David Barral

Regulatory T cells modulate inflammation and reduce infarct volume in experimental brain ischaemia.

Brain ischaemia (stroke) triggers an intense inflammatory response predominately mediated by the accumulation of inflammatory cells and mediators in the ischaemic brain. In this context, regulatory T (Treg) cells, a subpopulation of CD4+ T cells with immunosuppressive and anti‐inflammatory properties, are activated in the late stages of the disease. To date, the potential therapeutic usefulness of Treg cells has not been tested. In this study, we aimed to investigate whether Treg cells exert protection/repair following stroke. Both the adoptive transfer of Treg cells into ischaemic rats and the stimulation of endogenous T‐cell proliferation using a CD28 superagonist reduced the infarct size at 3–28 days following the ischaemic insult. Moreover, T cell‐treated animals had higher levels of FoxP3 and lower levels of IL‐1β, CD11b+ and CD68+ cells in the infarcted hemisphere when compared with control animals. However, T‐cell treatment did not alter the rate of proliferation of NeuN‐, NCAM‐ or CD31‐positive cells, thereby ruling out neurogenesis and angiogenesis in protection. These results suggest that adoptive transfer of T cells is a promising therapeutic strategy against the neurological consequences of stroke.

Glutamate excitoxicity is the key molecular mechanism which is influenced by body temperature during the acute phase of brain stroke.

Glutamate excitotoxicity, metabolic rate and inflammatory response have been associated to the deleterious effects of temperature during the acute phase of stroke. So far, the association of temperature with these mechanisms has been studied individually. However, the simultaneous study of the influence of temperature on these mechanisms is necessary to clarify their contributions to temperature-mediated ischemic damage. We used non-invasive Magnetic Resonance Spectroscopy to simultaneously measure temperature, glutamate excitotoxicity and metabolic rate in the brain in animal models of ischemia. The immune response to ischemia was measured through molecular serum markers in peripheral blood. We submitted groups of animals to different experimental conditions (hypothermia at 33°C, normothermia at 37°C and hyperthermia at 39°C), and combined these conditions with pharmacological modulation of glutamate levels in the brain through systemic injections of glutamate and oxaloacetate. We show that pharmacological modulation of glutamate levels can neutralize the deleterious effects of hyperthermia and the beneficial effects of hypothermia, however the analysis of the inflammatory response and metabolic rate, demonstrated that their effects on ischemic damage are less critical than glutamate excitotoxity. We conclude that glutamate excitotoxicity is the key molecular mechanism which is influenced by body temperature during the acute phase of brain stroke.

Neuroprotection afforded by antagonists of endothelin-1 receptors in experimental stroke.

Endothelin-1 (ET-1) is involved on the development of cerebral edema in acute ischemic stroke. As edema is a therapeutic target in cerebral ischemia, our aim was to study the effect of antagonists for ET-1 receptors (Clazosentan® and BQ-788, specific antagonists for receptors A and B, respectively) on the development of edema, infarct volume and sensorial-motor deficits in rats subjected to ischemia by occlusion of the middle cerebral artery (MCAO). We used Wistar rats (280-320 g) submitted to ischemia by intraluminal transient (90 min) MCAO. After ischemia, rats were randomized into 4 groups (n = 6) treated with; 1) control group (saline), 2) Clazosentan® group (10 mg/kg iv), 3) BQ-788 group (3 mg/kg iv), and 4) combined treatment (Clazosentan® 10 mg/kg plus BQ-788 3 mg/kg iv). We observed that rats treated with Clazosentan® showed a reduction of edema, measured by MRI, at 72 h (hours) and at day 7 (both p < 0.0001), and a decrease in the serum levels of ET-1 at 72 h (p < 0.0001) and at day 7 (p = 0.009). The combined treatment also induced a reduction of edema at 24 h (p = 0.004), 72 h (p < 0.0001) and at day 7 (p < 0.0001), a reduction on infarct volume, measured by MRI, at 24 and 72 h, and at day 7 (all p < 0.01), and a better sensorimotor recovery at 24 and 72 h, and at day 7 (all p < 0.01). Moreover, Clazosentan® induced a decrease in AQP4 expression, while BQ-788 induced an increase in AQP9 expression. These results suggest that antagonists for ET-1 receptors may be a good therapeutic target for cerebral ischemia.

Influence of temperature on ischemic brain: Basic and clinical principles

In the last decades, the interest in the association between body temperature and stroke outcome has reemerged, and the use of animal models has made it possible to know the underlying pathogenic mechanisms involved, most of them with pending confirmation in human clinics. In this work, we will review the effects of hyperthermia and hypothermia and its pathogenesis on ischemic stroke, and the evidence of the efficacy and safety of anti-hyperthermic and hypothermic treatments. We will describe how treatment of hyperthermia on ischemic stroke patients, improves patient comfort and outcome, both in the short and the long term, but new clinical studies are needed in this field. Despite the theoretical and experimental bases in favor of hypothermia for the treatment of brain ischemia, there is no definitive clinical evidence that has proved its benefits, so far. With current knowledge, an objective of a body temperature between 35.5 and 36.5 °C seems an optimal therapeutic target for both hyperthermic and normothermic patients.

