Tolerance-inducing immunosuppressive strategies in clinical transplantation: an overview.

The significant development of immunosuppressive drug therapies within the past 20 years has had a major impact on the outcome of clinical solid organ transplantation, mainly by decreasing the incidence of acute rejection episodes and improving short-term patient and graft survival. However, long-term results remain relatively disappointing because of chronic allograft dysfunction and patient morbidity or mortality, which is often related to the adverse effects of immunosuppressive treatment. Thus, the induction of specific immunological tolerance of the recipient towards the allograft remains an important objective in transplantation. In this article, we first briefly describe the mechanisms of allograft rejection and immune tolerance. We then review in detail current tolerogenic strategies that could promote central or peripheral tolerance, highlighting the promises as well as the remaining challenges in clinical transplantation. The induction of haematopoietic mixed chimerism could be an approach to induce robust central tolerance, and we describe recent encouraging reports of end-stage kidney disease patients, without concomitant malignancy, who have undergone combined bone marrow and kidney transplantation. We discuss current studies suggesting that, while promoting peripheral transplantation tolerance in preclinical models, induction protocols based on lymphocyte depletion (polyclonal antithymocyte globulins, alemtuzumab) or co-stimulatory blockade (belatacept) should, at the current stage, be considered more as drug-minimization rather than tolerance-inducing strategies. Thus, a better understanding of the mechanisms that promote peripheral tolerance has led to newer approaches and the investigation of individualized donor-specific cellular therapies based on manipulated recipient regulatory T cells.

Promotion de l'activité physique chez les aînés: enjeux et stratégies spécifiques. [Promotion of exercise in older people: issues and strategies].

Regular physical activity is among the most effective interventions to prevent or delay functional decline and disability, even in older persons. Despite relatively strong scientific evidence supporting these benefits, the majority of older persons remain mostly sedentary. For these persons, concerns about injury or fear of negative consequences on their chronic diseases are among the most powerful barriers to participation in regular physical activity. Promotion of physical activity among older persons has therefore become one of the five main themes of the health promotion project "Via", a project that aims at promoting good practice in prevention and health promotion directed toward older adults in Switzerland. This paper summarizes the main recommendations issued from this national project supported by the Swiss Health Promotion Foundation.

ESPEN endorsed recommendations: nutritional therapy in major burns.

BACKGROUND & AIMS: Nutrition therapy is a cornerstone of burn care from the early resuscitation phase until the end of rehabilitation. While several aspects of nutrition therapy are similar in major burns and other critical care conditions, the patho-physiology of burn injury with its major endocrine, inflammatory, metabolic and immune alterations requires some specific nutritional interventions. The present text developed by the French speaking societies, is updated to provide evidenced-based recommendations for clinical practice. METHODS: A group of burn specialists used the GRADE methodology (Grade of Recommendation, Assessment, Development and Evaluation) to evaluate human burn clinical trials between 1979 and 2011. The resulting recommendations, strong suggestions or suggestions were then rated by the non-burn specialized experts according to their agreement (strong, moderate or weak). RESULTS: Eight major recommendations were made. Strong recommendations were made regarding, 1) early enteral feeding, 2) the elevated protein requirements (1.5-2 g/kg in adults, 3 g/kg in children), 3) the limitation of glucose delivery to a maximum of 55% of energy and 5 mg/kg/h associated with moderate blood glucose (target ≤ 8 mmol/l) control by means of continuous infusion, 4) to associated trace element and vitamin substitution early on, and 5) to use non-nutritional strategies to attenuate hypermetabolism by pharmacological (propranolol, oxandrolone) and physical tools (early surgery and thermo-neutral room) during the first weeks after injury. Suggestion were made in absence of indirect calorimetry, to use of the Toronto equation (Schoffield in children) for energy requirement determination (risk of overfeeding), and to maintain fat administration ≤ 30% of total energy delivery. CONCLUSION: The nutritional therapy in major burns has evidence-based specificities that contribute to improve clinical outcome.

