Axonal regeneration of retinal ganglion cells after optic nerve pre-lesions and attachment of normal or pre-degenerated peripheral nerve grafts

Axonal regeneration of retinal ganglion cells (RGCs) into a normal or pre-degenerated peripheral nerve graft after an optic nerve pre-lesion was investigated. A pre-lesion performed 1-2 weeks before a second lesion has been shown to enhance axonal regeneration in peripheral nerves (PN) but not in optic nerves (ON) in mammals. The lack of such a beneficial pre-lesion effect may be due to the long delay (1-6 weeks) between the two lesions since RGCs and their axons degenerate rapidly 1-2 weeks following axotomy in adult rodents. The present study examined the effects of the proximal and distal ON pre-lesions with a shortened delay (0-8 days) on axonal regeneration of RGCs through a normal or pre-degenerated PN graft. The ON of adult hamsters was transected intraorbitallv at 2 mm. (proximal lesion) or intracranially at 7 mm (distal lesion) from the optic disc. The pre-lesioned ON was re-transected at 0.5 mm from the disc after 0, 1, 2, 4, or 8 days and a normal or a pre-degenerated PN graft was attached onto the ocular stump. The number of RGCs regenerating their injured axons into the PN graft was estimated by retrograde labeling with FluoroGold 4 weeks after grafting. The number of regenerating RGCs decreased significantly when the delay-time increased in animals with both the ON pre-lesions (proximal or distal) compared to control animals without an ON pre-lesion. The proximal ON pre-lesion significantly reduced the number of regenerating RGCs after a delay of 8 days in comparison with the distal lesion. However, this adverse effect can be overcome, to some degree, by a pre-degenerated PN graft applied 2, 4, or 8 days after the distal ON pre-lesion enhanced more RGCs to regenerate than the normal PN graft. Thus, in order to obtain the highest number of regenerating RGCs, a pre-degenerated PN should be grafted immediately after an ON lesion.

Attachment and infant difficultness in postnatal depression

This project investigated the relationship between attachment style and postnatal depression. In a sample of mothers with infants, those identifying themselves as depressed reported a more preoccupied attachment style by comparison with their nondepressed counterparts. Maternal attachment style was not related to perceived infant characteristics or to the reported mother-child relationship. Postnatal depression, however, was related to both perceived infant characteristics and the reported mother-child relationship. Although postnatal depression was not significantly related to marital quality, a trend did emerge between attachment style and marital quality. These findings suggest that further research is warranted to clarify the relationship between attachment style and postnatal depression.

IL-10 Mediates Suppression of the CD8 T Cell IFN-γ Response to a Novel Viral Epitope in a Primed Host

Priming to Ag can inhibit subsequent induction of an immune response to a new epitope incorporated into that Ag, a phenomenon referred to as original antigenic sin. In this study, we show that prior immunity to a virus capsid can inhibit subsequent induction of the IFN-gamma effector T cell response to a novel CD8-restricted antigenic epitope associated with the virus capsid. Inhibition does not involve Ab to the virus capsid, as it is observed in animals lacking B cells. CD8-restricted virus-specific T cell responses are not required, as printing to virus without CTL induction is associated with inhibition. However, IL-10(-/-) mice, in contrast to IL-10(+/+) mice, generate CD8 T cell and Ab responses to novel epitopes incorporated into a virus capsid, even when priming to the capsid has resulted in high titer Ab to the capsid. Furthermore, capsid-primed mice, unable to mount a response to a novel epitope in the capsid protein, are nevertheless able to respond to the same novel epitope delivered independently of the capsid. Thus, inhibition of responsiveness to a novel epitope in a virus-primed animal is a consequence of secretion of IL-10 in response to presented Ag, which inhibits local generation of new CD8 IFN-gamma-secreting effector T cells. Induction of virus- or tumor Ag-specific CD8 effector T cells in the partially Ag-primed host may thus be facilitated by local neutralization of IL-10.

