Intranasal immunization with pneumococcal polysaccharide conjugate vaccines with nontoxic mutants of Escherichia coli heat-labile enterotoxins as adjuvants protects mice against invasive pneumococcal infections

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldHost defenses against Streptococcus pneumoniae depend largely on phagocytosis following opsonization by polysaccharide-specific immunoglobulin G (IgG) antibodies and complement. Since colonization of the respiratory mucosa is the first step in pneumococcal pathogenesis, mucosal immune responses may play a significant role. In addition to inducing systemic immune responses, mucosal vaccination with an effective adjuvant has the advantage of inducing mucosal IgA antibodies. The heat-labile enterotoxin (LT) of Escherichia coli is a well-studied mucosal adjuvant, and adjuvant activity of nontoxic LT mutants has been demonstrated for several protein antigens. We investigated the immunogenicity of pneumococcal polysaccharide conjugate vaccines (PNC) of serotypes 1 and 3 in mice after intranasal (i.n.) immunization by using as an adjuvant the nontoxic LT mutant LT-K63 or LT-R72, which has minimal residual toxicity. Pneumococcal serotype-specific antibodies were measured in serum (IgM, IgG, and IgA) and saliva (IgA), and vaccine-induced protection was evaluated by i.n. challenge with virulent pneumococci of the homologous serotype. When administered with LT mutants, i.n. immunization with both conjugates induced systemic and mucosal immune responses, and serum IgG antibody levels were significantly higher than after subcutaneous immunization. All mice immunized i.n. with PNC-1 and LT mutants were protected against bacteremia and cleared the pneumococci from the lung 24 h after i.n. challenge; pneumococcal density correlated significantly with serum IgG antibody levels. Similarly, the survival of mice immunized i.n. with PNC-3 and LT mutants was significantly prolonged. These results demonstrate that i.n. vaccination with PNC and potent adjuvants can protect mice against invasive and lethal pneumococcal infections, indicating that mucosal vaccination with PNC may be an alternative vaccination strategy for humans

Vaccination of COPD patients with a pneumococcus type 6B tetanus toxoid conjugate vaccine

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldThis paper examines how pneumococcal type 6B polysaccharide conjugated to tetanus toxoid (Pn6B-TT) compares to a 23 valent pneumococcal vaccine (pneumococcal polysaccharide (PPS)-23) with respect to immunogenicity and serum opsonic activity in patients with chronic obstructive pulmonary disease (COPD). Patients with COPD aged 55-75 yrs were vaccinated with Pn6B-TT (n=10) or with PPS-23 (n=9). Healthy young adults (HA) were vaccinated with Pn6B-TT as controls. Total antibodies to serotype 6B polysaccharide were measured by radioimmunoassay and immunoglobulin (Ig)G antibodies by enzyme-linked immunosorbent assay. Opsonic activity was measured by a phagocytosis assay using human neutrophils as effector cells. The patient groups were comparable by age, smoking history, lung function and use of steroids. COPD patients vaccinated with Pn6B-TT or PPS-23 showed an increase in IgG antibodies and a nonsignificant increase in opsonic activity. This was similar to the increase in IgG and opsonic activity seen in HA. There was a significant correlation between antibody levels and opsonic activity in COPD patients vaccinated both with Pn6B-TT and PPS-23. Pneumococcal antibodies have been shown to confer protection from infection. The results of the present study indicate that protective immunity can be expected in elderly chronic obstructive pulmonary disease patients vaccinated with conjugate vaccines

Transitional B Cells and TLR9 Responses Are Defective in Selective IgA Deficiency.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesSelective IgA deficiency (IgAD) is the most common primary antibody deficiency in the western world with affected individuals suffering from an increased burden of autoimmunity, atopic diseases and infections. It has been shown that IgAD B cells can be induced with germinal center mimicking reactions to produce IgA. However, IgA is the most prevalent antibody in mucosal sites, where antigen-independent responses are important. Much interest has recently focused on the role of TLR9 in both naïve and mature B cell differentiation into IgA secreting plasma cells. Here, we analyze the phenotype and function of T and B cells in individuals with IgAD following IgA-inducing CpG-TLR9 stimulations. The IgAD individuals had significantly lower numbers of transitional B cells (CD19+CD24hiCD38hi) and class-switched memory B cells (CD20+CD27+IgD-) ex vivo. However, proportions of T cell populations ex vivo as well as in vitro induced T effector cells and T regulatory cells were comparable to healthy controls. After CpG stimulation, the transitional B cell defect was further enhanced, especially within its B regulatory subset expressing IL-10. Finally, CpG stimulation failed to induce IgA production in IgAD individuals. Collectively, our results demonstrate a defect of the TLR9 responses in IgAD that leads to B cell dysregulation and decreased IgA production.Icelandic Research Fund University hospital of Iceland research fun

