Immunotherapy With Apitopes Blocks the Immune Response to TSH Receptor in HLA-DR Transgenic Mice.

We have combined major histocompatibility complex-binding assays with immunization and tolerance induction experiments in HLA-DR3 transgenic mice to design apitopes (antigen-processing independent epitopes) derived from thyrotropin receptor (TSHR) for treatment of patients with Graves' disease (GD). A challenge model was created by using an adenovirus-expressing part of the extracellular domain of the thyrotropin receptor (TSHR289). This model was used to test whether current drug treatments for GD would have an impact on effective antigen-specific immunotherapy using the apitope approach. Furthermore, selected peptides were assessed for their antigenicity using peripheral blood mononuclear cell samples from patients with GD. A mixture of two immunodominant apitopes was sufficient to suppress both the T-cell and antibody response to TSHR when administered in soluble form to HLA-DR transgenic mice. Tolerance induction was not disrupted by current drug treatments. These results demonstrate that antigen-specific immunotherapy with apitopes from TSHR is a suitable approach for treatment of GD.

The battle of Alzheimer's Disease - the beginning of the future Unleashing the potential of academic discoveries.

Alzheimer's Disease (AD) is the most common form of dementia, affecting approximately 36 million people worldwide. To date there is no preventive or curative treatment available for AD, and in absence of major progress in therapeutic development, AD manifests a concrete socioeconomic threat. The awareness of the growing problem of AD is increasing, exemplified by the recent G8 Dementia Summit, a meeting held in order to set the stage and steer the compass for the future. Simultaneously, and paradoxically, we have seen key players in the pharmaceutical industry that have recently closed or significantly decreased their R&D spending on AD and other CNS disorders. Given the pressing need for new treatments in this area, other actors need to step-in and enter this drug discovery arena complementing the industrial efforts, in order to turn biological and technological progress into novel therapeutics. In this article, we present an example of a novel drug discovery initiative that in a non-profit setting, aims to integrate with both preclinical and clinical academic groups and pharmaceutical industry to explore the therapeutic potential of new concepts in patients, using novel biology, state of the art technologies and rapid concept testing.

Exposure to mother's pregnancy and lactation in infancy is associated with sexual attraction to pregnancy and lactation in adulthood.

INTRODUCTION: Several theories, including psychodynamic theories, sexual imprinting and early conditioning have been formulated to explain sexual development. Empirical data, however, remain insufficient for a thorough evaluation of these theories. AIM: In this study, we test the hypothesis that a critical period exists for the acquisition of sexual preferences, as suggested by empirical findings in birds and mammals (sexual imprinting). METHODS: An Internet questionnaire was used. MAIN OUTCOME MEASURES: We gather data from individuals with a sexual preference for pregnant and/or lactating women, under the hypothesis that pregnancy or lactation may become sexually attractive in adulthood following an exposure to pregnant or lactating women in infancy. RESULTS: We find that these preferences are more common in older siblings, i.e., in individuals who have been exposed to more maternal pregnancy and lactation. This result is independent of respondent and sibling sex. In addition, only maternal pregnancies and lactations experienced between 1.5 and 5 years of age are associated with the preferences. CONCLUSIONS: We discuss our findings in relation to theories of sexual development and to earlier reports of birth order effects on sexual behavior. We suggest that this age range may constitute a sensitive period for the acquisition of sexual preferences.

Internet-delivered exposure and mindfulness based therapy for irritable bowel syndrome--a randomized controlled trial.

The aim of this study was to investigate if cognitive behavior therapy (CBT) based on exposure and mindfulness exercises delivered via the Internet would be effective in treating participants with irritable bowel syndrome (IBS). Participants were recruited through self-referral. Eighty-six participants were included in the study and randomized to treatment or control condition (an online discussion forum). One participant was excluded after randomization. The main outcome measure was IBS-symptom severity and secondary measures included IBS-related quality of life, GI-specific anxiety, depression and general functioning. Participants were assessed at pre-treatment, post-treatment and 3 month follow-up (treatment condition only). Four participants (5% of total sample) in the treatment condition did not participate in post-treatment assessment. Participants in the treatment condition reported a 42% decrease and participants in the control group reported a 12% increase in primary IBS-symptoms. Compared to the control condition, participants in the treatment group improved on all secondary outcome measures with a large between group effect size on quality of life (Cohen's d = 1.21). We conclude that CBT-based on exposure and mindfulness delivered via the Internet can be effective in treating IBS-patients, alleviating the total burden of symptoms and increasing quality of life.

