The Role of TNF-α and Anti-TNF-α Agents during Preconception,Pregnancy, and Breastfeeding

Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.     

The Potential Role of Small-Molecule PERK Inhibitor LDN-0060609 in Primary Open-Angle Glaucoma Treatment

Primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma. Emerging evidence suggests that Endoplasmic Reticulum (ER) stress and the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated Unfolded Protein Response (UPR) signaling pathway play a key role in POAG pathogenesis. Thus, the main aim of the study was to evaluate the effectiveness of the PERK inhibitor LDN-0060609 in cellular model of glaucoma using primary human trabecular meshwork (HTM) cells. To evaluate the level of the ER stress marker proteins, Western blotting and TaqMan gene expression assay were used. The cytotoxicity was measured by XTT, LDH assays and Giemsa staining, whereas genotoxicity via comet assay. Changes in cell morphology were assessed by phase-contrast microscopy. Analysis of apoptosis was performed by caspase-3 assay and flow cytometry (FC), whereas cell cycle progression by FC. The results obtained have demonstrated that LDN-0060609 triggered a significant decrease of ER stress marker proteins within HTM cells with induced ER stress conditions. Moreover, LDN-0060609 effectively increased viability, reduced DNA damage, increased proliferation, restored normal morphology, reduced apoptosis and restored normal cell cycle distribution of HTM cells with induced ER stress conditions. Thereby, PERK inhibitors, such as LDN-0060609, may provide an innovative, ground-breaking treatment strategy against POAG.     

Maximum throughput of multiple access channels in adversarial environments

We consider deterministic distributed broadcasting on multiple access channels in the framework of adversarial queuing. Packets are injected dynamically by an adversary that is constrained by the injection rate and the number of packets that may be injected simultaneously; the latter we call burstiness. A protocol is stable when the number of packets in queues at the stations stays bounded. The maximum injection rate that a protocol can handle in a stable manner is called the throughput of the protocol. We consider adversaries of injection rate 1, that is, of one packet per round, to address the question if the maximum throughput 1 can be achieved, and if so then with what quality of service. We develop a protocol that achieves throughput 1 for any number of stations against leaky-bucket adversaries. The protocol has O(n²+\textburstiness){\mathcal{O}(n^2+\text{burstiness})} packets queued simultaneously at any time, where n is the number of stations; this upper bound is proved to be best possible. A protocol is called fair when each packet is eventually broadcast. We show that no protocol can be both stable and fair for a system of at least two stations against leaky-bucket adversaries. We study in detail small systems of exactly two and three stations against window adversaries to exhibit differences in quality of broadcast among classes of protocols. A protocol is said to have fair latency if the waiting time of packets is O(\textburstiness){\mathcal{O}(\text{burstiness})}. For two stations, we show that fair latency can be achieved by a full sensing protocol, while there is no stable acknowledgment based protocol. For three stations, we show that fair latency can be achieved by a general protocol, while no full sensing protocol can be stable. Finally, we show that protocols that either are fair or do not have the queue sizes affect the order of transmissions cannot be stable in systems of at least four stations against window adversaries.     

Optimal Deterministic Broadcasting in Known Topology Radio Networks

We consider deterministic broadcasting in radio networks whose nodes have full topological information about the network. The aim is to design a polynomial algorithm, which, given a graph G with source s, produces a fast broadcast scheme in the radio network represented by G. The problem of finding a fastest broadcast scheme for a given graph is NP-hard, hence it is only possible to get an approximation algorithm. We give a deterministic polynomial algorithm which produces a broadcast scheme of length , for every n-node graph of diameter D, thus improving a result of Gąsieniec et al. (PODC 2005) [17] and solving a problem stated there. Unless the inclusion NP BPTIME( holds, the length of a polynomially constructible deterministic broadcast scheme is optimal.A preliminary version of this paper (with a weaker result) appeared in the Proc. 7th International Workshop on Approximation Algorithms for Combinatorial Optimization Problems (APPROX’2004), August 2004, Harvard University, Cambridge, USA, LNCS 3122, 171–182. Research of the second author supported in part by NSERC discovery grant and by the Research Chair in Distributed Computing of the Université du Québec en Outaouais. Part of this work was done during the second author’s visit at the Max-Planck-Institut für Informatik.     

