Common Variable Immunodeficiency: molecular pathways and clinical manifestations

Common variable immunodeficiency (CVID), is a disease that is characterized by hypogammaglobulinemia as well as a defect in T, B and dendritic cells. This leads to recurrent bacterial infection mainly caused by Streptococcus pneumoniae, Klebsiella pneumoniae and Haemophilus influenzae, as well as inflammatory manifestations, i.e. granulomateous disease, gastro-intestinal disorders and chronic lung disease. Intravenous Immunoglobulin (IVIg) therapy reduces CVID susceptibility to bacterial infections to some extend. We analyzed clinical aspects of patients from our database. We recently showed that bacteria-specific CD4 T cells of CVID patients were impaired. We therefor postulated that CVID patients may harbor an acquired T-cell deficiency also called exhaustion. To test this hypothesis, we performed a comprehensive investigation of the functional profiles of bacteria-specific CD4 T cells isolated from 31 healthy individuals and 30 CVID patients. In the present study, we demonstrated that bacteria-specific but not virus-specific CD4 T cells in CVID patients harbored reduced proliferation capacity and expressed high level of PD-1. Interestingly, the blockade of PD-1/PD-1 ligands interactions restored partially bacteria but not virus-specific CD4 T-cell proliferation. Finally, we showed that 1) the level of endotoxins inversely correlates with IgG concentration, 2) IVIG treated CVID patients harbored reduced endotoxemia and 3) IgG concentration exceeding 7 mg/mL strongly reduces both the proportion of CVID patients with detectable endotoxemia and the concentration of endotoxins in plasma. Taken together our observations, suggest that primary B-cell defect(s) in CVID patients leads to recurrent bacterial infections that are associated to an acquired (secondary) impairment of CD4 T cells which may in turn exacerbate the lack of protection against extracellular bacteria.

A common ancestor DNA motif for invertebrate and vertebrate hormone response elements.

The ecdysone-responsive DNA sequence of the Drosophila hsp27 gene promoter contains four direct and inverted repeats reminiscent of those that compose the vertebrate palindromic estrogen response element (ERE) and the thyroid hormone/retinoic acid response element (TRE/RRE). Interestingly, a 3 bp substitution in the wild-type Hsp27 ecdysone response element (EcdRE) increases both its similarity with the vertebrate ERE and TRE/RRE and its capacity to confer ecdysone responsiveness to a heterologous promoter. Remarkably, increasing the spacing between the inverted repeats of this strong EcdRE by two nucleotides converts it into an ERE. Inversely, decreasing the spacing between the two inverted repeats of the vertebrate consensus palindromic ERE, from three to one nucleotide, converts it into a functional EcdRE. Thus, the only difference between an invertebrate EcdRE and a vertebrate palindromic ERE or TRE/RRE is in the spacing between the conserved inverted repeated motifs forming these palindromic HREs. The finding that the sequence motif 5'-GGTCA-3' present in the vertebrate ERE and TRE/RRE is also a functionally important characteristic of an invertebrate HRE, suggests that a common ancestor regulatory DNA sequence gave rise to all HREs known so far. We discuss the possibility that this progenitor motif is the GGTCA sequence.

Trauma et mémoire - quand la douleur infiltre le corps et l'âme: un regard sur les toxicodépendances graves

This article describes the long-lasting psychological after-effects of a traumatic experience. There is growing lmowledge of the biomedical underpinnings of these phenomena: the underlying mechanisms belong to an implicit learning process whereby the victim remains under the influence of painful past experiences. One of these mechanisms concerns the development of a traumatic bonding which Iioticeably impedes the establishment of interpersona! relationships. The other mechanism, called "contextualisation deficit", is the difficulty of adjusting a person's emotional and behavioural reactivity to the context of present day !ife. This capacity of a traumatic experience to become incrusted long-termina human being's mind, and to haunt the victim with various forms of psychological and physical suffering, can be compared with the presence of a tumour or an abscess in somatic medicine. Th us, severe drug addiction can be conceptualised as a disorder in which the patient tries - in most cases ineffectively - to soothe the pain of today's world in cmmection with the trauma of the past. In conclusion, this article urges the development of psychiatrie care programmes which operate at the centre of the suffering encountered by the se patients, as a complement to the already well-established offers such as harm reduction, substitution therapy and social support.

Blood corticosterone levels and intersexual selection games: best-of-bad-job strategies of male common lizards

Glucocorticoids affect physiology and behaviour, reproduction and potentially sexual selection as well. Shortterm and moderate glucocorticoid elevations are suggested to be adaptive, and prolonged and high elevations may be extremely harmful. This suggests that optimal reproductive strategies, and thus sexual selection, may be dose dependent. Here, we investigate effects of moderate and high elevations of blood corticosterone levels on intra- and intersexual behaviour and mating success of male common lizards Lacerta vivipara. Females showed less interest and more aggressive behaviour towards high corticosterone males and blood corticosterone levels affected male reproductive strategy. Males of moderate and high corticosterone elevations, compared with Control males, showed increased interest (i.e., higher number of chases, tongue extrusions, and approaches) towards females and high corticosterone males initiated more copulation attempts. However, neither increased male interest nor increased copulation attempts resulted in more copulations. This provides evidence for a best-of-a-bad-job strategy, where males with higher corticosterone levels compensated for reduced female interest and increased aggressive female behaviour directed towards them, by showing higher interest and by conducting more copulation attempts. Blood corticosterone levels affected intrasexual selection as well since moderate corticosterone levels positively affected male dominance, but dominance did not affect mating success. These findings underline the importance of female mate choice and are in line with adaptive compensatory behaviours of males. They further show that glucocorticoid effects on behaviour are dose dependent and that they have important implications for sexual selection and social interactions, and might potentially affect Darwinian fitness.

