Effect of Soluble ICAM-1 on a Sj?gren's Syndrome-like Phenotype in NOD Mice Is Disease Stage Dependent

Introduction

Intercellular adhesion molecule-1 (ICAM-1) is involved in migration and co-stimulation of T and B cells. Membrane bound ICAM-1 is over expressed in the salivary glands (SG) of Sjögren''s syndrome (SS) patients and has therefore been proposed as a potential therapeutic target. To test the utility of ICAM-1 as a therapeutic target, we used local gene therapy in Non Obese Diabetic (NOD) mice to express soluble (s)ICAM-1 to compete with membrane bound ICAM-1 for binding with its receptor. Therapy was given prior to and just after the influx of immune cells into the SG.

Methods

A recombinant serotype 2 adeno associated virus (rAAV2) encoding ICAM-1/Fc was constructed and its efficacy tested in the female NOD mice after retrograde instillation in SG at eight (early treatment) and ten (late treatment) weeks of age. SG inflammation was evaluated by focus score and immunohistochemical quantification of infiltrating cell types. Serum and SG tissue were analyzed for immunoglobulins (Ig).

Results

Early treatment with ICAM-1/Fc resulted in decreased average number of inflammatory foci without changes in T and B cell composition. In contrast, late treated mice did not show any change in focus scores, but immunohistochemical staining showed an increase in the overall number of CD4+ and CD8+ T cells. Moreover, early treated mice showed decreased IgM within the SGs, whereas late treated mice had increased IgM levels, and on average higher IgG and IgA.

Conclusions

Blocking the ICAM-1/LFA-1 interaction with sICAM-1/Fc may result in worsening of a SS like phenotype when infiltrates have already formed within the SG. As a treatment for human SS, caution should be taken targeting the ICAM-1 axis since most patients are diagnosed when inflammation is clearly present within the SG.     

Immunohistochemical detection of the CXCR4 expression in tumor tissue using the fluorescent peptide antagonist Ac-TZ14011-FITC

Pathology is fundamental in grading, staging, and treatment planning of malignancies. One relatively novel biomarker that may become more important in therapy and diagnostics is the chemokine receptor 4 (CXCR4). Ac-TZ14011 peptide derivatives, functionalized with a radiolabel, can be used for molecular imaging of tumors. Direct fluorescent labeling of the small peptide Ac-TZ14011 with the fluorescent dye fluorescein isothiocyanate (FITC), however, provides an alternative for the detection of CXCR4 expression levels in cells and tumor tissue. In this study, Ac-TZ14011-FITC was validated for CXCR4 staining in human breast cancer cell lines MDAMB231 and MDAMB231(CXCR4+) during flow cytometric analysis. Its efficacy was compared to commercially available antibodies. Competition experiments validated the staining specificity. Confocal imaging revealed that CXCR4 staining was predominantly found on the cell membrane and/or in vesicles formed after endocytosis. Next to being able to differentiate "high" and "low" CXCR4-expressing tumor cells, the fluorescent peptide demonstrates potential in fluorescent immunohistochemistry of tumor tissue. Ac-TZ14011-FITC was able to differentiate MDAMB231 from MDAMB231(CXCR4+) tumor cells and tissue, proving its applicability in the detection of differences in CXCR4 expression levels.     

Reef Odor: A Wake Up Call for Navigation in Reef Fish Larvae

The behavior of reef fish larvae, equipped with a complex toolbox of sensory apparatus, has become a central issue in understanding their transport in the ocean. In this study pelagic reef fish larvae were monitored using an unmanned open-ocean tracking device, the drifting in-situ chamber (DISC), deployed sequentially in oceanic waters and in reef-born odor plumes propagating offshore with the ebb flow. A total of 83 larvae of two taxonomic groups of the families Pomacentridae and Apogonidae were observed in the two water masses around One Tree Island, southern Great Barrier Reef. The study provides the first in-situ evidence that pelagic reef fish larvae discriminate reef odor and respond by changing their swimming speed and direction. It concludes that reef fish larvae smell the presence of coral reefs from several kilometers offshore and this odor is a primary component of their navigational system and activates other directional sensory cues. The two families expressed differences in their response that could be adapted to maintain a position close to the reef. In particular, damselfish larvae embedded in the odor plume detected the location of the reef crest and swam westward and parallel to shore on both sides of the island. This study underlines the critical importance of in situ Lagrangian observations to provide unique information on larval fish behavioral decisions. From an ecological perspective the central role of olfactory signals in marine population connectivity raises concerns about the effects of pollution and acidification of oceans, which can alter chemical cues and olfactory responses.     

