Human B19 parvovirus infetion: an example of multiple pathogenic effects determined by differences in host susceptibility

B19 infection offers some general lessons about human viruses and their possible effects on the human host, as follows: (1) Ubiquitous apparently benign viruses may have severe effects on a compromissed host. The virus may be invariable but the host can have diverse susceptibilities. (2) B19 and some other human viruses (through for none is the evidence so clear as for B19) have narrowly targetted effects. The host cell of B19 is a specialised progenitor of mature red cells: impairment of the function of this cell by B19 may cause profound anaemia. (3) The 'normal'host response to B19 may also cause disease, though this is slef limiting. (4) The effects of malfunction of the virus'target cell are exacerbated when the immune response is impaired by congenital or acquired immunodeficiency, immunosupressive therapy or, in the case of the fetus, developmental immaturity that allows the virus to persist.

Pharmacokinetic profile of two different pharmaceutical forms of theophylline (a slow release tablet and a syrup) after multiple dose administration to healthy human volunteers

Due to the narrow therapeutic range of theophyline, plasma concentrations of this drug are monitored in patients undergoing chronic therapy. Slow-release preparations avoid the fluctuations in plasma levels and improve patient compliance. In this study, we have compared the pharmacokinetic profiles of a theophylline slow-release tablet and a syrup form, when administered in multiple doses to healthy adult volunteers. The classification based upon releasing patterns is confirmed.

The Multiple-partners assignment game with heterogeneous sales and multi-unit demands: competitive equilibria

A multiple-partners assignment game with heterogeneous sales and multiunit demands consists of a set of sellers that own a given number of indivisible units of (potentially many different) goods and a set of buyers who value those units and want to buy at most an exogenously fixed number of units. We define a competitive equilibrium for this generalized assignment game and prove its existence by using only linear programming. In particular, we show how to compute equilibrium price vectors from the solutions of the dual linear program associated to the primal linear program defined to find optimal assignments. Using only linear programming tools, we also show (i) that the set of competitive equilibria (pairs of price vectors and assignments) has a Cartesian product structure: each equilibrium price vector is part of a competitive equilibrium with all optimal assignments, and vice versa; (ii) that the set of (restricted) equilibrium price vectors has a natural lattice structure; and (iii) how this structure is translated into the set of agents' utilities that are attainable at equilibrium.

Evidence for multiple B- and T-cell epitopes in Plasmodium falciparum liver-stage antigen 3.

Liver-stage antigen 3 (LSA-3) is a new vaccine candidate that can induce protection against Plasmodium falciparum sporozoite challenge. Using a series of long synthetic peptides (LSP) encompassing most of the 210-kDa LSA-3 protein, a study of the antigenicity of this protein was carried out in 203 inhabitants from the villages of Dielmo (n = 143) and Ndiop (n = 60) in Senegal (the level of malaria transmission differs in these two villages). Lymphocyte responses to each individual LSA-3 peptide were recorded, some at high prevalences (up to 43%). Antibodies were also detected to each of the 20 peptides, many at high prevalence (up to 84% of responders), and were directed to both nonrepeat and repeat regions. Immune responses to LSA-3 were detectable even in individuals of less than 5 years of age and increased with age and hence exposure to malaria, although they were not directly related to the level of malaria transmission. Thus, several valuable T- and B-cell epitopes were characterized all along the LSA-3 protein, supporting the antigenicity of this P. falciparum vaccine candidate. Finally, antibodies specific for peptide LSP10 located in a nonrepeat region of LSA-3 were found significantly associated with a lower risk of malaria attack over 1 year of daily clinical follow-up in children between the ages of 7 and 15 years, but not in older individuals.

Novel testis germ cell-specific transcript of the CREB gene contains an alternatively spliced exon with multiple in-frame stop codons.

The gene encoding the cAMP-responsive transcription factor CREB consists of multiple small exons some of which undergo alternative RNA splicing. We describe the finding of a novel transcript of the CREB gene expressed at high levels in the germ cells of the rat testis. The transcript contains an alternatively spliced exon inserted within the sequence encoding the transcriptional transactivation domain of CREB and this exon contains multiple in-frame stop codons. Furthermore, the exon is conserved in both rat and human genes (75% nucleotide identity). Although the function(s) of this RNA or the truncated CREB protein predicted to result from the translation of this unusual transcript is unknown, the high level of expression in the testicular germ cells and remarkable conservation of sequences in rat and human suggests that it may have a unique biological function in these cells.

Multiple expression control mechanisms of peroxisome proliferator-activated receptors and their target genes.