Effects of common origin and common rearing environment on variance in ectoparasite load and phenotype of nestling Alpine swifts

Knowledge of the quantitative genetics of resistance to parasitism is key to appraise host evolutionary responses to parasite selection. Here, we studied effects of common origin (i.e. genetic and pre-hatching parental effects) and common rearing environment (i.e. post-hatching parental effects and other environment effects) on variance in ectoparasite load in nestling Alpine swifts (Apus melba). This colonial bird is intensely parasitized by blood sucking louse-flies that impair nestling development and survival. By cross-fostering half of the hatchlings between pairs of nests, we show strong significant effect of common rearing environment on variance (90.7% in 2002 and 90.9% in 2003) in the number of louse-flies per nestling and no significant effect of common origin on variance in the number of louse-flies per nestling. In contrast, significant effects of common origin were found for all the nestling morphological traits (i.e. body mass, wing length, tail length, fork length and sternum length) under investigation. Hence, our study suggests that genetic and pre-hatching parental effects play little role in the distribution of parasites among nestling Alpine swifts, and thus that nestlings have only limited scope for evolutionary responses against parasites. Our results highlight the need to take into consideration environmental factors, including the evolution of post-hatching parental effects such as nest sanitation, in our understanding of host-parasite relationships.

The list of the chromosome races of the common shrew (Sorex araneus)

The list of chromosome races of the common shrew (Sorex araneus) was compiled, the vast literature has been scrutinized, and unpublished data have been added. Altogether, 50 chromosome races could be listed. The name and its synonyms, chromosomal constitution, author of the description, type locality, known distribution range, and additional information are reported for individual races. The present list should be considered a working document that will be regularly updated and supplemented.

Common variants in mendelian kidney disease genes and their association with renal function.

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

Habitat selection in zones of parapatric contact between the Common shrew Sorex araneus and Millet's shrew S. coronatus

(1) The common shrew Sorex araneus and Millet's shrew S. coronatus are sibling species.They are morphologically and genetically very similar but do not hybridize. Their parapatric distribution throughout south-western Europe, with a few narrow zones of distributional overlap, suggests that they are in competitive parapatry. (2) Two of these contact zones were studied; there was evidence of coexistence over periods of 2 years as well as habitat segregation. In both zones, the species segregated on litter thickness and humidity variables. (3) A simple analysis of spatial distribution showed that habitats visible in the field corresponded to the habitats selected by the species. Habitat selection was found throughout the annual life-cycle of the shrews. (4) In one contact zone, a removal experiment was performed to test whether habitat segregation is induced by interspecific interactions. The experiment showed that the species select habitats differentially when both are present and abandon habitat selection when their competitor is removed. (5) These results confirm the role of resource partitioning in promoting narrow rangesof distributional overlap between such parapatric species and qualitatively support the prediction of habitat selection theory that, in a two-species system, coexistence may be achieved by differential habitat selection to avoid competition. The results also support the view that the common shrew and Millet's shrew are in competitive parapatry.

Oui à la chasse au dopage pour la santé des athlètes et du sport [Sports and athletes deserve doping runting].

Cet article se veut une revue des effets ergogéniques et potentiellement délétères des principaux compléments alimentaires consommés par les sportifs populaires ou d'élite. De nombreux produits sont proposés sur le marché avec des allégations prometteuses, le plus souvent sans preuve scientifique sur leur validité ou leur innocuité. Les antioxydants n'augmentent ni la force ni l'endurance. La créatine améliore la capacité de récupération pour les exercices en intervalle anaérobie mais pas en course à pied ni en natation. L'hormone de croissance et les stéroïdes anabolisants augmentent la synthèse protéique et la masse maigre mais comportent des effets secondaires graves et souvent irréversibles. Les médecins, les diététiciens et les fédérations sportives ont un rôle important à jouer dans l'information et la prévention, afin d'éviter des attitudes néfastes pour la santé, pouvant même créer des addictions. This article reviews the evidence-based ergogenic potential adverse effects of the most common products in use by recreational and elite athletes today. This is an aggressively marketed and controversial area of sports medicine wordwide. It is therefore important for the scientific societies, clinicians, dieticians sports federations to be well versed in the more popular supplements and drugs in order to have an important role in information and prevention attitudes that can lead to health risks or addictions!