Effects of robot therapy on upper body kinematics and arm function in persons post stroke: a pilot randomized controlled trial

Background: Robot-based rehabilitation for persons post-stroke may improve arm function and daily-life activities as measured by clinical scales, but its effects on motor strategies during functional tasks are still poorly investigated. This study aimed at assessing the effects of robot-therapy versus arm-specific physiotherapy in persons post-stroke on motor strategies derived from upper body instrumented kinematic analysis, and on arm function measured by clinical scales. Methods: Forty persons in the sub-acute and chronic stage post-stroke were recruited. This sample included all those subjects, enrolled in a larger bi-center study, who underwent instrumented kinematic analysis and who were randomized in Center 2 into Robot (R_Group) and Control Group (C_Group). R_Group received robot-assisted training. C_Group received arm-specific treatment delivered by a physiotherapist. Pre- and post-training assessment included clinical scales and instrumented kinematic analysis of arm and trunk during a virtual untrained task simulating the transport of an object onto a shelf. Instrumented outcomes included shoulder/elbow coordination, elbow extension and trunk sagittal compensation. Clinical outcomes included Fugl-Meyer Motor Assessment of Upper Extremity (FM-UE), modified Ashworth Scale (MAS) and Functional Independence Measure (FIM). Results: R_Group showed larger post-training improvements of shoulder/elbow coordination (Cohen's d = - 0.81, p = 0.019), elbow extension (Cohen's d = - 0.71, p = 0.038), and trunk movement (Cohen's d = - 1.12, p = 0.002). Both groups showed comparable improvements in clinical scales, except proximal muscles MAS that decreased more in R_Group (Cohen's d = - 0.83, p = 0.018). Ancillary analyses on chronic subjects confirmed these results and revealed larger improvements after robot-therapy in the proximal portion of FM-UE (Cohen's d = 1.16, p = 0.019). Conclusions: Robot-assisted rehabilitation was as effective as arm-specific physiotherapy in reducing arm impairment (FM-UE) in persons post-stroke, but it was more effective in improving motor control strategies adopted during an untrained task involving vertical movements not practiced during training. Specifically, robot therapy induced larger improvements of shoulder/elbow coordination and greater reduction of abnormal trunk sagittal movements. The beneficial effects of robot therapy seemed more pronounced in chronic subjects. Future studies on a larger sample should be performed to corroborate present findings. Trial registration: www.ClinicalTrials.gov NCT03530358. Registered 21 May 2018. Retrospectively registered

A study of the association of HLA DR, DQ, and complement C4 alleles with systemic lupus erythematosus in Iceland

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldOBJECTIVE: To perform an exploratory analysis of the relative contribution of single MHC genes to the pathogenesis of systemic lupus erythematosus (SLE) in a homogenous white population. METHODS: MHC class II alleles and C4 allotypes were determined in 64 SLE patients and in ethnically matched controls. HLA-DR and DQ typing was performed by polymerase chain reaction amplification with sequence specific primers. C4 allotypes were determined by agarose gel electrophoresis. RESULTS: The frequency of C4A*Q0 was significantly higher in patients than in controls (46.9% v 25.3%, p = 0.002). HLA-DRB1, DQA1, and DQB1 alleles in the whole group of SLE patients were not significantly different from those of controls. On the other hand increase in DRB1*03 was observed in the group of patients with C4A*Q0, as compared with patients with other C4A allotypes (p = 0.047). There was no significant correlation between severe and mild disease, as judged by the SLEDAI, and HLADR, DQ alleles and comparing the patients with C4A*Q0 with those with other C4A allotypes there was no significant difference regarding clinical manifestations. CONCLUSION: The results are consistent with the argument that C4A deficiency contributes independently to susceptibility and the pathogenesis of SLE. C4A*Q0 in SLE patients in Iceland shows weaker linkage disequilibrium with DR3 genes than reported in most other white populations and emphasises the role of ethnicity

Differences in Protein Expression and Gene Amplification of Cyclins between Colon and Rectal Adenocarcinomas

