Investigating the effect of corneal herpes simplex virus infection on toll like receptor expression in human peripheral blood mononuclear cells

Herpes Simples Keratitis (HSK) is the commonest cause of infectious blindness in the developed world. It is caused by HSV-l which is a large double stranded DNA virus which can invade the cornea and after treatment remains latent in the trigeminal ganglia. Toll like receptors are key components of the innate immune system and are highly expressed in the corneal epithelium. HSV-l induces upregulation of several Toll Like Receptors (TLRs) and triggers the release of anti-viral cytokines. In certain cases HSV-l has evolved to avoid these innate anti-viral responses and can cause lifelong recurrent infection. This recurrent keratitis causes lesions which are immunoinflammatory in nature, can recur throughout life and cause progressive corneal scarring, vascularisation, thinning and may require a corneal transplant which does not have a good long-term outcome. Understanding the mechanisms that cause this disease may lead to improved or novel therapies that will help the long-term outcome of HSK patients. This study aims to examine the immune responses of HSK patient peripheral blood mononuclear cells (PBMC) before and after treatment compared to healthy donors. Our work has shown that peripheral blood mononuclear cells (PBMCs) show differences in their ability to respond to various TLR ligands both in relation to the cytokines they produce and upregulation of cell surface markers. In particular our results show that IL-1(3, a key proinflammatory cytokine is elevated in serum of active patients compared to inactive patients, thus demonstrating that peripheral immune responses are activated in response to HSV infection of the cornea. In addition our work has shown that although active patients expressed activation markers on T cells and B cells but differences were inconclusive based on patient numbers (active/inactive n=5, control n=4). Further data indicated that the TLR 3 pathway is compromised in active patient PBMCs, potentially having implications for HSV-l viral clearance and viral replication and HSK persists in the cornea

Platelet signalling networks: pathways perturbation demonstrates differential sensitivity of ADP secretion and fibinogen binding.

Platelet signalling responses to single agonists have been identified previously. However a model of the total platelet signalling network is still lacking. In order to gain insights into this network, we explored the effects of a range of platelet-function inhibitors in two independent assays of platelet function, namely fibrinogen binding and ADP secretion. In this study, we targeted the intracellular signalling molecules Syk and PI3K, the prostaglandin synthesis enzyme COX, surface receptors for TxA2 and ADP (P2Y1 and P2Y12) and the integrin cell adhesion molecule, aIIbb3. We demonstrate that the platelet responses of fibrinogen binding and secretion can be differentially affected by the individual inhibitors permitting the generation of a model delineating novel regulatory links in the platelet signal network. Importantly, the model illustrates the interconnections among portions that are traditionally studied as separate modules, promoting a more integrated view of the platelet

The threshold level of urinary cadmium associated with increased urinary excretion of retinol-binding protein and β2-microglobulin: a re-assessment in a large cohort of nickel-cadmium battery workers

OBJECTIVE: To evaluate the threshold value of urinary cadmium (CdU) for renal dysfunction on the basis of relationships unconfounded by protein degradation, diuresis and the renal effects associated with chronic smoking. Methods We studied 599 workers (451 men, mean age 45.4 years) who were employed in four nickel-cadmium battery plants for 18.8 years on average. After adjustment for covariates by multiple regression, the CdU threshold values for increased concentrations of retinol-binding protein (RBPU) and b(2)-microglobulin (b(2)-mU) were assessed by logistic regression and benchmark dose analyses using as referents workers with CdU10, respectively. The benchmark dose (BMD5) and the benchmark dose lower limit (BMDL5) for a 5% excess in the background prevalence of abnormal RBPU and b(2)-mU were estimated at 5.1/3.0 and 9.6/5.9. When excluding ever smokers, odds for abnormal RBPU and b(2)-mU were both increased only among workers with CdU>10 (OR, 21.8, 95% CI, 6.4-74.4 and OR, 15.1, 95% CI, 3.6-63.1, respectively). In never smokers, these BMD5/BMDL5 of CdU were estimated at 12.6/6.6 and 12.2/5.5 while in ever smokers they were 6.2/4.9 and 4.3/3.5. Conclusions On the basis of associations undistorted by smoking and adjusted for covariates, the BMDL5 of CdU for low-molecular-weight proteinuria induced by occupational exposure to Cd can be reliably estimated between 5.5 and 6.6 μg/g creatinine

Alpes et Pyrénées : descriptions et curiosités de la Suisse, de la Savoie, de la Navarre, du Béarn, du Bigorre et du Comminges,...

