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.

Separation and Mapping of Chromosomes of Parasitic Protozoa

Many protozoan parasites represent an important group of human pathogens. Pulsed Field Gradient Gel Electrophoresis (PFGE) analysis has been an important tool for fundamental genetic studies of parasites like Trypanosoma, Leishmania, Giardia or the human malaria parasite Plasmodium falciparum. We present PFGE conditions allowing a high resolution separation of chromosomes ranging from 500 to 4000 kb within a two day electrophoresis run. In addition, we present conditions for separating large chromosomes (2000-6000 kb) within 36 hr. We demontrate that the application of two dimentional PFGE (2D-PFGE) technique to parasite karyotypes is a very useful method for the analysis of dispersed gene families and comparative studies of the intrachomosomal genome organization

Genes and Chromosomes of Leishmania infantum

During recent years, several Leishmania infantum genes have been cloned and characterized. Here, we have summarized the available information on the gene organization and expression in this protozoan parasite. From a comparative analysis, the following outstanding features were found to be common to most of the genes characterized: tandemly organized genes with conserved coding regions and divergent untranslated regions, polycistronic transcription and post-transcriptional regulation of gene expression. The analysis of chromosomes of L. infantum by pulsed-field electrophoresis showed the existence of both size and number polymorphisms such that each strain has a distinctive molecular karyotype. Despite this variability, highly conserved physical linkage groups exists among different strains of L. infantum and even among Old World Leishmania species. Gene mapping on the L. infantum molecular karyotype evidenced a bias in chromosomal distribution of, at least, the evolutionary conserved genes

Girls like pink: explaining sex-typed occupational aspirations amongst young children

There is a high degree of sex-typing in young children's occupational aspirations and this has consequences for subsequent occupational segregation. Sociologists typically attribute early sex-differences in occupational preferences to gender socialization. Yet we still know surprisingly little about the mechanisms involved in the intergenerational transmission of sex-typical preferences and there is considerable theoretical controversy regarding the role of individual agency in the process of preference formation. This study analyzes the determinants of sex-typed occupational aspirations amongst British children aged between 11 and 15. We specify different mechanisms involved in the transmission of sex-typical preferences and propose an innovative definition of individual agency that is anchored in observable psychological traits linked to self-direction. This allows us to perform a simultaneous test of socialization and agency predictors of occupational sex-typing. We find that parental influences on occupational preferences operate mainly through three distinctive channels: 1) the effect that parental socio-economic resources have on the scope of children's occupational aspirations, 2) children's direct imitation of parental occupations, and 3) children's learning of sex-typed roles via the observation of parental behavior. We also find a strong net effect of children's own psychological predispositions -self-esteem in particular- on the incidence of sex-typical occupational preferences. Yet large differences in the occupational aspirations of girls and boys remain unexplained.

The Polytene Chromosomes of Cnesia dissimilis (Edwards) and Three Species of Gigantodax Enderlein (Diptera: Simuliidae) from Lanin National Park (Argentina)

Cytological studies were made on larvae of Gigantodax marginalis, G. chilensis, G. fulvescens and Cnesia dissimilis from four creeks in Lanin National Park, Neuquen province, Argentina. Chromosome maps and idiograms of these species are presented. The following inversions were observed: G. marginalis: IL-1 (X-linked inversion), IL-2 (Y-linked inversion), IIS-1.2, IIL-1, IIIL-4,5; G. chilensis: IL-4 (X-linked inversion), IIS-1.2, IIIL-4,5; G. fulvescens:IL-1 (X-linked inversion), IL-3 (Y-linked inversion), IIS-1.2, IIL-1, IIIL-4,5; C. dissimilis: IL-1, IL-5, IIIL-1. Karyological information was used to construct a cladogram and Cnesia sp. Was found to show close resemblance to the three Gigantodax spp.

Clonal heterogeneity and chromosomal instability at disease presentation in high hyperdiploid acute lymphoblastic leukemia.

Although aneuploidy has many possible causes, it often results from underlying chromosomal instability (CIN) leading to an unstable karyotype with cell-to-cell variation and multiple subclones. To test for the presence of CIN in high hyperdiploid acute lymphoblastic leukemia (HeH ALL) at diagnosis, we investigated 20 patients (10 HeH ALL and 10 non-HeH ALL), using automated four-color interphase fluorescence in situ hybridization (I-FISH) with centromeric probes for chromosomes 4, 6, 10, and 17. In HeH ALL, the proportion of abnormal cells ranged from 36.3% to 92.4%, and a variety of aneuploid populations were identified. Compared with conventional cytogenetics, I-FISH revealed numerous additional clones, some of them very small. To investigate the nature and origin of this clonal heterogeneity, we determined average numerical CIN values for all four chromosomes together and for each chromosome and patient group. The CIN values in HeH ALL were relatively high (range, 22.2-44.7%), compared with those in non-HeH ALL (3.2-6.4%), thus accounting for the presence of numerical CIN in HeH ALL at diagnosis. We conclude that numerical CIN may be at the origin of the high level of clonal heterogeneity revealed by I-FISH in HeH ALL at presentation, which would corroborate the potential role of CIN in tumor pathogenesis.