The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-activation, Coactivator Recruitment, and Activation by the Purine Anti-metabolite 6-Mercaptopurine

NOR-1/NR4A3 is an orphan member of the nuclear hormone receptor superfamily. NOR-1 and its close relatives Nurr1 and Nur77 are members of the NR4A subgroup of nuclear receptors. Members of the NR4A subgroup are induced through multiple signal transduction pathways. They have been implicated in cell proliferation, differentiation, T-cell apoptosis, chondrosarcomas, neurological disorders, inflammation, and atherogenesis. However, the mechanism of transcriptional activation, coactivator recruitment, and agonist-mediated activation remain obscure. Hence, we examined the molecular basis of NOR-1-mediated activation. We observed that NOR-1 trans-activates gene expression in a cell- and target-specific manner; moreover, it operates in an activation function (AF)-1-dependent manner. The N-terminal AF-1 domain delimited to between amino acids 1 and 112, preferentially recruits the steroid receptor coactivator (SRC). Furthermore, SRC-2 modulates the activity of the AF-1 domain but not the C-terminal ligand binding domain (LBD). Homology modeling indicated that the NOR-1 LBD was substantially different from that of hRORbeta, a closely related AF-2-dependent receptor. In particular, the hydrophobic cleft characteristic of nuclear receptors was replaced with a very hydrophilic surface with a distinct topology. This observation may account for the inability of this nuclear receptor LBD to efficiently mediate cofactor recruitment and transcriptional activation. In contrast, the N-terminal AF-1 is necessary for cofactor recruitment and can independently conscript coactivators. Finally, we demonstrate that the purine anti-metabolite 6-mercaptopurine, a widely used antineoplastic and anti-inflammatory drug, activates NOR-1 in an AF-1-dependent manner. Additional 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity. We hypothesize that the NR4A subgroup mediates the genotoxic stress response and suggest that this subgroup may function as sensors that respond to genotoxicity.

The relationship of adult attachment dimensions to depression and agoraphobia

We examined the unique relations between the five dimensions of the Attachment Style Questionnaire (ASQ; Feeney, Noller, & Hanrahan, 1994) and depression and agoraphobic behavior (i.e., avoidance of situations where high anxiety is experienced). In addition, we examined mediation models in an attempt to clarify the link between adult attachment and these two dimensions of psychopathology. In testing these models, we administered the ASQ, General Self-Efficacy Scale, Agoraphobic Catastrophic Cognitions Questionnaire, Beck Depression Inventory, and the Mobility Inventory for Agoraphobia (a measure of the degree to which situations are avoided that are typically anxiety provoking for people with agoraphobia) to 122 participants (44 with agoraphobia, 25 with a current major depressive disorder, and 53 with no current psychopathology). The results showed that the insecure attachment dimensions of need for approval, preoccupation with relationships, and relationships as secondary were uniquely associated with depression and that general self-efficacy partly mediated the relationship between need for approval and depression. In contrast, only preoccupation with relationships was uniquely associated with agoraphobic behavior, and catastrophic cognitions about bodily sensations partly mediated this association.

Expression of the CD44v2-10 isoform confers a metastatic phenotype: Importance of the heparan sulfate attachment site CD44v3

We expressed the full-length CD44v2-10 isoform in SKHep1 cells, a nonmetastatic human hepatocellular carcinoma cell line that does not express any endogenous CD44v isoforms. In SCID mice, expression of CD44v2-10 by SKHep1 cells had no effect on s.c. primary tumor development but caused pulmonary metastases in 41% (7 of 17) of animals compared with control SKHep1 cells (0 of 16; P < 0.01). CD44v2-10 expression by SKHep1 cells resulted in enhanced heparan sulfate (HS) attachment and an enhanced capacity to bind heparin-binding growth factors. Mutation of the v3 domain to prevent HS attachment and growth factor binding abolished the metastatic phenotype, demonstrating that HS modification of CD44v2-10 plays a critical role in the development of metastases in this model. However, in vitro proliferation, motility, and invasion were not altered by CD44v2-10 expression.

Attachment insecurity, depression, and the transition to parenthood

In a longitudinal study of adult attachment and depression during the transition to parenthood, 76 couples completed questionnaires on three occasions: during the second trimester of pregnancy, and six weeks and six months postbirth. On the first and second occasions, the couples were also interviewed about their experiences of pregnancy and parenthood, respectively. Measures were also completed at similar time intervals by a comparison group of 74 childless couples. Attachment security was assessed in terms of the dimensions of discomfort with closeness and relationship anxiety. Relationship anxiety was less stable for transition wives than for other participants. Relationship anxiety also predicted increases in new mothers' depressive symptoms, after controlling for a broad range of other risk factors. However, the association between relationship anxiety and maternal depression was moderated by husbands' caregiving style. Maternal depression was linked to increases in husbands' and wives' attachment insecurity and marital dissatisfaction. Results are discussed in terms of the impact of depression and negative working models of attachment on couple interaction.

