From current immunosuppressive strategies to clinical tolerance of allografts.

In order to prevent allograft rejection, most current immunosuppressive drugs nonspecifically target T-cell activation, clonal expansion or differentiation into effector cells. Experimental models have shown that it is possible to exploit the central and peripheral mechanisms that normally maintain immune homeostasis and tolerance to self-antigens, in order to induce tolerance to alloantigens. Central tolerance results from intrathymic deletion of T cells with high avidity for thymically expressed antigens. Peripheral tolerance to nonself-molecules can be achieved by various mechanisms including deletion of activated/effector T cells, anergy induction and active regulation of effector T cells. In this article, we briefly discuss the pathways of allorecognition and their relevance to current immunosuppressive strategies and to the induction of transplantation tolerance (through haematopoietic mixed chimerism, depleting protocols, costimulatory blockade and regulatory T cells). We then review the prospect of clinical applicability of these protocols in solid organ transplantation.

Concept de first responders en Suisse romande: état des lieux et perspectives [Concept of first responders in Western Switzerland: current situation and future perspectives].

The notion of "First Responder" (FR) refers to the system of first-aid volunteers who act to initiate the first-aid care before the classical emergency help arrives. In 2011, the French-speaking Switzerland counts 19 groups, divided up between four cantons (Fribourg, Vaud, Neuchâtel, Valais). The geographical distribution of those FR shows the stakes of these peripherical areas, with the accessibility difficulties for the emergency services, and a low demography of ambulances and doctors. The number of interventions carried out by the FR has significantly increased during the last years. The association of a quality formation, an excellent knowledge of the ground and a quick intervention has a positive impact on the survival of the patients with vital emergency or traumatic conditions.

Surrogate decision making for patients with end-stage dementia.

OBJECTIVE: We aim to explore how health surrogates of patients with dementia proceed in decision making, which considerations are decisive, and whether family surrogates and professional guardians decide differently. METHODS: We conducted an experimental vignette study using think aloud protocol analysis. Thirty-two family surrogates and professional guardians were asked to decide on two hypothetical case vignettes, concerning a feeding tube placement and a cardiac pacemaker implantation in patients with end-stage dementia. They had to verbalize their thoughts while deciding. Verbalizations were audio-recorded, transcribed, and analyzed according to content analysis. By experimentally changing variables in the vignettes, the impact of these variables on the outcome of decision making was calculated. RESULTS: Although only 25% and 31% of the relatives gave their consent to the feeding tube and pacemaker placement, respectively, 56% and 81% of the professional guardians consented to these life-sustaining measures. Relatives decided intuitively, referred to their own preferences, and focused on the patient's age, state of wellbeing, and suffering. Professional guardians showed a deliberative approach, relied on medical and legal authorities, and emphasized patient autonomy. Situational variables such as the patient's current behavior and the views of health care professionals and family members had higher impacts on decisions than the patient's prior statements or life attitudes. CONCLUSIONS: Both the process and outcome of surrogate decision making depend heavily on whether the surrogate is a relative or not. These findings have implications for the physician-surrogate relationship and legal frameworks regarding surrogacy. Copyright © 2011 John Wiley & Sons, Ltd.

Identification of amino acid residues in the alpha, beta, and gamma subunits of the epithelial sodium channel (ENaC) involved in amiloride block and ion permeation.

The amiloride-sensitive epithelial Na channel (ENaC) is a heteromultimeric channel made of three alpha beta gamma subunits. The structures involved in the ion permeation pathway have only been partially identified, and the respective contributions of each subunit in the formation of the conduction pore has not yet been established. Using a site-directed mutagenesis approach, we have identified in a short segment preceding the second membrane-spanning domain (the pre-M2 segment) amino acid residues involved in ion permeation and critical for channel block by amiloride. Cys substitutions of Gly residues in beta and gamma subunits at position beta G525 and gamma G537 increased the apparent inhibitory constant (Ki) for amiloride by > 1,000-fold and decreased channel unitary current without affecting ion selectivity. The corresponding mutation S583 to C in the alpha subunit increased amiloride Ki by 20-fold, without changing channel conducting properties. Coexpression of these mutated alpha beta gamma subunits resulted in a non-conducting channel expressed at the cell surface. Finally, these Cys substitutions increased channel affinity for block by external Zn2+ ions, in particular the alpha S583C mutant showing a Ki for Zn2+ of 29 microM. Mutations of residues alpha W582L, or beta G522D also increased amiloride Ki, the later mutation generating a Ca2+ blocking site located 15% within the membrane electric field. These experiments provide strong evidence that alpha beta gamma ENaCs are pore-forming subunits involved in ion permeation through the channel. The pre-M2 segment of alpha beta gamma subunits may form a pore loop structure at the extracellular face of the channel, where amiloride binds within the channel lumen. We propose that amiloride interacts with Na+ ions at an external Na+ binding site preventing ion permeation through the channel pore.