Adenocarcinomas of rectum and colon may be different with regard to the cellular biological basis for cancer development. A material of 246 rectal cancers removed surgically at Akershus University Hospital in the years 1992–2000 was investigated and was compared to a material of 219 colon cancers operated on at Akershus University Hospital during the years 1988, 1990 and 1997–2000. There were highly significant differences between the rectal and the colon cancers in the protein expression of cyclin D1, cyclin D3, cyclin E, nuclear β-catenin, and c-Myc and in gene amplification of cyclin A2, cyclin B1, cyclin D1, and cyclin E. Gene amplification and protein expression in the rectal cancers correlated significantly for the cyclins B1, D3, and E. A statistically significant relation was observed between overexpression of cyclin A2 and local relapse of rectal carcinomas, as higher expression of cyclin A2 was associated with lower local recurrence rate

Characterization of potential biomarkers of reactogenicity of licensed antiviral vaccines: randomized controlled clinical trials conducted by the BIOVACSAFE consortium

Funding text The authors are grateful for the vital contributions of the participating study volunteers, clinicians, nurses, and laboratory technicians at the Surrey study site. The work by Roberto Leone, laboratory technician at Humanitas Clinical and Research Center, is gratefully acknowledged. Finally, they thank Ellen Oe (GSK) for scientific writing assistance. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115308, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution. The contribution of the European Commission to the Advanced Immunization Technologies (ADITEC) project (grant agreement n° 280873) is also gratefully acknowledged. Publisher Copyright: © 2019, The Author(s).Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20–21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.Peer reviewe

Characterization of Antioxidant Potential of Seaweed Extracts for Enrichment of Convenience Food

In recent years, there has been a growing interest in natural antioxidants as replacements of synthetic compounds because of increased safety concerns and worldwide trend toward the usage of natural additives in foods. One of the richest sources of natural antioxidants, nowadays largely studied for their potential to decrease the risk of diseases and to improve oxidative stability of food products, are edible brown seaweeds. Nevertheless, their antioxidant mechanisms are slightly evaluated and discussed. The aims of this study were to suggest possible mechanism(s) of Fucus vesiculosus antioxidant action and to assess its bioactivity during the production of enriched rye snacks. Chemical and cell-based assays indicate that the efficient preventive antioxidant action of Fucus vesiculosus extracts is likely due to not only the high polyphenol content, but also their good Fe2+-chelating ability. Moreover, the data collected during the production of Fucus vesiculosus-enriched rye snacks show that this seaweed can increase, in appreciable measure, the antioxidant potential of enriched convenience cereals. This information can be used to design functional foods enriched in natural antioxidant ingredients in order to improve the health of targeted consumers

The connectivity of spring stopover sites for geese heading to arctic breeding grounds

During the spring migration arctic-breeding geese pause in temperate and sub-arctic staging areas in order to deposit body reserves for breeding. Focusing on a single arctic stopover site in West-Spitsbergen, Svalbard, Norway (Varsol-bukta, 77 degrees 45'N, 14 degrees 24'E), behavioural strategies of Barnacle Geese Branta leucopsis were investigated and body condition and presence of individually marked birds recorded. Individuals using different staging areas earlier along the migration route (Helgeland and Vesteralen on the Norwegian mainland) and heading to different breeding colonies (the close-by Nordenskioldkysten, and the distant Kongsfjorden) were compared during springs 2003-05. Birds in Vesteralen left the staging area earlier than those in Helgeland, and arrived earlier in Varsolbukta as well. In Varsolbukta, females gained body condition at a similar rate regardless of their colony affiliation, whereas males from Nordenskioldkysten exhibited a smaller overall increase in condition compared to males from Kongsfjorden. The Kongsfjorden birds stayed for a shorter period (average 2.8 days) than those from Nordenskioldkysten (average 4.0 days). Nordenskioldkysten birds frequently left Varsolbukta for short periods presumably visiting the breeding area in order to optimise nest initiation with respect to prevailing snow conditions. The date of final departure was also correlated with nest initiation date at Nordenskioldkysten. No such relationship for the Kongsfjorden birds was found. We suggest that the geese adopt a 'hopping' strategy, using a network of stopover sites in Svalbard during spring with a last stopover at a buffer area in the proximity to the breeding area. For this vulnerable population it is important to identify the sites forming the links in this chain, and to establish their function and utilisation by geese during the vital prebreeding period