Outcome of anxiety and depression in general health care:a three-wave 3.5-year study of psychopathology, disability and life stress

The outcome of anxiety and depression in general health care settings was examined. At follow-up, many cases no longer met the criteria of their baseline diagnosis and disability levels had substantially dropped. However, partial remission, not full recovery, was the rule, and was associated with residual disability. Depression had better outcomes than anxiety; mixed anxiety/depression did worst. Life events often triggered improvement except amongst mixed anxiety/depression patients.</p

Absence of AKT1 Mutations in Glioblastoma

Background: Oncogenic activation of the PI3K signalling pathway plays a pivotal role in the development of glioblastoma multiforme (GBM). A central node in PI3K downstream signalling is controlled by the serine-threonine kinase AKT1. A somatic mutation affecting residue E17 of the AKT1 gene has recently been identified in breast and colon cancer. The E17K change results in constitutive AKT1 activation, induces leukaemia in mice, and accordingly, may be therapeutically exploited to target the PI3K pathway. Assessing whether AKT1 is activated by somatic mutations in GBM is relevant to establish its role in this aggressive disease. Methodology/Principal Findings: We performed a systematic mutational analysis of the complete coding sequence of the AKT1 gene in a panel of 109 tumor GBM samples and nine high grade astrocytoma cell lines. However, no somatic mutations were detected in the coding region of AKT1. Conclusions/Significance: Our data indicate that in GBM oncogenic deregulation of the PI3K pathway does not involve somatic mutations in the coding region of AKT1

An addressable quantum dot qubit with fault-tolerant control fidelity

Exciting progress towards spin-based quantum computing has recently been made with qubits realized using nitrogen-vacancy (N-V) centers in diamond and phosphorus atoms in silicon, including the demonstration of long coherence times made possible by the presence of spin-free isotopes of carbon and silicon. However, despite promising single-atom nanotechnologies, there remain substantial challenges in coupling such qubits and addressing them individually. Conversely, lithographically defined quantum dots have an exchange coupling that can be precisely engineered, but strong coupling to noise has severely limited their dephasing times and control fidelities. Here we combine the best aspects of both spin qubit schemes and demonstrate a gate-addressable quantum dot qubit in isotopically engineered silicon with a control fidelity of 99.6%, obtained via Clifford based randomized benchmarking and consistent with that required for fault-tolerant quantum computing. This qubit has orders of magnitude improved coherence times compared with other quantum dot qubits, with T_2* = 120 mus and T_2 = 28 ms. By gate-voltage tuning of the electron g*-factor, we can Stark shift the electron spin resonance (ESR) frequency by more than 3000 times the 2.4 kHz ESR linewidth, providing a direct path to large-scale arrays of addressable high-fidelity qubits that are compatible with existing manufacturing technologies

The Sequence of Delta24-RGD and TMZ Administration in Malignant Glioma Affects the Role of CD8+T Cell Anti-tumor Activity

The conditionally replicating oncolytic adenovirus Delta24-RGD (Ad) is currently under investigation in clinical trials for glioblastoma, including in combination with temozolomide (TMZ), the standard chemotherapy for this tumor. Previously, we showed that the efficacy of Delta24-RGD in a murine model is primarily dependent on the virus-induced anti-tumor immune response. As observed with most chemotherapies, TMZ has pronounced immune-modulating effects. Here, we studied the combined effects of these treatments in a murine glioma model. In vitro, we observed a synergistic activity between Delta24-RGD and TMZ. In vivo, C57BL/6 mice bearing intracranial GL261 tumors were treated with TMZ for 5 days either prior to intratumoral Delta24-RGD injection (TMZ/Ad) or post virus injection (Ad/TMZ). Notably, the Ad/TMZ regimen led to similar tumoral CD8+ T cell influx as the virus-only treatment, but increased the ability of CD8+ T cells to specifically recognize the tumor cells. This was accompanied by improved survival. The TMZ/Ad regimen also improved survival significantly compared to controls, but not compared to virus alone. In this group, the influx of dendritic cells is impaired, followed by a significantly lower number of tumor-infiltrating CD8+ T cells and no recognition of tumor cells. Depletion of either CD4+ T cells or CD8+ T cells impaired the efficacy of Delta24-RGD, underscoring the role of these cells in therapeutic activity of the virus. Overall, we show that the addition of TMZ to Delta24-RGD treatment leads to a significant increase in survival and that the order of sequence of these treatments affects the CD8+T cell anti-tumor activity