A current-mode interface circuit for a piezoresistive pressure sensor

An interfacing circuit for piezoresistive pressure sensors based on CMOS current conveyors is presented. The main advantages of the proposed interfacing circuit include the use of a single piezoresistor, the capability of offset compensation, and a versatile current-mode configuration, with current output and current or voltage input. Experimental tests confirm linear relation of output voltage versus piezoresistance variation.

Prise en charge actuelle de l'incontinence anale [Current management of anal incontinence]

Even though anal incontinence affects a significant proportion of the population, causing a major burden to both patient and society, it still remains "the last closet issue". Less than a third of patients will share this problem with their physician. Consequently, the incidence of anal incontinence is difficult to determine, varying from 2-50%. Since this disabling condition is often associated with urinary incontinence and/or pelvic organ prolapse, a multidisciplinary team approach is required. A wide range of therapeutic options are available. When dietary, medical and rehabilitative treatments have failed, sacral neuromodulation should be considered in selected cases. More invasive surgery is usually undertaken in the presence of major structural defects. The aim of this article is to suggest a comprehensive way of identifying and treating anal incontinence.

Is the impact of public investment neutral across the regional income distribution?: evidence from Mexico

This paper investigates the contribution of public investment to the reduction of regional inqualities, with a specific application to Mexico. We use quantile regressions to examine the impact of public investment on regional disparities according to the position of each region in the conditional distribution of regional income. Results confirm the hypothesis that regional inequalities can indeed be atrributed to the regional distribution of public investment, where the observed pattern shows that public investment mainly helped to reduce regional inequalities between the richest regions

Vaccinia immune globulin: current policies, preparedness, and product safety and efficacy.

In 1980 the World Health Organization declared that smallpox was eradicated from the world, and routine smallpox vaccination was discontinued. Nevertheless, samples of the smallpox virus (variola virus) were retained for research purposes, not least because of fears that terrorist groups or rogue states might also have kept samples in order to develop a bioweapon. Variola virus represents an effective bioweapon because it is associated with high morbidity and mortality and is highly contagious. Since September 11, 2001, countries around the world have begun to develop policies and preparedness programs to deal with a bioterror attack, including stockpiling of smallpox vaccine. Smallpox vaccine itself may be associated with a number of serious adverse events, which can often be managed with vaccinia immune globulin (VIG). VIG may also be needed as prophylaxis in patients for whom pre-exposure smallpox vaccine is contraindicated (such as those with eczema or pregnant women), although it is currently not licensed in these cases. Two intravenous formulations of VIG (VIGIV Cangene and VIGIV Dynport) have been licensed by the FDA for the management of patients with progressive vaccinia, eczema vaccinatum, severe generalized vaccinia, and extensive body surface involvement or periocular implantation following inadvertent inoculation.

Current-density-functional approach to large quantum dots in intense magnetic fields

Within current-density-functional theory, we have studied a quantum dot made of 210 electrons confined in a disk geometry. The ground state of this large dot exhibits some features as a function of the magnetic field (Beta) that can be attributed in a clear way to the formation of compressible and incompressible states of the system. The orbital and spin angular momenta, the total energy, ionization and electron chemical potentials of the ground state, as well as the frequencies of far-infrared edge modes are calculated as a function of Beta, and compared with available experimental and theoretical results.