En la port.:"Ascensions de Montagnes, pics et glaciers, traversées de mers de glace,oules, cols et ports, visites de lacs,cascades et vallées, excursions aux ruines, courses a pied,a cheval, en steamers, en poste, en voiturins

Controlled non uniform random generation of decomposable structures

Consider a class of decomposable combinatorial structures, using different types of atoms \Atoms = \{\At_1,\ldots ,\At_{|{\Atoms}|}\}. We address the random generation of such structures with respect to a size $n$ and a targeted distribution in $k$ of its \emph{distinguished} atoms. We consider two variations on this problem. In the first alternative, the targeted distribution is given by $k$ real numbers \TargFreq_1, \ldots, \TargFreq_k such that 0 < \TargFreq_i < 1 for all $i$ and \TargFreq_1+\cdots+\TargFreq_k \leq 1. We aim to generate random structures among the whole set of structures of a given size $n$, in such a way that the {\em expected} frequency of any distinguished atom \At_i equals \TargFreq_i. We address this problem by weighting the atoms with a $k$-tuple \Weights of real-valued weights, inducing a weighted distribution over the set of structures of size $n$. We first adapt the classical recursive random generation scheme into an algorithm taking \bigO{n^{1+o(1)}+mn\log{n}} arithmetic operations to draw $m$ structures from the \Weights-weighted distribution. Secondly, we address the analytical computation of weights such that the targeted frequencies are achieved asymptotically, i. e. for large values of $n$. We derive systems of functional equations whose resolution gives an explicit relationship between \Weights and \TargFreq_1, \ldots, \TargFreq_k. Lastly, we give an algorithm in \bigO{k n^4} for the inverse problem, {\it i.e.} computing the frequencies associated with a given $k$-tuple \Weights of weights, and an optimized version in \bigO{k n^2} in the case of context-free languages. This allows for a heuristic resolution of the weights/frequencies relationship suitable for complex specifications. In the second alternative, the targeted distribution is given by a $k$ natural numbers $n_1, \ldots, n_k$ such that $n_1+\cdots+n_k+r=n$ where $r \geq 0$ is the number of undistinguished atoms. The structures must be generated uniformly among the set of structures of size $n$ that contain {\em exactly} $n_i$ atoms \At_i ($1 \leq i \leq k$). We give a \bigO{r^2\prod_{i=1}^k n_i^2 +m n k \log n} algorithm for generating $m$ structures, which simplifies into a \bigO{r\prod_{i=1}^k n_i +m n} for regular specifications

Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice

An imbalance between inhibitory and excitatory neurotransmission has been proposed to contribute to altered brain function in individuals with Down syndrome (DS). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and accordingly treatment with GABA-A antagonists can efficiently restore cognitive functions of Ts65Dn mice, a genetic model for DS. However, GABA-A antagonists are also convulsant which preclude their use for therapeutic intervention in DS individuals. Here, we have evaluated safer strategies to release GABAergic inhibition using a GABA-A-benzodiazepine receptor inverse agonist selective for the α5-subtype (α5IA). We demonstrate that α5IA restores learning and memory functions of Ts65Dn mice in the novel-object recognition and in the Morris water maze tasks. Furthermore, we show that following behavioural stimulation, α5IA enhances learning-evoked immediate early gene products in specific brain regions involved in cognition. Importantly, acute and chronic treatments with α5IA do not induce any convulsant or anxiogenic effects that are associated with GABA-A antagonists or non-selective inverse agonists of the GABA-A-benzodiazepine receptors. Finally, chronic treatment with α5IA did not induce histological alterations in the brain, liver and kidney of mice. Our results suggest that non-convulsant α5-selective GABA-A inverse agonists could improve learning and memory deficits in DS individuals