The application and relevance of ex vivo culture systems for assessment of IBD treatment in murine models of colitis.

The aim of this study was to investigate the relevance of mouse ex vivo cultures as a first screening model for new therapeutic agents of Inflammatory Bowel Disease (IBD). Two murine models (dextran sodium sulphate (DSS)-induced colitis and Galphai2-deficient mice) and two anti-inflammatory agents (methyl-prednisolone and the proteasome inhibitor MG132) were evaluated. The in vivo effects of methyl-prednisolone were assessed in both models. Ex vivo colonic tissue from both mouse models were cultured in the presence or absence of the drugs and TaqMan Low-Density arrays were used to assess the regulation of inflammatory genes before and after drug treatment. Colitis induced a similar inflammatory gene profile in both mouse models in in vivo studies and in ex vivo cultures. The differences encountered reflected the different phases of colitis in the models, e.g. innate cytokine/chemokine profile in the DSS model and T cell related markers in Galphai2-deficient mice. After steroid treatment, a similar pattern of genes was suppressed in the two mouse models. We confirmed the suppression of inflammatory gene expression for IL-1beta, IL-6 and iNOS in ex vivo and in vivo colons from both mouse models by quantitative RT-PCR. Importantly, the inflammatory responses in the murine ex vivo culture system reflected the in vivo response in the inflamed colonic tissue as assessed by changes in inflammatory gene expression, suggesting that the murine culture system can be used for validation of future IBD therapies.

Validation of murine dextran sulfate sodium-induced colitis using four therapeutic agents for human inflammatory bowel disease.

Dextran sulfate sodium (DSS)-induced colitis is one of the most frequently used rodent models for inflammatory bowel disease (IBD). The aim of this study was to validate the murine DSS-induced colitis model using four therapeutic agents for IBD. C57BL/6 mice were exposed to 3% DSS for 5days followed by 7-9 days of water (acute inflammation) or 20-31 days of water (chronic phase). Clinical symptoms, plasma and colonic inflammatory markers and histology were assessed for the efficacy of cyclosporine A (CsA), methotrexate or anti-IL-12p40 in acute colitis and of anti-IL-12p40 or an agonistic anti-CD3 antibody in chronic colitis. Cyclosporine A and anti-IL-12p40 (in the acute phase) and anti-CD3 (in the chronic phase) treatment attenuated local cytokine levels, improved clinical symptoms (CsA and anti-IL-12p40) and histology (CsA and anti-CD3). Further, anti-IL-12p40 treatment was partly efficacious in the chronic phase, whereas methotrexate showed no efficacy in the acute colitis. Thus, three of the current tested agents showed efficacy in the disease model, arguing that DSS-induced colitis can be used as a relevant model for the translation of mice data to human disease.

Predicting and monitoring colitis development in mice by micro-computed tomography.

BACKGROUND: Computed tomography (CT) has been developed as a tool for monitoring human inflammatory bowel disease (IBD). The aim of this study was to evaluate colon wall thickness as a noninvasive marker in the dextran sodium sulfate (DSS) mouse model of colitis using micro-CT. METHODS: Mice were examined by micro-CT 1, 2, or 4 times between day 0 (d0) and d26 after induction of colitis to document the kinetics of changes in colon wall thickness and its relation to colitis development. RESULTS: DSS-treated mice displayed a significantly thicker colon wall at all timepoints (days 5, 8, 12, 19, and 26) investigated compared to healthy controls. Colon wall thickness showed a good correlation to the macroscopic grading of colitis (r = 0.81). The increase in colon wall thickness occurred mainly during the acute phase of colitis (between days 5 and 12) and did not progress much further in the chronic phase of colitis (d26). Colon wall thickness at d26 was thereby predicted by measurements at d12. All mice did not respond equally to DSS and this difference was manifest during the first 2 weeks of colitis, providing an important tool in stratifying responders from nonresponders. CONCLUSIONS: While the potential impact of handling and anesthesia should be considered on repeated micro-CT, irradiation exposure during repeated micro-CT did not affect the development of colitis. Thus, the results suggest that micro-CT can be used for monitoring and prediction of the inflammatory response in mouse colitis in future therapeutic studies.

