Rotavirus vaccines: a story of success.

By January 2015, rotavirus vaccination had been implemented in national vaccination programmes in 75 countries worldwide. Two live oral rotavirus vaccines are internationally available: human, monovalent vaccine and human-bovine pentavalent reassortant vaccine. Since January 2014, another live, oral human-bovine monovalent vaccine has been available in India. After implementation of rotavirus vaccines in childhood immunization programmes, there has been an over 90% reduction of rotavirus hospitalizations in industrialized and resource-deprived countries. Additionally, in Latin America, significant reduction of rotavirus-associated deaths has been recorded. Still, numerous countries do not recommend rotavirus mass vaccination because of assumed lack of cost-effectiveness and potential risk of intussusception, which is estimated at 1 per 50 000-70 000 doses of rotavirus vaccines. Cost-effectiveness of vaccination is affected in some countries by high price. Inclusion of herd protection and indirect costs in calculations for cost-effectiveness results in clear benefit: costs saved by health systems due to reduced rotavirus gastroenteritis hospitalizations far exceed the costs for implementation of rotavirus vaccination. There have been objections that high rotavirus vaccination coverage could put selective pressure on certain rotavirus strains against which protection after vaccination is less distinct. However, data now strongly suggest that even if there might be a relative increase of some specific genotypes after the use of rotavirus vaccines, this is not an absolute increase in incidence from certain genotypes and does not affect the overall effectiveness of rotavirus mass vaccination, which resulted in a major decrease of severe cases of rotavirus gastroenteritis in both industrialized and resource deprived countries.

Structure, function, and pharmacology of NMDA receptor channels.

NMDA receptors have received much attention over the last few decades, due to their role in many types of neural plasticity on the one hand, and their involvement in excitotoxicity on the other hand. There is great interest in developing clinically relevant NMDA receptor antagonists that would block excitotoxic NMDA receptor activation, without interfering with NMDA receptor function needed for normal synaptic transmission and plasticity. This review summarizes current understanding of the structure of NMDA receptors and the mechanisms of NMDA receptor activation and modulation, with special attention given to data describing the properties of various types of NMDA receptor inhibition. Our recent analyses point to certain neurosteroids as NMDA receptor inhibitors with desirable properties. Specifically, these compounds show use-dependent but voltage-independent block, that is predicted to preferentially target excessive tonic NMDA receptor activation. Importantly, neurosteroids are also characterized by use-independent unblock, compatible with minimal disruption of normal synaptic transmission. Thus, neurosteroids are a promising class of NMDA receptor modulators that may lead to the development of neuroprotective drugs with optimal therapeutic profiles.

The burden of pneumococcal meningitis in Austrian children between 2001 and 2008.

UNLABELLED: The present study was conducted to evaluate the burden of pneumococcal meningitis in Austrian children between 2001 and 2008. Clinical outcome was retrospectively analyzed both on discharge and on follow-up investigations. This study was based on a prospective multicentre surveillance study on hospitalized invasive pneumococcal infections in Austrian children with a total annual "study population" of about 399,000 children aged below 5 years per year. Between 2001 and 2008, 74 cases of pneumococcal meningitis were identified in children aged below 5 years. The mean annual incidence rate for pneumococcal meningitis was 2.3 per 100,000 children in this age group. In 57/74 children (mean age on admission 14.5 ± 13.3 months), outcome data on hospital discharge were available: 5 deaths (8.8%), 20 children (35.1%) with sequelae and 32 children (56.1%) without sequelae were observed. Sequelae on discharge included motor impairment in 8 children (14.0%), hearing impairment in 9 children (15.8%) and/or other complications in 14 children (24.6%). In 7/8 children with motor deficits, matching cerebral lesions were identified by neuroimaging: cerebral infarction in five children, cerebral vasculitis and cerebral abscess in one child each. In 40/57 children, long-term outcome (18.9 ± 20.2 months after discharge) could be assessed: 1 child (2.5%) died 9 months after hospital discharge, 11 children (27.5%) had one or two long-term sequelae and 28 children (70.0%) had no sequelae. Long-term sequelae included motor impairment in three children (7.5%), hearing impairment in nine children (22.5%) and other deficits in two children (5.0%). CONCLUSION: Our study confirms that pneumococcal meningitis causes high mortality and severe long-term sequelae. On long-term follow-up, we observed improvements of motor impairment, but not of hearing impairment.

Temperature dependence of N-methyl-D-aspartate receptor channels and N-methyl-D-aspartate receptor excitatory postsynaptic currents.

