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Mutations in theamyloid β precursor protein(APP) gene cosegregate with autosomal dominant Alzheimer disease (AD). Brain pathology of AD is characterized by amyloid deposition in senile plaques and by neurofibrillary tangles. Amyloid deposits in AD brains consist of amyloid β (Aβ), a 4-kDa proteolytic product of APP. In contrast, two other mutations inAPP, the FlemishAPP692and DutchAPP693mutations, are associated with autosomal dominant cerebral hemorrhages due to congophilic amyloid angiopathy (CAA) in the presence or absence of AD pathology, respectively. Both mutations are located within Aβ near the constitutive cleavage site. While a common effect of AD-linked mutations is to elevate Aβ42 extracellular concentrations, not much is known about the effect ofAPP692andAPP693. Here we provide evidence thatAPP692andAPP693have a different effect on Aβ secretion as determined by cDNA transfection experiments. WhileAPP692upregulates both Aβ40 and Aβ42 secretion,APP693does not. These data corroborate with previous findings that increased Aβ secretion and particularly of Aβ42, is specific for AD pathology.

Doel Delier komt frequent voor bij ouderen opgenomen in het ziekenhuis. Informatie verkregen van mantelzorgers zou kunnen bijdragen aan het herkennen van delier. Ons doel was om een vragenlijst voor mantelzorgers te ontwikkelen, de Informant Assessment of Geriatric Delirium (I-AGeD), om zo bij te dragen aan betere diagnostiek van delier bij oudere patiënten. Methode Een cross-sectionele observationele studie met een constructiecohort en twee valideringscohorten vond plaats op de afdeling Klinische Geriatrie van twee opleidingsziekenhuizen. Een diagnose delier, gebaseerd op de DSM-IV-criteria, werd direct bij binnenkomst in het ziekenhuis gesteld door arts-assistenten geriatrie en werd herbeoordeeld binnen 48 uur na opname. Mantelzorgers vulden bij aanvang van de opname een vragenlijst met 37 items in, hiervan werden uiteindelijk tien items geselecteerd die symptomen van delier beschreven. De items werden geselecteerd op het vermogen onderscheid te maken tussen aanwezigheid en afwezigheid van een delier, interne consistentie en inter-item correlaties. Resultaten 88 Patiënten werden in het ontwikkelcohort geïncludeerd. De gemiddelde leeftijd was 86.4 (SD 8.5) en 31/88 patiënten hadden een delier bij aanvang van opname. Interne consistentie van de tien item I-AGeD was hoog (Cronbachs alfa = 0,85). Bij een afkapwaarde van >4 was de sensitiviteit 77,4% en de specificiteit 63,2%. Bij patiënten zonder dementie, was de sensitiviteit 100% en de specificiteit 65,2%. Sensitiviteit en specificiteit verschilden in de twee valideringscohorten van 70,0 en 88,9% (n = 59) respectievelijk 66,7% en 100% (n = 39). Conclusie De nieuw ontwikkelde I-AGeD vragenlijst voor de mantelzorger is een valide screeningsinstrument voor delier bij aanvang van ziekenhuisopname van geriatrische patiënten.

Background. Features that may allow early identification of patients at risk of prolonged delirium, and therefore of poorer outcomes, are not well understood. The aim of this study was to determine if preoperative delirium risk factors and delirium symptoms (at onset and clinical symptomatology during the course of delirium) are associated with delirium duration. Methods. This study was conducted in prospectively identified cases of incident delirium. We compared patients experiencing delirium of short duration (1 or 2 days) with patients who had more prolonged delirium (≥3 days) with regard to DRS-R-98 (Delirium Rating Scale Revised-98) symptoms on the first delirious day. Delirium symptom profile was evaluated daily during the delirium course. Results. In a homogenous population of 51 elderly hip-surgery patients, we found that the severity of individual delirium symptoms on the first day of delirium was not associated with duration of delirium. Preexisting cognitive decline was associated with prolonged delirium. Longitudinal analysis using the generalised estimating equations method (GEE) identified that more severe impairment of long-term memory across the whole delirium episode was associated with longer duration of delirium. Conclusion. Preexisting cognitive decline rather than severity of individual delirium symptoms at onset is strongly associated with delirium duration.

