Perampanel in the general population and in people with intellectual disability: Differing responses

This is the author accepted manuscript. The final version is available under a Creative Commons Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/) from the publisher via the DOI in this record.PURPOSE: There is a shortfall of suitably powered studies to provide evidence for safe prescribing of AEDs to people with Intellectual Disability (ID). We report clinically useful information on differences in response to Perampanel (PER) adjunctive treatment for refractory epilepsy between ID sub-groups and general population from the UK Ep-ID Research Register. METHOD: Pooled retrospective case notes data of consented people with epilepsy (PWE) prescribed PER from 6 UK centres was classified as per WHO guidance into groups of moderate -profound ID, mild ID and General population. Demographics, concomitant AEDs, starting and maximum dosage, exposure length, adverse effects, dropout rates, seizure type and frequency were collected. Group differences were reported as odds ratios estimated from univariable logistic regression models. RESULTS: Of the 144 PWE (General population 71, Mild ID 48, Moderate to profound ID 48) examined the association between withdrawal and ID type was marginally statistically significant (p=0.07). Moderate to profound ID PWE were less likely to come off PER compared to mild ID (OR=0.19, CI=0.04-0.92, p=0.04). Differences in mental health side effects by groups was marginally statistically significant (p=0.06). Over 50% seizure improvement was seen in 11% of General population, 24% mild ID and 26% Moderate to profound ID. CONCLUSIONS: PER seems safe in PWE with ID. It is better tolerated by PWE with Moderate to profound ID than PWE with higher functioning. Caution is advised when history of mental health problems is present. The standardised approach of the Ep-ID register UK used confirms that responses to AEDs by different ID groups vary between themselves and General population

Generalized Painleve-Gullstrand descriptions of Kerr-Newman black holes

Generalized Painleve-Gullstrand metrics are explicitly constructed for the Kerr-Newman family of charged rotating black holes. These descriptions are free of all coordinate singularities; moreover, unlike the Doran and other proposed metrics, an extra tunable function is introduced to ensure all variables in the metrics remain real for all values of the mass M, charge Q, angular momentum aM, and cosmological constant \Lambda > - 3/(a^2). To describe fermions in Kerr-Newman spacetimes, the stronger requirement of non-singular vierbein one-forms at the horizon(s) is imposed and coordinate singularities are eliminated by local Lorentz boosts. Other known vierbein fields of Kerr-Newman black holes are analysed and discussed; and it is revealed that some of these descriptions are actually not related by physical Lorentz transformations to the original Kerr-Newman expression in Boyer-Lindquist coordinates - which is the reason complex components appear (for certain ranges of the radial coordinate) in these metrics. As an application of our constructions the correct effective Hawking temperature for Kerr black holes is derived with the method of Parikh and Wilczek.Comment: 5 pages; extended to include application to derivation of Hawking radiation for Kerr black holes with Parikh-Wilczek metho

A hybrid radiation detector for simultaneous spatial and temporal dosimetry

In this feasibility study an organic plastic scintillator is calibrated against ionisation chamber measurements and then embedded in a polymer gel dosimeter to obtain a quasi-4D experimental measurement of a radiation field. This hybrid dosimeter was irradiated with a linear accelerator, with temporal measurements of the dose rate being acquired by the scintillator and spatial measurements acquired with the gel dosimeter. The detectors employed in this work are radiologically equivalent; and we show that neither detector perturbs the intensity of the radiation field of the other. By employing these detectors in concert, spatial and temporal variations in the radiation intensity can now be detected and gel dosimeters can be calibrated for absolute dose from a single irradiation

Anthrax Toxins Inhibit Neutrophil Signaling Pathways in Brain Endothelium and Contribute to the Pathogenesis of Meningitis

Anthrax meningitis is the main neurological complication of systemic infection with Bacillus anthracis approaching 100% mortality. The presence of bacilli in brain autopsies indicates that vegetative bacteria are able to breach the blood-brain barrier (BBB). The BBB represents not only a physical barrier but has been shown to play an active role in initiating a specific innate immune response that recruits neutrophils to the site of infection. Currently, the basic pathogenic mechanisms by which B. anthracis penetrates the BBB and causes anthrax meningitis are poorly understood.Using an in vitro BBB model, we show for the first time that B. anthracis efficiently invades human brain microvascular endothelial cells (hBMEC), the single cell layer that comprises the BBB. Furthermore, transcriptional profiling of hBMEC during infection with B. anthracis revealed downregulation of 270 (87%) genes, specifically key neutrophil chemoattractants IL-8, CXCL1 (Gro alpha) and CXCL2 (Gro beta), thereby strongly contrasting hBMEC responses observed with other meningeal pathogens. Further studies using specific anthrax toxin-mutants, quantitative RT-PCR, ELISA and in vivo assays indicated that anthrax toxins actively suppress chemokine production and neutrophil recruitment during infection, allowing unrestricted proliferation and dissemination of the bacteria. Finally, mice challenged with B. anthracis Sterne, but not the toxin-deficient strain, developed meningitis.These results suggest a significant role for anthrax toxins in thwarting the BBB innate defense response promoting penetration of bacteria into the central nervous system. Furthermore, establishment of a mouse model for anthrax meningitis will aid in our understanding of disease pathogenesis and development of more effective treatment strategies

A 2017 Horizon Scan of Emerging Issues for Global Conservation and Biological Diversity

