The perpetuation and epidemic recurrence of communicable diseases in human populations

Recurrence of communicable diseases is a looming threat for human populations. Factors explaining the recurrences are partially known, involving demographics, biology, and complex relationships with the environment, but no comprehensive theory exists today. Here, we review some recent results obtained in modelling studies with a view to understanding better the mechanisms of perpetuation. Factors intrinsic to the interaction of pathogen and host have regained interest in this respect, especially with multiple pathogen and multiple population interactions. Extrinsic factors, including pure demography and environmental forcing are also strong predictors. With increasingly detailed data available, large-scale integrated models will help sorting out the multiple influences on recurrence.     

Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain

The number and localization of effector cells to the tumor site are crucial elements for immune rejection of solid tumors. However, for cerebral malignancies, antitumor responses need to be finely tuned to avoid neuropathologic consequences. In this study, we determine factors that regulate CTL localization and tumoricidal function after intracerebral implantation of tumors expressing model Ag. H-2(bxd) mice implanted with a CW3(+) murine glioma lacking H-2K(d) molecules necessary to present the CW3(170-179) epitope demonstrate cross-priming of H-2K(d)-restricted CTL, and moreover, Ag-dependent accumulation of functional H-2K(d)/CW3(170-179)-specific CTL within the tumor bed. This implicates a role for cross-presentation not only in priming, but also in retention of fully differentiated CTL in the tumor stroma at the effector stage of the response. Modulating cross-presentation of Ag may be the key in regulating specific immune responses in the brain: either by augmenting protective responses or by down-modulating destructive autoimmune reactions.     

Vaccination with a Melan-A peptide selects an oligoclonal T cell population with increased functional avidity and tumor reactivity

Both the underlying molecular mechanisms and the kinetics of TCR repertoire selection following vaccination against tumor Ags in humans have remained largely unexplored. To gain insight into these questions, we performed a functional and structural longitudinal analysis of the TCR of circulating CD8(+) T cells specific for the HLA-A2-restricted immunodominant epitope from the melanocyte differentiation Ag Melan-A in a melanoma patient who developed a vigorous and sustained Ag-specific T cell response following vaccination with the corresponding synthetic peptide. We observed an increase in functional avidity of Ag recognition and in tumor reactivity in the postimmune Melan-A-specific populations as compared with the preimmune blood sample. Improved Ag recognition correlated with an increase in the t(1/2) of peptide/MHC interaction with the TCR as assessed by kinetic analysis of A2/Melan-A peptide multimer staining decay. Ex vivo analysis of the clonal composition of Melan-A-specific CD8(+) T cells at different time points during vaccination revealed that the response was the result of asynchronous expansion of several distinct T cell clones. Some of these T cell clones were also identified at a metastatic tumor site. Collectively, these data show that tumor peptide-driven immune stimulation leads to the selection of high-avidity T cell clones of increased tumor reactivity that independently evolve within oligoclonal populations.     

Analysis of the collapsibility of the upper airway in a spectrum of sleep-disordered breathing: a modelling approach

Using a simplified model of the upper airways with two independent collapsible elements (nostrils and hypo-pharynx), we calculated the cross-sectional area of these two elements, taking into account pressure drops. We experimentally measured flow and pressure in the fossa and hypo-pharynx in various syndromes. This allowed us to compare the behaviour of the area supplied by our model with the aerodynamic resistance that is often used to analyse upper airway flow limitation events. We showed that nostril and hypo-pharyngeal areas are better correlated than the resistance values and thus concluded that the pressure divided by the square of the flow is a better parameter for analysing flow limitation in upper airways than resistance. Owing to its simplicity, our model is able to supply the area of the collapsible element in real time, which is impossible with more sophisticated models.     

Structural features of two distinct molecular complexes of copper(II) cationic porphyrin and deoxyribonucleotides

The associations of the water-soluble cationic copper(II)-5,10,15,20-meso-tetrakis(4-N-methylpyridyl) porphyrin (CuP) with d(pT)9 oligothymidylate and its building blocks deoxythymidine (dT) and deoxythymidine 5'-monophosphate (dTMP) were investigated by spectrophotometric titration [absorption, nanosecond transient resonance Raman (ns-RR) and picosecond time-resolved resonance Raman (ps-TR3) spectroscopies] to elucidate the structural requirements for the CuP exciplex formation in molecular complexes with unchained mononucleotides. In the d(pT)9 a factor analysis and global fit of the CuP absorption spectra revealed the formation of a single spectral species attributable to a 1 : 1 CuP. d(pT)9 complex throughout a wide range of d(pT)9/CuP ratios (0-10). Using ps-TR3 spectroscopy, the CuP. d(pT)9 complex was shown to be fully responsible for exciplex formation. In contrast, CuP mixed with dTMP ([dTMP]/[CuP] < 3000) yielded two spectroscopically distinct types of molecular complexes with 1 : 1 (CuP. dTMP) and 1 : 2 (CuP. (dTMP)2) (or even higher for [dTMP]/[CuP] > 3000) stoichiometry, the latter being spectroscopically identical to the CuP. d(pT)9 and providing a microenvironment favorable for exciplex formation to the same extent as the oligothymidylate. On the other hand, the 1 : 1 CuP. dTMP complex (prevailing for [dTMP]/[CuP] < 100) yielded no exciplex features. Similar behavior was observed for the CuP complexed with dT. To explain the difference in the ability of the CuP. dTMP and CuP. (dTMP)2 species to form the exciplex, two types of molecular complexes were suggested and discussed, differing in the orientation of the thymine planes with respect to the porphyrin macrocycle.     