An efficient algorithm for finding ideal schedules

We study the problem of scheduling unit execution time jobs with release dates and precedence constraints on two identical processors. We say that a schedule is ideal if it minimizes both maximum and total completion time simultaneously. We give an instance of the problem where the min-max completion time is exceeded in every preemptive schedule that minimizes total completion time for that instance, even if the precedence constraints form an intree. This proves that ideal schedules do not exist in general when preemptions are allowed. On the other hand, we prove that, when preemptions are not allowed, then ideal schedules do exist for general precedence constraints, and we provide an algorithm for finding ideal schedules in O(n ³) time, where n is the number of jobs. In finding such ideal schedules we resolve a conjecture of Baptiste and Timkovsky (Math. Methods Oper. Res. 60(1):145–153, 2004) Further, our algorithm for finding min-max completion-time schedules requires only O(n ³) time, while the most efficient solution to date has required O(n ⁹) time.     

Agent-based guided local search

The main contribution of the paper is to propose and validate a new hybrid approach for solving combinatorial optimization problems in which guided local search metaheuristic is incorporated into a cooperative multi-agent framework based on the concept of asynchronous teams (A-Teams). Generally, an A-Team assumes that a collection of software agents, each representing a particular problem solving method, cooperate to solve a problem by dynamically evolving a population of solutions. In the suggested implementation each software agent carries out a guided local search. The proposed approach has been extensively validated experimentally on one of the best known combinatorial optimization problem – the vehicle routing problem. The promising results of experiments have confirmed the effectiveness of the suggested approach.     

The Etiology of Cholelithiasis in Children and Adolescents—A Literature Review

The incidence of gallstone disease has increased in recent years. The pathogenesis of cholelithiasis is not fully understood. The occurrence of the disease is influenced by both genetic and environmental factors. This article reviews the literature on cholelithiasis in children, with the exception of articles on hematological causes of cholelithiasis and cholelithiasis surgery. The aim of this review is to present the latest research on the pathogenesis of gallstone disease in children. The paper discusses the influence of all factors known so far, such as genetic predisposition, age, infections, medications used, parenteral nutrition, and comorbidities, on the development of gallstone disease. The course of cholelithiasis in the pediatric population is complex, ranging from asymptomatic to life-threatening. Understanding the course of the disease and predisposing factors can result in a faster diagnosis of the disease and administration of appropriate treatment.     

Involvement of circRNAs in the Development of Heart Failure

In recent years, interest in non-coding RNAs as important physiological regulators has grown significantly. Their participation in the pathophysiology of cardiovascular diseases is extremely important. Circular RNA (circRNA) has been shown to be important in the development of heart failure. CircRNA is a closed circular structure of non-coding RNA fragments. They are formed in the nucleus, from where they are transported to the cytoplasm in a still unclear mechanism. They are mainly located in the cytoplasm or contained in exosomes. CircRNA expression varies according to the type of tissue. In the brain, almost 12% of genes produce circRNA, while in the heart it is only 9%. Recent studies indicate a key role of circRNA in cardiomyocyte hypertrophy, fibrosis, autophagy and apoptosis. CircRNAs act mainly by interacting with miRNAs through a “sponge effect” mechanism. The involvement of circRNA in the development of heart failure leads to the suggestion that they may be promising biomarkers and useful targets in the treatment of cardiovascular diseases. In this review, we will provide a brief introduction to circRNA and up-to-date understanding of their role in the mechanisms leading to the development of heart failure.     

Polyphenol-Enriched Composite Bone Regeneration Materials: A Systematic Review of In Vitro Studies

One of the possible alternatives for creating materials for the regeneration of bone tissue supporting comprehensive reconstruction is the incorporation of active substances whose controlled release will improve this process. This systematic review aimed to identify and synthesize in vitro studies that assess the suitability of polyphenolics as additives to polymer-ceramic composite bone regeneration materials. Data on experimental studies in terms of the difference in mechanical, wettability, cytocompatibility, antioxidant and anti-inflammatory properties of materials were synthesized. The obtained numerical data were compiled and analyzed in search of percentage changes of these parameters. The results of the systematic review were based on data from forty-six studies presented in nineteen articles. The addition of polyphenolic compounds to composite materials for bone regeneration improved the cytocompatibility and increased the activity of early markers of osteoblast differentiation, indicating a high osteoinductive potential of the materials. Polyphenolic compounds incorporated into the materials presumably give them high antioxidant properties and reduce the production of reactive oxygen species in macrophage cells, implying anti-inflammatory activity. The evidence was limited by the number of missing data and the heterogeneity of the data.