Tailoring the Antibody Response to Aggregated Aß Using Novel Alzheimer-Vaccines

Recent evidence suggests Alzheimer-Disease (AD) to be driven by aggregated Aß. Capitalizing on the mechanism of molecular mimicry and applying several selection layers, we screened peptide libraries for moieties inducing antibodies selectively reacting with Aß-aggregates. The technology identified a pool of peptide candidates; two, AFFITOPES AD01 and AD02, were assessed as vaccination antigens and compared to Aβ1-6, the targeted epitope. When conjugated to Keyhole Limpet Hemocyanin (KLH) and adjuvanted with aluminum, all three peptides induced Aß-targeting antibodies (Abs). In contrast to Aß1-6, AD01- or AD02-induced Abs were characterized by selectivity for aggregated forms of Aß and absence of reactivity with related molecules such as Amyloid Precursor Protein (APP)/ secreted APP-alpha (sAPPa). Administration of AFFITOPE-vaccines to APP-transgenic mice was found to reduce their cerebral amyloid burden, the associated neuropathological alterations and to improve their cognitive functions. Thus, the AFFITOME-technology delivers vaccines capable of inducing a distinct Ab response. Their features may be beneficial to AD-patients, a hypothesis currently tested within a phase-II-study

Proof for trivalent Sc ions in Sc2@C84 from high-energy spectroscopy

The electronic structure and the valency of the Sc ions in the endohedral dimetallofullerene Sc 2 @C 84 with D 2d symmetry are probed using high-energy spectroscopy. Comparison of the Sc 2p ! 3d x-ray-absorption spectrum with calculated ionic multiplet spectra shows that the Sc ions are trivalent. Detailed multiplet calcu-lations including covalency indicate that the effective valency of the Sc~III! ions can be described by a formal charge transfer to the fullerene cage of 2.660.1. This illustrates that a purely ionic picture is not valid for the electronic structure of Sc 2 @C 84 , and that a more complex picture including finite hybridization between the Sc and the fullerene cage has to be applied

Maleimide-functionalised platinum(IV) complexes as synthetic platform for targeted drug delivery

Maleimide-functionalised Pt(IV) complexes with highly selective binding properties to thiol groups were synthesised as precursors for binding of thiol-containing tumour targeting molecules like human serum albumi

No neurodevelopmental benefit of cerebral oximetry in the first randomised trial (SafeBoosC II) in preterm infants during the first days of life

Aim: Cerebral hypoxia has been associated with neurodevelopmental impairment. We studied whether reducing cerebral hypoxia in extremely preterm infants during the first 72 hours of life affected neurological outcomes at two years of corrected age. Methods: In 2012‐2013, the phase II randomised Safeguarding the Brains of our smallest Children trial compared visible cerebral near‐infrared spectroscopy (NIRS) monitoring in an intervention group and blinded NIRS monitoring in a control group. Cerebral hy oxia was significantly reduced in the intervention group. We followed up 115 survivors from eight European centres at two years of corrected age, by conducting a medical examination and assessing their neurodevelopment with the Bayley Scales of Infant and Toddler Development, Second or Third Edition, and the parental Ages and Stages Questionnaire (ASQ). Results: There were no differences between the intervention (n = 65) and control (n = 50) groups with regard to the mean mental developmental index (89.6 ± 19.5 versus 88.4 ± 14.7, p = 0.77), ASQ score (215 ± 58 versus 213 ± 58, p = 0.88) and the number of children with moderate‐to‐severe neurodevelopmental impairment (10 versus six, p = 0.58). Conclusions: Cerebral NIRS monitoring was not associated with long‐term benefits or harm with regard to neurodevelopmental outcome at two years of corrected age

Mit Menschen mit Demenz forschen – ethische Reflexionen einer qualitativen Forschungspraxis zur Mobilität im öffentlichen Raum

In diesem Beitrag reflektieren wir ethische Fragen der qualitativen Forschung mit Menschen mit Demenz anhand konkreter Projekterfahrungen und stellen theoretische Bezüge her. In dem Forschungsprojekt "Demenz in Bewegung: Studie und Handlungsempfehlungen für demenzfreundliches Unterwegssein im öffentlichen Verkehrssystem" partizipieren Menschen mit Demenz am Forschungsprozess. Im Rahmen des Forschungsprojektes wurden narrative Interviews zu Alltagserfahrungen und Mobilitätsbedürfnissen, eine Begehungsstudie mit Spaziergängen sowie eine Machbarkeitstestung von bestehenden technischen Hilfsmitteln durchgeführt. Zentrale ethische Herausforderungen zeigten sich sowohl in der theoretischen Fundierung als auch bei Vorbereitung und Durchführung der Untersuchung. Wir diskutieren den Grundsatz des informierten Einverständnisses als prozessorientierte Einwilligung (process consent) vor dem Hintergrund von Anforderungen institutionalisierter Prüfverfahren durch Ethikkommissionen. Darüber hinaus zeigen wir, dass unsere Entscheidung, "Demenz" im Gespräch mit betroffenen Menschen offen anzusprechen, im Spannungsfeld zwischen transparenter Information, dem Risiko zu verletzen und der Chance, ermächtigend zu wirken, steht

