Affinity Constants of Naturally Acquired and Vaccine-Induced Anti-Pseudomonas aeruginosa Antibodies in Healthy Adults and Cystic Fibrosis Patients

Naturally acquired anti-Pseudomonas aeruginosa antibody fails to afford protection against repeated P. aeruginosa bronchopulmonary exacerbations in cystic fibrosis (CF) patients. In an effort to explain this phenomenon, the titer and affinity constants of serum anti-lipopolysaccharide (LPS) IgG were determined in five study groups: healthy adults before and after immunization with a polyvalent LPS-based vaccine, healthy noncolonized CF patients before and after immunization, nonimmunized CF patients with significantly elevated anti-LPS antibody titers without documented colonization, recently colonized CF patients before and after immunization, and nonimmunized CF patients chronically colonized with P. aeruginosa. Immunization elicited a significant rise in total anti-LPS immunoglobulin levels and affinity constants in both healthy adults and CF patients. Although chronically colonized patients had elevated levels of total anti-LPS antibody, these antibodies possessed affinities at least tOO-fold less than those of vaccine-induced antibodie

Immunization of Noncolonized Cystic Fibrosis Patients against Pseudomonas aeruginosa

The long-term safety and immunogenicity of a polyvalent Pseudomonas aeruginosa conjugate vaccine was evaluated in 30 noncolonized cystic fibrosis patients. Four doses were administered over 3 years, and patients were followed for a mean of 38 months. No acute or long-term adverse effects were noted. Immunization engendered a significant antibody response to all vaccine components. A decline in titers during year 3 of observation was associated with a marked rise in the isolation of P. aeruginosa. This organism was isolated repeatedly from the respiratory tract of 4 patients and only once from 7 patients. The remaining patients were repeatedly culture-negative. Only 1 patient showed clinical deterioration associated with multiple isolations of P. aeruginos

Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein

Monoclonal antibodies (mAbs) play an increasing important role in the therapeutic armamentarium against multiple sclerosis (MS), an inflammatory and degenerative disorder of the central nervous system. Most of the mAbs currently developed for MS are immunomodulators blocking the inflammatory immune process. In contrast with mAbs targeting immune function, GNbAC1, a humanized IgG4 mAb, targets the multiple sclerosis associated retrovirus envelope (MSRVEnv) protein, an upstream factor in the pathophysiology of MS. MSRV-Env protein is of endogenous retroviral origin, expressed in MS brain lesions, and it is pro-inflammatory and toxic to the remyelination process, by preventing the differentiation of oligodendrocyte precursor cells. We present the preclinical and early clinical development results of GNbAC1. The specificity of GNbAC1 for its endogenous retroviral target is described. Efficacy of different mAb versions of GNbAC1 were assessed in MSRV-Env induced experimental allergic encephalitis (EAE), an animal model of MS. Because the target MSRV-Env is not expressed in animals, no relevant animal model exists for a proper in vivo toxicological program. An off-target 2-week toxicity study in mice was thus performed, and it showed an absence of safety risk. Additional in vitro analyses showed an absence of complement or antibody-dependent cytotoxicity as well as a low level of cross-reactivity to human tissues. The first-in-man clinical study in 33 healthy subjects and a long-term clinical study in 10 MS patients showed that GNbAC1 is well tolerated in humans without induction of immunogenicity and that it induces a pharmacodynamic response on MSRV biomarkers. These initial results suggest that the mAb GNbAC1 could be a safe long-term treatment for patients with MS with a unique therapeutic mechanism of action.GeNeuro SA, Geneva, Switzerlandhttp://www.tandfonline.com/loi/kmab202016-01-31hb201

Role of Repetitive Antigen Patterns for Induction of Antibodies Against Antibodies

Antibody responses against antibodies, such as rheumatoid factors, are found in several immunopathological diseases and may play a role in disease pathogenesis. Experience shows that they are usually difficult to induce experimentally. Antibodies specific for immunoglobulin constant regions (anti-allotypic) or for variable regions (anti-idiotypic) have been investigated in animal models; the latter have even been postulated to regulate antibody and T cell responses via network-like interactions. Why and how such anti-antibodies are induced during autoimmune diseases, has remained largely unclear. Because repetitively arranged epitopes in a paracrystalline structure of a viral envelope cross-link B cell receptors efficiently to induce a prompt T-independent IgM response, this study used immune complexes containing viruses or bacteria to evaluate the role of antigen pattern for induction of anti-antibody responses. We present evidence that antibodies bound to strictly ordered, but not to irregularly arranged, antigens dramatically enhance induction of anti-antibodies, already after a single immunization and without using adjuvants. The results indicate a novel link between anti-antibody responses and infectious agents, and suggest a similar role for repetitive self-antigens such as DNA or collagen involved in chronic immunopathological diseases

Buried, forgotten and rediscovered - prospecting the Roman villae rusticae in the area of Flachgau in Salzburg, Austria

