A European project on health problems, mental disorders and cross-cultural aspects of developing effective rehabilitation procedures for refugee and immigrant youth

The present paper describes the conceptual framework, rationale and methods of an international comparative study on risk and protective factors of adolescent health and well-being, with particular focus on youth with immigrant (or refugee) experience. This is a comprehensive study on the quality of life and health outcomes of adolescent youth that looks at group-specific differences within different socio-cultural contexts across six European countries, including those of post-conflict communities. The research project combines both quantitative and qualitative methods, using a common set-up across all countries involved with the goal of collecting data on 3,500 adolescents that are strictly comparable to allow cross-country analyses. It is particularly aimed at increasing the understanding of acculturation processes of a particularly sensitive population of adolescent refugees and immigrants and of the influence that the interaction of contextual and developmental factors has on their mental health and psychological well-being.     

Changes in small intestinal homeostasis, morphology, and gene expression during rotavirus infection of infant mice

Rotavirus is the most important cause of infantile gastroenteritis. Since in vivo mucosal responses to a rotavirus infection thus far have not been extensively studied, we related viral replication in the murine small intestine to alterations in mucosal structure, epithelial cell homeostasis, cellular kinetics, and differentiation. Seven-day-old suckling BALB/c mice were inoculated with 2 x 10(4) focus-forming units of murine rotavirus and were compared to mock-infected controls. Diarrheal illness and viral shedding were recorded, and small intestinal tissue was evaluated for rotavirus (NSP4 and structural proteins)- and enterocyte-specific (lactase, SGLT1, and L-FABP) mRNA and protein expression. Morphology, apoptosis, proliferation, and migration were evaluated (immuno)histochemically. Diarrhea was observed from days 1 to 5 postinfection, and viral shedding was observed from days 1 to 10. Two peaks of rotavirus replication were observed at 1 and 4 days postinfection. Histological changes were characterized by the accumulation of vacuolated enterocytes. Strikingly, the number of vacuolated cells exceeded the number of cells in which viral replication was detectable. Apoptosis and proliferation were increased from days 1 to 7, resulting in villous atrophy. Epithelial cell turnover was significantly higher (<4 days) than that observed in controls (7 days). Since epithelial renewal occurred within 4 days, the second peak of viral replication was most likely caused by infection of newly synthesized cells. Expression of enterocyte-specific genes was downregulated in infected cells at mRNA and protein levels starting as early as 6 h after infection. In conclusion, we show for the first time that rotavirus infection induces apoptosis in vivo, an increase in epithelial cell turnover, and a shutoff of gene expression in enterocytes showing viral replication. The shutoff of enterocyte-specific gene expression, together with the loss of mature enterocytes through apoptosis and the replacement of these cells by less differentiated dividing cells, likely leads to a defective absorptive function of the intestinal epithelium, which contributes to rotavirus pathogenesis.     

Sunless skin tanning with dihydroxyacetone delays broad-spectrum ultraviolet photocarcinogenesis in hairless mice

Sunless tanning with dihydroxyacetone (DHA) is not considered to be a sunscreen although it does absorb parts of the ultraviolet (UV) spectrum. We investigated the protection with topical application of DHA against solar UV-induced skin carcinogenesis in lightly pigmented hairless hr/hr C3H/Tif mice. Broad-spectrum UV radiation, simulating the UV part of the solar spectrum was obtained from one Philips TL12 and five Bellarium-S SA-1-12 tubes. Three groups of mice were UV-exposed four times a week to a dose-equivalent of four times the standard erythema dose (SED), without or with application of 5 or 20% DHA only twice a week. Similarly, three groups of mice were treated with DHA and irradiated with a high UV dose (8 SED), simulating a skin burn. Two groups (controls) were not irradiated, but either left untreated or treated with 20% DHA alone. The UV-induced skin pigmentation by melanogenesis could easily be distinguished from DHA-induced browning and was measured by a non-invasive, semi-quantitative method. Application of 20% DHA reduced by 63% the pigmentation produced by 4 SED, however, only by 28% the pigmentation produced by 8 SED. Furthermore, topical application of 20% DHA significantly delayed the time to appearance of the first tumor >or=1mm (P=0.0012) and the time to appearance of the third tumor (P=2 x 10(-6)) in mice irradiated with 4 SED. However, 20% DHA did not delay tumor development in mice irradiated with 8 SED. Application of 5% DHA did not influence pigmentation or photocarcinogenesis.In conclusion, this is the first study to show that the superficial skin coloring generated by frequent topical application of DHA in high concentrations may delay skin cancer development in hairless mice irradiated with moderate UV doses.     

The guanylate binding protein-1 GTPase controls the invasive and angiogenic capability of endothelial cells through inhibition of MMP-1 expression

Expression of the large GTPase guanylate binding protein-1 (GBP-1) is induced by inflammatory cytokines (ICs) in endothelial cells (ECs), and the helical domain of the molecule mediates the repression of EC proliferation by ICs. Here we show that the expression of GBP-1 and of the matrix metalloproteinase-1 (MMP-1) are inversely related in vitro and in vivo, and that GBP-1 selectively inhibits the expression of MMP-1 in ECs, but not the expression of other proteases. The GTPase activity of GBP-1 was necessary for this effect, which inhibited invasiveness and tube-forming capability of ECs in three-dimensional collagen-I matrices. A GTPase-deficient mutant (D184N-GBP-1) operated as a transdominant inhibitor of wild-type GBP-1 and rescued MMP-1 expression in the presence of ICs. Expression of D184N-GBP-1, as well as paracrine supplementation of MMP-1, restored the tube-forming capability of ECs in the presence of wild-type GBP-1. The latter finding indicated that the inhibition of capillary formation is specifically due to the repression of MMP-1 expression by GBP-1, and is not affected by the anti-proliferative activity of the helical domain of GBP-1. These findings substantiate the role of GBP-1 as a major regulator of the anti-angiogenic response of ECs to ICs.     