Photoinduced electron transfer (PET) across molecular/bulk interfaces has gained attention only recently and is still poorly understood. These interfaces offer an excellent case study, pertinent to a variety of photovoltaic systems, photo- and electrochemistry, molecular electronics, analytical detection, photography, and quantum confinement devices. They play in particular a key role in the emerging fields of third-generation photovoltaic energy converters and artificial photosynthetic systems aimed at the production of solar fuels, creating a need for a better understanding and theoretical treatment of the dynamics and mechanisms of interfacial PET processes. We aim to achieve a fundamental understanding of these phenomena by designing experiments that can be used to test and alter modern theory and computational modeling. One example illustrating recent investigations into the details of the ultrafast processes that form the basis for photoinduced charge separation at a molecular/bulk interface relevant to dye-sensitized solar cells is briefly presented here: Kinetics of interfacial PET and charge recombination processes were measured by fs and ns transient spectroscopy in a heterogeneous donor-bridge-acceptor (D-B-A) system, where D is a RuII(terpyridyl-PO3)(NCS)3 complex, B an oligo-p-phenylene bridge, and A nanocrystalline TiO2. The forward ET reaction was found to be faster than vibrational relaxation of the vibronic excited state of the donor. Instead, the back ET occurred on the ?s time scale and involved fully thermalized species. The D-A distance dependence of the electron transfer rate was studied by varying the number of p-phenylene units contained in the bridge moiety. The remarkably low damping factor ? = 0.16 Å?1 observed for the ultrafast charge injection from the dye excited state into the conduction band of TiO2 is attributed to the coupling of electron tunneling with nonequilibrium vibrations redistributed on the bridge, giving rise to polaronic transport of charges from the donor ligand to the acceptor solid oxide surface.

Nanostructured liquid|solid and solid|solid bulk heterojunctions designed for the conversion of solar energy offer ideal models for the investigation of light-induced ET dynamics at surfaces. Despite significant study of processes leading to charge generation in third-generation solar cells, a conclusive picture of the photophysics of these photovoltaic converters is still missing. More specifically searched is the link between the molecular structure of the interface and the kinetics of surface photoredox reactions. Fundamental scientific issues in this field are addressed by there search project undertaken in the frame of the NCCR MUST endeavor, an outline of whic his given here.

Doel: De MoCA is een nieuwe screeningstest voor Mild Cognitive Impairment (MCI). Doel van dit onderzoek is validering van de Nederlandse versie (MoCA-D). Methode: De MoCA-D werd afgenomen bij gezonde ouderen en patiënten met MCI of dementie afkomstig van een geheugenpolikliniek en een (poli)kliniek geriatrie (n = respectievelijk 30, 32, 37; leeftijd≥60). Neuropsychologisch onderzoek maakte deel uit van het standaard onderzoek bij patiënten om de diagnose MCI te stellen. Sensitiviteit, specificiteit en predictieve waarden (positief: PPW en negatief: NPW) werden voor de MoCA-D bepaald. Resultaten: Er werd een significant effect van groep op MoCA-D totaalscore gevonden (F(2,95)=67,9; p

A déjà vu experience is a dissociative phenomenon, which can be characterized as a subjectively inappropriate impression of familiarity of the present with an undefined past. This paper reviews empirical studies on déjà vu experiences and summarizes the most salient findings. Overall, the findings appear to be inconsistent and inconclusive. The authors conclude that the available empirical research is of limited significance due to various methodological and conceptual issues. In order to evaluate the clinical psychiatric relevance of déjà vu experiences, further research which also addresses its qualitative features is warranted.

A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene, SCN9A encoding Na(v)1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine Scn9a ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous Scn9a(N641Y/N641Y) knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the SCN9A p.N641Y mutation as disease-causing in this family. To confirm the role of SCN9A in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Na(v)1.7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome (severe myoclonic epilepsy of infancy), we sequenced the SCN1A gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Na(v)1.7 missense variants (8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with SCN9A missense variants also harbored either missense or splice site SCN1A mutations and three had no SCN1A mutations. This study provides evidence for a role of SCN9A in human epilepsies, both as a cause of FS and as a partner with SCN1A mutations.