Correlation of protection against varicella in a randomized Phase III varicella-containing vaccine efficacy trial in healthy infants

Background: Varicella vaccination confers high and long-lasting protection against chickenpox and induces robust immune responses, but an absolute correlate of protection (CoP) against varicella has not been established. This study models the relationship between varicella humoral response and protection against varicella. Methods: This was a post-hoc analysis of data from a Phase IIIb, multicenter, randomized trial (NCT00226499) conducted in ten varicella-endemic European countries. Healthy children aged 12–22 months were randomized 3:3:1 to receive one dose of measles-mumps-rubella and one dose of varicella vaccine (one-dose group) or two doses of measles-mumps-rubella-varicella vaccine (two-dose group) or two doses of measles-mumps-rubella vaccine (control group) six weeks apart. The study remained observer-blind until completion, except in countries with obligatory additional immunizations. The objective was to correlate varicella-specific antibody concentrations with protection against varicella and probability of varicella breakthrough, using Cox proportional hazards and Dunning and accelerated failure time statistical models. The analysis was guided by the Prentice framework to explore a CoP against varicella. Results: The trial included 5803 participants, 5289 in the efficacy (2266: one-dose group, 2279: two-dose group and 744: control group) and 5235 (2248, 2245 and 742 in the same groups) in the immunogenicity cohort. The trial ended in 2016 with a median follow-up time of 9.8 years. Six weeks after vaccination with one- or two-dose varicella-containing vaccine, more than 93.0% of vaccinees were seropositive for varicella-specific antibodies. Estimated vaccine efficacy correlated positively with antibody concentrations. The fourth Prentice CoP criterion was not met, due to predicted positive vaccine efficacy in seronegative participants. Further modelling showed decreased probability of moderate to severe varicella breakthrough with increasing varicella-specific antibody concentrations (ten-year probability <0.1 for antibody concentrations ≥2-fold above the seropositivity cut-off). Conclusions: Varicella-specific antibody concentrations are a good predictor of protection, given their inverse correlation with varicella occurrence. Clinical trial: NCT00226499

Case-Control Study of Lung Function in World Trade Center Health Registry Area Residents and Workers

Rationale: Residents and area workers who inhaled dust and fumes from the World Trade Center disaster reported lower respiratory symptoms in two World Trade Center Health Registry surveys (2003–2004 and 2006–2007), but lung function data were lacking. Objectives: To examine the relationship between persistent respiratory symptoms and pulmonary function in a nested case–control study of exposed adult residents and area workers 7–8 years after September 11, 2001. Methods: Registrants reporting post September 11th onset of a lower respiratory symptom in the first survey and the same symptom in the second survey were solicited as potential cases. Registrants without lower respiratory symptoms in either Registry survey were solicited as potential control subjects. Final case–control status was determined by lower respiratory symptoms at a third interview (the study), when spirometry and impulse oscillometry were also performed. Measurements and Main Results: We identified 180 cases and 473 control subjects. Cases were more likely than control subjects to have abnormal spirometry (19% vs. 11%; P,0.05), and impulse oscillometry measurements of elevated airway resistance (R5; 68% vs. 27%; P,0.0001) and frequency dependence of resistance (R5–20; 36% vs. 7%; P , 0.0001). When spirometry was normal, cases were more likely than control subjects to have elevated R5 and R5–20 (62% vs. 25% and 27% vs. 6%, respectively; both P , 0.0001). Associations between symptoms and oscillometry held when factors significant in bivariate comparisons (body mass index, spirometry, and exposures) were analyzed using logistic regression. Conclusions: This study links persistent respiratory symptoms and oscillometric abnormalities in World Trade Center–exposed residents and area workers. ElevatedR5andR5–20 in cases despite normal spirometry suggested distal airway dysfunction as a mechanism for symptoms

All-d-Enantiomer of β-Amyloid Peptide Forms Ion Channels in Lipid Bilayers

Alzheimer’s disease (AD) is the most common type of senile dementia in aging populations. Amyloid β (Aβ)-mediated dysregulation of ionic homeostasis is the prevailing underlying mechanism leading to synaptic degeneration and neuronal death. Aβ-dependent ionic dysregulation most likely occurs either directly via unregulated ionic transport through the membrane or indirectly via Aβ binding to cell membrane receptors and subsequent opening of existing ion channels or transporters. Receptor binding is expected to involve a high degree of stereospecificity. Here, we investigated whether an Aβ peptide enantiomer, whose entire sequence consists of d-amino acids, can form ion-conducting channels; these channels can directly mediate Aβ effects even in the absence of receptor–peptide interactions. Using complementary approaches of planar lipid bilayer (PLB) electrophysiological recordings and molecular dynamics (MD) simulations, we show that the d-Aβ isomer exhibits ion conductance behavior in the bilayer indistinguishable from that described earlier for the l-Aβ isomer. The d isomer forms channel-like pores with heterogeneous ionic conductance similar to the l-Aβ isomer channels, and the d-isomer channel conductance is blocked by Zn2+, a known blocker of l-Aβ isomer channels. MD simulations further verify formation of β-barrel-like Aβ channels with d- and l-isomers, illustrating that both d- and l-Aβ barrels can conduct cations. The calculated values of the single-channel conductance are approximately in the range of the experimental values. These findings are in agreement with amyloids forming Ca2+ leaking, unregulated channels in AD, and suggest that Aβ toxicity is mediated through a receptor-independent, nonstereoselective mechanism

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Not AvailableThe melatonin, a hormone secreted by the pineal gland, was assayed in three she-camels located in the South of France. It was revealed that, like in other farm animals, there is a nyctohemeral rhythm of melatonin secretion in camel (Camelus dromedarius).Not Availabl

Not Available

Not AvailableThe melatonin, a hormone secreted by the pineal gland, was assayed in three she-camels located in the South of France. It was revealed that, like in other farm animals, there is a nyctohemeral rhythm of melatonin secretion in camel (Camelus dromedarius).Not Availabl

Evolution des secretions hormonales (LH,FSH,prolactine,E2 17beta) pendant la phase folliculaire du cycle sexuel chez la truie.

National audienc

Study of the specific lipid binding properties of Abeta 11-22 fragment at endosomal pH.

peer reviewedIncreasing evidence implicates interactions between Abeta peptide and lipids in the development of Alzheimer's disease. More generally, Abeta peptide interactions with membranes seem to depend on the composition of the lipid bilayer and the structural features of the peptide. One key parameter should be pH, since one site of intracellular Abeta peptide production and/or accumulation is likely to be endosomes. This intracellular endosomal accumulation was suggested to contribute to disease progression. In this paper, we report a study on the 11-22 amphiphilic domain of Abeta in interaction with model membrane; this region contains most of the charged residues of the N-terminal domain of Abeta. We show that the peptide charge, and more precisely the protonation state of histidines 13 and/or 14, is important for the interaction with lipids. Hence, it is only at endosomal pH that a conformational change of the peptide is observed in the presence of negatively charged lipid vesicles, that is, when both lipid headgroups and histidines can interact through electrostatic interactions. Specific interactions of the fragment with phosphatidylserine and to a lesser extent with phosphatidylcholine, but not phosphatidylethanolamine, are further evidenced by the Langmuir monolayer technique. From our results, we suggest that the protonation state of His residues could have a role in the pathogenic surface interaction of the whole Abeta peptide with membranes