Safety and Immunogenicity of a Live Attenuated RSV Vaccine in Healthy RSV-Seronegative Children 5 to 24 Months of Age

Despite substantial morbidity associated with respiratory syncytial virus (RSV) infection, there is no licensed vaccine. MEDI-559 is a live attenuated intranasal vaccine candidate being developed for prevention of lower respiratory illness due to RSV in young children. This randomized, placebo-controlled study evaluated safety of MEDI-559 in healthy, RSV-seronegative children. MEDI-559 or placebo was administered on 3 occasions, 2 months apart. Primary safety was based on solicited symptoms (SSs) and adverse events (AEs) collected for 28 days after each dose. Nasal wash samples were collected 3 times after each dose (days 7-10, 12-18, 28-34) and at sick visits. Serum was collected for measuring antibody immune responses to RSV prior to first vaccination and 28 days post final dose. Long-term safety was monitored for 365 days from first dose. SSs were mild and frequent (MEDI-559 84%; placebo 91%); most common SSs were runny/stuffy nose, cough, and irritability/fussiness. AEs occurred in 67% MEDI-559 and 57% placebo recipients: most common AE was upper respiratory tract infection (MEDI-559 35%; placebo 23%). Higher incidence of medically attended lower respiratory illness within 28 days after dosing occurred in the MEDI-559 arm compared to placebo (none associated with vaccine virus shedding). There was no evidence of enhanced RSV disease. Vaccine virus was detected only in MEDI-559 recipients; shedding occurred in 56%subjects, primarily post dose 1. A functional immune response was observed in 59% and 9% MEDI-559 and placebo recipients, respectively, by an RSV microneutralization assay. Vaccine take, assessed by proportion that shed vaccine-type virus or had a seroresponse against RSV, was seen in 95% MEDI-559 subjects. MEDI-559 is therefore biologically active and immunogenic in this seronegative pediatric population. Although the frequency of SSs and AEs was not considered clinically significant, the increase in medically attended lower respiratory illnesses in the vaccine group warrants expanded safety studies.

Trial Registration

ClinicalTrials.gov NCT00767416     

The insulinotropic effect of GIP is impaired in patients with chronic pancreatitis and secondary diabetes mellitus as compared to patients with chronic pancreatitis and normal glucose tolerance

BACKGROUND: The incretin effect is reduced and the insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is abolished in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE AND DESIGN: To evaluate the causality of this deficiency we investigated 8 patients with chronic pancreatitis (CP) and normal glucose tolerance (NGT) (fasting plasma glucose (FPG): 5.5 (4.5-6.0) mM (mean (range); HbA(1c): 5.8 (5.4-6.3) %) and 8 patients with CP and secondary diabetes not requiring insulin (FPG: 7.1 (6.0-8.8) mM; HbA(1c): 7.0 (5.8-10.0) %) during three 15-mM hyperglycaemic clamps with continuous iv infusion of saline, glucagon-like peptide-1 (GLP-1) or GIP. RESULTS: The initial (0-20 min) insulin and C-peptide responses were enhanced significantly in both groups by GLP-1 and GIP, respectively, compared to saline (P<0.05). In both groups GLP-1 infusion resulted in significantly greater insulin and C-peptide responses from 20-120 min compared with saline infusion. During GIP infusion the late-phase insulin response (20-120 min) was 3.1+/-1.0 fold greater than during saline infusion in the group of patients with CP and NGT (P<0.05), whereas there was no significant differences in patients with CP and DM. CONCLUSIONS: The lack of GIP amplification of the late insulin response to iv glucose develops alongside the deterioration of glucose tolerance in patients with CP, suggesting that the same may be true for the loss of the GIP effect in patients with T2DM.     

The Curvilinear Relationship between State Neuroticism and Momentary Task Performance

A daily diary and two experience sampling studies were carried out to investigate curvilinearity of the within-person relationship between state neuroticism and task performance, as well as the moderating effects of within-person variation in momentary job demands (i.e., work pressure and task complexity). In one, results showed that under high work pressure, the state neuroticism–task performance relationship was best described by an exponentially decreasing curve, whereas an inverted U-shaped curve was found for tasks low in work pressure, while in another study, a similar trend was visible for task complexity. In the final study, the state neuroticism–momentary task performance relationship was a linear one, and this relationship was moderated by momentary task complexity. Together, results from all three studies showed that it is important to take into account the moderating effects of momentary job demands because within-person variation in job demands affects the way in which state neuroticism relates to momentary levels of task performance. Specifically, we found that experiencing low levels of state neuroticism may be most beneficial in high demanding tasks, whereas more moderate levels of state neuroticism are optimal under low momentary job demands.     

First description of monogenean parasites in Lake Tanganyika: the cichlid Simochromis diagramma (Teleostei, Cichlidae) harbours a high diversity of Gyrodactylus species (Platyhelminthes, Monogenea)

Lake Tanganyika harbours the most diverse endemic cichlid fish assemblage of Africa, but its monogenean fish parasites have not been investigated. Here we report, for the first time, on the Gyrodactylus parasites in this hotspot of fish biodiversity. Haptor morphometrics and nuclear ribosomal DNA sequences revealed 3 new species on Zambian Simochromis diagramma: Gyrodactylus sturmbaueri n. sp., G. thysi n. sp. and G. zimbae n. sp. Their distinct morphology and strong genetic differentiation suggest that they belong to distant lineages within the genus Gyrodactylus, and phylogenetic reconstructions suggest affinities with other genera of gyrodactylids. Additional U-shaped haptoral plates in G. thysi n. sp. and a second large spine-like structure in the male copulatory organ of G. zimbae seem to represent new features for the genus. Such large diversity on a single host species can probably be explained by host-switching events during the course of evolution, in agreement with the generally accepted concept that ecological transfer is an important aspect of gyrodactylid speciation. Additional parasitological surveys on other host species, covering a broader phylogenetic and geographical range, should clarify the evolutionary history of Gyrodactylidae on cichlids in the African Great Lake and other parts of Africa.     

SUMOylation Is Required for Glycine-Induced Increases in AMPA Receptor Surface Expression (ChemLTP) in Hippocampal Neurons

Multiple pathways participate in the AMPA receptor trafficking that underlies long-term potentiation (LTP) of synaptic transmission. Here we demonstrate that protein SUMOylation is required for insertion of the GluA1 AMPAR subunit following transient glycine-evoked increase in AMPA receptor surface expression (ChemLTP) in dispersed neuronal cultures. ChemLTP increases co-localisation of SUMO-1 and the SUMO conjugating enzyme Ubc9 and with PSD95 consistent with the recruitment of SUMOylated proteins to dendritic spines. In addition, we show that ChemLTP increases dendritic levels of SUMO-1 and Ubc9 mRNA. Consistent with activity dependent translocation of these mRNAs to sites near synapses, levels of the mRNA binding and dendritic transport protein CPEB are also increased by ChemLTP. Importantly, reducing the extent of substrate protein SUMOylation by overexpressing the deSUMOylating enzyme SENP-1 or inhibiting SUMOylation by expressing dominant negative Ubc9 prevent the ChemLTP-induced increase in both AMPAR surface expression and dendritic SUMO-1 mRNA. Taken together these data demonstrate that SUMOylation of synaptic protein(s) involved in AMPA receptor trafficking is necessary for activity-dependent increases in AMPAR surface expression.