Stem Cell Transplantation for Retinal Degenerations

Within the last few years, several reports have revealed that cell transplantation can be an effective way to replace lost neurons in the central nervous system (CNS) of patients affected with neurodegenerative diseases. Concerning the retina, the concept that newborn photoreceptors can integrate the retina and restore some visual functions was univocally demonstrated recently in the mouse eye (MacLaren et al. 2006) and remains to be achieved in human. These results pave the way to a standard approach in regenerative medicine aiming to replace lost photoreceptors. With the discovery of stem cells a great hope has appeared towards elaborating protocols to generate adequate cells to restore visual function in different retinal degeneration processes. Retinal stem cells (RSCs) are good candidates to repair the retina and are present throughout the retina development, including adulthood. However, neonatal mouse RSCs derived from the radial glia population have a different potential to proliferate and differentiate in comparison to adult RSCs. Moreover, we observed that adult mouse RSCs, depending on the culture conditions, have a marked tendency to transform, whereas neonatal RSCs show subtle chromosome abnormalities only after extensive expansion. These characteristics should help to identify the optimal cell source and culture conditions for cell transplantation studies. These results will be discussed in light of other studies using RSCs as well as embryonic stem cells. Another important factor to consider is the host environment, which plays a crucial role for cell integration and which was poorly studied in the normal and the diseased retina. Nonetheless, important results were recently generated to reconsider cell transplantation strategy. Perspectives to enhance cell integration by manipulating the environment will also be presented.

Surveillance active du cancer de la prostate [Active surveillance in prostate cancer].

Active surveillance in prostate cancer The spread of PSA in the screening of prostate cancer has almost doubled the incidence of this disease in the last twenty years. An improved understanding of the natural history of this cancer allows for risk stratification of the disease and to better predict insignificant prostate cancer. Active surveillance has recently been proposed as a new option to delay or avoid a radical treatment for patients with low-risk disease. The principle, results and future perspectives of this treatment modality are discussed in this review.

Secondary amyloidosis: a severe complication of ankylosing spondylitis. Two case-reports.

STUDY OBJECTIVE: To report two cases of amyloidosis secondary to ankylosing spondylitis. PATIENTS AND RESULTS: Of the 47 ankylosing spondylitis patients who have received follow-up at our department over the last few years, two have developed AA amyloidosis. Both have extremely severe, long-standing joint disease, with virtually complete spinal ankylosis and destructive peripheral arthritis of the hips and wrists; one also has tarsal joint destruction. Renal dysfunction was the first manifestation of amyloidosis in both cases. One patient required chronic hemodialysis and developed peritonitis due to colonic perforation, probably at a site of amyloid deposition. CONCLUSIONS: Secondary amyloidosis is a rare complication of ankylosing spondylitis that can cause severe renal and gastrointestinal complications. No treatment capable of clearing established amyloid deposits is available to date.

Clinicopathologic correlates in the oldest-old: Commentary on "No disease in the brain of a 115-year-old woman".

den Dunnen et al. [den Dunnen, W.F.A., Brouwer, W.H., Bijlard, E., Kamphuis, J., van Linschoten, K., Eggens-Meijer, E., Holstege, G., 2008. No disease in the brain of a 115-year-old woman. Neurobiol. Aging] had the opportunity to follow up the cognitive functioning of one of the world's oldest woman during the last 3 years of her life. They performed two neuropsychological evaluations at age 112 and 115 that revealed a striking preservation of immediate recall abilities and orientation. In contrast, working memory, retrieval from semantic memory and mental arithmetic performances declined after age 112. Overall, only a one-point decrease of MMSE score occurred (from 27 to 26) reflecting the remarkable preservation of cognitive abilities. The neuropathological assessment showed few neurofibrillary tangles (NFT) in the hippocampal formation compatible with Braak staging II, absence of amyloid deposits and other types of neurodegenerative lesions as well as preservation of neuron numbers in locus coeruleus. This finding was related to a striking paucity of Alzheimer disease (AD)-related lesions in the hippocampal formation. The present report parallels the early descriptions of rare "supernormal" centenarians supporting the dissociation between brain aging and AD processes. In conjunction with recent stereological analyses in cases aged from 90 to 102 years, it also points to the marked resistance of the hippocampal formation to the degenerative process in this age group and possible dissociation between the occurrence of slight cognitive deficits and development of AD-related pathologic changes in neocortical areas. This work is discussed in the context of current efforts to identify the biological and genetic parameters of human longevity.