Smad3 mediates the TGF-beta-induced contraction of type I collagen gels by mouse embryo fibroblasts

TGF-beta signals through TGF-beta receptors and Smad proteins. TGF-beta also augments fibroblast-mediated collagen gel contraction, an in vitro model of connective tissue remodeling. To investigate the importance of Smad2 or Smad3 in this augmentation process, embryo-derived fibroblasts from mice lacking expression of Smad2 or Smad3 genes were cast into native type I collagen gels. Fibroblast-populated gels were then released into 0.2% FCS-DMEM alone or with recombinant human TGF-beta1, beta2, beta3, or recombinant rat PDGF-BB. Gel contraction was determined using an image analyzer. All three isoforms of TGF-beta significantly augmented contraction of collagen gels mediated by fibroblasts with genotypes of Smad2 knockout (S2KO), Smad2 wildtype (S2WT), and Smad3 wildtype (S3WT), but not Smad3 knockout (S3KO) mice. PDGF-BB augmented collagen gel contraction by all fibroblast types. These results suggest that expression of Smad3 but not Smad2 may be critical in TGF-beta augmentation of fibroblast-mediated collagen gel contraction. Thus, the Smad3 gene could be a target for blocking contraction of fibrotic tissue induced by TGF-beta.     

Deletion of all Cochliobolus heterostrophus monofunctional catalase-encoding genes reveals a role for one in sensitivity to oxidative stress but none with a role in virulence

The genome of the maize pathogen Cochliobolus heterostrophus encodes three unlinked monofunctional catalase-encoding (CAT) genes that singly or in combination could offer protection against the harmful effects of oxidative stress. Phylogenetic analysis placed the CAT2 and CAT3 proteins in a cluster with large subunit catalases (CAT3 has a secretory signal sequence and was grouped with known secreted catalases), whereas CAT1 clustered with small subunit catalases. Single, double, and triple cat mutants were created and screened for sensitivity to hydrogen peroxide and altered virulence on maize. All mutants deficient in CAT3 had enhanced sensitivity to hydrogen peroxide, as compared with wild type or with mutants deficient in CAT1, CAT2, or both. All catalase-deficient mutants had normal virulence to maize. Thus, the secreted CAT3 protein protects the fungus from oxidative stress during vegetative growth, but members of this enzyme family, alone or in combination, are not essential for virulence.     

Deracemization of an axially chiral biphenylic derivative as a tool for investigating chiral recognition in self-assemblies

Two diastereomeric cationic surfactants derived from L-proline, in which the second chiral center is a quaternary nitrogen, have been separated and fully characterized. The recognition properties of the aggregates formed by the two diastereomeric surfactants have been investigated by circular dichroism and (1)H NMR through deracemization of racemic 2-carboxy-2'-dodecyloxy-6-nitrobiphenyl.     

Interaction of sertraline with Candida species selectively attenuates fungal virulence in vitro

This study investigated whether the interaction between isolates of Candida albicans (n=7), Candida parapsilosis (n=3), Candida krusei (n=2), Candida dubliniensis (n=1) and sertraline, a typical selective serotonin reuptake inhibitor, alters candidal virulence. Sertraline treatment of Candida spp. significantly (P<0.05) affected hyphal elongation, phospholipase activity, production of secreted aspartyl proteinases and fungal viability. In addition, monocyte-derived macrophages (MDMs) treated with sertraline reduced inhibition of blastoconidia germination in comparison to MDMs alone. In conclusion, our findings suggest that the interaction between sertraline and Candida spp. may also diminish the virulence properties of this fungal pathogen in vivo.     

Linkage-dependent gene flow in a house mouse chromosomal hybrid zone

In the alpine valley of Valtellina there are two Robertsonian chromosomal races of house mouse, the Poschiavo (POS: 2n = 24-26) characterized by metacentric 8.12 and acrocentrics 2 and 10 and the Upper Valtellina (UV: 2n = 22-24) characterized by metacentrics 2.8 and 10.12. The races inhabit separate villages in the valley except in Sommacologna and Sondalo, where they both occur together with hybrids. A total of 179 mice from 16 villages were typed at 13 microsatellite loci. Seven of these loci were localized close to the centromeres of chromosomes 10 and 12, with the prediction that these regions on the race-specific chromosomes would be the most likely to experience a barrier to gene flow. The remaining six loci were localized at the telomeres of chromosomes 10 and 12 and at the centromeres of chromosomes that do not differ between the races. Substantial differences in allelic frequencies were found between the villages with POS and UV races at five of the loci at the centromeres of chromosomes 10 and 12 but at none of the other loci. These differences were not found to distinguish the two races in Sommacologna and Sondalo. Therefore, the centromeric regions of race-specific chromosomes do appear to experience a barrier to gene flow, although this can break down under intense interbreeding between the races. These results are considered in the context of Harrison's (1990) concept of the semipermeability of hybrid zones to gene exchange and in relation to parapatric speciation.