicting AD-related neurodegeneration, comparable to positron emission tomography or cerebrospinal fluid assessment with high specificity for AD neurodegeneration. [ABSTRACT FROM AUTHOR]

Abstract: The Center for Educational Development in Health (CEDH) field tested its text, Systematic Course Design for the Health Fields. a manual on the application of competency-based curriculum development techniques. A competency-based approach to curriculum design derives instructional objectives, content, and evaluation from the on-the-job responsibilities for the health worker being trained. For purpose of the field test, ten national field directors from Cameroon, Colombia, Honduras, Lebanon, Malaysia, Nepal, and Vietnam trained by CEDH in Boston taught teacher training workshops based on the Systematic Course Design (SCD) model to a range of health professionals in their own countries. The purpose of the field test was to ascertain whether the systematic course design method was applicable in developing countries. Evaluation of the teacher training workshops was conducted during and immediately after instruction, and again a year later. Men and women numbering 167, representing a range of 29 health professions, participated in the workshops. Participants designed 132 courses based on the SCD model and taught 54 courses to about 2,000 students. In Colombia, Honduras, Malaysia, and Lebanon, the national field directors applied the method to a range of activities. During 1975 and 1976 (the period of study) they taught 11 additional teacher training workshops on SCD to 140 health professionals, developed and taught 11 courses themselves, and provided consultation to 12 other health professional schools and governmental agencies... [ABSTRACT FROM AUTHOR]

Chronic inflammatory liver disease with an acute deterioration of liver function is named acute-on-chronic inflammation and could be regulated by the metabolic impairments related to the liver dysfunction. In this way, the experimental cholestasis model is excellent for studying metabolism in both types of inflammatory responses. Along the evolution of this model, the rats develop biliary fibrosis and an acute-on-chronic decompensation. The acute decompensation of the liver disease is associated with encephalopathy, ascites, acute renal failure, an acute phase response and a splanchnic increase of pro- and anti-inflammatory cytokines. This multiorgan inflammatory dysfunction is mainly associated with a splanchnic and systemic metabolic switch with dedifferentiation of the epithelial, endothelial and mesothelial splanchnic barriers. Furthermore, a splanchnic infiltration by mast cells occurs, which suggests that these cells could carry out a compensatory metabolic role, especially through the modulation of hepatic and extrahepatic mitochondrial-peroxisome crosstalk. For this reason, we propose the hypothesis that mastocytosis in the acute-on-chronic hepatic insufficiency could represent the development of a survival metabolic mechanisms that mitigates the noxious effect of the hepatic functional deficit. A better understanding the pathophysiological response of the mast cells in liver insufficiency and portal hypertension would help to find new pathways for decreasing the high morbidity and mortality rate of these patients. [ABSTRACT FROM AUTHOR]

Abstract We propose that the circulatory impairments produced, in both portal hypertension and liver cirrhosis, to a certain degree resemble those characterizing prenatal life in the fetus. In fact, the left-right circulatory syndrome is common in cirrhotic patients and in the fetus. Thus, in patients with portal hypertension and chronic liver failure, the re-expression of a blood circulation comparable to fetal circulation is associated with the development of similar amniotic functions, i.e., ascites production and placenta functions, and portal vascular enteropathy. Therefore, these re-expressed embryonic functions are extra-embryonic and responsible for prenatal trophism and development. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy is a severe complication of both chronic and acute liver diseases. The term hepatic encephalopathy stems from the belief that hepatic insufficiency is its fundamental etiopathogenic factor. However, most clinical cases show liver failure along with mesenteric venous portal hypertension. This portal hypertension would explain the abnormal mechanical forces suffered by the digestive tract in the early stages of the disorder. These forces could regulate some gut biochemical pathological pathways in a process known as mechanotransduction. Thus, portal hypertension would begin with the establishment of a mechanotransduced afferent or sensory inflammatory gut‐brain pathway, resulting in functional and structural changes in the central nervous system. In this review, we will revisit the term "hepatic encephalopathy" in light of new results where portal hypertension occurs before liver failure and is accompanied by brain changes. Moreover, we will point out cellular links that can explain the microbiota, immune, gut, and brain axis disturbances found in this disorder. [ABSTRACT FROM AUTHOR]