Oral insecticidal activity of root colonizing Pseudomonas fluorescens CHA0: a biocontrol agent with potential to control plant pests and diseases

The application of microbial biocontrol agents for the control of fungal plant diseases and plant insect pests is a promising approach in the development of environmentally benign pest management strategies. The ideal biocontrol organism would be a bacterium or a fungus with activity against both, insect pests and fungal pathogens. Here we demonstrate the oral insecticidal activity of the root colonizing Pseudomonas fluorescens CHA0, which is so far known for its capacity to efficiently suppress fungal plant pathogens. Feeding assays with CHA0-sprayed leaves showed that this strain displays oral insecticidal activity and is able to efficiently kill larvae of three important insect pests. We further show data indicating that the Fit insect toxin produced by CHA0 and also metabolites controlled by the global regulator GacA contribute to oral insect toxicity.

Vaccine strategies against schistosomiasis

In this review the authors analyze the effector and regulatory mechanisms in the immune response to schistosomiasis. To study these mechanisms two animal models were used, mouse and rat. The mouse totaly permissive host like human, show prominent-T cell control in the acquisition of resistance. But other mechanisms like antibody mediated cytotoxity (ADCC) involving eosinophils and IgG antibodies described in humans, are observed in rats. Also in this animal, it is observed specific IgE antibody high production and blood and tisssue eosinophilia. Using the rat model and schistosomula as target, some ADCC features have emerged: the cellular population involved are bone marrow derived inflammatory cell (mononuclear phagocytes, eosinophils and platelets), interacting with IgE through IgE Fc receptors. Immunization has been attempted using the recombinant protein Sm28/GST. Protection has been observed in rodents with significant decrease of parasite fecundity and egg viability affecting the number, size and volume of liver egg granulomas. The association of praziquantel and immunization with with Sm28/GST increases the resistance to infection and decreases egg viability. The authors suggest the possibility of the stablishment of a future vaccine against Schistosoma mansoni.

Vaccine strategies against schistosomiasis

Schistosomiasis, the second major parasitic disease in the world after malaria affects at least 200 million people, 500 million being exposed to the risk of infection. It is widely agreed that a vaccine strategy wich could lead to the induction of effector mechanisms reducing the level of reinfection and ideally parasite fecundity would deeply affect the incidence of pathological manifestations as well as the parasite transmission potentialities. Extensive studies performed in the rat model have allowed the identification of novel effector mechanisms involving IgE antibodies and various inflammatory cell populations (eosinophils, macrophages and platelets) whereas regulation of immune response by blocking antibodies has been evidencial. Recent epidemiological studies have now entirely confirmed in human populations the the role of IgE antibodies in the acquisition of resistance and the association of IgG4 blocking antibodies with increased susceptibility. On the basis of these concepts, several schistosome glutathion S-transferase (Sm 28 GST) appears as a pronising vaccine candidate. Immunization experiments have shown that two complementary goals can be achieved: (a) a partial but significant reduction of the worm population (up to 60//in rats); (b) a significant reduction of parasite fecundity (up in the mice and 85//in cattle) and egg viability (up to 80//). At least two distinct immunological mechanisms account for these two effects. IgE antibodies appear as a major humoral component of acquired resistance whereas IgA antibodies appear as a major humoral factor affecting parasite fecundity. These studies seem to represent a parasite diseases through the identification of potentially protective antigens and of the components of the immune response which vaccination should aim at inducing.

Nash equilibrium strategies in discrete-time finite-horizon dynamic games with risk-and effort-averse players

The objective of this paper is to re-examine the risk-and effort attitude in the context of strategic dynamic interactions stated as a discrete-time finite-horizon Nash game. The analysis is based on the assumption that players are endogenously risk-and effort-averse. Each player is characterized by distinct risk-and effort-aversion types that are unknown to his opponent. The goal of the game is the optimal risk-and effort-sharing between the players. It generally depends on the individual strategies adopted and, implicitly, on the the players' types or characteristics.

Life cycle and influence of age and feeding on the first mating of Triatoma mazzottii (Hemiptera: Reduviidae)

A cohort of 100 eggs of Triatoma mazzottii Usinger was studied to obtain information on its life cycle. Egg incubation took 24 days; mean duration of 1st, 2nd, 3rd, 4th, and 5th instar nymphs was 27, 36, 39, 46 and 64 days respectively; mean time from egg to adult was 236 days. The total duration of the nymphal stages was 212 days. The total nymph mortality in cohort was 16.3% and the embryonic egg mortality was 14.0%. The grater mortality occured in the 2nd instar. The average number of eggs/female/week was 9.8 during 15 weeks of observation. Of the total eggs laid (2,514), only 58.7% hatched. The total of insects that achieved the adult stage (72), 38 were females (52.8%), and 34 were males (47.2%). The influence of age and feeding on the first mating of T. mazzottii were also studied. It was found that the first mating depended on the male's age and it was on the average 30 days after the last imaginal molt. The female could be mating since 2nd days after the imaginal life. The nutritional status did not play an important role in the capacity of the insect for the first mating.

