Nanoparticles: A Challenging Vehicle for Neural Stimulation

Neurostimulation represents a powerful and well-established tool for the treatment of several diseases affecting the central nervous system. Although, effective in reducing the symptoms or the progression of brain disorders, the poor accessibility of the deepest areas of the brain currently hampers the possibility of a more specific and controlled therapeutic stimulation, depending on invasive surgical approaches and long-term stability, and biocompatibility issues. The massive research of the last decades on nanomaterials and nanoscale devices favored the development of new tools to address the limitations of the available neurostimulation approaches. This mini-review focuses on the employment of nanoparticles for the modulation of the electrophysiological activity of neuronal networks and the related transduction mechanisms underlying the nanostructure-neuron interfaces

Striatal dopamine neurotransmission is altered in age- and region-specific manner in a Parkinson's disease transgenic mouse

Dopamine (DA) plays a critical role in striatal motor control. The drop in DA level within the dorsal striatum is directly associated with the appearance of motor symptoms in Parkinson's disease (PD). The progression of the disease and inherent disruption of the DA neurotransmission has been closely related to accumulation of the synaptic protein alpha-synuclein. However, it is still unclear how alpha-synuclein affects dopaminergic terminals in different areas of dorsal striatum. Here we demonstrate that the overexpression of human alpha-synuclein (h-alpha-syn) interferes with the striatal DA neurotransmission in an age-dependent manner, preferentially in the dorsolateral striatum (DLS) of PDGF-h-alpha-syn mice. While 3-month-old mice showed an increase at the onset of h-alpha-syn accumulation in the DLS, 12-month-old mice revealed a decrease in electrically-evoked DA release. The enhanced DA release in 3-month-old mice coincided with better performance in a behavioural task. Notably, DA amplitude alterations were also accompanied by a delay in the DA clearance independently from the animal age. Structurally, dopamine transporter (DAT) was found to be redistributed in larger DAT-positive clumps only in the DLS of 3- and 12-month-old mice. Together, our data provide new insight into the vulnerability of DLS and suggest DAT-related dysfunctionalities from the very early stages of h-alpha-syn accumulation

Sub-millisecond Control of Neuronal Firing by Organic Light-Emitting Diodes.

Optogenetics combines optics and genetics to enable minimally invasive cell-type-specific stimulation in living tissue. For the purposes of bio-implantation, there is a need to develop soft, flexible, transparent and highly biocompatible light sources. Organic semiconducting materials have key advantages over their inorganic counterparts, including low Young's moduli, high strain resistances, and wide color tunability. However, until now it has been unclear whether organic light emitting diodes (OLEDs) are capable of providing sufficient optical power for successful neuronal stimulation, while still remaining within a biologically acceptable temperature range. Here we investigate the use of blue polyfluorene- and orange poly(p-phenylenevinylene)-based OLEDs as stimuli for blue-light-activated Sustained Step Function Opsin (SFFO) and red-light-activated ChrimsonR opsin, respectively. We show that, when biased using high frequency (multi-kHz) drive schemes, the OLEDs permit safe and controlled photostimulation of opsin-expressing neurons and were able to control neuronal firing with high temporal-resolution at operating temperatures lower than previously demonstrated

Long-Term Pioglitazone Treatment Has No Significant Impact on Microglial Activation and Tau Pathology in P301S Mice

Neuroinflammation is one disease hallmark on the road to neurodegeneration in primary tauopathies. Thus, immunomodulation might be a suitable treatment strategy to delay or even prevent the occurrence of symptoms and thus relieve the burden for patients and caregivers. In recent years, the peroxisome proliferator-activated receptor & gamma;(PPAR & gamma;) has received increasing attention as it is immediately involved in the regulation of the immune system and can be targeted by the anti-diabetic drug pioglitazone. Previous studies have shown significant immunomodulation in amyloid-& beta;(A & beta;) mouse models by pioglitazone. In this study, we performed long-term treatment over six months in P301S mice as a tauopathy model with either pioglitazone or placebo. We performed serial 18 kDa translocator protein positron-emission-tomography (TSPO-PET) imaging and terminal immunohistochemistry to assess microglial activation during treatment. Tau pathology was quantified via immunohistochemistry at the end of the study. Long-term pioglitazone treatment had no significant effect on TSPO-PET, immunohistochemistry read-outs of microglial activation, or tau pathology levels in P301S mice. Thus, we conclude that pioglitazone modifies the time course of A & beta;-dependent microglial activation, but does not significantly modulate microglial activation in response to tau pathology

