Protective effects of maternal nutritional supplementation with lactoferrin on growth and brain metabolism.

Background:Intrauterine growth restriction (IUGR) is a major risk factor for both perinatal and long-term morbidity. Bovine lactoferrin (bLf) is a major milk glycoprotein considered as a pleiotropic functional nutrient. The impact of maternal supplementation with bLf on IUGR-induced sequelae, including inadequate growth and altered cerebral development, remains unknown.Methods:IUGR was induced through maternal dexamethasone infusion (100 μg/kg during last gestational week) in rats. Maternal supplementation with bLf (0.85% in food pellet) was provided during both gestation and lactation. Pup growth was monitored, and Pup brain metabolism and gene expression were studied using in vivo (1)H NMR spectroscopy, quantitative PCR, and microarray in the hippocampus at postnatal day (PND)7.Results:Maternal bLf supplementation did not change gestational weight but increased the birth body weight of control pups (4%) with no effect on the IUGR pups. Maternal bLf supplementation allowed IUGR pups to recover a normalized weight at PND21 (weaning) improving catch-up growth. Significantly altered levels of brain metabolites (γ-aminobutyric acid, glutamate, N-acetylaspartate, and N-acetylaspartylglutamate) and transcripts (brain-derived neurotrophic factor (BDNF), divalent metal transporter 1 (DMT-1), and glutamate receptors) in IUGR pups were normalized with maternal bLf supplementation.Conclusion:Our data suggest that maternal bLf supplementation is a beneficial nutritional intervention able to revert some of the IUGR-induced sequelae, including brain hippocampal changes.

Regulation of protective immunity against Leishmania major in mice.

Resolution of lesions induced by Leishmania major in mice results from the development of Th1 responses. Cytokines produced by Th1 cells activate macrophages to a parasiticidal state. The development of Th2 responses in mice from a few strains underlies susceptibility to infection. Cytokines produced by Th2 cells exacerbate the development of lesions because of their deactivating properties for macrophages. This murine model of infection has provided significant insight into the mechanisms intrinsic to the differentiation of disparate CD4+ T cell subsets in vivo in animals from different genetic backgrounds.

Protective role of early aquaporin 4 induction against postischemic edema formation.

Aquaporin 4 (AQP4) is a water channel involved in water movements across the cell membrane and is spatially organized on the cell surface in orthogonal array particles (OAPs). Its role in edema formation or resolution after stroke onset has been studied mainly at late time points. We have shown recently that its expression is rapidly induced after ischemia coinciding in time with an early swelling of the ischemic hemisphere. There are two isoforms of AQP4: AQP4-M1 and AQP4-M23. The ratio of these isoforms influences the size of the OAPs but the functional impact is not known. The role of the early induction of AQP4 is not yet known. Thrombin preconditioning in mice provides a useful model to study endogenous protective mechanisms. Using this model, we provide evidence for the first time that the early induction of AQP4 may contribute to limit the formation of edema and that the AQP4-M1 isoform is predominantly induced in the ischemic tissue at this time point. Although it prevents edema formation, the early induction of the AQP4 expression does not prevent the blood-brain barrier disruption, suggesting an effect limited to the prevention of edema formation possibly by removing of water from the tissue.

Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy.

Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

Effects of an early intervention on maternal post-traumatic stress symptoms and the quality of mother-infant interaction: The case of preterm birth

Preterm birth may represent a traumatic situation for both parents and a stressful situation for the infant, potentially leading to difficulties in mother-infant relationships. This study aimed to investigate the impact of an early intervention on maternal posttraumatic stress symptoms, and on the quality of mother-infant interactions, in a sample of very preterm infants and their mothers. Half of the very preterm infants involved in the study (n=26) were randomly assigned to a 3-step early intervention program (at 33 and 42 weeks after conception and at 4 months' corrected age). Both groups of preterm infants (with and without intervention) were compared to a group of full-term infants. The impact of the intervention on maternal posttraumatic stress symptoms was assessed 42 weeks after conception and when the infants were 4 and 12 months of age. The impact of the intervention on the quality of mother-infant interactions was assessed when the infants were 4 months old. Results showed a lowering of mothers' posttraumatic stress symptoms between 42 weeks and 12 months in the group of preterm infants who received the intervention. Moreover, an enhancement in maternal sensitivity and infant cooperation during interactions was found at 4 months in the group with intervention. In the case of a preterm birth, an early intervention aimed at enhancing the quality of the mother-infant relationship can help to alleviate maternal post-traumatic stress symptoms and may have a positive impact on the quality of mother-infant interactions.