Intra-colonic administration of the TLR7 agonist R-848 induces an acute local and systemic inflammation in mice.

Imidazoquinoline compounds, such as resiquimod (R-848), are well known topically active immune modifiers that bind to toll-like receptor 7 (TLR7). The aim of this study was to characterize the R-848 induced inflammatory response in mice and to validate the response using methyl-prednisolone and anti-TNF antibody. Intra-colonic application of R-848 to BALB/c mice induced a systemic transient elevation of TNF, CXCL1, IL-6, and IL-12p40 and a colonic elevation of cytokines/chemokines and iNOS, without infiltration of immune cells or epithelial destruction. Treatment with methyl-prednisolone or anti-TNF antibody attenuated the systemic (TNF, IL-6, IL-12p40, and CXCL1) and local (colonic TNF and iNOS mRNA expression) response induced by R-848. In summary, intra-colonic administration of R-848 induces an acute systemic and local inflammatory response, which can be attenuated by steroids or anti-TNF antibody. We suggest that the R-848 inflammatory model can be useful in future validation of new drugs for gastrointestinal inflammatory conditions.

Local production of chemokines and prostaglandin E2 in the acute, chronic and recovery phase of murine experimental colitis.

Increased levels of chemokines and prostaglandins have been reported in patients with inflammatory bowel disease, although their changes during disease development are less understood. The aim of this study was to investigate the local production of nine selected chemokines and prostaglandin E(2) (PGE(2)) to elucidate their role in colitis progression in BALB/c and C57BL/6 mice exposed to dextran sulphate sodium. The acute inflammation in both strains was accompanied by a significant up-regulation of CXCL1, CXCL2/3, CXCL10, CCL2, CCL4 and CCL22 and a downregulation of PGE(2). In the recovery phase in BALB/c, one-week post-DSS, PGE(2) levels were significantly increased with a concomitant downregulation of CXCL1, CXCL2/3, CXCL10, CCL2, and CCL4. In contrast, in C57BL/6 mice CXCL1, CXCL2/3, CXCL10, CCL2, CCL3 and CCL4 production remained high during the chronic phase, without any up-regulation of PGE(2). In addition, CCL5 was significantly increased at d26 and 33 compared to d5. Interestingly, the number of macrophages was significantly increased during the acute phase, whereas T cells were significantly increased in both the acute and chronic phase in C57BL/6 mice. Thus, our results show that chemokines are produced in a dynamic manner during colitis progression.

Interaction before conflict and conflict resolution in pre-school boys with language impairment.

BACKGROUND: Children with language impairment (LI) experience social difficulties, including conflict management. The factors involved in peer-conflict progression in pre-school children with LI, and which of these processes may differ from pre-school children with typical language development (TL), is therefore examined. AIMS: To describe the relationship between opponents interacting before conflict, aberrant conflict causes, the conflict-resolution strategy reconciliation (i.e. friendly contact between former opponents shortly following conflict termination), and conflict outcome in the form of social interaction after a conflict has run its course. It is hypothesized that without social interaction before conflict, children with LI will experience increased difficulties attaining reconciliation. METHODS AND PROCEDURES: Unstructured play of 11 boys with LI (4-7 years old), at a specialized language pre-school, and 20 boys with TL (4-6 years old), at mainstream pre-schools, were video filmed. Conflicts were identified and recorded according to a validated coding system. Recorded conflict details include social interaction between conflict in the pre-conflict period, behavioural sequences constituting conflict cause (conflict period), reconciliatory behaviours in the post-conflict period, and social interaction between former opponents in the succeeding non-conflict period. The group's mean proportion of individual children's conflicts in which specific behavioural sequences occurred were calculated and compared between and within the groups. OUTCOMES AND RESULTS: When conflicts with and without pre-conflict social interaction were analysed separately, aberrant caused conflicts occurred more often in LI group conflicts than in TL group conflicts. However, in conflicts without social interaction in the pre-conflict period, boys with LI exhibit reconciliatory behaviours in, and reconcile a comparatively smaller proportion of, conflicts. Social interaction in the succeeding non-conflict period was proportionately less for boys with LI. This appears to stem from lower reconciliation rates in LI conflicts that do not begin with social interaction in the pre-conflict period. It was also confounded by the larger number of aberrant caused LI conflicts that were rarely reconciled. In turn, non-reconciliation and aberrant caused conflicts were independently associated with comparatively less social interaction in the succeeding non-conflict period. CONCLUSIONS: The results suggest that in addition to traditional psycholinguistic training, children with LI may gain from interventions that support concluding behavioural turns, as in aberrant caused conflicts; and in initiating contact in conflict situations, even when a frame of reference is not immediately available, as was the case when opponents have not established social interaction in the pre-conflict period.