The peroxisome proliferator-activated receptors (PPAR) alpha, beta/delta and gamma belong to the nuclear hormone receptor superfamily. As ligand-activated receptors, they form a functional transcriptional unit upon heterodimerization with retinoid X receptors (RXRs). PPARs are activated by fatty acids and their derivatives, whereas RXR is activated by 9-cis retinoic acid. This heterodimer binds to peroxisome proliferator response elements (PPRE) residing in target genes and stimulates their expression. Recent reports now indicate that PPARs and RXRs can function independently, in the absence of a hetero-partner, to modulate gene expression. Of importance, these non-canonical mechanisms underscore the impact of both cofactors and DNA on gene expression. Furthermore, these different mechanisms reveal the increasing repertoire of PPAR 'target' genes that now encompasses non-PPREs containing genes. It is also becoming apparent that understanding the regulation of PPAR expression and activity, can itself have a significant influence on how the expression of subgroups of target genes is studied and integrated in current knowledge.

Immunogenicity of multiple antigen peptides containing Plasmodium vivax CS epitopes in BALB/c mice

Multiple antigen peptide systems (MAPs) allow the incorporation of various epitopes in to a single synthetic peptide immunogen. We have characterized the immune response of BALB/c mice to a series of MAPs assembled with different B and T cell epitopes derived from the Plasmodium vivax circumsporozoite (CS) protein. A B-cell epitope from the central repeat domain and two T-cell epitopes from the amino and carboxyl flanking regions were used to assembled eight different MAPs. An additional universal T cell epitope (ptt-30) from tetanus toxin protein was included. Immunogenicity in terms of antibody responses and in vitro T lymphocyte proliferation was evaluated. MAPs containing B and T cell epitopes induced high titers of anti-peptides antibodies, which recognized the native protein on sporozoites as determined by IFAT. The antibody specificity was also determined by a competitive inhibition assay with different MAPs. A MAP containing the B cell epitope (p11) and the universal epitope ptt-30 together with another composed of p11 and the promiscuous T cell epitope (p25) proved to be the most immunogenic. The strong antibody response and specificity for the cognate protein indicates that further studies designed to assess the potential of these proteins as human malaria vaccine candidates are warranted.

Monophyletic origin of multiple clonal lineages in an asexual fish (Poecilia formosa).

Despite the advantage of avoiding the costs of sexual reproduction, asexual vertebrates are very rare and often considered evolutionarily disadvantaged when compared to sexual species. Asexual species, however, may have advantages when colonizing (new) habitats or competing with sexual counterparts. They are also evolutionary older than expected, leaving the question whether asexual vertebrates are not only rare because of their 'inferior' mode of reproduction but also because of other reasons. A paradigmatic model system is the unisexual Amazon molly, Poecilia formosa, that arose by hybridization of the Atlantic molly, Poecilia mexicana, as the maternal ancestor, and the sailfin molly, Poecilia latipinna, as the paternal ancestor. Our extensive crossing experiments failed to resynthesize asexually reproducing (gynogenetic) hybrids confirming results of previous studies. However, by producing diploid eggs, female F(1) -hybrids showed apparent preadaptation to gynogenesis. In a range-wide analysis of mitochondrial sequences, we examined the origin of P. formosa. Our analyses point to very few or even a single origin(s) of its lineage, which is estimated to be approximately 120,000 years old. A monophyletic origin was supported from nuclear microsatellite data. Furthermore, a considerable degree of genetic variation, apparent by high levels of clonal microsatellite diversity, was found. Our molecular phylogenetic evidence and the failure to resynthesize the gynogenetic P. formosa together with the old age of the species indicate that some unisexual vertebrates might be rare not because they suffer the long-term consequences of clonal reproduction but because they are only very rarely formed as a result of complex genetic preconditions necessary to produce viable and fertile clonal genomes and phenotypes ('rare formation hypothesis').

Peroxisome proliferator-activated receptors: insight into multiple cellular functions.

Peroxisome proliferator-activated receptors, PPARs, (NR1C) are nuclear hormone receptors implicated in energy homeostasis. Upon activation, these ligand-inducible transcription factors stimulate gene expression by binding to the promoter of target genes. The different structural domains of PPARs are presented in terms of activation mechanisms, namely ligand binding, phosphorylation, and cofactor interaction. The specificity of ligands, such as fatty acids, eicosanoids, fibrates and thiazolidinediones (TZD), is described for each of the three PPAR isotypes, alpha (NR1C1), beta (NR1C2) and gamma (NR1C3), so as the differential tissue distribution of these isotypes. Finally, general and specific functions of the PPAR isotypes are discussed, namely their implication in the control of inflammatory responses, cell proliferation and differentiation, the roles of PPARalpha in fatty acid catabolism and of PPARgamma in adipogenesis.