The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression.

Candidate gene and genome-wide association studies have not identified common variants, which are reliably associated with depression. The recent identification of obesity predisposing genes that are highly expressed in the brain raises the possibility of their genetic contribution to depression. As variation in the intron 1 of the fat mass- and obesity-associated (FTO) gene contributes to polygenic obesity, we assessed the possibility that FTO gene may contribute to depression in a cross-sectional multi-ethnic sample of 6561 depression cases and 21 932 controls selected from the EpiDREAM, INTERHEART, DeCC (depression case-control study) and Cohorte Lausannoise (CoLaus) studies. Major depression was defined according to DSM IV diagnostic criteria. Association analyses were performed under the additive genetic model. A meta-analysis of the four studies showed a significant inverse association between the obesity risk FTO rs9939609 A variant and depression (odds ratio=0.92 (0.89, 0.97), P=3 × 10(-4)) adjusted for age, sex, ethnicity/population structure and body-mass index (BMI) with no significant between-study heterogeneity (I(2)=0%, P=0.63). The FTO rs9939609 A variant was also associated with increased BMI in the four studies (β 0.30 (0.08, 0.51), P=0.0064) adjusted for age, sex and ethnicity/population structure. In conclusion, we provide the first evidence that the FTO rs9939609 A variant may be associated with a lower risk of depression independently of its effect on BMI. This study highlights the potential importance of obesity predisposing genes on depression.

Insight in the factors associated with the presence of protective antiviral T-cell response.

T cells play a primordial role in antiviral immunity. Virus-specific T-cell responses can be characterized by a number of independent variables. These include the magnitude of the response; the functional quality of the response, i.e. the types of cytokines secreted after stimulation and the proliferative or lytic potential; the tissue distribution of the T cells; the breadth of the response; and the avidity of the response. All of these together constitute the T-cell response to antigen (Ag) and comprise potential variables that may correlate with antiviral protective immunity. Substantial advances have recently been obtained in the characterization of virus-specific T-cell responses. These studies have shown that the quality (in term of functional profile) rather than the quantity of Ag-specific T cells was associated with protection. Recently, the term polyfunctional has been used to define T-cell responses that, in addition to typical effector functions such as secretion of IFN-g, TNF-a and MIP-1b and cytotoxic activity, comprise distinct T-cell populations, also able to secrete IL-2 and retaining Ag-specific proliferation capacity. The term \only effector" defines T-cell responses/ populations able to secrete cytokines such as IFN-g, TNF-a and MIP-1b and endowed with cytotoxic activity but lacking IL-2 and proliferation capacity. Several models of virus infections (HIV-1, cytomegalovirus [CMV], Epstein Barr virus [EBV], influenza [Flu] and Herpes Simplex virus) exclusively differentiated on the basis of Ag exposure and persistence, were investigated: 1) antigen clearance, 2) protracted Ag exposure and persistence and low Ag levels, 3) Ag persistence and high Ag levels, and 4) acute Ag exposure/re-exposure. These analyses have demonstrated that polyfunctional and not \only effector" T-cell responses were associated with protective antiviral immunity. However, the factors and mechanisms governing the generation of functionally distinct T-cell populations remain to be elucidated. Recently, several studies have shown a major influence of HLA genotype in the evolution of HIV and the progression of HIV-associated disease. In particular, certain HLA-B alleles were most closely associated with non-progressive disease and low viral load or disease and had a dominant involvement on the clinical course of HIV-associated diseases. In this study, we have investigated the relationship between HLA restriction and the functional profile of Tcell responses in order to determine whether HLA-B influenced the generation of polyfunctional CD8 T-cell responses. To be able to address this issue, we studied CD8 T-cell responses against HIV-1, CMV, EBV and Flu in 128 subjects. These analyses enabled us to demonstrate that HLA-Arestricted epitopes were mostly associated with \only effector" T-cell responses while, in contrast, polyfunctional CD8 T-cell responses were predominantly driven by virus epitopes restricted by HLA-B alleles. We then characterized eventual differences in the responsiveness of CD8 T-cell populations restricted by different HLA-A and HLA-B alleles. For this purpose, we investigated the T-cell receptor (TCR) avidity for the cognate epitope of polyfunctional and \only effector" CD8 T-cell populations. Our results indicated that overall virus-specific CD8 T-cell populations recognizing virus epitopes restricted by HLA-B alleles were equipped with lower avidity TCR for the cognate epitopes when compared to those recognizing epitopes restricted by HLA-A alleles. In conclusion, these results provide the rationale for the observed protective role of HLA-B genotypes in HIV-1- infection and new insights into the relationship between TCR avidity and functional profile of virus-specific CD8 Tcells.