At six different villae rusticae sites in the Salzburger Flachgau high resolution motorized and non motorized magnetic and radar data was gained. The sites are well preserved due to sustainable agricultural use

Detection of Enterobacterial Lipopolysaccharides and Experimental Endotoxemia by Means of an Immunolimulus Assay Using Both SerotypeSpecific and Cross-Reactive Antibodies

The immunolimulus (IML) assay system uses solid-phase endotoxin antibodies to capture lipopolysaccharide (LPS), which is then quantified by a modification of the chromogenic limulus amebocyte lysate (CLAL) method. Monoclonal antibodies (MAbs) reactive with selected 0 antigen serotypes of Escherichia coli (O18) and Salmonella typhimurium (O-9,12), when used in the IML, were shown to be highly specific in detecting their respective endotoxins in purified form and in plasma samples from experimentally infected animals. A murine MAb that was broadly cross-reactive with E. coli, Salmonella, and Shigella endotoxins also proved to be highly effective in the IML assay for capturing LPS molecules from both E. coli and S. typhimurium strains. These results indicate that IML assays can detect smooth-type enterobacterial endotoxins in plasma and suggest that such assays have potential for use in the rapid diagnosis of sepsis and endotoxemia caused by different enterobacterial specie

Multiferroicity in an organic charge-transfer salt: Electric-dipole-driven magnetism

Multiferroics, showing simultaneous ordering of electrical and magnetic degrees of freedom, are remarkable materials as seen from both the academic and technological points of view. A prominent mechanism of multiferroicity is the spin-driven ferroelectricity, often found in frustrated antiferromagnets with helical spin order. There, similar to conventional ferroelectrics, the electrical dipoles arise from an off-centre displacement of ions. However, recently a different mechanism, namely purely electronic ferroelectricity, where charge order breaks inversion symmetry, has attracted considerable interest. Here we provide evidence for this exotic type of ferroelectricity, accompanied by antiferromagnetic spin order, in a two-dimensional organic charge-transfer salt, thus representing a new class of multiferroics. Quite unexpectedly for electronic ferroelectrics, dipolar and spin order arise nearly simultaneously. This can be ascribed to the loss of spin frustration induced by the ferroelectric ordering. Hence, here the spin order is driven by the ferroelectricity, in marked contrast to the spin-driven ferroelectricity in helical magnets.Comment: 8 pages, 9 figures (including 4 pages and 6 figures in supplementary information). Version 2 with minor errors corrected (legend of Fig. 3c and definition of vectors e and Q

Cognitive Impairment, Sexual Activity and Physical Tenderness in Community-Dwelling Older Adults: A Cross-Sectional Exploration

Background: The ability to engage in sexual activity and better cognitive functioning are both associated with better health. However, the association between cognitive functioning and sexual activity is understudied. Objective: To examine the association between cognitive functioning with sexual activity and physical tenderness among community-dwelling older adults. Methods: From the Rotterdam Study, cognitive impairment and sexual activity were assessed in 4,201 community-dwelling, 60+ year olds between 2008 and 2014 in the Netherlands. Mild cognitive impairment (MCI) was based upon subjective complaints related to age and education-adjusted test scores. Mini-Mental State Examination (MMSE) impairment was defined by a score of < 26. Sexual activity and physical tenderness (e.g., fondling or kissing) in the last 6 months were assessed at an interview. Analyses were stratified by gender and partner status, with prevalence rates for the "no impairment" categories weighted based on age from the cognitive impairment categories. Inter-rater reliability was examined utilising 74 cohabiting couples of opposite gender. Results: It was found that 14% were categorised as having cognitive impairment, and < 1% as dementia (excluded from subsequent analyses). There was strong evidence that the odds of engaging in physical tenderness (observed through MMSE < 26, OR 2.14, 95% CI 1.32-3.48, p = 0.002) and sexual activity (MCI, OR 2.36, 95% CI 1.35-4.12, p = 0.003) among partnered females with no impairment was twice that observed among cognitively impaired partnered females. There was weak evidence that the odds of engaging in physical tenderness (MMSE < 26, OR 1.59, 95% CI 1.04-2.42, p = 0.03) and sexual activity (MMSE < 26, OR 1.51, 95% CI 1.02-2.24, p = 0.04) among partnered males with no impairment was 50% greater than observed among cognitively impaired partnered males. The associations between cognitive functioning and physical tenderness continued to remain after adjustment for physical function, diabetes, cardiovascular disease and cancer. There was no clear evidence of a difference between amnestic and non-amnestic MCI for sexual behaviour. There was moderate to substantial agreement among the coupled adults who had 1 partner categorised with MCI. Conclusion: Having no cognitive impairment was associated with more engagement in sexual activity and physical tenderness among community-dwelling older adults. Sexuality is an important aspect of active aging and our findings illustrate a potential barrier to maintaining or instigating intimate relationships as we age. Longitudinal analyses are required to explore the direction of effect