Background: In mammals, inflammation is required for wound repair and tumorigenesis. However, the events that lead to inflammation, particularly in non-healing wounds and cancer, are only partly understood.Findings: Mast cells, due to their great plasticity, could orchestrate the inflammatory responses inducing the expression of extraembryonic programs of normal and pathological tissue formation. This heterogeneity of mast cells could allow a microenvironment to be recreated similar to the extraembryonic structures, i.e., amnion and yolk sac, which are needed for embryonic development. Mast cells could provide a framework for understanding the connection between inflammation and tumor growth, invasion and metastasis. In this way, the mast cells could express inflammatory phenotypes, which would enable the cancer stem cells to develop. Thus, the cancer cell uses mast cells to express the extraembryonic functions that are needed to allow the cancer stem cell to proliferate and invade. If so, then by using this appropriate inflammatory interstitial microenvironment, a cancer stem cell can reach maximum levels of growth and invasion inside the host.Conclusion: Therefore, the comparison of tumors with wounds that do not heal would be supported since both pathological processes use extraembryonic mechanisms by mast cells. The adoption of these mechanisms warrants tumor survival in an embryonic-like state. [ABSTRACT FROM AUTHOR]

The inflammatory response expressed after wound healing would be the recapitulation of systemic extra-embryonic functions, which would focus on the interstitium of the injured tissue. In the injured tissue, mast cells, provided for a great functional heterogeneity, could play the leading role in the re-expression of extra-embryonic functions, i.e., coelomic-amniotic and trophoblastic-vitelline. Moreover, mast cells would favor the production of a gastrulation-like process, which in certain tissues and organs would induce the regeneration of the injured tissue. Therefore, the engraftment of mesenchymal stem cells and mast cells, both with an extra-embryonic regenerative phenotype, would achieve a blastema, from the repaired and regenerated injured tissue, rather than by fibrosis, which is commonly made through wound-healing. [ABSTRACT FROM AUTHOR]

A serious complication of chronic hepatic insufficiency is acute-on-chronic liver failure, a recognized syndrome characterized by acute decompensation of cirrhosis and organ/system failure. We investigated the use of adipose-derived mesenchymal stem cells (AD-MSCs) in an experimental model of acute-on-chronic liver failure, developed by microsurgical extrahepatic cholestasis in rats. Rats undergoing microsurgical extrahepatic cholestasis were treated by intraparenchymal liver injection of human or rat AD-MSCs, undifferentiated or previously differentiated in vitro toward the hepatocyte lineage. The groups treated with rat AD-MSCs showed less ascites, lower hepato- and splenomegaly, less testicular atrophy, and an improvement in serum biochemical hepatic parameters. There was also an improvement in histological liver changes, in which the area of fibrosis and bile duct proliferation were significantly decreased in the group treated with predifferentiated rat AD-MSCs. In conclusion, an isograft of hepatocyte-predifferentiated AD-MSCs injected intraparenchymally 2 weeks after microsurgery in extrahepatic cholestatic rats prevents secondary complications of acute-on-chronic hepatic failure. These data support the potential use of autologous AD-MSCs in the treatment of human cholestasis, and specifically of newborn biliary atresia, which could be beneficial for patients awaiting transplant. [ABSTRACT FROM AUTHOR]

Background & aims Minimal hepatic encephalopathy (mHE) has been shown to affect daily functioning, quality of life, driving and overall mortality. However, little is known about treating or diagnosing early impairments in mHE. We studied one of its precipitating factors, portal hypertension which is driving the inflammatory process behind mHE. The purpose was to describe an indirect diagnostic method able to detect the pathology at early stages based on the study of the vascularization and mast cells conjunctival hyperplasia as secondary inflammatory response associated to portal hypertension. Finally, we correlated the presence of histological changes in the eye in mHE with deficits in behavioral task acquisition. Methods Rats were trained on a stimulus-response task and a spatial working memory task using the Morris water maze. Two groups of animals were used: a SHAM (sham-operated) group (n = 10) and a portal hypertension (HT) group (n = 10). The triple portal vein ligation method was used to create an animal model of mHE. Latencies to reach the platform, number of glial fibrillary acidic protein-immunoreactive astrocytes (GFAP-IR), mast cell expression and presence/absence of blood and lymphatic vessels were examined. Results There were differences in stimulus-response behavioral performance, with a deficit in the acquisition in the HT group. However, no differences between groups were found on the spatial working memory task. At the same time, differences between groups were found in the GFAP-IR density, which was lower in the HT group, and in the number of mast cells and the presence of vessels, which were higher in the HT group. Conclusions In this study, we provide the first preliminary insight into the validity of exploring the eye as a possible tool to assess the diagnosis of mHE conditions. [ABSTRACT FROM AUTHOR]