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are highly expressed in the CNS and mediate the slow component of excitatory transmission. The present study was aimed at characterizing the temperature dependence of the kinetic properties of native NMDARs, with special emphasis on the deactivation of synaptic NMDARs. We used patch-clamp recordings to study synaptic NMDARs at layer II/III pyramidal neurons of the rat cortex, recombinant GluN1/GluN2B receptors expressed in human embryonic kidney (HEK293) cells, and NMDARs in cultured hippocampal neurons. We found that time constants characterizing the deactivation of NMDAR-mediated excitatory postsynaptic currents (EPSCs) were similar to those of the deactivation of responses to a brief application of glutamate recorded under conditions of low NMDAR desensitization (whole-cell recording from cultured hippocampal neurons). In contrast, the deactivation of NMDAR-mediated responses exhibiting a high degree of desensitization (outside-out recording) was substantially faster than that of synaptic NMDA receptors. The time constants characterizing the deactivation of synaptic NMDARs and native NMDARs activated by exogenous glutamate application were only weakly temperature sensitive (Q(10)=1.7-2.2), in contrast to those of recombinant GluN1/GluN2B receptors, which are highly temperature sensitive (Q(10)=2.7-3.7). Ifenprodil reduced the amplitude of NMDAR-mediated EPSCs by approximately 50% but had no effect on the time course of deactivation. Analysis of GluN1/GluN2B responses indicated that the double exponential time course of deactivation reflects mainly agonist dissociation and receptor desensitization. We conclude that the temperature dependences of native and recombinant NMDAR are different; in addition, we contribute to a better understanding of the molecular mechanism that controls the time course of NMDAR-mediated EPSCs.

Safety and immunogenicity of concomitant vaccination with the cell-culture based Japanese Encephalitis vaccine IC51 and the hepatitis A vaccine HAVRIX1440 in healthy subjects: A single-blind, randomized, controlled Phase 3 study.

In travellers often several pre-departure immunizations are indicated, thus data are needed about possible interactions between vaccines. This Phase 3 study investigated the immunogenicity and safety of IC51 (JE vaccine) and HAVRIX1440 (hepatitis A vaccine) when administered alone or concomitantly to healthy subjects. The immune response was compared between single and concomitant vaccination in terms of geometric mean titre (GMT) and seroconversion rate (SCR) on Days 28 and 56. Immunogenicity was comparable for the 2 vaccines whether given together or separately which suggests that travellers to such regions could receive the vaccinations concomitantly.

National paediatric immunization program of high risk groups: no effect on the incidence of invasive pneumococcal diseases.

This study monitors the epidemiology of invasive pneumococcal diseases (IPD) in hospitalized children up to 60 months of age before (February 2001-October 2004) and after (November 2004-January 2007) the introduction of a national risk group immunization program with "Prevenar" in Austria. The IPD incidence rates, per 100,000, for IPD were 7.6 before and 6.4 after the risk group immunization program, while there was a significant reduction (p<0.05) for meningitis, 3.1 before and 1.6 after. Overall, the most commonly observed serotypes were 14 (34.2%), 6B (11.7%), and 23F (6.7%). 71.7% of the identified strains were vaccine types; 12.5% were vaccine-related serotypes. No clinically relevant changes in the incidence rate of IPDs or shift/replacement of serotypes was documented. Antimicrobial resistance predominated against erythromycin (32.5%) and clarithromycin (26.7%). Our data show that this risk group vaccination program had no impact on the incidence of IPD in young children.

Neurosteroid modulation of ionotropic glutamate receptors and excitatory synaptic transmission.

Ionotropic glutamate receptors function can be affected by neurosteroids, both positively and negatively. N-methyl-D-aspartate (NMDA) receptor responses to exogenously applied glutamate are potentiated or inhibited (depending on the receptor subunit composition) by pregnenolone sulphate (PS) and inhibited by pregnanolone sulphate (3alpha5betaS). While PS effect is most pronounced when its application precedes that of glutamate, 3alpha5betaS only binds to receptors already activated. Synaptically activated NMDA receptors are inhibited by 3alpha5betaS, though to a lesser extent than those tonically activated by exogenous glutamate. PS, on the other hand, shows virtually no effect on any of the models of synaptically activated NMDA receptors. The site of neurosteroid action at the receptor molecule has not yet been identified, however, the experiments indicate that there are at least two distinct extracellularly located binding sites for PS mediating its potentiating and inhibitory effects respectively. Experiments with chimeric receptors revealed the importance of the extracellular loop connecting the third and the fourth transmembrane domain of the receptor NR2 subunit for the neurosteroid action. alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors are inhibited by both PS and 3alpha5betaS. These neurosteroids also affect AMPA receptors-mediated synaptic transmission, however, in a rather indirect way, through presynaptically located targets of action.

Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomised controlled trial.

BACKGROUND: Japanese encephalitis virus (JEV) is the leading cause of viral encephalitis in southeast Asia. Although no treatment is currently available, vaccination effectively prevents the disease. In a non-inferiority study, we aimed to compare the safety and immunogenicity of a novel, second-generation, inactivated candidate vaccine for JEV with a licensed, mouse-brain-derived vaccine. METHODS: We included 867 adults in a multicentre, multinational, observer-blinded, randomised controlled phase III trial. Study sites were located in the USA, Germany, and Austria. Volunteers received either the JEV test vaccine intramuscularly on a two-dose schedule (on days 0 and 28; n=430) or the licensed vaccine subcutaneously according to its recommended three-dose schedule (on days 0, 7, and 28; n=437). The primary endpoint was immunogenicity, with respect to neutralising JEV-specific antibodies assessed by a plaque-reduction neutralisation test, which was assessable in 725 patients in the per-protocol population. This trial is registered as a clinical trial, EudraCT number 2004-002474-36. FINDINGS: The safety profile of the test vaccine was good, and its local tolerability profile was more favourable than that of the licensed vaccine. Frequency of adverse events was similar between treatment groups, and vaccine-related adverse events were generally mild. The seroconversion rate of the test vaccine was 98% compared with 95% for the licensed vaccine on day 56 (95% CI for the difference -1.33 to 3.43). Geometric mean titre for recipients of the test vaccine was 244 (range 5-19 783), compared with 102 (5-1864) for the licensed vaccine (ratio 2.3 [95% CI 1.967-2.75]). INTERPRETATION: The test JEV vaccine has a promising immunogenicity and safety profile.

The influence of human serum albumin on the photogeneration of singlet oxygen by meso-tetra(4-sulfonatophenyl)porphyrin. An infrared phosphorescence study.

meso-Tetra(4-sulfonatophenyl)porphyrin (TPPS4) is a water soluble photosensitizer, which is currently clinically tested as a PDT drug. In our contribution, we present IR spectral- and time-resolved phosphorescence data reflecting the influence of human serum albumin (HSA) on singlet oxygen photogeneration by TPPS4. IR emission of TPPS4 was studied in samples containing various concentrations of HSA in phosphate buffer. The observed changes in spectral and temporal behaviour of TPPS4 and singlet oxygen phosphorescence caused by the addition of HSA are equivalent to the effect of nitrogen purging of HSA-free solutions of TPPS4. The main feature induced by addition of HSA appears to be the occurrence of a long-lived (tens of microseconds) photosensitizer phosphorescence at 900 nm besides ordinary short-lived (approximately 2 micros) one at 820 nm. It is accompanied by presence of a long-lived component of singlet oxygen emission with lifetime roughly corresponding to that of the long photosensitizer phosphorescence component. Moreover, the quantum yield of singlet oxygen phosphorescence decreases with increasing HSA concentration, while total quantum yield of TPPS4 phosphorescence rises. These facts are explained by a shielding effect of HSA on bound molecules of TPPS4 against quenching by oxygen which is analogous to oxygen removal by nitrogen purging.

Concentrations of free mg2+, pH and 31P MR metabolite ratios in calf muscles of healthy controls and patients with primary juvenile hypertension.

31P MR spectroscopy was used to measure the signal intensity ratios of high-energy metabolites for the calculation of free cytosolic magnesium concentration [fMg(2+)] and pH in the calf muscles of patients with primary juvenile hypertension and of healthy controls. Surface coil and spectroscopic imaging techniques were used. In patients with hypertension, the concentrations of [fMg(2+)] was 788 +/- 33 micromol/l and intracellular pH was 7.05 +/- 0.02; these values were not significantly different from the results obtained in healthy controls ([fMg(2+)], 776 +/- 21 micromol/l and pH, 7.06 +/- 0.01). Biochemical assays of magnesium in the serum (S-Mg) and in urine (DU-Mg) confirmed this finding. Significant differences in the relative signal intensities of high-energy phosphates between patients with primary juvenile hypertension and healthy controls were observed: a) signal intensity ratios of PCr/Pi, PCr/PbetaATP, PDE/PbetaATP were increased, and b) Pi/PDe, Pi/PATP were decreased. The results were the same irrespective of whether the surface coil method or 31P spectroscopic imaging were employed.