Reproductive effort accelerates actuarial senescence in wild birds: an experimental study

Optimality theories of ageing predict that the balance between reproductive effort and somatic maintenance determines the rate of ageing. Laboratory studies find that increased reproductive effort shortens lifespan, but through increased short‐term mortality rather than ageing. In contrast, high fecundity in early life is associated with accelerated senescence in free‐living vertebrates, but these studies are non‐experimental. We performed lifelong brood size manipulation in free‐living jackdaws. Actuarial senescence – the increase in mortality rate with age – was threefold higher in birds rearing enlarged‐ compared to reduced broods, confirming a key prediction of the optimality theory of ageing. Our findings contrast with the results of single‐year brood size manipulation studies carried out in many species, in which there was no overall discernible manipulation effect on mortality. We suggest that our and previous findings are in agreement with predictions based on the reliability theory of ageing and propose further tests of this proposition.     

Efficient light harvesting in a dark, hot, acidic environment: the structure and function of PSI-LHCI from Galdieria sulphuraria

Photosystem I-light harvesting complex I (PSI-LHCI) was isolated from the thermoacidophilic red alga Galdieria sulphuraria, and its structure, composition, and light-harvesting function were characterized by electron microscopy, mass spectrometry, and ultrafast optical spectroscopy. The results show that Galdieria PSI is a monomer with core features similar to those of PSI from green algae, but with significant differences in shape and size. A comparison with the crystal structure of higher plant (pea) PSI-LHCI indicates that Galdieria PSI binds seven to nine light-harvesting proteins. Results from ultrafast optical spectroscopy show that the functional coupling of the LHCI proteins to the PSI core is tighter than in other eukaryotic PSI-LHCI systems reported thus far. This tight coupling helps Galdieria perform efficient light harvesting under the low-light conditions present in its natural endolithic habitat.     

Social life histories: jackdaw dominance increases with age,terminally declines and shortens lifespan

Behaviour may contribute to changes in fitness prospects with age, for example through effects of age-dependent social dominance on resource access. Older individuals often have higher dominance rank, which may reflect a longer lifespan of dominants and/or an increase in social dominance with age. In the latter case, increasing dominance could mitigate physiological senescence. We studied the social careers of free-living jackdaws over a 12 year period, and found that: (i) larger males attained higher ranks, (ii) social rank increased with age within individuals, and (iii) high-ranked individuals had shorter lifespan suggesting that maintaining or achieving high rank and associated benefits comes at a cost. Lastly, (iv) social rank declined substantially in the last year an individual was observed in the colony, and through its effect on resource access this may accelerate senescence. We suggest that behaviour affecting the ability to secure resources is integral to the senescence process via resource effects on somatic state, where behaviour may include not only social dominance, but also learning, memory, perception and (sexual) signalling. Studying behavioural effects on senescence via somatic state may be most effective in the wild, where there is competition for resources, which is usually avoided in laboratory conditions.     

Critical Environmental Factors for Transportation Cycling in Children: A Qualitative Study Using Bike-Along Interviews

Background

Environmental factors are found to influence transport-related physical activity, but have rarely been studied in relation with cycling for transport to various destinations in 10–12 yr old children. The current qualitative study used ‘bike-along interviews’ with children and parents to allow discussion of detailed environmental factors that may influence children''s cycling for transport, while cycling in the participant''s neighborhood.

