Long-term use of pharmacological treatment in Alzheimer's disease: a retrospective cohort study in real-world clinical practice.

PURPOSE: To assess the impact of long-term use of different drugs commonly prescribed in Alzheimer's disease (AD) on its clinical course and to identify clinical and therapeutic factors associated with a delay in AD progression. METHODS: We retrospectively enrolled 50 patients visited at the Neurology Unit, Careggi University Hospital (Florence), followed for at least 24 months. AD diagnosis was made according to clinical diagnostic criteria for probable/possible AD dementia, always supported at least by one biomarker. Clinical features, MMSE scores evaluated at diagnosis and every 6 months, and AD drugs used for at least 6 months, were recorded. Cox regression analysis was performed to estimate the hazard ratio (HR) for AD progression, assuming as the "final event," the progression to a more severe disease stage, defined as the achievement of an MMSE score less than 10. RESULTS: At baseline, the median MMSE score was 22. During follow-up (median of 41 months), 56% of patients progressed to a more severe disease stage. The use of memantine, either alone (HR 0.24; 95% CI 0.09-0.60) or combined with acetylcholinesterase inhibitors (HR 0.35; 95% CI 0.14-0.88) and a higher MMSE score at baseline (HR 0.82; 95% CI 0.70-0.96) were associated with a significantly lower risk of AD progression. CONCLUSION: Nowadays, effective disease-modifying therapy for AD is missing. Nevertheless, when the diagnosis is established, our results support the advantage of long-term use of available pharmacological treatments, especially in combination, in delaying AD progression to its more severe disease stage.

Behçet's syndrome as a tool to dissect the mechanisms of thrombo-inflammation: clinical and pathogenetic aspects.

Behçet's syndrome (BS) is a complex disease with different organ involvement. The vascular one is the most intriguing, considering the existence of a specific group of patients suffering from recurrent vascular events involving the venous and, more rarely, the arterial vessels. Several clinical clues suggest the inflammatory nature of thrombosis in BS, especially of the venous involvement, thus BS is considered a model of inflammation-induced thrombosis. Unique among other inflammatory conditions, venous involvement (together with the arterial one) is currently treated with immunosuppressants, rather than with anti-coagulants. Although many in-vitro studies have suggested the different roles of the multiple players involved in clot formation, in-vivo models are crucial to study this process in a physiological context. At present, no clear mechanisms describing the pathophysiology of thrombo-inflammation in BS exist. Recently, we focused our attention on BS patients as a human in-vivo model of inflammation-induced thrombosis to investigate a new mechanism of clot formation. Indeed, fibrinogen displays a critical role not only in inflammatory processes, but also in clot formation, both in the fibrin network and in platelet aggregation. Reactive oxygen species (ROS)-derived modifications represent the main post-translational fibrinogen alterations responsible for structural and functional changes. Recent data have revealed that neutrophils (pivotal in the pathogenetic mechanisms leading to BS damage) promote fibrinogen oxidation and thrombus formation in BS. Altogether, these new findings may help understand the pathogenetic bases of inflammation-induced thrombosis and, more importantly, may suggest potential targets for innovative therapeutic approaches.

Antidepressants and the risk of arrhythmia in elderly affected by a previous cardiovascular disease: a real-life investigation from Italy.

PURPOSE: The study aimed to fill existing knowledge gaps on the safety of antidepressant drugs (ADs) by estimating the risk of hospitalization for arrhythmia associated with use of selective serotonin reuptake inhibitors (SSRIs) and newer atypical ADs (NAAs) among elderly with previous cardiovascular (CV) events. METHODS: The cohort was composed by 199,569 individuals aged ≥ 65 years from five Italian healthcare territorial units who were discharged for cardiovascular outcomes in the years 2008-2010. The 17,277 patients who experienced hospital admission for arrhythmia during follow-up were included as cases. Odds of current ADs use among cases (i.e., 14 days before hospital admission) was compared with (i) odds of current use of 1:5 matched controls (between-patients case-control) and with (ii) odds of previous use during 1:5 matched control periods (within-patient case-crossover). The risk of arrhythmia associated with ADs current use was modelled fitting a conditional logistic regression. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. RESULTS: Current users of SSRIs and NAAs were at increased risk of arrhythmia with case-control odds ratios (OR) of 1.37 (95% confidence interval, CI 1.18 to 1.58) and 1.41 (1.16 to 1.71) and case-crossover OR of 1.48 (1.20 to 1.81) and 1.72 (1.31 to 2.27). An increased risk of arrhythmia was associated with current use of trazodone (NAA) consistently in case-control and case-crossover designs. CONCLUSIONS: Evidence that current use of SSRIs and NAAs is associated to an increased risk of arrhythmia among elderly with CV disease was consistently supplied by two observational approaches.

3D map distribution of metallic nanoparticles in whole cells using MeV ion microscopy.

In this work, a new tool was developed, the MORIA program that readily translates Rutherford backscattering spectrometry (RBS) output data into visual information, creating a display of the distribution of elements in a true three-dimensional (3D) environment. The program methodology is illustrated with the analysis of yeast Saccharomyces cerevisiae cells, exposed to copper oxide nanoparticles (CuO-NP) and HeLa cells in the presence of gold nanoparticles (Au-NP), using different beam species, energies and nuclear microscopy systems. Results demonstrate that for both cell types, the NP internalization can be clearly perceived. The 3D models of the distribution of CuO-NP in S. cerevisiae cells indicate the nonuniform distribution of NP in the cellular environment and a relevant confinement of CuO-NP to the cell wall. This suggests the impenetrability of certain cellular organelles or compartments for NP. By contrast, using a high-resolution ion beam system, discretized agglomerates of Au-NP were visualized inside the HeLa cell. This is consistent with the mechanism of entry of these NPs in the cellular space by endocytosis enclosed in endosomal vesicles. This approach shows RBS to be a powerful imaging technique assigning to nuclear microscopy unparalleled potential to assess nanoparticle distribution inside the cellular volume.

