Living on three time scales: the dynamics of plasma cell and antibody populations illustrated for hepatitis a virus.

Understanding the mechanisms involved in long-term persistence of humoral immunity after natural infection or vaccination is challenging and crucial for further research in immunology, vaccine development as well as health policy. Long-lived plasma cells, which have recently been shown to reside in survival niches in the bone marrow, are instrumental in the process of immunity induction and persistence. We developed a mathematical model, assuming two antibody-secreting cell subpopulations (short- and long-lived plasma cells), to analyze the antibody kinetics after HAV-vaccination using data from two long-term follow-up studies. Model parameters were estimated through a hierarchical nonlinear mixed-effects model analysis. Long-term individual predictions were derived from the individual empirical parameters and were used to estimate the mean time to immunity waning. We show that three life spans are essential to explain the observed antibody kinetics: that of the antibodies (around one month), the short-lived plasma cells (several months) and the long-lived plasma cells (decades). Although our model is a simplified representation of the actual mechanisms that govern individual immune responses, the level of agreement between long-term individual predictions and observed kinetics is reassuringly close. The quantitative assessment of the time scales over which plasma cells and antibodies live and interact provides a basis for further quantitative research on immunology, with direct consequences for understanding the epidemiology of infectious diseases, and for timing serum sampling in clinical trials of vaccines.

Deeply gapped vegetation patterns: on crown/root allometry, criticality and desertification.

The dynamics of vegetation is formulated in terms of the allometric and structural properties of plants. Within the framework of a general and yet parsimonious approach, we focus on the relationship between the morphology of individual plants and the spatial organization of vegetation populations. So far, in theoretical as well as in field studies, this relationship has received only scant attention. The results reported remedy to this shortcoming. They highlight the importance of the crown/root ratio and demonstrate that the allometric relationship between this ratio and plant development plays an essential part in all matters regarding ecosystems stability under conditions of limited soil (water) resources. This allometry determines the coordinates in parameter space of a critical point that controls the conditions in which the emergence of self-organized biomass distributions is possible. We have quantified this relationship in terms of parameters that are accessible by measurement of individual plant characteristics. It is further demonstrated that, close to criticality, the dynamics of plant populations is given by a variational Swift-Hohenberg equation. The evolution of vegetation in response to increasing aridity, the conditions of gapped pattern formation and the conditions under which desertification takes place are investigated more specifically. It is shown that desertification may occur either as a local desertification process that does not affect pattern morphology in the course of its unfolding or as a gap coarsening process after the emergence of a transitory, deeply gapped pattern regime. Our results amend the commonly held interpretation associating vegetation patterns with a Turing instability. They provide a more unified understanding of vegetation self-organization within the broad context of matter order-disorder transitions.

Spatial decoupling of facilitation and competition at the origin of gapped vegetation patterns.

Spatially periodic vegetation patterns, forming gaps, bands, labyrinths, or spots, are characteristic of arid and semiarid landscapes. Self-organization models can explain this variety of structures within a unified conceptual framework. All these models are based on the interplay of positive and negative effects of plants on soil water, but they can be divided according to whether they assume the interactions to be mediated by water redistribution through runoff/diffusion or by plants' organs. We carried out a multi-proxy approach of the processes operating in a gapped pattern in southwest Niger dominated by a shrub species. Soil moisture within the root layer was monitored in time and space over one month of the rainy season. Soil water recharge displayed no spatial variation with respect to vegetation cover, but the stock half-life under cover was twice that of bare areas. A kernel of facilitation by the aboveground parts of shrubs was parameterized, and soil water half-life was significantly correlated to the cumulated facilitative effects of shrubs. The kernel range was found to be smaller than the canopy radius (81%). This effect of plants on soil water dynamics, probably through a reduction of evaporation by shading, is shown to be a better explanatory variable than potentially relevant soil and topography parameters. The root systems of five individuals of Combretum micranthum G. Don were excavated. Root density data were used as a proxy to parameterize a kernel function of interplant competition. The range of this kernel was larger than the canopy radius (125%). The facilitation-to-competition range ratio, reflecting the above-to-belowground ratio of plant lateral extent, was smaller than 1 (0.64), a result supporting models assuming that patterning may emerge from an adaptation of plant morphology to aridity and shallow soils by means of an extended lateral root system. Moreover, observed soil water gradients had directions opposite to those assumed by alternative mathematical models based on underground water diffusion. This study contributes to the growing awareness that combined facilitative and competitive plant interactions can induce landscape-scale patterns and shape the two-way feedback loops between environment and vegetation.