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.

Early expression of the type III secretion system of Parachlamydia acanthamoebae during a replicative cycle within its natural host cell Acanthamoeba castellanii.

The type three secretion system (T3SS) operons of Chlamydiales bacteria are distributed in different clusters along their chromosomes and are conserved at both the level of sequence and genetic organization. A complete characterization of the temporal expression of multiple T3SS components at the transcriptional and protein levels has been performed in Parachlamydia acanthamoebae, replicating in its natural host cell Acanthamoeba castellanii. The T3SS components were classified in four different temporal clusters depending on their pattern of expression during the early, mid- and late phases of the infectious cycle. The putative T3SS transcription units predicted in Parachlamydia are similar to those described in Chlamydia trachomatis, suggesting that T3SS units of transcriptional expression are highly conserved among Chlamydiales bacteria. The maximal expression and activation of the T3SS of Parachlamydia occurred during the early to mid-phase of the infectious cycle corresponding to a critical phase during which the intracellular bacterium has (1) to evade and/or block the lytic pathway of the amoeba, (2) to differentiate from elementary bodies (EBs) to reticulate bodies (RBs), and (3) to modulate the maturation of its vacuole to create a replicative niche able to sustain efficient bacterial growth.

The separate and combined effects of MHC genotype, parasite clone, and host gender on the course of malaria in mice.

BACKGROUND: The link between host MHC (major histocompatibility complex) genotype and malaria is largely based on correlative data with little or no experimental control of potential confounding factors. We used an experimental mouse model to test for main effects of MHC-haplotypes, MHC heterozygosity, and MHC x parasite clone interactions. We experimentally infected MHC-congenic mice (F2 segregants, homo- and heterozygotes, males and females) with one of two clones of Plasmodium chabaudi and recorded disease progression. RESULTS: We found that MHC haplotype and parasite clone each have a significant influence on the course of the disease, but there was no significant host genotype by parasite genotype interaction. We found no evidence for overdominance nor any other sort of heterozygote advantage or disadvantage. CONCLUSION: When tested under experimental conditions, variation in the MHC can significantly influence the course of malaria. However, MHC heterozygote advantage through overdominance or dominance of resistance cannot be assumed in the case of single-strain infections. Future studies might focus on the interaction between MHC heterozygosity and multiple-clone infections.

Sex differences in nuclear receptor-regulated liver metabolic pathways.

Liver metabolism is markedly sex-dimorphic; accordingly, the prevalence of liver diseases is different between sexes. The superfamily of nuclear receptors (NRs) governs the proper expression of key liver metabolism genes by sensing lipid-soluble hormones and dietary lipids. When the expression of those genes is deregulated, disease development is favored. However, we lack a comprehensive picture of the differences between NR actions in males and females. Here, we reviewed explorative studies that assessed NR functions in both sexes, and we propose a first map of sex-dimorphic NR expression in the liver. Our analysis suggested that NRs in the female liver exhibited cross-talk with more liver-protective potential than NRs in male liver. This study provides empirical support to the hypothesis that women are more resilient to some liver diseases than men, based on a more compensative NR network. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