Influence of Exposure History on the Immunology and Development of Resistance to Human Schistosomiasis Mansoni

Schistosomiasis is a parasitic blood fluke infection of 200 million people worldwide. We have shown that humans can acquire immunity to reinfection after repeated exposures and cures with the drug praziquantel. The increase in resistance to reinfection was associated with an increase in schistosome-specific IgE. The ability to develop resistance and the rate at which resistance was acquired varied greatly in two cohorts of men within close geographic proximity and with similar occupational exposures to schistosomes. These differences are likely attributable to differences in history of exposure to Schistosoma mansoni infection and immunologic status at baseline, with those acquiring immunity faster having lifelong S. mansoni exposure and immunologic evidence of chronic S. mansoni infection. As many conflicting results have been reported in the literature regarding immunologic parameters associated with the development of resistance to schistosome infection, exposure history and prior immune status should be considered in the design of future immuno-epidemiologic studies

Absence of the MGMT protein as well as methylation of the MGMT promoter predict the sensitivity for temozolomide

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) can cause resistance to the alkylating drug temozolomide (TMZ). The purpose of this study was to determine the relationship between the MGMT status, determined by means of several techniques and methods, and the cytotoxic response to TMZ in 11 glioblastoma multiforme (GBM) cell lines and 5 human tumour cell lines of other origins. Cell survival was analysed by clonogenic assay. The MGMT protein levels were assessed by western blot analysis. The MGMT promoter methylation levels were determined using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and quantitative real-time methylation-specific PCR (qMSP). On the basis of the results of these techniques, six GBM cell lines were selected and subjected to bisulphite sequencing. The MGMT protein was detected in all TMZ-resistant cell lines, whereas no MGMT protein could be detected in cell lines that were TMZ sensitive. The MS-MLPA results were able to predict TMZ sensitivity in 9 out of 16 cell lines (56%). The qMSP results matched well with TMZ sensitivity in 11 out of 12 (92%) glioma cell lines. In addition, methylation as detected by bisulphite sequencing seemed to be predictive of TMZ sensitivity in all six cell lines analysed (100%). The MGMT protein expression more than MGMT promoter methylation status predicts the response to TMZ in human tumour cell line

Utility of Repeated Praziquantel Dosing in the Treatment of Schistosomiasis in High-Risk Communities in Africa: A Systematic Review

Infection by Schistosoma worms causes serious disease among people who live in areas of Africa, South America, and Asia where these parasites are regularly transmitted. Although yearly treatment with the drug praziquantel is fairly effective in reducing or eliminating active infection, it does not cure everyone, and reinfection remains a continuing problem in high-risk communities. Studies have suggested that a repeat dose of praziquantel, given 2 to 8 weeks after the first dose, can improve cure rates and reduce remaining intensity of infections in population-based programs. Our systematic review of published research found that, on average, in Africa, such repeated dosing appears to offer particular advantages in the treatment of S. mansoni, the cause of intestinal schistosomiasis, but there was less consistent improvement after double-dosing for S. haematobium, the cause of urogenital schistosomiasis. Based on this evidence, we used a calibrated life-path model to predict the costs and benefits of a single-dose vs. a double-dose strategy in a typical high-risk community. Our projections suggest cost-effective incremental benefits from double dosing in terms of i) limiting a person's total years spent infected and ii) limiting the number of years they spend with heavy infection, with consequent improvements in quality of life

