Cellular Infiltrates and NF kappa B Subunit c-Rel Signaling in Kidney Allografts of Patients With Clinical Operational Tolerance

Background. Nuclear factor kappa B (NF kappa B) plays a potential role in tolerance by orchestrating onset and resolution of inflammation and regulatory T cell differentiation through subunit c-Rel. We characterized cellular infiltrates and expression of NF kappa B1, c-Rel and its upstream regulators phosphatidylinositol 3-kinase/RAC-alpha serine/threonine kinase, in allograft biopsies from patients with spontaneous clinical operational tolerance (COT). Methods. Paraffin-fixed kidney allograft biopsies from 40 patients with COT (n=4), interstitial rejection (IR; n=12), borderline changes (BC; n=12), and long-term allograft function without rejection (NR; n=12) were used in the study. Cellular infiltrates and immunohistochemical expression of key proteins of the NF kappa B pathway were evaluated in the cortical tubulointerstitium and in cellular infiltrates using digital image analysis software. Results were given as mean +/- SEM. Results. Biopsies from patients with COT exhibited a comparable amount of cellular infiltrate to IR, BC, and NR (COT, 191 +/- 81; IR, 291 +/- 62; BC, 178 +/- 45; and NR, 210 +/- 42 cells/mm(2)) but a significantly higher proportion of forkhead box P3-positive cells (COT, 11%+/- 1.7%; IR, 3.5%+/- 0.70%; BC, 3.4%+/- 0.57%; and NR, 3.7%+/- 0.78% of infiltrating cells; P=0.02). c-Rel expression in cellular infiltrates was significantly elevated in IR, BC, and NR when analyzing the number of positive cells per mm(2) (P=0.02) and positive cells per infiltrating cells (P=0.04). In contrast, tubular PI3K and c-Rel expression were significantly higher in IR and BC but not in NR compared with COT (P=0.03 and P=0.006, respectively). With RAC-alpha serine-threonine kinase, similar tendencies were observed (P=0.2). Conclusions. Allografts from COT patients show significant cellular infiltrates but a distinct expression of proteins involved in the NF kappa B pathway and a higher proportion of forkhead box P3-positive cells.

Preserving the B-Cell Compartment Favors Operational Tolerance in Human Renal Transplantation

Transplanted individuals in operational tolerance (OT) maintain long-term stable graft function after completely stopping immunosuppression. Understanding the mechanisms involved in OT can provide valuable information about pathways to human transplantation tolerance. Here we report that operationally tolerant individuals display quantitative and functional preservation of the B-c ell compartment in renal transplantation. OT exhibited normal numbers of circulating total B cells, naive, memory and regulatory B cells (Bregs) as well as preserved B-cell receptor repertoire, similar to healthy individuals. In addition, OT also displayed conserved capacity to activate the cluster of differentiation 40 (CD40)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in Bregs, in contrast, with chronic rejection. Rather than expansion or higher activation, we show that the preservation of the B-cell compartment favors OT. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00281

GATA3 and a dominant regulatory gene expression profile discriminate operational tolerance in human transplantation

Some organ-transplanted patients achieve a state of "operational tolerance" (01) in which graft function is maintained after the complete withdrawal of immunosuppressive drugs. We used a gene panel of regulatory/inflammatory molecules (FOXP3, GATA3, 100, TGFB1, TGFBR1/TBX21, TNF and IFNG) to investigate the gene expression profile in peripheral blood mononuclear cells of renal-transplanted individuals experiencing OT compared to transplanted individuals not displaying OT and healthy individuals (HI). OT subjects showed a predominant regulatory (REG) profile with higher gene expression of GATA3, FOXP3, TGFB1 and TGFB receptor 1 compared to the other groups. This predominant REG gene expression profile displayed stability over time. The significant GATA3 gene and protein expressions in OT individuals suggest that a Th2 deviation may be a relevant pathway to OT. Moreover, the capacity of the REG/INFLAMMA gene panel to discriminate OT by peripheral blood analysis indicates that this state has systemic repercussions. (C) 2011 Elsevier Inc. All rights reserved.

The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients.

BACKGROUND Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. METHODS Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency. RESULTS One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still TOL. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death-censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively. CONCLUSIONS In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival.