Light-Evoked Modulation of Neuronal Activity with Conjugated Polymers

Organic bioelectronics aims at the intimate integration between organic materials and biological tissues in order to obtain a targeted functional outcome. In the last decades, conductive polymers have been successfully employed to interface excitable cells through biocompatible probes and devices. We previously reported the possibility to culture primary neurons on photosensitive conjugated polymers, such as poly(3-hexylthiophene) (P3HT), without altering either the polymer or the neuronal properties. These neurons displayed a depolarizing response to a brief (< 50 ms) green light stimulus and a consequent control over the action potential firing rate. The same interface was also shown to elicit activation of retinal circuitry and ganglion cell firing in explanted degenerate retinas upon light stimulation. However, while neuronal excitation has been extensively proved via planar or protruding electrodes, carbon nanotubes, and conjugated polymers, the hyperpolarization of neurons and silencing of their firing activity has been achieved with optogenetics, but rarely documented for functionalized planar devices and structures. We show here a method to induce both depolarization and hyperpolarization of cells interfaced with conjugated polymers upon prolonged (500 ms) light stimulation. Patch-clamp experiments showed that HEK293 cells grown on P3HT displayed a biphasic response composed of an initial depolarization followed by a sustained hyperpolarization during light illumination. We also documented that the amplitude of the light-induced hyperpolarization was reduced in the absence of intracellular potassium, but was insensitive to changes in the intracellular chloride concentration. A prolonged illumination was equally able to hyperpolarize primary neurons cultured over P3HT and significantly reduced both spontaneous and electrically elicited action potential frequency. We further assessed the translatability of our findings to tissue stimulation by describing the modulation of ganglion cell firing in explanted blind retinas from Royal College of Surgeons rats, a model of Retinitis pigmentosa. By coupling conjugated polymers with multi-electrode arrays and conventional metal electrodes, single-unit activity of ganglion cells was inhibited by prolonged illumination. We similarly investigated the phenomenon in acute hippocampal brain slices placed onto a conjugated polymer thin film. These results indicate that conjugated polymers can be used to non-invasively excite and inhibit the electrical activity of cells cultured on its surface. Furthermore, the translation of our findings from in vitro cultures to different central nervous system tissues, suggests a potential application of these organic devices as a tool for modulation of neuronal activity in vivo

Impacts of Europe's Changing Climate - 2008 Indicator Based Assessment

Background and objective This report is an update and extension of the 2004 EEA report 'Impacts of Europe's changing climate'. Since 2004, there has been much progress in monitoring and assessing the impacts of climate change in Europe. The objectives of this report are to present this new information on past and projected climate change and its impacts through indicators, to identify the sectors and regions most vulnerable to climate change with a need for adaptation, and to highlight the need to enhance monitoring and reduce uncertainties in climate and impact modelling. To reflect the broadening of coverage of indicators and make use of the best available expertise, the report has been developed jointly by EEA, JRC and WHO Regional Office for Europe. Global developments in science and policy The Intergovernmental Panel on Climate Change (IPCC) in its 4th Assessment report reconfirmed and strengthened earlier scientific findings about key aspects of climate change. Increased monitoring and research efforts have enhanced understanding of climate change impacts and vulnerability. At the 2007 Bali climate change conference, the urgency of responding effectively to climate change through both adaptation and mitigation activities was recognised by a larger number of countries than ever before. The EU has proposed a target of a maximum global temperature increase of 2 °C above the pre-industrial level. A post-Kyoto regime that would include both adaptation and mitigation is expected to be agreed by end of 2009. There has been progress in implementing the Nairobi work programme on impacts, vulnerability and adaptation to climate change, developed to help countries improve their understanding of climate change impacts. European developments in science and policy European research on impacts and vulnerability in the context of national programmes and the 5th and 6th Framework Programmes has advanced considerably, making a major contribution to international assessments such as those of the IPCC, the Arctic Impact Assessment, the UNEP Global Outlook for Ice and Snow and WHO reports. New research programmes focusing on impacts, vulnerability and adaptation are currently being developed in many member countries and in the context of the 7th Framework Programme. On the policy side, the European Commission published its Green Paper on adaptation in 2007, to be followed by a White Paper by the end of 2008 with concrete proposals for action. This report The main part of this report summarises the relevance, past trends and future projections for about 40 indicators (from 22 in the 2004 report). The indicators address atmosphere and climate, the cryosphere, marine systems, terrestrial systems and biodiversity, agriculture and forestry, soil, water quantity (including floods and droughts), water quality and fresh water ecology, and human health. After a brief introduction, several chapters deal in a general way with the changes in the climate system and the observed and projected impacts. The report ends with chapters on adaptation and the economics of climate change impacts and adaptation strategies and policies, and data availability and uncertainty.JRC.H.7-Land management and natural hazard

Implementation of a program for type 2 diabetes based on the Chronic Care Model in a hospital-centered health care system: "the Belgian experience"