Change in individual growth rate and its link to gill-net fishing in two sympatric whitefish species

Size-selective fishing is expected to affect traits such as individual growth rate, but the relationship between the fishery-linked selection differentials and the corresponding phenotypic changes is not well understood. We analysed a 25-year monitoring survey of sympatric populations of the two Alpine whitefish Coregonus albellus and C. fatioi. We determined the fishing-induced selection differentials on growth rates, the actual change of growth rates over time, and potential indicators of reproductive strategies that may change over time. We found marked declines in adult growth rate and significant selection differentials that may partly explain the observed declines. However, when comparing the two sympatric species, the selection differentials on adult growth were stronger in C. albellus while the decline in adult growth rate seemed more pronounced in C. fatioi. Moreover, the selection differential on juvenile growth was significant in C. albellus but not in C. fatioi, while a significant reduction in juvenile growth over the last 25 years was only found in C. fatioi. Our results suggest that size-selective fishing affects the genetics for individual growth in these whitefish, and that the link between selection differentials and phenotypic changes is influenced by species-specific factors.

Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels.

Chronic disorders, such as obesity, diabetes, inflammation, non-alcoholic fatty liver disease and atherosclerosis, are related to alterations in lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPAR)α, PPARβ/δ and PPARγ are involved. These receptors form a subgroup of ligand-activated transcription factors that belong to the nuclear hormone receptor family. This review discusses a selection of novel PPAR functions identified during the last few years. The PPARs regulate processes that are essential for the maintenance of pregnancy and embryonic development. Newly found hepatic functions of PPARα are the mediation of female-specific gene repression and the protection of the liver from oestrogen induced toxicity. PPARα also controls lipid catabolism and is the target of hypolipidaemic drugs, whereas PPARγ controls adipocyte differentiation and regulates lipid storage; it is the target for the insulin sensitising thiazolidinediones used to treat type 2 diabetes. Activation of PPARβ/δ increases lipid catabolism in skeletal muscle, the heart and adipose tissue. In addition, PPARβ/δ ligands prevent weight gain and suppress macrophage derived inflammation. In fact, therapeutic benefits of PPAR ligands have been confirmed in inflammatory and autoimmune diseases, such as encephalomyelitis and inflammatory bowel disease. Furthermore, PPARs promote skin wound repair. PPARα favours skin healing during the inflammatory phase that follows injury, whilst PPARβ/δ enhances keratinocyte survival and migration. Due to their collective functions in skin, PPARs represent a major research target for our understanding of many skin diseases. Taken altogether, these functions suggest that PPARs serve as physiological sensors in different stress situations and remain valuable targets for innovative therapies.

TNF-alpha blockers in inflammatory bowel diseases: practical consensus recommendations and a user's guide.

More than seventy years after their initial characterisation, the aetiology of inflammatory bowel diseases remains elusive. A recent review evaluating the incidence trends of the last 25 years concluded that an increasing incidence has been observed almost worldwide. A north-south gradient is still found in Europe. Genetic associations are variably reproduced worldwide and indicate a strong impact of environmental factors. Tumour necrosis factor alpha (TNF-alpha) has been shown to play a critical role in the pathogenesis of inflammatory bowel disease (IBD). TNF-alpha blockers are biological agents that specifically target this key cytokine in the inflammatory process and have become a mainstay in the therapy of inflammatory bowel diseases. This paper reviews the necessary investigations before using such agents, the use of such agents in pregnancy and lactation, the role of co-immunosuppression, how to monitor efficacy and safety, dose-adaptation, and the decision as to when to switch to another TNF-alpha blocker. Finally it gives recommendations for special situations. Currently there are three TNF-alpha blockers available for clinical use in IBD in Switzerland: infliximab (Remicade), adalimumab (Humira) and certolizumab pegol (Cimzia). Infliximab is a chimeric monoclonal antibody composed of a human IgG1 constant region and a murine variable region and is administered intravenously. Adalimumab is a humanised monoclonal antibody, with both human IgG1 constant and variable regions. Certolizumab pegol is a pegylated, humanised monoclonal anti-TNF fragment antigen binding fragment. Both adalimumab and certolizumab pegol are administered by subcutaneous injection. The efficacy and safety of TNF-alpha blockers in Crohn's disease has been reviewed. The authors conclude that the three above-mentioned agents are effective in luminal Crohn's disease. In fistulizing Crohn's disease, TNF-alpha blockers other than infliximab require additional investigation.

Treatment algorithm for moderate to severe ulcerative colitis.