How multiple repetitions influence the processing of self-, famous and unknown names and faces: an ERP study.

Because we live in an extremely complex social environment, people require the ability to memorize hundreds or thousands of social stimuli. The aim of this study was to investigate the effect of multiple repetitions on the processing of names and faces varying in terms of pre-experimental familiarity. We measured both behavioral and electrophysiological responses to self-, famous and unknown names and faces in three phases of the experiment (in every phase, each type of stimuli was repeated a pre-determined number of times). We found that the negative brain potential in posterior scalp sites observed approximately 170 ms after the stimulus onset (N170) was insensitive to pre-experimental familiarity but showed slight enhancement with each repetition. The negative wave in the inferior-temporal regions observed at approximately 250 ms (N250) was affected by both pre-experimental (famous>unknown) and intra-experimental familiarity (the more repetitions, the larger N250). In addition, N170 and N250 for names were larger in the left inferior-temporal region, whereas right-hemispheric or bilateral patterns of activity for faces were observed. The subsequent presentations of famous and unknown names and faces were also associated with higher amplitudes of the positive waveform in the central-parietal sites analyzed in the 320-900 ms time-window (P300). In contrast, P300 remained unchanged after the subsequent presentations of self-name and self-face. Moreover, the P300 for unknown faces grew more quickly than for unknown names. The latter suggests that the process of learning faces is more effective than learning names, possibly because faces carry more semantic information.

Immunological mechanism of action and clinical profile of disease-modifying treatments in multiple sclerosis.

Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials.

Teaching foreign languages through translation: considering multiple intelligences

Aquest treball de recerca tracta de la relació existent entre pedagogia, traducció, llengües estrangeres i intel•ligències múltiples. El debat sobre si la traducció és una eina útil a la classe de llengües estrangeres és un tema actual sobre el qual molts investigadors encara indaguen. Estudis recents, però, han demostrat que qualsevol tasca de traducció -en la qual s’hi poden incloure treballs amb les diferents habilitats- és profitosa si la considerem un mitjà, no una finalitat en ella mateixa. Evidentment, l’ús de la traducció dins l’aula és avantatjosa, però també hem de tenir presents certs desavantatges d’aquesta aplicació. Un possible desavantatge podria ser la creença que, al principi, molta gent té referent a l’equivalència, paraula per paraula, d’una llengua vers una altra. Però després de presentar vàries tasques de traducció als estudiants, aquests poden arribar a controlar, fins i tot, les traduccions inconscients i poden assolir un cert nivell de precisió i flexibilitat que val la pena mencionar. Però l’avantatge principal és que s’enfronten a una activitat molt estesa dins la societat actual que combina dues llengües, la llengua materna i la llengua objecte d’estudi, per exemple. De tot això en podem deduir que utilitzar la llengua materna a la classe no s’ha de considerar un crim, com fins ara, sinó una virtut, evidentment si és emprada correctament. En aquest treball de recerca s’hi pot trobar una síntesi tant de les principals teories d’adquisició i aprenentatge de llengües com de les teories de traducció. A la pregunta de si les teories, tant de traducció com de llengües estrangeres, s’haurien d’ensenyar implícita o explícitament, es pot inferir que segons el nivell d’estudis on estiguin els aprenents els convindrà aprendre les teories explícitament o les aprendran, de totes maneres, implícitament. Com que qualsevol grup d’estudiants és heterogeni -és a dir que cada individu té un ritme i un nivell d’aprenentatge concret i sobretot cadascú té diferents estils de percepció (visual, auditiu, gustatiu, olfactiu, de moviment) i per tant diferents intel•ligències-, els professors ho han de tenir en compte a l’hora de planificar qualsevol programa d’actuació vers els alumnes. Per tant, podem concloure que les tasques o projectes de traducció poden ajudar als alumnes a aprendre millor, més eficaçment i a aconseguir un aprenentatge més significatiu.