National laboratory-based surveillance system for antimicrobial resistance: a successful tool to support the control of antimicrobial resistance in the Netherlands

An important cornerstone in the control of antimicrobial resistance (AMR) is a well-designed quantitative system for the surveillance of spread and temporal trends in AMR. Since 2008, the Dutch national AMR surveillance system, based on routine data from medical microbiological laboratories (MMLs), has developed into a successful tool to support the control of AMR in the Netherlands. It provides background information for policy making in public health and healthcare services, supports development of empirical antibiotic therapy guidelines and facilitates in-depth research. In addition, participation of the MMLs in the national AMR surveillance network has contributed to sharing of knowledge and quality improvement. A future improvement will be the implementation of a new semantic standard together with standardised data transfer, which will reduce errors in data handling and enable a more real-time surveillance. Furthermore, the

Observational studies of depression in primary care: what do we know?

<p>Abstract</p> <p>Background</p> <p>We undertook a systematic review of observational studies of depression in primary care to determine 1) the nature and scope of the published studies 2) the methodological quality of the studies; 3) the identified recovery and risk factors for persistent depression and 3) the treatment and health service use patterns among patients.</p> <p>Methods</p> <p>Searches were conducted in MEDLINE, CINAHL and PsycINFO using combinations of topic and keywords, and Medical Subject Headings in MEDLINE, Headings in CINAHL and descriptors in PsycINFO. Searches were limited to adult populations and articles published in English during 1985–2006.</p> <p>Results</p> <p>40 articles from 17 observational cohort studies were identified, most were undertaken in the US or Europe. Studies varied widely in aims and methods making it difficult to meaningfully compare the results. Methodological limitations were common including: selection bias of patients and physicians; small sample sizes (range 35–108 patients at baseline and 20–59 patients at follow-up); and short follow-up times limiting the extent to which these studies can be used to inform our understanding of recovery and relapse among primary care patients with depression. Risk factors for the persistence of depression identified in this review were: severity and chronicity of the depressive episode, the presence of suicidal thoughts, antidepressant use, poorer self-reported quality of life, lower self-reported social support, experiencing key life events, lower education level and unemployment.</p> <p>Conclusion</p> <p>Despite the growing interest in depression being managed as a chronic illness, this review identified only 17 observational studies of depression in primary care, most of which have included small sample sizes and been relatively short-term. Future research should be large enough to investigate risk factors for chronicity and relapse, and should be conducted over a longer time frame.</p

IL-10 Blocks the Development of Resistance to Re-Infection with Schistosoma mansoni

Despite effective chemotherapy to treat schistosome infections, re-infection rates are extremely high. Resistance to reinfection can develop, however it typically takes several years following numerous rounds of treatment and re-infection, and often develops in only a small cohort of individuals. Using a well-established and highly permissive mouse model, we investigated whether immunoregulatory mechanisms influence the development of resistance. Following Praziquantel (PZQ) treatment of S. mansoni infected mice we observed a significant and mixed anti-worm response, characterized by Th1, Th2 and Th17 responses. Despite the elevated anti-worm response in PBMC's, liver, spleen and mesenteric lymph nodes, this did not confer any protection from a secondary challenge infection. Because a significant increase in IL-10-producing CD4+CD44+CD25+GITR+ lymphocytes was observed, we hypothesised that IL-10 was obstructing the development of resistance. Blockade of IL-10 combined with PZQ treatment afforded a greater than 50% reduction in parasite establishment during reinfection, compared to PZQ treatment alone, indicating that IL-10 obstructs the development of acquired resistance. Markedly enhanced Th1, Th2 and Th17 responses, worm-specific IgG1, IgG2b and IgE and circulating eosinophils characterized the protection. This study demonstrates that blocking IL-10 signalling during PZQ treatment can facilitate the development of protective immunity and provide a highly effective strategy to protect against reinfection with S. mansoni