Protective immunization against inhalational anthrax: a comparison of minimally invasive delivery platforms

A new anthrax vaccine under clinical investigation is based on recombinant Bacillus anthracis protective antigen (rPA). Here, we investigated microneedle-based cutaneous and nasal mucosal delivery of rPA in mice and rabbits. In mice, intradermal (id) delivery achieved up to 90% seroconversion after a single dose, compared with 20% after intramuscular (im) injection. Intranasal (inl) delivery of a liquid formulation required 3 doses to achieve responses that were comparable with those achieved via the id or im routes. In rabbits, id delivery provided complete protection against aerosol challenge with anthrax spores; in addition, novel powder formulations administered inl provided complete protection, whereas a liquid formulation provided only partial protection. These results demonstrate, for the first time, that cutaneous or nasal mucosal administration of rPA provides complete protection against inhalational anthrax in rabbits. The novel vaccine/device combinations described here have the potential to improve the efficacy of rPA and other biodefense vaccines.     

Clinimetric evaluation of shoulder disability questionnaires: a systematic review of the literature

OBJECTIVE: To identify all available shoulder disability questionnaires designed to measure physical functioning and to evaluate evidence for the clinimetric quality of these instruments. METHODS: Systematic literature searches were performed to identify self administered shoulder disability questionnaires. A checklist was developed to evaluate and compare the clinimetric quality of the instruments. RESULTS: Two reviewers identified and evaluated 16 questionnaires by our checklist. Most studies were found for the Disability of the Arm, Shoulder, and Hand scale (DASH), the Shoulder Pain and Disability Index (SPADI), and the American Shoulder and Elbow Surgeons Standardised Shoulder Assessment Form (ASES). None of the questionnaires demonstrated satisfactory results for all properties. Most questionnaires claim to measure several domains (for example, pain, physical, emotional, and social functioning), yet dimensionality was studied in only three instruments. The internal consistency was calculated for seven questionnaires and only one received an adequate rating. Twelve questionnaires received positive ratings for construct validity, although depending on the population studied, four of these questionnaires received poor ratings too. Seven questionnaires were shown to have adequate test-retest reliability (ICC >0.70), but five questionnaires were tested inadequately. In most clinimetric studies only small sample sizes (n<43) were used. Nearly all publications lacked information on the interpretation of scores. CONCLUSION: The DASH, SPADI, and ASES have been studied most extensively, and yet even published validation studies of these instruments have limitations in study design, sample sizes, or evidence for dimensionality. Overall, the DASH received the best ratings for its clinimetric properties.     

Correlates of resistance to HIV-1 infection in homosexual men with high-risk sexual behaviour

OBJECTIVE: To investigate possible correlates of HIV resistance in participants from the Amsterdam Cohort of Homosexual men who have remained HIV seronegative despite high-risk sexual behaviour. DESIGN/METHODS: We studied in vitro HIV-1 susceptibility and adaptive and innate immunity in 29 high-risk seronegative (HRSN) and 15 HIV-negative pre-seroconversion (pre-SC) homosexual men from the same Amsterdam Cohort Study (ACS) who seroconverted to HIV-1 positive during active follow-up. Host genetics were compared between HRSN and HIV-positive ACS participants. RESULTS: We found lower in vitro susceptibility for a CCR5-using (R5) HIV-1 variant, higher RANTES production levels, but no difference in coreceptor expression in HRSN as compared with pre-SC controls. Reduced R5 in vitro susceptibility of two HRSN tested was restored to normal levels by addition of antibodies against beta-chemokines. A higher proportion of HRSN carried the SDF-1 3'A variant and HLA-A*11, A*31 and Cw*15 alleles. ELIspot analysis with HIV-1 peptide stimulation revealed low frequencies of HIV-1-specific CD8 interferon-gamma producing cytotoxic T cells in both HRSN and pre-SC controls. CONCLUSIONS: Low in vitro R5 susceptibility of cells from the HRSN men was due to beta-chemokine mediated inhibition of virus replication. The presence of HIV-1 specific cytotoxic T cells in both HRSN and pre-SC participants may signify exposure to the virus rather than protection from infection. Host genetic characteristics and other factors affecting innate immunity may contribute to differential resistance to HIV-1 infection among exposed seronegative individuals.     

Das IMIRA-Projekt am Robert Koch-Institut

Die Diabetologie - Deutschland ist ein Einwanderungsland und 2019 hatte mehr als jede vierte hier lebende Person einen sog. Migrationshintergrund. Bei dieser statistisch definierten Gruppe handelt...     

Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination

Females have generally more robust immune responses than males for reasons that are not well-understood. Here we used a systems analysis to investigate these differences by analyzing the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine (TIV) and a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli, in 53 females and 34 males of different ages. We found elevated antibody responses to TIV and expression of inflammatory cytokines in the serum of females compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated STAT3 proteins in monocytes but not with the serological response to the vaccine. In contrast, using a machine learning approach, we identified a cluster of genes involved in lipid biosynthesis and previously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to TIV. These results demonstrate a strong association between androgens and genes involved in lipid metabolism, suggesting that these could be important drivers of the differences in immune responses between males and females.The variability in the biology of human populations poses significant challenges in understanding different disease outcomes and developing successful therapeutics. The sources of this variation are likely the consequence of genetics, epigenetics, and the history of antigenic exposure (1, 2). As therapies targeting immune function are developed to improve clinical outcomes in cancer, viral and bacterial infections, autoimmune diseases, and transplantation, identifying the sources of immunological variation and finding biomarkers for immune health and dysfunction are crucial for their success (3).An important source of immunological variation is known to be the sex of the individual. Males experience a greater severity and prevalence of bacterial, viral, fungal, and parasitic infections than females, who also exhibit a more robust response to antigenic challenges such as infection and vaccination (4, 5). This stronger immune response in females could also explain why they more frequently develop immune-mediated pathologies during influenza infection, such as an overproduction of cytokines (cytokine storm) that contribute to an increase in capillary permeability and lung failure (6). Furthermore, females are at a higher risk for developing autoimmune diseases. In this later context, it is interesting to note that a recent study showed that females had, on average, 1.7 times the frequency of self-specific T cells as males (7). Despite the fact that initial observations relating the sex of the individual with the immune response were made many years ago (8), little is known about the mechanisms underlying these differences.Some sex-specific variations in the immune response can be directly attributed to sex hormones (9). In humans, sex steroids can bind to intracellular receptors located in immune cells such as monocytes, B cells, and T cells and activate hormone-responsive genes, suggesting that they can directly affect sex-related differences in both innate and adaptive immune responses (10). Whereas estrogens are associated with inflammation and can stimulate proliferation and differentiation of lymphocytes and monocytes, androgens suppress the activity of immune cells by increasing the synthesis of anti-inflammatory cytokines (11, 12).To date, no clear associations have been found between biological and clinical differences in the immune response between males and females in humans. In one study, results from public gene expression data (13) showed that many of the genes induced by a yellow fever vaccine were preferentially activated in females (14). However, whether these differences correlate with poor antibody outcomes remains to be determined.In this study, we sought to determine whether we could identify biomarkers from peripheral blood that could explain the sex-related differences in the serological response to the trivalent inactivated seasonal influenza vaccine (TIV) in both young and older cohorts.Young and older females had higher neutralizing antibodies than age-matched males, consistent with previous reports (15). Females also showed higher expression of inflammatory markers. However, none of these specific sex-related differences correlated with the observed disparities in the antibody response to TIV. Nevertheless, using a machine learning approach, we identified a set of genes previously shown to be regulated by testosterone and participating in lipid biosynthesis, whose expression was negatively associated with antibody responses to TIV in the male subjects in our study. Moreover, males with high levels of serum testosterone and expressing related gene signatures in blood cells showed the lowest neutralizing responses to TIV. These results suggest that testosterone might be immunosuppressive in vivo in humans, and indicate that its effect on an influenza vaccine and other immune responses could be due to the regulation of genes implicated in the metabolism of lipids.     

Implicit versus explicit measures of self-concept of self-control and their differential predictive power for spontaneous trait-relevant behaviors

Background and objectives

Low trait self-control constitutes a core criterion in various psychiatric disorders. Personality traits such as low self-control are mostly indexed by self-report measures. However, several theorists emphasized the importance of differentiating between explicit and implicit indices of personality traits, Therefore, the present study examined the unique predictive validity of an implicit measure of trait self-control for spontaneous dysfunctional behavior.

Methods

As a measure of implicit trait self-control, we used an irrelevant feature task: a speeded reaction time task comprising a task-relevant stimulus feature (i.e., capital vs. lower case letter type) and a task-irrelevant feature (high vs. low self-control word type). The irrelevant feature had to be ignored, while participants (n = 34) responded to the relevant stimulus feature. However, their response was either congruent or incongruent with the irrelevant stimulus feature, resulting in facilitated or deteriorated task performance. As indicators of trait-related spontaneous dysfunctional behavior, we included indices of frustration tolerance and the preference for short-term reward over meeting long-term goals. We also included two explicit measures of trait self-control: a self-report questionnaire and an explicit self-relevance rating of the implicit task stimuli.

Results

Specifically the implicit measure of trait self-control showed predictive validity for the target self-control behaviors.

Limitations

The predictive validity of implicit measures of personality traits requires further study in larger, non-student samples.

Conclusions

As predicted, the implicit measure of trait self-control showed superior predictive power for spontaneous trait-related behavior. This finding points to the relevance of complementing the routinely used self-report measures with implicit measures of trait self-control.     

Plant neighbor detection through touching leaf tips precedes phytochrome signals

Plants in dense vegetation compete for resources, including light, and optimize their growth based on neighbor detection cues. The best studied of such behaviors is the shade-avoidance syndrome that positions leaves in optimally lit zones of a vegetation. Although proximate vegetation is known to be sensed through a reduced ratio between red and far-red light, we show here through computational modeling and manipulative experiments that leaves of the rosette species Arabidopsis thaliana first need to move upward to generate sufficient light reflection potential for subsequent occurrence and perception of a reduced red to far-red ratio. This early hyponastic leaf growth response is not induced by known neighbor detection cues under both climate chamber and natural sunlight conditions, and we identify a unique way for plants to detect future competitors through touching of leaf tips. This signal occurs before light signals and appears to be the earliest means of above-ground plant-plant signaling in horizontally growing rosette plants.