Genetic knockdown of Klk8 has sex-specific multi-targeted therapeutic effects on Alzheimer's pathology in mice.

AIMS: Previous work in our lab has identified the protease kallikrein-8 (KLK8) as a potential upstream mover in the pathogenesis of Alzheimer's disease (AD). We showed pathologically elevated levels of KLK8 in the cerebrospinal fluid and blood of patients with mild cognitive impairment or dementia due to AD, and in brains of patients and transgenic CRND8 (TgCRND8) mice in incipient stages of the disease. Furthermore, short-term antibody-mediated KLK8 inhibition in moderate stage disease alleviated AD pathology in female mice. However, it remains to be shown whether long-term reversal of KLK8 overexpression can also counteract AD. Therefore, the effects of genetic Klk8-knockdown were determined in TgCRND8 mice. METHODS: The effects of heterozygous ablation of murine Klk8 (mKlk8) gene on AD pathology of both sexes were examined by crossbreeding TgCRND8 [hAPP+/-] with mKlk8-knockdown [mKlk8+/-] mice resulting in animals with or without AD pathology which revealed pathologically elevated or normal KLK8 levels. RESULTS: mKlk8-knockdown had negligible effects on wildtype animals but led to significant decline of amyloid beta (Aß) and tau pathology as well as an improvement of structural neuroplasticity in a sex-specific manner in transgenics. These changes were mediated by a shift to non-amyloidogenic cleavage of the human amyloid precursor protein (APP), recovery of the neurovascular unit and maintaining microglial metabolic fitness. Mechanistically, Klk8-knockdown improved Aß phagocytosis in primary glia and Aß resistance in primary neurons. Most importantly, transgenic mice revealed less anxiety and a better memory performance. CONCLUSIONS: These results reinforce the potential of KLK8 as a therapeutic target in AD.

The virtual articulator in dentistry: concept and development.

Virtual Reality (VR) technology is one of the most important innovations for research, development, and industrial production. In dentistry, VR technology will be useful in providing better education through simulation and in enhancing working procedures that are conventionally limited, e.g., the mechanical articulator. It is the purpose of this article to present concepts and strategies for a future replacement of the mechanical articulator by a virtual one.

Intra-operative support via augmented reality techniques in endoscopic surgery.

Computer assisted operation planning systems are gaining increasing recognition in the field of surgery. These systems offer new possibilities for preparing an intervention, with the goal of reducing the amount of expensive operating-room time required for the intervention. The safest and most effective surgical approach should always be selected, but it is often difficult to transfer the output of the planning system to the intra-operative situation so that the planning results can be considered during the actual intervention. At the Fraunhofer Institute for Computer Graphics (IGD) in Darmstadt and the Centre for Advanced Media Technology (CAMTech) in Singapore methods are being developed to bridge the gap between the external planning session and the intra-operative case: Augmented Reality (AR) techniques are used to overlay preoperative scanned image data, as well as results of the planning session, on the operation field.

Nasal airflow diagnosis--comparison of experimental studies and computer simulations.

The lack of suited diagnostic tools providing insight into patient specific flow characteristics of the nasal airflow is one of the main problems in functional diagnosis. Diagnostic methods currently used do not provide the necessary information for flow analysis. But the flow distribution is essential for a physiological respiration, in particular for cleaning, moistening and tempering of the inhaled air as well as for the olfactory function of the nose. To overcome this current situation a cooperation project of the ENT surgeons and computer graphic engineers was established to develop the computer assisted planning system STAN (Simulation Tool for Airflow in the human Nose) combining Computer Fluid Dynamics (CFD) with advanced Computer Graphic Technology. The idea of the STAN system is to perform patient specific airflow simulations in the patient's nasal cavities. Therefore a geometrical model of the nasal airways is derived from the patient's tomography scans. A discretization of the surrounded flow volume is made by a computational grid. To establish the flow simulation Finite Element Methods are performed on the grid. A tailored visualization is offered to the surgeon that overlaps the flow pattern to the patient's tomography data shown in the coronal, sagittal and transversal plane. The surgeon can not only analyze the patient's current respiratory situation he has also the possibility to describe the planned surgical intervention. The goal is to simulate the flow distribution that can be expected after the surgical intervention and to offer a possibility to validate various surgical strategies. To verify the simulation results experimental investigations and measurements are made in nasal models. Silicon Models of patient's nose channels are made to analyze flow characteristics. The CT or MR scans of the same patients are used as input data for the simulation. The experimental outcome is compared to the simulation results to validate this diagnostic approach.