E-learning initiatives in forensic interpretation: report on experiences from current projects and outlook

This paper reports on the purpose, design, methodology and target audience of E-learning courses in forensic interpretation offered by the authors since 2010, including practical experiences made throughout the implementation period of this project. This initiative was motivated by the fact that reporting results of forensic examinations in a logically correct and scientifically rigorous way is a daily challenge for any forensic practitioner. Indeed, interpretation of raw data and communication of findings in both written and oral statements are topics where knowledge and applied skills are needed. Although most forensic scientists hold educational records in traditional sciences, only few actually followed full courses that focussed on interpretation issues. Such courses should include foundational principles and methodology - including elements of forensic statistics - for the evaluation of forensic data in a way that is tailored to meet the needs of the criminal justice system. In order to help bridge this gap, the authors' initiative seeks to offer educational opportunities that allow practitioners to acquire knowledge and competence in the current approaches to the evaluation and interpretation of forensic findings. These cover, among other aspects, probabilistic reasoning (including Bayesian networks and other methods of forensic statistics, tools and software), case pre-assessment, skills in the oral and written communication of uncertainty, and the development of independence and self-confidence to solve practical inference problems. E-learning was chosen as a general format because it helps to form a trans-institutional online-community of practitioners from varying forensic disciplines and workfield experience such as reporting officers, (chief) scientists, forensic coordinators, but also lawyers who all can interact directly from their personal workplaces without consideration of distances, travel expenses or time schedules. In the authors' experience, the proposed learning initiative supports participants in developing their expertise and skills in forensic interpretation, but also offers an opportunity for the associated institutions and the forensic community to reinforce the development of a harmonized view with regard to interpretation across forensic disciplines, laboratories and judicial systems.

