Identification and Characterization of the Intra-Articular Microbiome in the Osteoarthritic Knee

Osteoarthritis (OA) is the most common joint disorder in the United States, and the gut microbiome has recently emerged as a potential etiologic factor in OA development. Recent studies have shown that a microbiome is present at joint synovia. Therefore, we aimed to characterize the intra-articular microbiome within osteoarthritic synovia and to illustrate its role in OA disease progression. RNA-sequencing data from OA patient synovial tissue was aligned to a library of microbial reference genomes to identify microbial reads indicative of microbial abundance. Microbial abundance data of OA and normal samples was compared to identify differentially abundant microbes. We computationally explored the correlation of differentially abundant microbes to immunological gene signatures, immune signaling pathways, and immune cell infiltration. We found that microbes correlated to OA are related to dysregulation of two main functional pathways: increased inflammation-induced extracellular matrix remodeling and decreased cell signaling pathways crucial for joint and immune function. We also confirmed that the differentially abundant and biologically relevant microbes we had identified were not contaminants. Collectively, our findings contribute to the understanding of the human microbiome, well-known OA risk factors, and the role microbes play in OA pathogenesis. In conclusion, we present previously undiscovered microbes implicated in the OA disease progression that may be useful for future treatment purposes.     

PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease

Non-alcoholic fatty liver disease (NAFLD) is characterized by an enhanced activation of the immune system, which predispose the evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Resident macrophages and leukocytes exert a key role in the pathogenesis of NAFLD. In particular, CD4+ effector T cells are activated during the early stages of liver inflammation and are followed by the increase of natural killer T cells and of CD8+ T cytotoxic lymphocytes which contribute to auto-aggressive tissue damage. To counteract T cells activation, programmed cell death 1 (PD-1) and its ligand PDL-1 are exposed respectively on lymphocytes and liver cells’ surface and can be targeted for therapy by using specific monoclonal antibodies, such as of Nivolumab, Pembrolizumab, and Atezolizumab. Despite the combination of Atezolizumab and Bevacizumab has been approved for the treatment of advanced HCC, PD-1/PD-L1 blockage treatment has not been approved for NAFLD and adjuvant immunotherapy does not seem to improve survival of patients with early-stage HCC. In this regard, different ongoing phase III trials are testing the efficacy of anti-PD-1/PD-L1 antibodies in HCC patients as first line therapy and in combination with other treatments. However, in the context of NAFLD, immune checkpoints inhibitors may not improve HCC prognosis, even worse leading to an increase of CD8+PD-1+ T cells and effector cytokines which aggravate liver damage. Here, we will describe the main pathogenetic mechanisms which characterize the immune system involvement in NAFLD discussing advantages and obstacles of anti PD-1/PDL-1 immunotherapy.     

Analyses of pressure perturbation events in boiling water reactor

In order to design more stable and safer core configurations, experimental and theoretical studies about BWR (Boiling Water Reactor) instability have been performed to characterize the phenomenon and to predict the conditions for its occurrence. The instabilities can be caused by interdependencies between thermal-hydraulic and reactivity feedback parameters such as the void-coefficient, for example, during a pressure perturbation event. In this work, the RELAP5-MOD3.3 thermal-hydraulic system code and the PARCS-2.4 3D neutron kinetic code were coupled to simulate BWR transients. The pressure perturbation is considered in order to study in detail this type of transient. Two different algorithms developed at the University of Pisa were used to calculate the Decay Ratio (DR) and the natural frequency (NF) from the power oscillation signals obtained from the transient calculations. The validation of a code model set up for the Peach Bottom-2 BWR plant is performed against Low-Flow Stability Tests (LFST). The four series of Stability Tests were performed at Peach Bottom Unit 2 in 1977 at the end of cycle 2 in order to measure the reactor core stability margins at the limiting conditions used in design and safety analysis.     

Simulation of an hypothetical out-of-phase instability case in boiling water reactor by RELAP5/PARCS coupled codes

A very complex type of power instability occurring in boiling water reactor (BWR) consists of out-of-phase regional oscillations, in which normally subcritical neutronic modes are excited by thermal-hydraulic feedback mechanisms. The out-of-phase mode of oscillation is a very challenging type of instability and its study is relevant because of the safety implications related to the capability to promptly detect any such inadvertent occurrence by in-core neutron detectors, thus triggering the necessary countermeasures in terms of selected rod insertion or even reactor shutdown. In this work, simulations of out-of-phase instabilities in a BWR obtained by assuming an hypothetical continuous control rod bank withdrawal are being presented. The RELAP5/Mod3.3 thermal-hydraulic system code coupled with the PARCS/2.4 3D neutron kinetic code has been used to simulate the instability phenomenon. Data from a real BWR nuclear power plant (NPP) have been used as reference conditions and reactor parameters. Simulated neutronic power signals from local power range monitors (LPRM) have been used to detect and study the local power oscillations. The decay ratio (DR) and the natural frequency (NF) of the power oscillations (typical parameters used to evaluate the instabilities) have been used in the analysis. The results are discussed also making use of two-dimensional plots depicting relative core power distribution during the transient, in order to clearly illustrate the out-of-phase behavior.     

On the imperfection of replacement

In this paper the replacement process for a N modules parallel structure is characterised by an imperfect nature.Intermediate series states are added to the state transition diagram such that a second procedure is now required to fully attain a complete regenerative process. This is quantified in term of the steady state availability.As an extention of the analysis, the effect of hard core components is presented. This has been proved that under certain circumstances it is not a necessary condition of degradation.     

Therapeutic engagements with children: Integrating infant research and clinical practice.

Integrates recent infant research and psychoanalytic practice with children. Babies seem more agentic and autonomous and more relationally sensitive and responsive than previously thought. When the child is viewed neither as victim and deprivant nor as a bundle of impulses that needs to be tamed, but as an agentic force within an interpersonal matrix, notions of what is central in treatment change accordingly. Central to work with children are the understanding and use of (1) transference and countertransference issues as they emerge both in fantasy play and more directly in relationship with the analyst and (2) issues of parental projective identification. Clinical examples of 2 boys (aged 4 and 7 yrs) and 2 girls (aged 5 and 8 yrs) are provided. (PsycINFO Database Record (c) 2010 APA, all rights reserved)