Linfócitos T : uma análise do perfil diferencial da expressão gênica na imunorregulação

Tese (doutorado)—Universidade de Brasília, Faculdade de Medicina, Pós-Graduação em Patologia Molecular, 2016.

Impacto de los Niveles de Tacrolimus en el Rechazo al Injerto y la Tasa de Filtración Glomerular en Pacientes con Trasplante Hepático realizado en la FCI-IC entre 2009 y 2014

Introducción: El tacrolimus es el medicamento de elección para evitar el rechazo al injerto hepático. Su dosis se ajusta a partir de los niveles séricos que se toman periódicamente para asegurar rango terapéutico. Además, niveles elevados se asocian con disfunción renal postrasplante. Sin embargo, no hay consenso frente a los niveles adecuados para pacientes con trasplante hepático. Objetivo: Determinar la relación entre los niveles de tacrolimus y la presencia de rechazo agudo al injerto hepático en pacientes con trasplante hepático realizado en la Fundación Cardioinfantil – Instituto de Cardiología (FCI-IC). Determinar la relación entre los niveles de tacrolimus y la TFG en pacientes con trasplante hepático realizado en la FCI-IC. Métodos: Estudio observacional tipo cohorte histórica en pacientes adultos con trasplante hepático realizado en la FCI-IC entre 2009-2014. Resultados: No se encontró una asociación estadísticamente significativa entre los niveles de tacrolimus y la presencia de rechazo agudo, en sus diferentes definiciones (OR=1,02, p=0,14 y OR=1,01, p=0,29) incluso al ajustar por otras covariables (OR=1,03, p=0,10 y OR=1,02, p=0,25). No fue posible corroborar el diagnóstico con biopsia porque no todos la tenían. Si bien la relación entre los niveles de tacrolimus y la TFG fue estadísticamente significativa (p≤0,001), tiene bajo impacto clínico, pues la TFG disminuyó menos de un punto por cada incremento en 1 ng/ml en los niveles de tacrolimus. Conclusiones: Se necesitan más estudios para establecer la relación entre la exposición a tacrolimus y estos desenlaces para definir si es seguro disminuir su dosis con el fin de reducir los eventos adversos.

The effects of operational and design parameters on the tolerance of ADSR fuel pin cladding to beam interruptions

This paper investigates the effects of design parameters, such as cladding and coolant material choices, and operational phenomena, such as creep and fission product decay heat, on the tolerance of Accelerator Driven Subcritical Reactor (ADSR) fuel pin cladding to beam interruptions. This work aims to provide a greater understanding of the integration between accelerator and nuclear reactor technologies in ADSRs. The results show that an upper limit on cladding operating temperature of 550 °C is appropriate, as higher values of temperature tend to accelerate creep, leading to cladding failure much sooner than anticipated. The effect of fission product decay heat is to reduce significantly the maximum stress developed in the cladding during a beam-trip-induced transient. The potential impact of irradiation damage and the effects of the liquid metal coolant environment on the cladding are discussed. © 2013 Elsevier Ltd. All rights reserved.

Impact of gate-source/drain channel architecture on the performance of an operational transconductance amplifier (OTA)

In this work, we report on the significance of gate-source/drain extension region (also known as underlap design) optimization in double gate (DG) FETs to improve the performance of an operational transconductance amplifier (OTA). It is demonstrated that high values of intrinsic voltage gain (A(VO_OTA)) > 55 dB and unity gain frequency (f(T_OTA)) similar to 57 GHz in a folded cascode OTA can be achieved with gate-underlap channel design in 60 nm DG MOSFETs. These values correspond to 15 dB improvement in A(VO_OTA) and three fold enhancement in f(T_OTA) over a conventional non-underlap design. OTA performance based on underlap single gate SOI MOSFETs realized in ultra-thin body (UTB) and ultra-thin body BOX (UTBB) technologies is also evaluated. A(VO_OTA) values exhibited by a DG MOSFET-based OTA are 1.3-1.6 times higher as compared to a conventional UTB/UTBB single gate OTA. f(T_OTA) values for DG OTA are 10 GHz higher for UTB OTAs whereas a twofold improvement is observed with respect to UTBB OTAs. The simultaneous improvement in A(VO_OTA) and f(T_OTA) highlights the usefulness of underlap channel architecture in improving gain-bandwidth trade-off in analog circuit design. Underlap channel OTAs demonstrate high degree of tolerance to misalignment/oversize between front and back gates without compromising the performance, thus relaxing crucial process/technology-dependent parameters to achieve 'idealized' DG MOSFETs. Results show that underlap OTAs designed with a spacer-to-straggle (s/sigma) ratio of 3.2 and operated below a bias current (IBIAS) of 80 mu A demonstrate optimum performance. The present work provides new opportunities for realizing future ultra-wide band OTA design with underlap DG MOSFETs.

