Underwater Acoustic Imaging: One-bit Digitisation

In underwater acoustic imaging (UAI), the combination of a two-dimensional (2-D) array and replicate correlation can produce 3-D images, typically of objects at a range of 2 m. A system already developed achieves the high data acquisition rate needed through one-bit sampling (sensing only the sign of the received signal). Noise added before the one-bit sampling avoids the production of 'ghosts' in the image. By simulation and mathematical analysis, the effects of one-bit and added noise are studied for a chirp signal, with a restriction so far to 1-D images (image amplitude versus range). Conditions are given for the avoidance of ghosts and the minimisation of 'image noise' - noise in the image due to one-bit and added noise. A model of image noise is proposed, which is corroborated by the tests carried out to date. A general formula for the root-mean-square image noise is obtained. It has previously been suggested that filtering the singal after sampling would improve the image. However, it is shown that filtering is unnecessary and indeed makes the image worse. It is shown that a strong target can suppress evidence of a weak target because, when the strength of the return signal is raised, essentially the amplitude of the added noise must be raised to avoid 'ghosts'. A general formula, giving the ratio of target strengths such that the weak target has a 50% probability of detection, is obtained

Socio-economic status over the life-course and depressive symptoms in men and women in Eastern Europe

Objective: Research into social inequalities in depression has studied western populations but data from non-western countries are sparse. In this paper, we investigate the extent of social inequalities in depression in Eastern Europe, the relative importance of social position at different points of the life-course, and whether social patterning of depression differs between men and women.Method: A cross-sectional study examined 12,053 men and 13,582 women in Russia, Poland and the Czech Republic. Depressive symptoms (16 or above on the CESD-20) were examined in relation to socio-economic circumstances at three phases of the life-course: childhood (household amenities and father's education); own education; current circumstances (financial difficulties and possession of household items).Results: Pronounced social differences in depression exist in men and women throughout Eastern Europe. Depression was largely influenced by current circumstances rather than by early life or education, with effects stronger in Poland and Russia. Odds ratios in men for current disadvantage were 3.16 [95% CI: 2.57-3.89], 3.16 [2.74-3.64] and 2.17 [1.80-2.63] in Russia, Poland and the Czech Republic respectively. Social variables did not explain the female excess in depression, which varied from 2.91 [2.58-3.27] in Russia to 1.90 [1.74-2.08] in Poland. Men were more affected by adult disadvantage than women, leading to narrower sex differentials in the presence of disadvantage.Limitations: Cross-sectional data with recall of childhood conditions were used.Conclusion: Current social circumstances are the strongest influence on increased depressive symptoms in countries which have recently experienced social changes. (C) 2007 Elsevier B.V. All rights reserved

Gene therapy for articular cartilage repair

Articular cartilage serves as the gliding surface of joints. It is susceptible to damage from trauma and from degenerative diseases. Restoration of damaged articular cartilage may be achievable through the use of cell-regulatory molecules that augment the reparative activities of the cells, inhibit the cells'; degradative activities, or both. A variety of such molecules have been identified. These include insulin-like growth factor I, fibroblast growth factor 2, bone morphogenetic proteins 2, 4, and 7, and interleukin-1 receptor antagonist. It is now possible to transfer the genes encoding such molecules into articular cartilage and synovial lining cells. Although preliminary, data from in-vitro and in-vivo studies suggest that gene therapy can deliver such potentially therapeutic agents to protect existing cartilage and to build new cartilage. Keywords: gene therapy, vectors, articular cartilage, arthritis, animal model

Microglial ramification, surveillance and interleukin-1beta release are regulated by the two-pore domain K+ channel THIK-1

Microglia exhibit two modes of motility: they constantly extend and retract their processes to survey the brain, but they also send out targeted processes to envelop sites of tissue damage. We now show that these motility modes differ mechanistically. We identify the two-pore domain channel THIK-1 as the main K+ channel expressed in microglia in situ. THIK-1 is tonically active, and its activity is potentiated by P2Y12 receptors. Inhibiting THIK-1 function pharmacologically or by gene knockout depolarizes microglia, which decreases microglial ramification and thus reduces surveillance, whereas blocking P2Y12 receptors does not affect membrane potential, ramification, or surveillance. In contrast, process outgrowth to damaged tissue requires P2Y12 receptor activation but is unaffected by blocking THIK-1. Block of THIK-1 function also inhibits release of the pro-inflammatory cytokine interleukin-1β from activated microglia, consistent with K+ loss being needed for inflammasome assembly. Thus, microglial immune surveillance and cytokine release require THIK-1 channel activity

Safety and dose modification for patients receiving niraparib

Background: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved in the United States and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to TEAE was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was performed to identify clinical parameters that predict dose reductions. Patients and methods: All analyses were performed on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (ie, as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cutoff points for chosen variables. Results: Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150,000/μL in effect received an average daily dose approximating 200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 mg or 100 mg was consistent with that of patients who remained at the 300 mg starting dose. Conclusions: The analysis presented suggests that patients with baseline body weight of < 77 kg or baseline platelets of < 150,000/μL may benefit from a starting dose of 200 mg per day. (ClinicalTrials.gov ID: NCT01847274)

Analysis of Signaling Mechanisms Regulating Microglial Process Movement

Microglia, the brain’s innate immune cells, are extremely motile cells, continuously surveying the CNS to serve homeostatic functions and to respond to pathological events. In the healthy brain, microglia exhibit a small cell body with long, branched and highly motile processes, which constantly extend and retract, effectively ‘patrolling’ the brain parenchyma. Over the last decade, methodological advances in microscopy and the availability of genetically encoded reporter mice have allowed us to probe microglial physiology in situ. Beyond their classical immunological roles, unexpected functions of microglia have been revealed, both in the developing and the adult brain: microglia regulate the generation of newborn neurons, control the formation and elimination of synapses, and modulate neuronal activity. Many of these newly ascribed functions depend directly on microglial process movement. Thus, elucidating the mechanisms underlying microglial motility is of great importance to understand their role in brain physiology and pathophysiology. Two-photon imaging of fluorescently labelled microglia, either in vivo or ex vivo in acute brain slices, has emerged as an indispensable tool for investigating microglial movements and their functional consequences. This chapter aims to provide a detailed description of the experimental data acquisition and analysis needed to address these questions, with a special focus on key dynamic and morphological metrics such as surveillance, directed motility and ramification