Background: Most research publications on Chronic Care Model (CCM) implementation originate from organizations or countries with a well-structured primary health care system. Information about efforts made in countries with a less well-organized primary health care system is scarce. In 2003, the Belgian National Institute for Health and Disability Insurance commissioned a pilot study to explore how care for type 2 diabetes patients could be organized in a more efficient way in the Belgian healthcare setting, a setting where the organisational framework for chronic care is mainly hospital-centered. Methods: Process evaluation of an action research project (2003-2007) guided by the CCM in a well-defined geographical area with 76,826 inhabitants and an estimated number of 2,300 type 2 diabetes patients. In consultation with the region a program for type 2 diabetes patients was developed. The degree of implementation of the CCM in the region was assessed using the Assessment of Chronic Illness Care survey (ACIC). A multimethod approach was used to evaluate the implementation process. The resulting data were triangulated in order to identify the main facilitators and barriers encountered during the implementation process. Results: The overall ACIC score improved from 1.45 (limited support) at the start of the study to 5.5 (basic support) at the end of the study. The establishment of a local steering group and the appointment of a program manager were crucial steps in strengthening primary care. The willingness of a group of well-trained and motivated care providers to invest in quality improvement was an important facilitator. Important barriers were the complexity of the intervention, the lack of quality data, inadequate information technology support, the lack of commitment procedures and the uncertainty about sustainable funding. Conclusion: Guided by the CCM, this study highlights the opportunities and the bottlenecks for adapting chronic care delivery in a primary care system with limited structure. The study succeeded in achieving a considerable improvement of the overall support for diabetes patients but further improvement requires a shift towards system thinking among policy makers. Currently primary care providers lack the opportunities to take up full responsibility for chronic care

A fully organic retinal prosthesis restores vision in a rat model of degenerative blindness

The degeneration of photoreceptors in the retina is one of the major causes of adult blindness in humans. Unfortunately, no

Will drought events become more frequent and severe in Europe?

As a result of climate change in recent past and unsustainable land management, drought became one of the most impacting disasters and, with the projected global warming, it is expected to progressively cause more damages by the end of the 21st century. This study investigates changes in drought occurrence, frequency, and severity in Europe in the next decades. A combined indicator based on the predominance of the drought signal over normal/wet conditions has been used. The indicator, which combines the standardized precipitation index (SPI, which accounts for anomalous low rainfall), the standardized precipitation evapotranspiration index (SPEI, which accounts for high temperatures and scarce precipitations), and the reconnaissance drought indicator (RDI, similar to SPEI but more affected by extreme events), has been computed at 3- and 12-month accumulation scales to characterize trends in seasonal and annual events from 1981 to 2100. Climate data from 11 bias-adjusted high-resolution (0.11°) simulations from the EURO-CORDEX (coordinated regional climate downscaling experiment) have been used in the analyses. For each simulation, the frequency and severity of drought and extreme drought events for 1981–2010, 2041–2070, and 2071–2100 have been analysed. Under the moderate emission scenario (RCP4.5), droughts are projected to become increasingly more frequent and severe in the Mediterranean area, western Europe, and Northern Scandinavia, whereas the whole European continent, with the exception of Iceland, will be affected by more frequent and severe extreme droughts under the most severe emission scenario (RCP8.5), especially after 2070. Seasonally, drought frequency is projected to increase everywhere in Europe for both scenarios in spring and summer, especially over southern Europe, and less intensely in autumn; on the contrary, winter shows a decrease in drought frequency over northern Europe.Fil: Spinoni, Jonathan. European Commission Joint Research Centre; ItaliaFil: Vogt, Jürgen V.. European Commission Joint Research Centre; ItaliaFil: Naumann, Gustavo. European Commission Joint Research Centre; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barbosa, Paulo. European Commission Joint Research Centre; ItaliaFil: Dosio, Alessandro. European Commission Joint Research Centre; Itali

Climate Impacts in Europe - The JRC PESETA II Project

The objective of the JRC PESETA II project is to gain insights into the sectoral and regional patterns of climate change impacts in Europe by the end of this century. The study uses a large set of climate model runs and impact categories (ten impacts: agriculture, energy, river floods, droughts, forest fires, transport infrastructure, coasts, tourism, habitat suitability of forest tree species and human health). The project integrates biophysical direct climate impacts into a macroeconomic economic model, which enables the comparison of the different impacts based on common metrics (household welfare and economic activity). Under the reference simulation the annual total damages would be around €190 billion/year, almost 2% of EU GDP. The geographical distribution of the climate damages is very asymmetric with a clear bias towards the southern European regions. More than half of the overall annual EU damages are estimated to be due to the additional premature mortality (€120 billion). Moving to a 2°C world would reduce annual climate damages by €60 billion, to €120 billion (1.2% of GDP)