2011 Road Use Tax Fund (RUTF) Study A report to the Iowa Legislature, per 2011 Iowa Code Section 307.31

The transportation system is in demand 24/7 and 365 days a year irrespective of neither the weather nor the conditions. Iowa’s transportation system is an integral and essential part of society serving commerce and daily functions of all Iowans across the state. A high quality transportation system serves as the artery for economic activity and, the condition of the infrastructure is a key element for our future growth opportunities. A key component of Iowa’s transportation system is the public roadway system owned and maintained by the state, cities and counties. In order to regularly re-evaluate the conditions of Iowa’s public roadway infrastructure and assess the ability of existing revenues to meet the needs of the system, the Iowa Department of Transportation’s 2006 Road Use Tax Fund (RUTF) report to the legislature included a recommendation that a study be conducted every five years. That recommendation was included in legislation adopted in 2007 and signed into law. The law specifically requires the following (2011 Iowa Code Section 307.31): •“The department shall periodically review the current revenue levels of the road use tax fund and the sufficiency of those revenues for the projected construction and maintenance needs of city, county, and state governments in the future. The department shall submit a written report to the general assembly regarding its findings by December 31 every five years, beginning in 2011. The report may include recommendations concerning funding levels needed to support the future mobility and accessibility for users of Iowa's public road system.” •“The department shall evaluate alternative funding sources for road maintenance and construction and report to the general assembly at least every five years on the advantages and disadvantages and the viability of alternative funding mechanisms.” Consistent with this requirement, the Iowa Department of Transportation (DOT) has prepared this study. Recognizing the importance of actively engaging with the public and transportation stakeholders in any discussion of public roadway conditions and needs, Governor Terry E. Branstad announced on March 8, 2011, the creation of, and appointments to, the Governor’s Transportation 2020 Citizen Advisory Commission (CAC). The CAC was tasked with assisting the Iowa DOT as they assess the condition of Iowa’s roadway system and evaluate current and future funding available to best address system needs. In particular the CAC was directed to gather input from the public and stakeholders regarding the condition of Iowa’s public roadway system, the impact of that system, whether additional funding is needed to maintain/improve the system, and, if so, what funding mechanisms ought to be considered. With this input, the CAC prepared a report and recommendations that were presented to Governor Branstad and the Iowa DOT in November 2011 for use in the development of this study. The CAC’s report is available at www.iowadot.gov/transportation2020/pdfs/CAC%20REPORT%20FINAL%20110211.pdf. The CAC’s report was developed utilizing analysis and information from the Iowa DOT. Therefore, the report forms the basis for this study and the two documents are very similar. Iowa is fortunate to have an extensive public roadway system that provides access to all areas of the state and facilitates the efficient movement of goods and people. However, it is also a tremendous challenge for the state, cities and counties to maintain and improve this system given flattening revenue, lost buying power, changing demands on the system, severe weather, and an aging system. This challenge didn’t appear overnight and for the last decade many studies have been completed to look into the situation and the legislature has taken significant action to begin addressing the situation. In addition, the Iowa DOT and Iowa’s cities and counties have worked jointly and independently to increase efficiency and streamline operations. All of these actions have been successful and resulted in significant changes; however, it is apparent much more needs to be done. A well-maintained, high-quality transportation system reduces transportation costs and provides consistent and reliable service. These are all factors that are critical in the evaluation companies undertake when deciding where to expand or locate new developments. The CAC and Iowa DOT heard from many Iowans that additional investment in Iowa’s roadway system is vital to support existing jobs and continued job creation in the state of Iowa. Beginning June 2011, the CAC met regularly to review material and discuss potential recommendations to address Iowa’s roadway funding challenges. This effort included extensive public outreach with meetings held in seven locations across Iowa and through a Transportation 2020 website hosted by the Iowa DOT (www.iowadot.gov/transportation2020). Over 500 people attended the public meetings held through the months of August and September, with 198 providing verbal or written comment at the meetings or through the website. Comments were received from a wide array of individuals. The public comments demonstrated overwhelming support for increased funding for Iowa’s roads. Through the public input process, several guiding principles were established to guide the development of recommendations. Those guiding principles are: • Additional revenues are restricted for road and bridge improvements only, like 95 percent of the current state road revenue is currently. This includes the fuel tax and registration fees. • State and local governments continue to streamline and become more efficient, both individually and by looking for ways to do things collectively. • User fee concept is preserved, where those who use the roads pay for them, including non¬residents. • Revenue-generating methods equitable across users. • Increase revenue generating mechanisms that are viable now but begin to implement and set the stage for longer-term solutions that bring equity and stability to road funding. • Continue Iowa’s long standing tradition of state roadway financing coming from pay-as-you-go financing. Iowa must not fall into the situation that other states are currently facing where the majority of their new program dollars are utilized to pay the debt service of past bonding. Based on the analysis of Iowa’s public roadway needs and revenue and the extensive work of the Governor’s Transportation 2020 Citizen Advisory Commission, the Iowa DOT has identified specific recommendations. The recommendations follow very closely the recommendations of the CAC (CAC recommendations from their report are repeated in Appendix B). Following is a summary of the recommendations which are fully documented beginning on page 21. 1. Through a combination of efficiency savings and increased revenue, a minimum of $215 million of revenue per year should be generated to meet Iowa’s critical roadway needs. 2. The Code of Iowa should be changed to require the study of the sufficiency of the state’s road funds to meet the road system’s needs every two years instead of every five years to coincide with the biennial legislative budget appropriation schedule. 3.Modify the current registration fee for electric vehicles to be based on weight and value using the same formula that applies to most passenger vehicles. 4.Consistent with existing Code of Iowa requirements, new funding should go to the TIME-21 Fund up to the cap ($225 million) and remaining new funding should be distributed consistent with the Road Use Tax Fund distribution formula. 5.The CAC recommended the Iowa DOT at least annually convene meetings with cities and counties to review the operation, maintenance and improvement of Iowa’s public roadway system to identify ways to jointly increase efficiency. In direct response to this recommendation, Governor Branstad directed the Iowa DOT to begin this effort immediately with a target of identifying $50 million of efficiency savings that can be captured from the over $1 billion of state revenue already provided to the Iowa DOT and Iowa’s cities and counties to administer, maintain and improve Iowa’s public roadway system. This would build upon past joint and individual actions that have reduced administrative costs and resulted in increased funding for improvement of Iowa’s public roadway system. Efficiency actions should be quantified, measured and reported to the public on a regular basis. 6.By June 30, 2012, Iowa DOT should complete a study of vehicles and equipment that use Iowa’s public roadway system but pay no user fees or substantially lower user fees than other vehicles and equipment.

Relationship of breast fillet deboning time to shear force, pH, cooking loss and color in broilers stunned by high electrical current

Selostus: Korkealla virranvoimakkuudella tainnutettujen broilereiden rintafileen irroitushetken vaikutus lihaksen leikkausvoiman vastukseen, pH:hon, keittohävikkiin ja väriin