Conservation of a threatened European tree frog (Hyla arborea) metapopulation

Summary: Amphibians are among the most vulnerable animals of the world. One third of all species are currently threatened with extinction. Habitat loss is the major menace to pond- and stream-breeding species in the old world. In highly urbanized landscape like the Swiss Plateau, most species suffer from habitat reduction and fragmentation. Among all indigenous species, the European tree frog (Hyla arborea L., 1758) is one of the most endangered. It experienced an alarming decline during the last century and its regional long-term persistence is not guaranteed. We developed a monitoring framework based on calling male counts which included multiple visits to each wetland during the reproduction period in order to precisely determine its distribution on the Lemanic coast. Our results indicate that visiting populations 3 limes under suitable climatic conditions (temperature >20°C) provides reliable presence/absence data. Based on our monitoring data, we analyzed the species requirements regarding its breeding habitat. It appeared that anthropogenic activities had paradoxical effects on the species. On one hand, urbanization, traffic and intensive agriculture had a strong detrimental effect on tree frog distribution. On the other hand, large tree frog populations were frequently associated with gravel pits and military training grounds. Our results allowed us to create a habitat suitability map taking into account detrimental landscape elements around ponds (>1100m away from urban areas and >500m away from first class roads). In parallel, we developed a metapopulation model of the European tree frog in order to identify the critical threats to the long term persistence of the species. Our results indicated that suitable pond density is at the low end of the species requirements. Pond creation must therefore be considered an essential complementary approach to pond conservation and restoration. Our model also provided a mapping solution permitting the location of the must suitable area for pond creation from a metapopulation perspective. As many other amphibians, the European tree frog is not only exposed to an aquatic habitat (breeding and larval period), but also to a terrestrial stage (summer and overwintering habitats). Unfortunately, animals in their terrestrial phase are less conspicuous and, as a consequence, their terrestrial needs are relatively unknown. Using a recent tracking method (the Harmonic Direction Finder), we followed post-breeding frogs and identified favored terrestrial habitats, thus providing another practical conservation tool. We conclude that only the combination of multiple spatially explicit approaches (landscape-scale habitat suitability, metapopulation dynamics and terrestrial needs) is likely to provide wildlife managers with effective tools for the conservation of highly endangered amphibians. Résumé: Les amphibiens font partie des animaux les plus vulnérables du monde. Un tiers des espèces est actuellement menacé d'extinction. Dans l'ancien monde, la disparition des habitats constitue la principale menace pour les grenouilles, crapauds, tritons et salamandres. Dans les paysages fortement urbanisés comme le Plateau Suisse, la plupart des espèces souffrent d'une réduction et d'une fragmentation de leurs habitats. Parmi toutes les espèces indigènes, la rainette verte (Hyla arborea L., 1758) est l'une des plus menacée. Sa distribution a régressé de manière alarmante durant le siècle passé et sa survie régionale à long terme n'est pas assurée. Nous avons développé une méthode de suivi des populations se basant sur le comptage des mâles chanteurs durant la période de reproduction. Cette méthode requiert plusieurs visites à chaque plan d'eau de manière à déterminer précisément la distribution de l'espèce. Nos résultats démontrent que 3 visites par population dans des conditions climatiques favorable (température >20°C) permettent d'obtenir des données de présence/ absence valables. Sur la base de nos comptages sur la Côte lémanique, nous avons analysé les exigences de l'espèce concernant ses sites de reproduction. Il est apparu que les activités humaines avaient un effet paradoxal sur l'espèce. D'une part, l'urbanisation, le trafic routier et l'intensification de l'agriculture ont un effet fortement préjudiciable, tandis que d'autre part les plus grandes populations sont souvent associées à des gravières et autres places d'armes. Nos résultats ont permis de créer une carte de qualité d'habitat prenant en compte les éléments paysagers préjudiciables à la rainette (situé à plus de 1100m de zones urbaines et à plus de 500m de routes de première classe). En parallèle, nous avons développé un modèle métapopulationnel (incluant l'ensemble des populations) de manière à identifier les menaces prépondérantes sur la survie à long terme de l'espèce. Nos résultats ont permis de déterminer que la densité actuelle de plans d'eau adéquats est à la limite inférieure des exigences de l'espèce. La création d'étangs doit donc être considérée comme une approche indispensable et complémentaire à la protection et à la restauration des sites existants. Notre modèle a également fourni des résultats cartographiables permettant l'identification des sites les plus appropriés dans une perspective métapopulationnelle. Comme de nombreux autres amphibiens, la rainette verte est exposée à un habitat aquatique (reproduction et développement larvaire) ainsi qu'à un habitat terrestre (été et hiver). Les animaux étant particulièrement cryptiques dans cette seconde phase, leurs besoins terrestres sont relativement mal connus. Nous avons donc développé une nouvelle méthode de télémétrie basée sur le goniomètre harmonique. Cette méthode nous a permis de suivre des rainettes dans leurs migrations jusqu'à leurs habitats d'été et d'établir ainsi des recommandations pratiques pour la conservation de la rainette. Nous concluons que la combinaison de multiples approches spatialement explicites (qualité d'habitat, dynamique de métapopulation et habitats terrestres) est seule à même de produire des outils efficaces pour la conservation des espèces menacées d'amphibiens.