Reduced peroxisomal citrate synthase activity increases substrate availability for polyhydroxyalkanoate biosynthesis in plant peroxisomes.

Polyhydroxyalkanoates (PHAs) are bacterial carbon storage polymers used as renewable, biodegradable plastics. PHA production in plants may be a way to reduce industrial PHA production costs. We recently demonstrated a promising level of peroxisomal PHA production in the high biomass crop species sugarcane. However, further production strategies are needed to boost PHA accumulation closer to commercial targets. Through exogenous fatty acid feeding of Arabidopsis thaliana plants that contain peroxisome-targeted PhaA, PhaB and PhaC enzymes from Cupriavidus necator, we show here that the availability of substrates derived from the β-oxidation cycle limits peroxisomal polyhydroxybutyrate (PHB) biosynthesis. Knockdown of peroxisomal citrate synthase activity using artificial microRNA increased PHB production levels approximately threefold. This work demonstrates that reduction of peroxisomal citrate synthase activity may be a valid metabolic engineering strategy for increasing PHA production in other plant species.

Motion compensation strategies in magnetic resonance imaging.

Image quality in magnetic resonance imaging (MRI) is considerably affected by motion. Therefore, motion is one of the most common sources of artifacts in contemporary cardiovascular MRI. Such artifacts in turn may easily lead to misinterpretations in the images and a subsequent loss in diagnostic quality. Hence, there is considerable research interest in strategies that help to overcome these limitations at minimal cost in time, spatial resolution, temporal resolution, and signal-to-noise ratio. This review summarizes and discusses the three principal sources of motion: the beating heart, the breathing lungs, and bulk patient movement. This is followed by a comprehensive overview of commonly used compensation strategies for these different types of motion. Finally, a summary and an outlook are provided.

Withdrawal, "serosorting" and "strategic positioning": use of risk reduction strategies with casual sex partners in men who have sex with men (MSM) in Switzerland, 2007

Introduction: 1) Withdrawal before ejaculation, "serosorting" (to choose a partner of same serostatus) and "strategic positioning" (only insertive vs. only receptive role in anal sex according to serostatus) are known to be used by MSM as alternatives to condom use. 2) Despite their questionable levels of effectiveness they are collectively labelled as "risk reduction strategies" (RRS). Objectives: The aim of this study is to estimate the prevalence and factors related to RRS in men who report unprotected anal intercourse (UAI) with occasional partners in the last 12 months. Methods: 1) In 2007, a module on RRS was included in a repeated national survey conducted among readers of gay newspapers, members of gay organizations and visitors of gay websites (N=2953). 2) Using an anonymous self-completed questionnaire, participants were asked whether, with the aim of avoiding HIV infection, RRS were used with occasional partners. Analysis: 1) Prevalences were calculated in participants who reported UAI with occasional partners in the last 12 months (n=416). 2) A logistic regression was performed, using "at least one RRS" as dependent variable. Number of partners in the last 12 months, HIV-status and usual socio-demographic characteristics were used as independent factors. Result : 1) 70% (292/416) of the participants reporting UAI used at least one RRS when they had unprotected sex with casual partners in the last 12 months (Table 1). 2) Withrawal before ejaculation was the most frequently reported strategy, followed by serosorting and strategic positioning (Table 1). 3) Participants who reported at least one RRS were more likely to be over 30 years and to belong to a gay organisation. HIV-positive and non-tested participants were less likely to report RRS than HIV-negative participants (Table 2). Conclusions: 1) The majority of MSM who reported UAI in the last 12 months tried to reduce risk of HIV transmission by using specific strategies (withdrawal, serosorting, strategic positioning). It is not known, however, to what extent the use of these strategies was systematic. 2) It is necessary to provide MSM with balanced information on these strategies and their respective level of effectiveness. 3) It is important to monitor the use of RRS in HIV behavioural surveillance surveys in MSM.