The care for a patient with ulcerative colitis (UC) remains challenging despite the fact that morbidity and mortality rates have been considerably reduced during the last 30 years. The traditional management with intravenous corticosteroids was modified by the introduction of ciclosporin and infliximab. In this review, we focus on the treatment of patients with moderate to severe UC. Four typical clinical scenarios are defined and discussed in detail. The treatment recommendations are based on current literature, published guidelines and reviews, and were discussed at a consensus meeting of Swiss experts in the field. Comprehensive treatment algorithms were developed, aimed for daily clinical practice.

Shift of spawning season and effects of climate warming on developmental stages of a grayling (Salmonidae)

River-dwelling fish, such as European graylings (Thymallus thymallus), are susceptible to changes in climate because they can often not avoid suboptimal temperatures, especially during early developmental stages. We analyzed data collected in a 62-year-long (1948-2009) population monitoring program. Male and female graylings were sampled about three times/week during the yearly spawning season in order to follow the development of the population. The occurrence of females bearing ripe eggs was used to approximate the timing of each spawning season. In the last years of the study, spawning season was more than 3 weeks earlier than in the first years. This shift was linked to increasing water temperatures as recorded over the last 39 years with a temperature logger at the spawning site. In early spring water temperatures rose more slowly than in later spring. Thus, embryos and larvae were exposed to increasingly colder water at a stage that is critical for sex determination and pathogen resistance in other salmonids. In summer, however, fry were exposed to increasingly warmer temperatures. The changes in water temperatures that we found embryos, larvae, and fry were exposed to could be contributing to the decline in abundance that has occurred over the last 30-40 years.

Neuromodulation by oxytocin and vasopressin in the central nervous system as a basis for their rapid behavioral effects.

The last several years have seen an increasing number of studies that describe effects of oxytocin and vasopressin on the behavior of animals or humans. Studies in humans have reported behavioral changes and, through fMRI, effects on brain function. These studies are paralleled by a large number of reports, mostly in rodents, that have also demonstrated neuromodulatory effects by oxytocin and vasopressin at the circuit level in specific brain regions. It is the scope of this review to give a summary of the most recent neuromodulatory findings in rodents with the aim of providing a potential neurophysiological basis for their behavioral effects. At the same time, these findings may point to promising areas for further translational research towards human applications.

Heart transplantation: current practice and outlook to the future.

QUESTIONS UNDER STUDY: The field of heart transplantation has seen substantial progress in the last 40 years. The breakthroughs in long-term survival were followed by a period of stagnation in the last decade. This review summarises current recommendations for the identification of candidates for heart transplantation and their immunological and non-immunological postoperative follow-up. RESULTS: The progress made in the treatment of patients with advanced heart failure has considerably changed the profile of candidates for heart transplantation. Patients are older, and the load of co-morbidities is more important requiring careful evaluation for candidacy. Long-standing research in the field of immunosuppression made available various drugs, which decrease the risk of acute allograft rejection and prolong survival after heart transplantation. Powerful new molecules are entering early phase clinical studies, suggesting further improvement in the near future. As a consequence, treatment of non-immunological co-morbidity after heart transplantation will gain in importance, however, the base of evidence guiding current recommendations is poor. CONCLUSIONS: The substantial progress in heart failure treatment and immunosuppression after heart transplantation has changed the profile of heart transplant recipients. The arrival of new molecules will provide additional alternatives for immunosuppressive treatment while studies have to address non-immunological treatment in order to improve long-term survival after heart transplantation.

Quantitative multiparameter assays to measure the effect of adjuvants on human antigen-specific CD8 T-cell responses.

Large numbers and functionally competent T cells are required to protect from diseases for which antibody-based vaccines have consistently failed (1), which is the case for many chronic viral infections and solid tumors. Therefore, therapeutic vaccines aim at the induction of strong antigen-specific T-cell responses. Novel adjuvants have considerably improved the capacity of synthetic vaccines to activate T cells, but more research is necessary to identify optimal compositions of potent vaccine formulations. Consequently, there is a great need to develop accurate methods for the efficient identification of antigen-specific T cells and the assessment of their functional characteristics directly ex vivo. In this regard, hundreds of clinical vaccination trials have been implemented during the last 15 years, and monitoring techniques become more and more standardized.

Significant decrease in in-hospital mortality and major adverse cardiac events in Swiss STEMI patients between 2000 and December 2007.