Fault tolerance logging-based model for deterministic systems

Fault tolerance allows a system to remain operational to some degree when some of its components fail. One of the most common fault tolerance mechanisms consists on logging the system state periodically, and recovering the system to a consistent state in the event of a failure. This paper describes a general fault tolerance logging-based mechanism, which can be layered over deterministic systems. Our proposal describes how a logging mechanism can recover the underlying system to a consistent state, even if an action or set of actions were interrupted mid-way, due to a server crash. We also propose different methods of storing the logging information, and describe how to deploy a fault tolerant master-slave cluster for information replication. We adapt our model to a previously proposed framework, which provided common relational features, like transactions with atomic, consistent, isolated and durable properties, to NoSQL database management systems.

The necessary alignment between technology innovation effectiveness and operational effectiveness

Organisations are increasingly investing in complex technological innovations such as enterprise information systems with the aim of improving the operations of the business, and in this way gaining competitive advantage. However, the implementation of technological innovations tends to have an excessive focus on either technology innovation effectiveness (also known as system effectiveness), or the resulting operational effectiveness; focusing on either one of them is detrimental to the long-term enterprise benefits through failure to achieve the real value of technological innovations. The lack of research on the dimensions and performance objectives that organisations must be focusing on is the main reason for this misalignment. This research uses a combination of qualitative and quantitative, three-stage methodological approach. Initial findings suggest that factors such as quality of information from technology innovation effectiveness, and quality and speed from operational effectiveness are important and significantly well correlated factors that promote the alignment between technology innovation effectiveness and operational effectiveness.

Workflow simulation for operational decision support

Simulation is widely used as a tool for analyzing business processes but is mostly focused on examining abstract steady-state situations. Such analyses are helpful for the initial design of a business process but are less suitable for operational decision making and continuous improvement. Here we describe a simulation system for operational decision support in the context of workflow management. To do this we exploit not only the workflow’s design, but also use logged data describing the system’s observed historic behavior, and incorporate information extracted about the current state of the workflow. Making use of actual data capturing the current state and historic information allows our simulations to accurately predict potential near-future behaviors for different scenarios. The approach is supported by a practical toolset which combines and extends the workflow management system YAWL and the process mining framework ProM.

The strategic and operational dimensions of staff training and professional development for information professionals : what neXus2 has revealed

The paper seeks to continue the debate about the need for professionals in the library and information services (LIS) sector to continually engage in career-long learning to sustain and develop their knowledge and skills in a dynamic industry. Aims: The neXus2 workforce study has been funded by the ALIA and the consortium of National and State Libraries Australasia (NSLA). It builds on earlier research work (the neXus census) that looked at the demographic, educational and career perspectives of individual library and information professions, to critically examine institutional policies and practices associated with the LIS workforce. The research aims to develop a clearer understanding of the issues impacting on workforce sustainability, workforce capability and workforce optimisation. Methods: The research methodology involved an extensive online survey conducted in March 2008 which collected data on organisational and general staffing; recruitment and retention; staff development and continuing professional education; and succession planning. Encouragement to participate was provided by key industry groups, including academic, public, health, law and government library and information agencies, with the result that around 150 institutions completed the questionnaire. Results: The paper will specifically discuss the research findings relating to training and professional development, to measure the scope and distribution of training activities across the workforce, to consider the interrelationship between the strategic and operational dimensions of staff development in individual institutions and to analyse the common and distinctive factors evident in the different sectors of the profession. Conclusion: The neXus2 project has successfully engaged LIS institutions in the collection of complex industry data that is relevant to the future education and workforce strategies for all areas of the profession. Cross-sector forums such as Information Online 2009 offer the opportunity for stimulating professional dialogue on the key issues.