This paper investigates problem areas related to energy efficiency implementation in Swedish multifamily buildings. The paper first presents a generic list of (theoretical) problem areas identified through a literature survey. Using a qualitative approach, the paper also investigates if the problem areas identified in the literature also have an impact on the Swedish building sector. Results from the interview study reveal a strong coherence between problem areas in the literature and those expressed by the interviewees. However, this paper identifies seven novel challenges that cannot be derived from the list of barriers in the literature. Moreover, results reveal that as many as 12 problem areas have their origin in national factors such as agreement structures, incentive schemes, and cost calculation methods. [ABSTRACT FROM AUTHOR]

A technique for tying the surgeon's knot is explained. This is based on considering that the active hand has two clasps, an inferior one formed by the thumb and the ring finger, which fixes the distal end of the ligature, and another superior clasp formed by the index and middle finger, whose rotating mobility makes it possible to wrap the proximal tips of the ligature around them one or more times and then to grasp the distal end and pull it through the proximal loops. [ABSTRACT FROM AUTHOR]

Cirrhosis is a common disease inWestern countries. Liver failure, hyperammonemia, and portal hypertension are themain factors that contribute to human cirrhosis that frequently leads to a neuropsychiatric disorder known as hepatic encephalopathy (HE). In this study, we examined the differential contribution of these leading factors to the oxidative metabolism of diverse brain limbic system regions frequently involved in memory process by histochemical labelling of cytochrome oxidase (COx). We have analyzed cortical structures such as the infralimbic and prelimbic cotices, subcortical structures such as hippocampus and ventral striatum, at thalamic level like the anterodorsal, anteroventral, and mediodorsal thalamus, and, finally, the hypothalamus, where the mammillary nuclei (medial and lateral) were measured. The severest alteration is found in the model that mimics intoxication by ammonia, followed by the thioacetamide-treated group and the portal hypertension group. No changes were found at the mammillary bodies for any of the experimental groups. [ABSTRACT FROM AUTHOR]

Cirrhosis is a common disease inWestern countries. Liver failure, hyperammonemia, and portal hypertension are themain factors that contribute to human cirrhosis that frequently leads to a neuropsychiatric disorder known as hepatic encephalopathy (HE). In this study, we examined the differential contribution of these leading factors to the oxidative metabolism of diverse brain limbic system regions frequently involved in memory process by histochemical labelling of cytochrome oxidase (COx). We have analyzed cortical structures such as the infralimbic and prelimbic cotices, subcortical structures such as hippocampus and ventral striatum, at thalamic level like the anterodorsal, anteroventral, and mediodorsal thalamus, and, finally, the hypothalamus, where the mammillary nuclei (medial and lateral) were measured. The severest alteration is found in the model that mimics intoxication by ammonia, followed by the thioacetamide-treated group and the portal hypertension group. No changes were found at the mammillary bodies for any of the experimental groups. [ABSTRACT FROM AUTHOR]

Abstract: Mast cells are involved in various liver diseases and appear to play a broader pathogenic role than originally thought. They may participate in the splanchnic alterations related to a porto-systemic shunt. To verify this hypothesis we studied the serum and hepatic histological changes in rats four weeks after an end-to-side portacaval shunt. In this experimental model of chronic liver insufficiency we also assessed the mucosal mast cells (MMC) and connective tissue mast cells (CTMC) in the liver, mesenteric lymph nodes and small intestine, as well as the serum levels of rat mast cell protease-II (RMCP-II). The results show liver and testes atrophy, with hypoalbuminemia (p =0.0001), hyperbilirubinemia (p =0.0001) and increase in aspartate aminotransferase (p =0.004) and alanine aminotransferase (p =0.0001). Hepatic histopathology demonstrates hepatocytic necrosis and apoptosis, portal inflammation, biliary proliferation, steatosis and fibrosis. There is a decrease of MMCs and CTMCs in the liver, while in the ileum CTMCs increase and MMCs decrease. These results suggest the involvement of mast cells in the pathophysiological splanchnic impairments in this experimental model. In particular, the decreased number of liver mast cells may be associated with the hepatic atrophy. If this is the case, we propose that the disruption of the hepato-intestinal axis after a portocaval shunt in the rat could inhibit the ability of the liver to developing an appropriate repair response mediated by mast cells. [Copyright &y& Elsevier]