On the dimensionality of the Attachment Style Questionnaire in Italian clinical and nonclinical participants

This study examined the utility of the Attachment Style Questionnaire (ASQ) in an Italian sample of 487 consecutively admitted psychiatric participants and an independent sample of 605 nonclinical participants. Minimum average partial analysis of data from the psychiatric sample supported the hypothesized five-factor structure of the items; furthermore, multiple-group component analysis showed that this five-factor structure was not an artifact of differences in item distributions. The five-factor structure of the ASQ was largely replicated in the nonclinical sample. Furthermore, in both psychiatric and nonclinical samples, a two-factor higher order structure of the ASQ scales was observed. The higher order factors of Avoidance and Anxious Attachment showed meaningful relations with scales assessing parental bonding, but were not redundant with these scales. Multivariate normal mixture analysis supported the hypothesis that adult attachment patterns, as measured by the ASQ, are best considered as dimensional constructs.

Personality disorders and adult attachment dimensions in a mixed psychiatric sample: A multivariate study

The associations between personality disorders and adult attachment dimensions were assessed in a sample of 487 consecutively admitted psychiatric subjects. Canonical correlation analysis showed that two sets of moderately correlated canonical variates explained the correlations between personality disorders and adult attachment patterns. The first and second attachment variates closely resembled the avoidance and anxiety attachment dimensions, respectively. The first personality disorder variate was mainly characterized by avoidant, depressive, paranoid, and schizotypal personality disorders, whereas dependent, histrionic, and borderline personality disorders loaded on the second canonical variate. However, these linear combinations of personality disorders were different from those obtained from principal component analysis. The results extend previous studies linking personality disorders and attachment patterns and suggest the importance of focusing on specific constellations of symptoms associated with dimensions of insecurity.

An attachment perspective on adult sibling relationships

This study investigated adult sibling relationships from an attachment perspective. A total of 817 adults (253 males; 564 females) ranging in age from 16 to 90 years completed a modified version of the WHO-TO measure of attachment strength (Hazan & Zeifman, 1994). This measure records multiple attachment figures, in order of importance, across four functions of attachment. One hundred and seventy four siblings of the participants also completed the measure as part of a larger sibling study. There were 29 brother dyads, 83 sister dyads and 62 brother-sister dyads. Results revealed that siblings have the potential to fulfil attachment-related functions, with 37% of the sample judged to be attached to a sibling. Females, and those not in romantic relationships reported stronger attachment to a sibling. Furthermore, sibling dyads were generally congruent in their perception of their relationship as an attachment bond. More than half of the sister-sister dyads (54%) agreed their relationship was an attachment bond, compared to 33% of brother-brother dyads and 24% of brother-sister dyads. Taken together, the findings support the applicability of attachment theory as a framework for investigating sibling relationships in adulthood.

Persistent colonization with Tannerella forsythensis and loss of attachment in adolescents

Colonization with Tannerella forsythensis may characterize the conversion of periodontally healthy sites into diseased sites. This three-year study describes the prevalence of T forsythensis and its relationship to clinical loss of attachment (LOA) in a group of adolescents considered at risk of developing early chronic periodontitis. Adolescents with (LOA+) and without (LOA-) loss of attachment were examined at baseline and 1.5 and 3 yrs subsequently. On each occasion, attachment loss was measured on selected teeth, and the presence of T. forsythensis in their subgingival plaque samples was determined by PCR. T. forsythensis prevalence in LOA+ subjects at baseline (64%) increased to 82% and 86% on subsequent examinations. In contrast, prevalence of T. forsythensis in LOA- subjects was always significantly lower (25%, 36%, and 32%, respectively). The odds of loss of attachment were 8.16 times greater in subjects infected with T. forsythensis at each examination. These results suggest that T. forsythensis is strongly associated with loss of attachment in this adolescent population.