Role of disease activity for decision making ability in early multiple sclerosis

Background and purpose: Decision making (DM) has been defined as the process through which a person forms preferences, selects and executes actions, and evaluates the outcome related to a selected choice. This ability represents an important factor for adequate behaviour in everyday life. DM impairment in multiple sclerosis (MS) has been previously reported. The purpose of the present study was to assess DM in patients with MS at the earliest clinically detectable time point of the disease. Methods: Patients with definite (n=109) or possible (clinically isolated syndrome, CIS; n=56) MS, a short disease duration (mean 2.3 years) and a minor neurological disability (mean EDSS 1.8) were compared to 50 healthy controls aged 18 to 60 years (mean age 32.2) using the Iowa Gambling Task (IGT). Subjects had to select a card from any of 4 decks (A/B [disadvantageous]; C/D [advantageous]). The game consisted of 100 trials then grouped in blocks of 20 cards for data analysis. Skill in DM was assessed by means of a learning index (LI) defined as the difference between the averaged last three block indexes and first two block indexes (LI=[(BI-3+BI-4+BI-5)/3-(BI-1+B2)/2]). Non parametric tests were used for statistical analysis. Results: LI was higher in the control group (0.24, SD 0.44) than in the MS group (0.21, SD 0.38), however without reaching statistical significance (p=0.7). Interesting differences were detected when MS patients were grouped according to phenotype. A trend to a difference between MS subgroups and controls was observed for LI (p=0.06), which became significant between MS subgroups (p=0.03). CIS patients who confirmed MS diagnosis by presenting a second relapse after study entry showed a dysfunction in the IGT in comparison to the other CIS (p=0.01) and definite MS (p=0.04) patients. In the opposite, CIS patients characterised by not entirely fulfilled McDonald criteria at inclusion and absence of relapse during the study showed an normal learning pattern on the IGT. Finally, comparing MS patients who developed relapses after study entry, those who remained clinically stable and controls, we observed impaired performances only in relapsing patients in comparison to stable patients (p=0.008) and controls (p=0.03). Discussion: These results raise the assumption of a sustained role for both MS relapsing activity and disease heterogeneity (i.e. infra-clinical severity or activity of MS) in the impaired process of decision making.

Plasticity in sex allocation in the plant Mercurialis annua is greater for hermaphrodites sampled from dimorphic than from monomorphic populations.

Plants are notoriously variable in gender, ranging in sex allocation from purely male through hermaphrodite to purely female. This variation can have both a genetic and an adaptive plastic component. In gynodioecious species, where females co-occur with hermaphrodites, hermaphrodites tend to shift their allocation towards greater maleness when growing under low-resource conditions, either as a result of hermaphrodites shifting away from an expensive female function, or because of enhanced siring advantages in the presence of females. Similarly, in the androdioecious plant Mercurialis annua, where hermaphrodites co-exist with males, hermaphrodites also tend to enhance their relative male allocation under low-resource conditions. Here, we ask whether this response differs between hermaphrodites that have been evolving in the presence of males, in a situation analogous to that supposed for gynodioecious populations, vs. those that have been evolving in their absence. We grew hermaphrodites of M. annua from populations in which males were either present or absent under different levels of nutrient availability and compared their reaction norms. We found that, overall, hermaphrodites from populations with males tended to be more female than those from populations lacking males. Importantly, hermaphrodites' investment in pollen and seed production was more plastic when they came from populations with males than without them, reducing their pollen production at low resource availability and increasing their seed production at high resource availability. These results are consistent with the hypothesis that plasticity in sex allocation is enhanced in hermaphrodites that have likely been exposed to variation in mating opportunities due to fluctuations in the frequency of co-occurring males.

Multiple facets of secretory immunoglobulin A at mucosal surfaces

Résumé : Le condylome acuminé anal (CAA), transmis par contact sexuel, résulte d'une infection par Human Papilloma Virus (HPV). Son traitement chirurgical est grevé d'un taux de récidive de 4-29%. Le but de cette étude était d'identifier une éventuelle corrélation entre type d'HPV présent dans les CAA excisés chirurgicalement et taux de récidive de la maladie, ? Cette étude rétrospective porte sur 140 patients opérés au Centre Hospitalier Universitaire Vaudois de CAA, entre 1990 et 2005. Le diagnostic lésionnel a été confirmé par un examen histomorphologique. Le(s) type(s) d'HPV présent(s) dans ces lésions a été déterminé par Polymerase Chain Reaction (PCR). Les patients ont donné leur accord à cette analyse et complété un questionnaire. Une éventuelle corrélation entre récidive de CAA, type d'HPV et status HIV a été recherchée. HPV 6 et 11 sont les virus les plus fréquemment découverts (51% et 28%, respectivement) chez les 140 patients (123H/17F). Trente-cinq (25%) d'entre eux ont présenté une récidive. HPV 11 était present chez 19 (41%) sujets. Ceci est statistiquement significatif (P<0.05), en comparaison aux autres HPVs. Il n'y a par contre pas de différence significative entre la fréquence de récidive des 33 (24%) patients HIV-positifs et le reste du collectif. HPV 11 est donc associé à un taux de récidive de CAA significativement élevé. Un suivi strict des patients atteints est nécessaire pour identifier une récidive et la traiter sans délai, notamment lorsque HPV 11 est present. Ces résultats innovateurs soulèvent la question de la nécessité de pratiquer une typisation virale systématique sur les lésions excisées. La justification d'une telle attitude demande toutefois encore d'être confirmée.