Behavioural patterns of conflict resolution strategies in preschool boys with language impairment in comparison with boys with typical language development.

BACKGROUND: Children with language impairment (LI) experience social difficulties, including conflict management. This paper is therefore motivated to examine behavioural processes guiding preschool peer conflict progression, which ultimately contributes to overall development. AIMS: To describe behavioural sequences in conflicts between children with typically developing language (TL) and between children with LI. Attention is particularly focused on the conflict resolution strategy reconciliation, i.e. friendly contact between former opponents shortly following conflict termination. It is hypothesized that children with LI, with weaker language skills, experience difficulties attaining effective reconciliation. METHODS & PROCEDURES: Unstructured play of 11 boys with LI (4-7-years-old), at a specialized language preschool, and 20 TL boys (4-6-years-old), at mainstream preschools, were video filmed. Conflicts were identified and recorded according to a validated coding system. Recorded conflict details included behavioural sequences constituting conflict cause (conflict period) and in the post-conflict period, reconciliatory behaviours that were classified into six 'categories' (Invitation to play, Body contact, Object offer, Verbal apology, Self-ridicule, Cognition, i.e. offering privileges/negotiating) and the verbal character of accepted behaviours were determined. The mean proportion of individual target children's conflicts in which specific behavioural sequences had occurred were calculated and thereafter compared between and within the groups. OUTCOMES & RESULTS: Boys with LI reconcile fewer conflicts than TL boys (LI: 47.3 +/- 4.5%; TL: 63.6 +/- 2.0%). Contributory factors include the occurrence of conflicts caused by aberrance, i.e. conflicts initiated by inappropriate behavioural play intensities (i.e. 'a pillow fight' where one partner swings so intensively the other partner cannot participate as a player in the game) and protests that are no longer directed to the opponent within reciprocal exchanges, but escalate to screaming/physical ranting. Aberrant caused conflicts were rarely observed as the conflict cause for TL boys, but represent nearly 15% of LI conflicts and aberrant caused conflicts are reconciled at lower rates than conflicts not caused by aberrance. Displayed reconciliatory behaviours were accepted by opponents at similar rates in both groups and the distribution of reconciliatory behavioural 'categories' was similar between the groups. However, boys with LI attempt reconciliation in relatively fewer conflicts. In addition, the individual boys with LI attain reconciliation with strictly verbal reconciliatory behaviours in a smaller proportion of conflicts. CONCLUSIONS: The findings suggest that in addition to traditional psycholinguistic remediation, intervention programmes for children with LI should address that learned language and communication skills are applied effectively in initiating and maintaining naturalistic peer interactions.

IL-4-deficient mice develop less acute but more chronic relapsing collagen-induced arthritis.

Rheumatoid arthritis as well as collagen-induced arthritis (CIA) is thought to involve T cell autoimmunity of the Th1 type and the Th2 cytokine IL-4 has been proposed to play a suppressive role. To exclude a possible skewing role of the mycobacteria used in the complete Freund's adjuvant (CFA) we induced CIA with type II collagen (CII) in incomplete Freund's adjuvant (IFA). Our results show that IL-4 deficiency leads to a lesser susceptibility to arthritis and lower B and T cell responses if induced with CII/IFA but not if induced with CII/CFA. In addition, IL-4-deficient mice were less susceptible to arthritis induced with monoclonal anti-CII antibodies. However, mice immunized with CII/IFA later developed a chronic relapsing disease, which was promoted by IL-4 deficiency. We conclude that IL-4 plays different roles depending on the type of adjuvant used and the phase (acute or chronic) of the clinical disease.

Chickens prefer beautiful humans.

We trained chickens to react to an average human female face but not to an average male face (or vice versa). In a subsequent test, the animals showed preferences for faces consistent with human sexual preferences (obtained from university students). This suggests that human preferences arise from general properties of nervous systems, rather than from face-specific adaptations. We discuss this result in the light of current debate on the meaning of sexual signals and suggest further tests of existing hypotheses about the origin of sexual preferences.