Clinical use of cerebral oximetry in extremely preterm infants is feasible

Introduction: The research programme Safeguarding the Brains of our smallest Children (SafeBoosC) aims to test the benefits and harms of cerebral near-infrared spectroscopy (NIRS) oximetry in infants born before 28 weeks of gestation. In a phase II trial, infants will be randomised to visible cerebral NIRS oximetry with pre-specified treatment guidelines compared to standard care with blinded NIRS-monitoring. The primary outcome is duration multiplied with the extent outside the normal range of regional tissue oxygen saturation of haemoglobin (rStO2) of 55 to 85% in percentage hours (burden). This study was a pilot of the Visible ­Oximetry Group. Material and methods: This was an observational study including ten infants. Results: The median gestational age was 26 weeks + three days, and the median start-up time was 133 minutes after delivery. The median recording time was 69.7 hours, mean rStO2 was 64.2 ± 4.5%, median burden of hyper- and hy­poxia was 30.3% hours (range 2.8-112.3). Clinical staff responded to an out of range value 29 times – only once to values above 85%. In comparison, there were 83 periods of more than ten minutes with an rStO2 below 55% and four episodes with an rStO2 above 85%. These periods accounted for 72% of the total hypoxia burden. A total of 18 of the 29 interventions were adjustments of FiO2 which in 13 of the 18 times resulted in an out-of-range SpO2. Two infants suffered second-degree burns from the sensor. Five infants died. In all cases, this was unrelated to NIRS monitoring and treatment. Conclusion: The intervention of early cerebral NIRS monitoring proved feasible, but prolonged periods of hypoxia went untreated. Thus, a revision of the treatment guideline and an alarm system is required

Cerebral near infrared spectroscopy oximetry in extremely preterm infants: phase II randomised clinical trial

Objective To determine if it is possible to stabilise the cerebral oxygenation of extremely preterm infants monitored by cerebral near infrared spectroscopy (NIRS) oximetry. Design Phase II randomised, single blinded, parallel clinical trial. Setting Eight tertiary neonatal intensive care units in eight European countries. Participants 166 extremely preterm infants born before 28 weeks of gestation: 86 were randomised to cerebral NIRS monitoring and 80 to blinded NIRS monitoring. The only exclusion criterion was a decision not to provide life support. Interventions Monitoring of cerebral oxygenation using NIRS in combination with a dedicated treatment guideline during the first 72 hours of life (experimental) compared with blinded NIRS oxygenation monitoring with standard care (control).Main outcome measures The primary outcome measure was the time spent outside the target range of 55-85% for cerebral oxygenation multiplied by the mean absolute deviation, expressed in %hours (burden of hypoxia and hyperoxia). One hour with an oxygenation of 50% gives 5%hours of hypoxia. Secondary outcomes were all cause mortality at term equivalent age and a brain injury score assessed by cerebral ultrasonography. Randomisation Allocation sequence 1:1 with block sizes 4 and 6 in random order concealed for the investigators. The allocation was stratified for gestational age (26 weeks).Blinding Cerebral oxygenation measurements were blinded in the control group. All outcome assessors were blinded to group allocation. Results The 86 infants randomised to the NIRS group had a median burden of hypoxia and hyperoxia of 36.1%hours (interquartile range 9.2-79.5%hours) compared with 81.3 (38.5-181.3) %hours in the control group, a reduction of 58% (95% confidence interval 35% to 73%, P<0.001). In the experimental group the median burden of hypoxia was 16.6 (interquartile range 5.4-68.1) %hours, compared with 53.6 (17.4-171.3) %hours in the control group (P=0.0012). The median burden of hyperoxia was similar between the groups: 1.2 (interquartile range 0.3-9.6) %hours in the experimental group compared with 1.1 (0.1-23.4) %hours in the control group (P=0.98). We found no statistically significant differences between the two groups at term corrected age. No severe adverse reactions were associated with the device. Conclusions Cerebral oxygenation was stabilised in extremely preterm infants using a dedicated treatment guideline in combination with cerebral NIRS monitoring.Trial registration ClinicalTrial.gov NCT0159031

A phase II randomized clinical trial on cerebral near-infrared spectroscopy plus a treatment guideline versus treatment as usual for extremely preterm infants during the first three days of life (SafeBoosC): study protocol for a randomized controlled trial.

BACKGROUND: Every year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2. METHODS/DESIGN: SafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the 'burden of hypoxia and hyperoxia' expressed in '%hours'. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected age, magnetic resonance imaging at term, blood biomarkers at 6 and 64 hours after birth, and adverse events. DISCUSSION: Cerebral oximetry guided interventions have the potential to improve neurodevelopmental outcome in extremely preterm infants. It is a logical first step to test if it is possible to reduce the burden of hypoxia and hyperoxia. TRIAL REGISTRATION: ClinicalTrial.gov, NCT01590316.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Cerebral near-infrared spectroscopy monitoring versus treatment as usual for extremely preterm infants:A protocol for the SafeBoosC randomised clinical phase III trial

Cerebral oxygenation monitoring may reduce the risk of death and neurologic complications in extremely preterm infants, but no such effects have yet been demonstrated in preterm infants in sufficiently powered randomised clinical trials. The objective of the SafeBoosC III trial is to investigate the benefits and harms of treatment based on near-infrared spectroscopy (NIRS) monitoring compared with treatment as usual for extremely preterm infants