Fabrication of 3D photonic components on bulk crystalline silicon.

We have fabricated three dimensional photonic components such as waveguides and beam splitters from crystalline silicon using a process based on one or more ion irradiation steps with different energies and fluences, followed by electrochemical anodization and thermal annealing. We first demonstrate the fabrication of multilevel silicon waveguides and then extend this process to make multilevel beam splitters, in which three output waveguides are distributed over two depths. The dimensions of the waveguides can be defined within a range from 0.5 µm to several micrometers simply by varying the ion beam fluence.

Flow effects in the laser-induced thermal loading of optical traps and optofluidic devices.

Flow effects on the thermal loading in different optofluidic systems (optical trap and various microfluidic channels) have been systematically explored by using dye-based ratiometric luminescence thermometry. Thermal images obtained by fluorescence microscopy demonstrate that the flow rate plays a key role in determining both the magnitude of the laser-induced temperature increment and its spatial distribution. Numerical simulations were performed in the case of the optical trap. A good agreement between the experimental results and those predicted by mathematical modelling was observed. It has also been found that the dynamics of thermal loading is strongly influenced by the presence of fluid flow.

Single-cell electroporation using proton beam fabricated biochips.

We report the design and fabrication of a novel single cell electroporation biochip featuring high aspect ratio nickel micro-electrodes with smooth side walls between which individual cells are attached. The biochip is fabricated using Proton Beam Writing (PBW), a new direct write lithographic technique capable of fabricating high quality high-aspect-ratio nano and microstructures. By applying electrical impulses across the biochip electrodes, SYTOX® Green nucleic acid stain is incorporated into mouse neuroblastoma (N2a) cells and observed via green fluorescence when the stain binds with DNA inside the cell nucleus. Three parameters; electric field strength, pulse duration, and numbers of pulses have been investigated for the single cell electroporation process. The results indicate high transfection rates as well as cell viability of 82.1 and 86.7% respectively. This single cell electroporation system may represent a promising method for the introduction of a wide variety of fluorophores, nanoparticles, quantum dots, DNAs and proteins into cells.

Microstructuring of Nd:YAG crystals by proton-beam writing.

We report on the microstructuring of Nd:YAG crystals by direct proton-beam writing. Buried channel waveguides have been fabricated with full spatial control by the combined variation of crystal position and proton energy. The fluorescence images of the obtained structures have been used to evaluate the potential application of the fabricated structures for laser gain as well as to elucidate the mechanism at the basis of the refractive index increment induced at the end of the proton path. We have concluded that this increment is very likely a local enhancement in the electronic polarizability caused by nuclear collisions.

Imaging using pulses: a simple and fast (>100 kHz) solution.

Imaging is an important component of spectroscopy. A good imaging system is expected to work with a high-pixel resolution using signals of high count-rates with as little dead time as possible to deliver an image quickly and reliably. It is not uncommon for such a system to be highly specialized, expensive and to consist of many dedicated electronic components. In this work, we present a simple imaging algorithm that can be used with a pulse (TTL) data signal, such as that produced by some photomultipliers and electron detectors. This algorithm works with only a simple general purpose data acquisition computer card (NI PXI/PCI-6259) from National Instruments residing in a computer. The system has been tested with signal rates in excess of 100 kHz to produce images at a pixel resolution of 512 x 512. The system's ability to handle such high count-rates hinges on utilizing the buffered data collection feature on the said card, in a hitherto unreported configuration. This system now offers a simple and cost-effective manner of incorporating high count-rate imaging features, such as in a scanning electron microscope, into a purely spectroscopic system. Further, since the use of the NI DAQ cards are supported under other computer platforms, the current imaging formalism is readily transferrable to computer platforms such as Linux or Mac OS.

Effects of oxide formation around core circumference of silicon-on-oxidized-porous-silicon strip waveguides.

We have studied the effect of oxidation on the propagation loss and surface roughness of silicon-on-oxidized-porous-silicon strip waveguides fabricated using proton-beam irradiation and electrochemical etching. A thin thermal oxide is formed around the core of the waveguide, enabling the symmetric reduction of core size and roughness on all sides. Significant loss reduction from about 10 dB/cm to 1 dB/cm has been obtained in TE and TM polarizations after oxidation smoothening of both the bottom and the sidewalls by 20 nm. This corresponds well with simulations using the beam-propagation method that show significant contributions from both surfaces.

Fabrication of low-loss silicon-on-oxidized-porous-silicon strip waveguide using focused proton-beam irradiation.

We have successfully fabricated low-loss silicon-on-oxidized-porous-silicon (SOPS) strip waveguides with high-index contrast using focused proton-beam irradiation and electrochemical etching. Smooth surface quality with rms roughness of 3.1 nm is achieved for a fluence of 1x10(15)/cm(2) after postoxidation treatment. Optical characterization at a wavelength of 1550 nm shows a loss of 1.1+/-0.4 dB/cm and 1.2+/-0.4 dB/cm in TE and TM polarization respectively, which we believe is the lowest reported loss for SOPS waveguides. This opens up new opportunities for all-silicon-based optoelectronics applications.

Water-Bridge-Assisted Ionic Conduction in Probe-Induced Conical Polymer Pattern Formation.

Formation of conical polymer structures by atomic force microscopy (AFM) nanolithography and the electrical-conduction mechanism involved in the AFM- probe-induced patterning process are reported. The current is dominated by water-bridge-assisted ionic conduction. Polymer phase transition and mass redistribution occur without modification or degradation of the poly(methyl methacrylate) (PMMA) material.