Do riverine barriers, history or introgression shape the genetic structuring of a common shrew (Sorex araneus) population?

The common shrew (Sorex araneus) is subdivided into numerous chromosome races. The Valais and Cordon chromosome races meet and hybridize at a mountain river in Les Houches (French Alps). Significant genetic structuring was recently reported among populations found on the Valais side of this hybrid zone. In this paper, a phylogenetic analysis and partial Mantel tests are used to investigate the patterns and causes of this structuring. A total of 185 shrews were trapped at 12 localities. All individuals were typed for nine microsatellite loci. Although several mountain rivers are found in the study area, riverine barriers do not have a significant influence on gene flow. Partial Mantel tests show that our result is caused by the influence of the hybrid zone with the Cordon race. The geographical patterns of this structuring are discussed in the context of the contact zone, which appears to extend up to a group of two rivers. The glacier they originate from is known to have cut the Arve valley as recently as 1818. The recent history of this glacier, its moraine and possibly rivers, may therefore be linked to the history of this hybrid zone.

Ligamentous and tendinous anatomy of the intermetacarpal and common carpometacarpal joints: evaluation with MR imaging and MR arthrography.

PURPOSE: The purpose of this work was to demonstrate the normal ligamentous and tendinous anatomy of the intermetacarpal (IMC) and common carpometacarpal (CCMC) joints with MRI and MR arthrography. METHOD: MR images of 22 wrists derived from fresh human cadavers were obtained before and after arthrography. The MR imaging features of the ligaments and tendons about the CCMC and IMC joints and the joints themselves were analyzed in a randomized fashion and correlated with those seen on anatomic sections. RESULTS: Six CCMC ligaments were visualized. The dorsal and palmar CCMC ligaments and the pisometacarpal ligament were best visualized in the sagittal plane. The radial and ulnar CCMC collateral ligaments and the capito-third metacarpal ligament were best visualized in the coronal plane. Three main IMC ligaments were observed: a dorsal and a palmar ligament and an interosseous ligament complex. All three ligaments were best visualized in the axial plane. Four tendinous insertions to the metacarpal bases were evident. CONCLUSION: The anatomy of the ligaments and tendinous insertions about the second to fifth IMC and the CCMC joints is well demonstrated by MR imaging and MR arthrography. MR arthrography does not significantly improve the visualization of these complex structures.

Thermal energetics and torpor in the common pipistrelle bat, Pipistrellus pipistrellus (Vespertilionidae: Mammalia).

Rate of metabolism and body temperature were studied between -6°C and 38°C in the common pipistrelle bat Pipistrellus pipistrellus (Vespertilionidae), a European species lying close to the lower end of the mammalian size range (body mass 4.9±0.8g, N=28). Individuals maintained only occasionally a normothermic body temperature averaging 35.4±1.1°C (N=4) and often showed torpor during metabolic runs. The thermoneutral zone was found above 33°C, and basal rate of metabolism averaged 7.6±0.8mL O(2)h(-1) (N=28), which is 69% of the value predicted on the basis of body mass. Minimal wet thermal conductance was 161% of the expected value. During torpor, the rate of metabolism was related exponentially to body temperature with a Q(10) value of 2.57. Torpid bats showed intermittent ventilation, with the frequency of ventilatory cycles increasing exponentially with body temperature. Basal rate of metabolism (BMR) varied significantly with season and body temperature, but not with body mass. It was lower before the hibernation period than during the summer. The patterns observed are generally consistent with those exhibited by other vespertilionids of temperate regions. However, divergences occur with previous measurements on European pipistrelles, and the causes of the seasonal variation in BMR, which has only rarely been searched for among vespertilionids, remain to be examined.

Secondhand smoke exposure in children is associated with common carotid artery intima-media thickness

Objective: To investigate the association between common carotid artery intima-media thickness (cIMT) and exposure to secondhand smoke (SHS) in children. Methods: Data were available at baseline in the Quebec Adiposity and Lifestyle investigation in Youth (QUALITY) study, an ongoing longitudinal investigation of Caucasian children aged 8e10 years at cohort inception, who had at least one obese parent. Data on exposure to parents, siblings and friends smoking were collected in interviewer-administered child, and self-report parent questionnaires. Blood cotinine was measured with a high sensitivity ELISA. cIMTwas measured by ultrasound. The association between blood cotinine and cIMT was investigated in multivariable linear regression analyses controlling for age, body mass index, and child smoking status. Results: Mean (SD) cIMT (0.5803 (0.04602)) did not differ across age or sex. Overall 26%, 6% and 3% of children were exposed to parents, siblings and friends smoking, respectively. Cotinine ranged from 0.13 ng/ml to 7.38 ng/ml (median (IQR)¼0.18 ng/ml)). Multivariately, a 1 ng/ml increase in cotinine was associated with a 0.090 mm increase in cIMT (p¼0.034). Conclusion: In children as young as age 8e10 years, exposure to SHS relates to cIMT, a marker of pre-clinical atherosclerosis. Given the wide range of health effects of SHS, increased public health efforts are needed to reduced exposure among children in homes an private vehicles.