Pituitary adenylate cyclase-activating polypeptide stimulates nitric-oxide synthase type I expression and potentiates the cGMP response to gonadotropin-releasing hormone of rat pituitary gonadotrophs

Nitric-oxide synthase type I (NOS I) is expressed primarily in gonadotrophs and in folliculo-stellate cells of the anterior pituitary. In gonadotrophs, the expression and the activity of NOS I are stimulated by gonadotropin-releasing hormone (GnRH) under both experimental and physiological conditions. In the present study, we show that pituitary adenylate cyclase-activating polypeptide (PACAP) is twice as potent as GnRH at increasing NOS I levels in cultured rat anterior pituitary cells. The action of PACAP is detectable after 4-6 h and maximal at 24 h, this effect is mimicked by 8-bromo-cAMP and cholera toxin and suppressed by H89 suggesting a mediation through the cAMP pathway. Surprisingly, NADPH diaphorase staining revealed that these changes occurred in gonadotrophs exclusively although PACAP and cAMP, in contrast to GnRH, have the potential to target several types of pituitary cells including folliculo-stellate cells. There was no measurable alteration in NOS I mRNA levels after cAMP or PACAP induction. PACAP also stimulated cGMP synthesis, which was maximal within 15 min and independent of cAMP, however, only part resulted from NOS I/soluble guanylate cyclase activation implying that in contrast to GnRH, PACAP has a dual mechanism in cGMP production. Interestingly, induction of NOS I by PACAP markedly enhanced the capacity of gonadotrophs to produce cGMP in response to GnRH. The fact that PACAP may act on gonadotrophs to alter NOS I levels, generate cGMP, and potentiate the cGMP response to GnRH, suggests that cGMP could play important cellular functions.     

Local survival after fire in Mediterranean shrublands: combining capture-recapture data over several bird species

Post-disturbance survival is a key factor in the onset of secondary successions. Here we analyse capture-recapture data from two before/after disturbance studies to estimate the effect of fire on local bird survival. Analyses of six bird species at two Mediterranean shrubland sites were combined using a meta-analysis approach. Two warblers, Sylvia undata and S. melanocephala, were studied at one site altered by prescribed burning, and five passerines (Luscinia megarhynchos, Turdus merula, Parus major, P. caeruleus and S. melanocephala) at one site disturbed by wildfire. Based on the combined analysis, annual survival probability significantly decreased from 0.49 to 0.18 (i.e. a 64% decline) after the fire. Our results further suggest a trend for a higher decrease in annual survival associated with wildfire (–72%, from 0.51 to 0.14) than with prescribed burning (–35%, from 0.41 to 0.27), although this should be properly tested with a specific experimental design. In S. undata, a decline in survival in the long-term cannot account for the drop in density observed the first spring after fire. We suggest that a decrease in recruitment rate and an increase in the proportion of non-breeders immediately after the fire may contribute more strongly to the decline in the breeding population. Our results tend to support the idea that bird populations may respond to moderate disturbances with noticeable time lags, because of individual site tenacity.     

Which future for the French Pyrenean brown bear (Ursus arctos) population? An approach using stage-structured deterministic and stochastic models

The Pyrenean brown bear (Ursus arctos) population is considered as one of the most seriously threatened with extinction in Western Europe. To assess its viability and possible needs of augmentation, we develop deterministic and stochastic stage-structured demographic models. The deterministic model reveals that a bear population cannot have a high annual growth rate and is particularly sensitive to breeder survival. High demographic parameters appear to be crucial to population persistence, especially for a small population that remains vulnerable to demographic and environmental stochasticities. The Pyrenean population cannot therefore be considered as viable. Successful conservation strategies for this population would require releasing more bears in both sub-populations in the near future.     

In vitro interactions between bone marrow stromal cells and hippocampal slice cultures

Bone marrow stromal cells (BMSCs) are capable of differentiating into various cell types including brain cells. Several groups have also demonstrated trophic effects of MSC grafts in experimental ischemia models. However, the underlying molecular mechanisms of these effects are not fully understood. We developed an “in vitro graft model” which consisted in a coculture of GFP-expressing BMSCs and hippocampal organotypic slice cultures. Total marrow cells (MCs) or BMSCs after one (BMSC^1P) or five passages (BMSC^5P) were transplanted on hippocampal slices. During the 10 days of our experiments, MCs and BMSC^1P migrated toward the tissue, but their total number remained constant. Conversely, the number of BMSC^5P decreased over the 10 days of the experiment, and no migration could be detected. Using immunohistochemistry, we observed that the hippocampal slices induced the expression of neural antigens in very few grafted cells, but MCs and BMSC^1P improved the conservation of the hippocampal slice culture. Similar experiments using BMSC^5P did not produce any significant change. We conclude that the number of passages greatly influence BMSCs survival rate, migration and neuroprotective capacities.