Quantization of coupled 1D vector modes in integrated photonic waveguides

A quantum mechanical analysis of the guided light in integrated photonics waveguides is presented. The analysis is made starting from one-dimensional (1D) guided vector modes by taking into account the modal orthonormalization property on a cross section of an optical waveguide, the vector structure of the guided optical modes and the reversal-time symmetry in order to quantize the 1D vector modes and to derive the quantum momentum operator and the Heisenberg equations. The results provide a quantum-consistent formulation of the linear and nonlinear quantum light propagations as a function of forward and backward creation and annihilation operators in integrated photonics. As an illustration, an application to an integrated nonlinear directional coupler is given, that is, both the nonlinear momentum and the Heisenberg equations of the nonlinear coupler are derived.

Optical field-strength generalized polarization of multimode single photon states in integrated directional couplers

A quantum analysis of the generalized polarization properties of multimode single photon states is presented. It is based on the optical field-strength probability distributions in such a way that generalized polarization is understood as a significant confinement of the probability distribution along certain regions of the multidimensional optical field-strength space. The analysis is addressed to multimode integrated waveguiding devices, such as N × N integrated directional couplers, whose modes fulfil a spatial modal orthogonality relationship. For that purpose a definition of the quantum generalized polarization degree in a N-dimensional space, based on the concept of distance to an unpolarized N-dimensional Gaussian distribution, is proposed. The generalized polarization degree of pure and mixture multimode single photon states and also of some multi-photon states such as coherent and chaotic ones, is evaluated and analyzed.

SPATIAL PROPAGATION OF QUANTUM LIGHT IN NONLINEAR WAVEGUIDING DEVICES: THEORY AND APPLICATIONS

We present the main theoretical results on spatial propagation of quantum light in nonlinear waveguiding devices together with a few applications. We show that the quantization of the classical momentum provides a consistent quantum mechanical formulation of both the linear and the nonlinear quantum light propagation in waveguiding devices. The momentum operator allows us to derive the correct spatial Heisenbergs equations for the forward and backward absorption and emission operators and consequently to analyze the spatial propagation in the multimode optical-field strength space. For that purpose we use the Feynmans path integral method in order to derive the quantum spatial optical propagators of different nonlinear waveguiding devices and accordingly to calculate the spatial propagation of the optical-field strength probability amplitude of quantum states in these nonlinear devices. Likewise, we present a preliminary and heuristic formulation of quantum dissipation in order to take into account the losses under spatial quantum propagation in lossy nonlinear waveguiding devices. It must be stressed that these optical-field strength probabilities have the advantage of being measured by homodyne techniques and therefore their theoretical analysis is of a remarkable interest in the optical characterization of quantum states obtained under linear and nonlinear propagation in waveguiding devices.

Optical field-strength polarization of two-mode single-photon states

We present a quantum analysis of two-mode single-photon states based on the probability distributions of the optical field strength (or position quadrature) in order to describe their quantum polarization characteristics, where polarization is understood as a significative confinement of the optical field-strength values on determined regions of the two-mode optical field-strength plane. We will show that the mentioned probability distributions along with the values of quantum Stokes parameters allow us to characterize the polarization of a two-mode single-photon state, in an analogous way to the classical case, and to distinguish conceptually between mixture and partially polarized quantum states; in this way, we propose a simple definition of the quantum polarization degree based on the recent concept of distance measure to an unpolarized distribution, which gives rise to a depolarization degree equivalent to an overlapping between the probability distribution of the quantum state and a non-polarized two-mode Gaussian distribution. The work is particularly intended to university physics teachers and graduate students as well as to physicists and specialists concerned with the issue of optical polarization.

Detection of two-mode spatial quantum states of light by electro-optic integrated directional couplers

We study both manipulation and detection of two-mode spatial quantum states of light by means of a reconfigurable integrated device built in an electro-optical material in a Kolgelnik–Schmidt configuration, which provides higher error tolerance to fabrication defects and larger integration density than other current schemes. SU(2) transformations are implemented on guided spatial modes in such a way that reconstruction of both the optical field-strength quantum probability distribution, via spatial two-mode homodyne detection, and the full optical field-strength wavefunction, by means of weak values, are carried out. This approach can be extended easily to spatial N-mode input quantum states. Apart from its usefulness to characterize optical quantum states, the approach also can be applied to the measurement of the so-called generalized quantum polarization.

Optical field-strength generalized polarization of non-stationary quantum states in waveguiding photonic devices

A quantum analysis of the generalized polarization properties of multimode non-stationary states based on their optical field-strength probability distributions is presented. The quantum generalized polarization is understood as a significant confinement of the probability distribution along certain regions of a multidimensional optical field-strength space. The analysis is addressed to quantum states generated in multimode linear and nonlinear waveguiding (integrated) photonic devices, such as multimode waveguiding directional couplers and waveguiding parametric amplifiers, whose modes fulfill a spatial modal orthogonality. In particular, the generalized polarization degree of coherent, squeezed and Schrödinger’s cat states is analyzed.