Interferon-based treatment of chronic hepatitis C.

The treatment of patients with chronic hepatitis C has rapidly evolved in the past 10 years centered on the use of interferon alpha 2 as an antiviral and immunomodulatory agent against hepatitis C virus. Firstly used as a monotherapy associated with a deceiving long-term efficacy, interferon alpha was then combined with ribavirin, a nucleoside analog with large antiviral properties. Combination of both drugs dramatically improved the efficacy of treatment with 50% of patients reaching a sustained viral response, characterized by the final eradication of the virus from the infected individual. Surprisingly, this synergistic effect remains greatly unexplained. The third step consisted in the use of pegylated interferon in order to adapt its pharmacokinetics and to allow a better efficacy with a more tolerable dosing schedule: once weekly subcutaneous injection instead of thrice weekly. Pegylated interferon combined with ribavirin during 24-48 weeks of treatment is the current standard of care with nearly 60% of sustained virologic response, overall. Development of new forms of interferon alpha are on the way with promising preliminary results.

Short-term effects of prone position in chronic obstructive pulmonary disease patients with severe acute hypoxemic and hypercapnic respiratory failure.

OBJECTIVE: To assess the short-term effects of prone positioning (PP) in chronic obstructive pulmonary disease (COPD) patients with severe hypoxemic and hypercapnic respiratory failure requiring invasive mechanical ventilation. DESIGN AND SETTING: Prospective observational study in the general intensive care unit of a university-affiliated hospital. PATIENTS: 11 consecutive COPD patients with persistent hypoxemia (PaO2/FIO2 < or = 200 mmHg with FIO2 > or = 0.6) and hypercapnia requiring invasive mechanical ventilation. Patients with adult respiratory distress syndrome or left ventricular failure were excluded. Mean age was 73+/-11 years, mean weight 86+/-31 kg, mean SAPS II 53+/-10, and ICU mortality 36%. INTERVENTIONS: Patients were turned every 6 h. MEASUREMENTS AND RESULTS: A response to PP (20% or greater PaO2/FIO2 increase) was noted in 9 (83%) patients. Blood gases were measured in the PP and supine (SP) positions 3 h after each turn, for 36 h, yielding six measurement sets (SP1, PP1, SP2, PP2, SP3, and PP3). PaO2/FIO2 was significantly better in PP: 190+/-26 vs. 113+/-9 mmHg for PP1/SP1, 175+/-22 vs. 135+/-16 mmHg for PP2/SP2, and 199+/-24 vs. 151+/-13 mmHg for PP3/SP3. After PP1 PaO2/FIO2 remained significantly improved, and the PaO2/FIO2 improvement from SP1 to SP2 was linearly related to PaO2/FIO2 during PP1 (r=0.8). The tracheal aspirate volume improved significantly from SP1 to PP1. PaCO2 was not significantly affected by position. CONCLUSIONS: PP was effective in treating severe hypoxemia in COPD patients. The first turn in PP was associated with increased tracheal aspirate.

Pleiotrophin mediates the neurotrophic effect of cyclic AMP on dopaminergic neurons: analysis of suppression-subtracted cDNA libraries and confirmation in vitro.

To better understand the particular vulnerability of mesencephalic dopaminergic neurons to toxins or gene mutations causing parkinsonism, we have taken advantage of a primary cell culture system in which these neurons die selectively. Antimitotic agents, such as cytosine arabinoside or cAMP, prevent the death of the neurons by arresting astrocyte proliferation. To identify factors implicated in either the death of the dopaminergic neurons or in the neuroprotective effect of cAMP, we constructed cDNA libraries enriched by subtractive hybridization and suppressive PCR in transcripts that are preferentially expressed in either control or cAMP-treated cultures. Differentially expressed transcripts were identified by hybridization of the enriched cDNAs with a commercially available cDNA expression array. The proteoglycan receptors syndecan-3 and the receptor protein tyrosine phosphatase zeta/beta were found among the transcripts preferentially expressed under control conditions, and their ligand, the cytokine pleiotrophin, was highly represented in the cDNA libraries for both conditions. Since pleiotrophin is expressed during embryonic and perinatal neural development and following lesions in the adult brain, we investigated its role in our cell culture model. Pleiotrophin was not responsible for the death of dopaminergic neurons under control conditions, or for their survival in cAMP-treated cultures. It was, however, implicated in the initial and cAMP-dependent enhancement of the differentiation of the dopaminergic neurons in our cultures. In addition, our experiments have provided evidence for a cAMP-dependent regulatory pathway leading to protease activation, and the identification of pleiotrophin as a target of this pathway.