Methods

Purposeful convenience sampling was used to recruit 35 children and one of their parents residing in (semi-) urban areas. Bike-along interviews were conducted to and from a randomly chosen destination (e.g. library) within a 15 minutes'' cycle trip in the participant''s neighborhood. Participants wore a GoPro camera to objectively assess environmental elements, which were subsequently discussed with participants. Content analysis and arising themes were derived using a grounded theory approach.

Results

The discussed environmental factors were categorized under traffic, urban design, cycling facilities, road design, facilities at destination, aesthetics, topography, weather, social control, stranger danger and familiar environment. Across these categories many environmental factors were (in)directly linked to road safety. This was illustrated by detailed discussions of the children''s visibility, familiarity with specific traffic situations, and degree of separation, width and legibility of cycle facilities.

Conclusion

Road safety is of major concern in this 10–12 yr old study population. Bike-along interviews were able to identify new, detailed and context-specific physical environmental factors which could inform policy makers to promote children''s cycling for transport. However, future studies should investigate whether hypothetical changes to such micro environmental features influence perceptions of safety and if this in turn could lead to changes in children''s cycling for transport.     

Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study

IntroductionVagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia.MethodsWe performed a randomized double-blind sham-controlled study in healthy male volunteers. A stimulation catheter was inserted in the left internal jugular vein at spinal level C5–C7, adjacent to the vagus nerve. In the tVNS group (n = 10), stimulation was continuously performed for 30 minutes (0–10 V, 1 ms, 20 Hz), starting 10 minutes before intravenous administration of 2 ng kg⁻¹Escherichia coli lipopolysaccharide (LPS). Sham-instrumented subjects (n = 10) received no electrical stimulation.ResultsNo serious adverse events occurred throughout the study. In the tVNS group, stimulation of the vagus nerve was achieved as indicated by laryngeal vibration. Endotoxemia resulted in fever, flu-like symptoms, and hemodynamic changes that were unaffected by tVNS. Furthermore, plasma levels of inflammatory cytokines increased sharply during endotoxemia, but responses were similar between groups. Finally, cytokine production by leukocytes stimulated with LPS ex vivo, as well as neutrophil phagocytosis capacity, were not influenced by tVNS.ConclusionstVNS is feasible and safe, but does not modulate the innate immune response in humans in vivo during experimental human endotoxemia.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01944228","term_id":"NCT01944228"}}NCT01944228. Registered 12 September 2013.     

Current Developments in Dementia Risk Prediction Modelling: An Updated Systematic Review

Background

Accurate identification of individuals at high risk of dementia influences clinical care, inclusion criteria for clinical trials and development of preventative strategies. Numerous models have been developed for predicting dementia. To evaluate these models we undertook a systematic review in 2010 and updated this in 2014 due to the increase in research published in this area. Here we include a critique of the variables selected for inclusion and an assessment of model prognostic performance.

Methods

Our previous systematic review was updated with a search from January 2009 to March 2014 in electronic databases (MEDLINE, Embase, Scopus, Web of Science). Articles examining risk of dementia in non-demented individuals and including measures of sensitivity, specificity or the area under the curve (AUC) or c-statistic were included.

Findings

In total, 1,234 articles were identified from the search; 21 articles met inclusion criteria. New developments in dementia risk prediction include the testing of non-APOE genes, use of non-traditional dementia risk factors, incorporation of diet, physical function and ethnicity, and model development in specific subgroups of the population including individuals with diabetes and those with different educational levels. Four models have been externally validated. Three studies considered time or cost implications of computing the model.

Interpretation

There is no one model that is recommended for dementia risk prediction in population-based settings. Further, it is unlikely that one model will fit all. Consideration of the optimal features of new models should focus on methodology (setting/sample, model development and testing in a replication cohort) and the acceptability and cost of attaining the risk variables included in the prediction score. Further work is required to validate existing models or develop new ones in different populations as well as determine the ethical implications of dementia risk prediction, before applying the particular models in population or clinical settings.