The Effectiveness of Domestic Abuse Protective Orders and Court Practices in Sentencing Violators, July 2011

Deterring abuse is important to ensuring safety among domestic violence and assault victims. Protective orders are tools aimed at restricting contact between the victim and the abuser to prevent subsequent violence. While empirical research has indicated that protective orders are effective, the extent of the effectiveness is uncertain because violation rates have varied widely from study to study. In addition, little research exists to explain how violations of protective orders are handled, which factors are considered when giving penalties, and whether certain situations lead to a given type of penalty.

A murine genital-challenge model is a sensitive measure of protective antibodies against human papillomavirus infection.

The available virus-like particle (VLP)-based prophylactic vaccines against specific human papillomavirus (HPV) types afford close to 100% protection against the type-associated lesions and disease. Based on papillomavirus animal models, it is likely that protection against genital lesions in humans is mediated by HPV type-restricted neutralizing antibodies that transudate or exudate at the sites of genital infection. However, a correlate of protection was not established in the clinical trials because few disease cases occurred, and true incident infection could not be reliably distinguished from the emergence or reactivation of prevalent infection. In addition, the current assays for measuring vaccine-induced antibodies, even the gold standard HPV pseudovirion (PsV) in vitro neutralization assay, may not be sensitive enough to measure the minimum level of antibodies needed for protection. Here, we characterize the recently developed model of genital challenge with HPV PsV and determine the minimal amounts of VLP-induced neutralizing antibodies that can afford protection from genital infection in vivo after transfer into recipient mice. Our data show that serum antibody levels >100-fold lower than those detectable by in vitro PsV neutralization assays are sufficient to confer protection against an HPV PsV genital infection in this model. The results clearly demonstrate that, remarkably, the in vivo assay is substantially more sensitive than in vitro PsV neutralization and thus may be better suited for studies to establish correlates of protection.

The N-terminal domain of Plasmodium falciparum circumsporozoite protein represents a target of protective immunity.

The N-terminal domain of the circumsporozoite protein (CSP) has been largely neglected in the search for a malaria vaccine in spite of being a target of inhibitory antibodies and protective T cell responses in mice. Thus, in order to develop this region as a vaccine candidate to be eventually associated with other candidates and, in particular, with the very advanced C-terminal counterpart, synthetic constructs representing N- and C-terminal regions of Plasmodium falciparum and Plasmodium berghei CSP were administered as single or combined formulations in mice. We show that the antisera generated against the combinations inhibit sporozoite invasion of hepatocytes in vitro better than antisera against single peptides. Furthermore, two different P. falciparum CSP N-terminal constructs (PfCS22-110 and PfCS65-110) were recognized by serum samples from people living in malaria-endemic regions. Importantly, recognition of the short N-terminal peptide (PfCS65-110) by sera from children living in a malaria-endemic region was associated with protection from disease. Taken together, these results underline the potential of using such fragments as malaria vaccine candidates.