To evaluate the in-hospital outcome of STEMI (ST elevation myocardial infarction) patients admitted to Swiss hospitals between 2000 and December 2007, and to identify the predictors of in-hospital mortality and major cardiac events. Data from the Swiss national registry AMIS Plus (Acute Myocardial Infarction and Unstable Angina in Switzerland) were used. All patients admitted between January 2000 and December 2007 with STEMI or a new LBBB (left bundle branch block) were included in the registry. We studied 12 026 STEMI patients admitted to 68 hospitals. The mean age was 64 +/- 13 years and 73% of the patients were male. Incidence of in-hospital death was 7.6% in 2000 and 6% in 2007. Reinfarction fell from 3.7% in 2000 to 0.9% in 2007. Thrombolysis decreased from 40.2% in 2000 to 2% in 2007. Clinical predictors of mortality were: age >65 years, Killips class III or IV, diabetes, Q wave myocardial infarction (at presentation). Patients undergoing percutaneous coronary intervention (PCI) had lower mortality and reinfarction rates (3.9% versus 11.2% and 1.1% versus 3.1% respectively, p <0.001) over time, although their numbers increased from 43% in 2000 to 85% in 2007. Patients admitted to hospitals with PCI facilities had lower mortality than patients hospitalised in hospitals without it, but the demographic characteristics differ widely between the two groups. Both in-hospital mortality and reinfarction decreased significantly over the time, parallel to an increased number of PCI. PCI was also the strongest predictor of survival. In-hospital mortality and reinfarction rate have decreased significantly in Swiss STEMI patients in the last seven years, parallel to a significant increase in the number of percutaneous coronary interventions in addition to medical therapy. Outcome is not related to the site of admission but to PCI access.

A spatial modelling framework for assessing climate change impacts on freshwater ecosystems: Response of brown trout (Salmo trutta L.) biomass to warming water temperature

Mountain regions worldwide are particularly sensitive to on-going climate change. Specifically in the Alps in Switzerland, the temperature has increased twice as fast than in the rest of the Northern hemisphere. Water temperature closely follows the annual air temperature cycle, severely impacting streams and freshwater ecosystems. In the last 20 years, brown trout (Salmo trutta L) catch has declined by approximately 40-50% in many rivers in Switzerland. Increasing water temperature has been suggested as one of the most likely cause of this decline. Temperature has a direct effect on trout population dynamics through developmental and disease control but can also indirectly impact dynamics via food-web interactions such as resource availability. We developed a spatially explicit modelling framework that allows spatial and temporal projections of trout biomass using the Aare river catchment as a model system, in order to assess the spatial and seasonal patterns of trout biomass variation. Given that biomass has a seasonal variation depending on trout life history stage, we developed seasonal biomass variation models for three periods of the year (Autumn-Winter, Spring and Summer). Because stream water temperature is a critical parameter for brown trout development, we first calibrated a model to predict water temperature as a function of air temperature to be able to further apply climate change scenarios. We then built a model of trout biomass variation by linking water temperature to trout biomass measurements collected by electro-fishing in 21 stations from 2009 to 2011. The different modelling components of our framework had overall a good predictive ability and we could show a seasonal effect of water temperature affecting trout biomass variation. Our statistical framework uses a minimum set of input variables that make it easily transferable to other study areas or fish species but could be improved by including effects of the biotic environment and the evolution of demographical parameters over time. However, our framework still remains informative to spatially highlight where potential changes of water temperature could affect trout biomass. (C) 2015 Elsevier B.V. All rights reserved.-

Transparency and trust in government (2007-2014): a comparative study

In a 2000 report entitled "Trust in government. Ethics measures in OECD countries," OECD Secretary-General Donald J. Johnston emphasized the fact that public ethics are considered as a keystone of good governance. Moreover, public ethics are a prerequisite to public trust, which is in turn vital not only to any public service, but also to any society in general. At the same time, transparency reforms have flourished over the last few years and have several times been designed as a response to public distrust. Therefore, ethics, transparency and trust are closely linked together in a supposed virtuous circle where transparency works as a factor of better public ethics and leads to more trust in government on the citizens' side. This article explores the links between transparency and levels of trust in 10 countries between 2007 and 2014, using open data indexes and access to information requests as proxies for transparency. A national ranking of transparency, based on requests submitted by citizens to the administration and open data indexes, is then proposed. Key findings show that there is no sharp decline of trust in government in all countries considered in this article, and that transparency and trust in government are not systematically positively associated. Therefore, this article challenges the common assumption, mostly found in the normative literature, about a positive interrelation between the two, where trust in government is conceived as a beneficial effect of administrative transparency.