Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes.

During T cell-dependent antibody responses lymph node B cells differentiate either to plasmablasts that grow in the medullary cords, or to blasts that proliferate in follicles forming germinal centers. Many plasmablasts differentiate to plasma cells locally, but some leave the medullary cords and migrate to downstream lymph nodes. To assess the basis for this migration, changes in the responsiveness of B cells to a range of chemokines have been studied as they differentiate. Naive B cells express high levels of CCR6, CCR7, CXCR4 and CXCR5. When activated B cells grow in follicles the expression of these chemokine receptors and the responsiveness to the respective chemokines is retained. During the extrafollicular response, plasmablast expression of CXCR5 and responsiveness to B-lymphocyte chemoattractant (CXCR5) as well as to secondary lymphoid tissue chemokine (CCR7) and stromal cell-derived factor (SDF)-1 (CXCR4) are lost while a weak response towards the CCR6 chemokine LARC is maintained. Despite losing responsiveness to SDF-1, extrafollicular plasmablasts still express high levels of CXCR4 on the cell surface. These results suggest that the combined loss of chemokine receptor expression and of chemokine responsiveness may be a necessary prerequisite for cells to migrate to the medullary cords and subsequently enter the efferent lymph.

Contribution of in vitro neurotoxicology studies to the elucidation of neurodegenerative processes.

Only a small percentage of neurodegenerative diseases like Alzheimer's disease and Parkinson's disease is directly related to familial forms. The etiology of the most abundant, sporadic forms seems to involve both genetic and environmental factors. Environmental compounds are now extensively studied for their possible contribution to neurodegeneration. Chemicals were found which were able to reproduce symptoms of known neurodegenerative diseases, others may either predispose to the onset of neurodegeneration, or exacerbate distinct pathogenic processes of these diseases. In any case, in vitro studies performed with models presenting various degrees of complexity have shown that many environmental compounds have the potential to cause neurodegeneration, through a variety of pathways similar to those described in neurodegenerative diseases. Since the population is exposed to a huge number of potentially neurotoxic compounds, there is an important need for rapid and efficient procedures for hazard evaluation. Xenobiotics elicit a cascade of reactions that, most of the time, involve numerous interactions between the different brain cell types. A reliable in vitro model for the detection of environmental toxins potentially at risk for neurodegenerative diseases should therefore allow maximal cell-cell interactions and multiparametric endpoints determination. The combined use of in vitro models and new analytical approaches using "omics" technologies should help to map toxicity pathways, and advance our understanding of the possible role of xenobiotics in the etiology of neurodegenerative diseases.

Changing healthcare: stakeholder perceptions of the burden of chronic disease and the value of teams, measurements and communication.

Canadian healthcare is changing. Over the course of the past decade, the Health Care in Canada Survey (HCIC) has annually measured the reactions of the public and professional stakeholders to many of these change forces. In HCIC 2008, for the first time, the public's perception of their health status and all stakeholders' views of the burden and effective management of chronic diseases were sought. Overall, Canadians perceive themselves as healthy, with 84% of adults reporting good-to-excellent health. However, good health decreased with age as the occurrence of chronic illness rose, from 12% in the age group 18-24 to 65% for the population =65 years. More than 70% of all stakeholders were strongly or somewhat supportive of the implementation of coordinated care, or disease management programs, to improve the care of patients with chronic illnesses. Concordant support was also expressed for key disease management components, including coordinated interventions to improve home, community and self-care; increased wellness promotion; and increased use of clinical measurements and feedback to all stakeholders. However, there were also important areas of non-concordance. For example, the public and doctors consistently expressed less support than other stakeholders for the value of team care, including the use of non-physician professionals to provide patient care; increased patient involvement in decision-making; and the use of electronic health records to facilitate communication. The actual participation in disease management programs averaged 34% for professionals and 25% for the public. We conclude that chronic diseases are common, age-related and burdensome in Canada. Disease management or coordinated intervention often delivered by teams is also relatively common, despite its less-than-universal acceptance by all stakeholders. Further insights are needed, particularly into the variable perceptions of the value and efficacy of team-delivered healthcare and its important components.

Haemodynamic consequences of changing bicarbonate and calcium concentrations in haemodialysis fluids.

BACKGROUND: In a previous study we demonstrated that mild metabolic alkalosis resulting from standard bicarbonate haemodialysis induces hypotension. In this study, we have further investigated the changes in systemic haemodynamics induced by bicarbonate and calcium, using non-invasive procedures. METHODS: In a randomized controlled trial with a single-blind, crossover design, we sequentially changed the dialysate bicarbonate and calcium concentrations (between 26 and 35 mmol/l for bicarbonate and either 1.25 or 1.50 mmol/l for calcium). Twenty-one patients were enrolled for a total of 756 dialysis sessions. Systemic haemodynamics was evaluated using pulse wave analysers. Bioimpedance and BNP were used to compare the fluid status pattern. RESULTS: The haemodynamic parameters and the pre-dialysis BNP using either a high calcium or bicarbonate concentration were as follows: systolic blood pressure (+5.6 and -4.7 mmHg; P < 0.05 for both), stroke volume (+12.3 and +5.2 ml; P < 0.05 and ns), peripheral resistances (-190 and -171 dyne s cm(-5); P < 0.05 for both), central augmentation index (+1.1% and -2.9%; ns and P < 0.05) and BNP (-5 and -170 ng/l; ns and P < 0.05). The need of staff intervention was similar in all modalities. CONCLUSIONS: Both high bicarbonate and calcium concentrations in the dialysate improve the haemodynamic pattern during dialysis. Bicarbonate reduces arterial stiffness and ameliorates the heart tolerance for volume overload in the interdialytic phase, whereas calcium directly increases stroke volume. The slight hypotensive effect of alkalaemia should motivate a probative reduction of bicarbonate concentration in dialysis fluid for haemodynamic reasons, only in the event of failure of classical tools to prevent intradialytic hypotension.

From radiobiology to technology: what is changing in radiotherapy for prostate cancer.

In the last decades, new technologies have been introduced in the daily clinical practice of the radiation oncologist: 3D-Conformal radiotherapy (RT) became almost universally available, thereafter, intensity modulated RT (IMRT) gained large diffusion, due to its potential impact in improving the clinical outcomes, and more recently, helical and volumetric arc IMRT with image-guided RT are becoming more and more diffused and used for prostate cancer patients. The conventional dose-fractionation results to be the best compromise between the efficacy and the safety of the treatment, but combining new techniques, modern RT allows to overcame one of the major limits of the 'older' RT: the impossibility of delivering higher total doses and/or high dose/fraction. The evidences regarding radiobiology, clinical and technological evolution of RT in prostate cancer have been reported and discussed.

MIGCLIM: Predicting plant distribution and dispersal in a changing climate

Many studies have forecasted the possible impact of climate change on plant distribution using models based on ecological niche theory. In their basic implementation, niche-based models do not constrain predictions by dispersal limitations. Hence, most niche-based modelling studies published so far have assumed dispersal to be either unlimited or null. However, depending on the rate of climatic change, the landscape fragmentation and the dispersal capabilities of individual species, these assumptions are likely to prove inaccurate, leading to under- or overestimation of future species distributions and yielding large uncertainty between these two extremes. As a result, the concepts of "potentially suitable" and "potentially colonisable" habitat are expected to differ significantly. To quantify to what extent these two concepts can differ, we developed MIGCLIM, a model simulating plant dispersal under climate change and landscape fragmentation scenarios. MIGCLIM implements various parameters, such as dispersal distance, increase in reproductive potential over time, barriers to dispersal or long distance dispersal. Several simulations were run for two virtual species in a study area of the western Swiss Alps, by varying dispersal distance and other parameters. Each simulation covered the hundred-year period 2001-2100 and three different IPCC-based temperature warming scenarios were considered. Our results indicate that: (i) using realistic parameter values, the future potential distributions generated using MIGCLIM can differ significantly (up to more than 95% decrease in colonized surface) from those that ignore dispersal; (ii) this divergence increases both with increasing climate warming and over longer time periods; (iii) the uncertainty associated with the warming scenario can be nearly as large as the one related to dispersal parameters; (iv) accounting for dispersal, even roughly, can importantly reduce uncertainty in projections.

Rate and processes of river network rearrangement during incipient faulting: The case of the Cahabon river, Guatemala

Deeply incised river networks are generally regarded as robust features that are not easily modified by erosion or tectonics. Although the reorganization of deeply incised drainage systems has been documented, the corresponding importance with regard to the overall landscape evolution of mountain ranges and the factors that permit such reorganizations are poorly understood. To address this problem, we have explored the rapid drainage reorganization that affected the Cahabon River in Guatemala during the Quaternary. Sediment-provenance analysis, field mapping, and electrical resistivity tomography (ERT) imaging are used to reconstruct the geometry of the valley before the river was captured. Dating of the abandoned valley sediments by the Be-10-Al-26 burial method and geomagnetic polarity analysis allow us to determine the age of the capture events and then to quantify several processes, such as the rate of tectonic deformation of the paleovalley, the rate of propagation of post-capture drainage reversal, and the rate at which canyons that formed at the capture sites have propagated along the paleovalley. Transtensional faulting started 1 to 3 million years ago, produced ground tilting and ground faulting along the Cahabon River, and thus generated differential uplift rate of 0.3 +/- 0.1 up to 0.7 +/- 0.4 mm . y(-1) along the river's course. The river responded to faulting by incising the areas of relative uplift and depositing a few tens of meters of sediment above the areas of relative subsidence. Then, the river experienced two captures and one avulsion between 700 ky and 100 ky. The captures breached high-standing ridges that separate the Cahabon River from its captors. Captures occurred at specific points where ridges are made permeable by fault damage zones and/or soluble rocks. Groundwater flow from the Cahabon River down to its captors likely increased the erosive power of the captors thus promoting focused erosion of the ridges. Valley-fill formation and capture occurred in close temporal succession, suggesting a genetic link between the two. We suggest that the aquifers accumulated within the valley-fills, increased the head along the subterraneous system connecting the Cahabon River to its captors, and promoted their development. Upon capture, the breached valley experienced widespread drainage reversal toward the capture sites. We attribute the generalized reversal to combined effects of groundwater sapping in the valley-fill, axial drainage obstruction by lateral fans, and tectonic tilting. Drainage reversal increased the size of the captured areas by a factor of 4 to 6. At the capture sites, 500 m deep canyons have been incised into the bedrock and are propagating upstream at a rate of 3 to 11 mm . y(-1) deepening at a rate of 0.7 to 1 5 mm . y(-1). At this rate, 1 to 2 million years will be necessary for headward erosion to completely erase the topographic expression of the paleovalley. It is concluded that the rapid reorganization of this drainage system was made possible by the way the river adjusted to the new tectonic strain field, which involved transient sedimentation along the river's course. If the river had escaped its early reorganization and had been given the time necessary to reach a new dynamic equilibrium, then the transient conditions that promoted capture would have vanished and its vulnerability to capture would have been strongly reduced.