We present the results of our eighth annual horizon scan of emerging issues likely to affect global biological diversity, the environment, and conservation efforts in the future. The potential effects of these novel issues might not yet be fully recognized or understood by the global conservation community, and the issues can be regarded as both opportunities and risks. A diverse international team with collective expertise in horizon scanning, science communication, and conservation research, practice, and policy reviewed 100 potential issues and identified 15 that qualified as emerging, with potential substantial global effects. These issues include new developments in energy storage and fuel production, sand extraction, potential solutions to combat coral bleaching and invasive marine species, and blockchain technology.Cambridge Conservation Initiative, funded by the Natural Environment Research Council and the Royal Society for the Protection of Birds, Arcadia, Natural Environment Research Council (Grant ID: NE/N014472/1

Carbon storage in soils of Southeastern Nigeria under different management practices

<p>Abstract</p> <p>Background</p> <p>Changes in agricultural practices-notably changes in crop varieties, application of fertilizer and manure, rotation and tillage practices-influence how much and at what rate carbon is stored in, or released from, soils. Quantification of the impacts of land use on carbon stocks in sub-Saharan Africa is challenging because of the spatial heterogeneity of soil, climate, management conditions, and due to the lack of data on soil carbon pools of most common agroecosystems. This paper provides data on soil carbon stocks that were collected at 10 sites in southeastern Nigeria to characterize the impact of soil management practices.</p> <p>Results</p> <p>The highest carbon stocks, 7906-9510 gC m^-2, were found at the sites representing natural forest, artificial forest and artificial grassland ecosystems. Continuously cropped and conventionally tilled soils had about 70% lower carbon stock (1978-2822 gC m^-2). Thus, the soil carbon stock in a 45-year old <it>Gmelina </it>forest was 8987 gC m^-2, whereas the parts of this forest, that were cleared and continuously cultivated for 15 years, had 75% lower carbon stock (1978 gC m^-2). The carbon stock of continuously cropped and conventionally tilled soils was also 25% lower than the carbon stock of the soil cultivated by use of conservation tillage.</p> <p>Conclusion</p> <p>Introducing conservation tillage practices may reduce the loss of soil carbon stocks associated with land conversion. However, the positive effect of conservation tillage is not comparable to the negative effect of land conversion, and may not result in significant accumulation of carbon in southeastern Nigeria soils.</p

The breadth of primary care: a systematic literature review of its core dimensions

Background: Even though there is general agreement that primary care is the linchpin of effective health care delivery, to date no efforts have been made to systematically review the scientific evidence supporting this supposition. The aim of this study was to examine the breadth of primary care by identifying its core dimensions and to assess the evidence for their interrelations and their relevance to outcomes at (primary) health system level. Methods: A systematic review of the primary care literature was carried out, restricted to English language journals reporting original research or systematic reviews. Studies published between 2003 and July 2008 were searched in MEDLINE, Embase, Cochrane Library, CINAHL, King's Fund Database, IDEAS Database, and EconLit. Results: Eighty-five studies were identified. This review was able to provide insight in the complexity of primary care as a multidimensional system, by identifying ten core dimensions that constitute a primary care system. The structure of a primary care system consists of three dimensions: 1. governance; 2. economic conditions; and 3. workforce development. The primary care process is determined by four dimensions: 4. access; 5. continuity of care; 6. coordination of care; and 7. comprehensiveness of care. The outcome of a primary care system includes three dimensions: 8. quality of care; 9. efficiency care; and 10. equity in health. There is a considerable evidence base showing that primary care contributes through its dimensions to overall health system performance and health. Conclusions: A primary care system can be defined and approached as a multidimensional system contributing to overall health system performance and health

Análise integrada de sistemas de produção de tomateiro com base em indicadores edafobiológicos.

A análise integrada de indicadores edafobiológicos ligados ao manejo do solo constitui uma ferramenta importante para estimar níveis de sustentabilidade do agroecossistema, detectando-se pontos críticos para a devida correção de manejo. Essa ferramenta foi empregada na avaliação de sistemas de produção orgânica e convencional de tomate, em cultivo protegido e a campo aberto, no estado de São Paulo. Tomaram-se como referência solos de mata nativa e/ou pastagem natural, dependendo do local de estudo. Em Serra Negra, o solo sob sistema orgânico apresentou maior capacidade de campo e teor de argila dispersa mais baixo, indicativos da estabilidade dos agregados. No sistema convencional observou-se uma elevada condutividade elétrica, evidenciando a alta disponibilidade de sais solúveis. A análise de componentes principais (ACP) permitiu concluir que há maior grau de similaridade entre o solo sob sistema orgânico e aqueles das bases referenciais, com respeito aos indicadores químicos e biológicos. Constatou-se que C org, N total, polissacarídeos, FDA (hidrólise de diacetato de fluoresceína) e atividade enzimática de desidrogenase estão positivamente relacionados com o sistema orgânico, a mata nativa e a pastagem. Em contrapartida, a saturação por bases (V%), pH, teores de Mn, Mg e Ca, bem como a razão de dispersão estão inversamente relacionadas ao manejo orgânico. Já em Araraquara, os resultados da ACP distinguiram as áreas organicamente cultivadas das matas nativas, principalmente, com base nos indicadores biológicos

Net1 and Myeov: computationally identified mediators of gastric cancer

Gastric adenocarcinoma (GA) is a significant cause of mortality worldwide. The molecular mechanisms of GA remain poorly characterised. Our aim was to characterise the functional activity of the computationally identified genes, NET 1 and MYEOV in GA. Digital Differential Display was used to identify genes altered expression in GA-derived EST libraries. mRNA levels of a subset of genes were quantitated by qPCR in a panel of cell lines and tumour tissue. The effect of pro- and anti-inflammatory stimuli on gene expression was investigated. Cell proliferation and invasion were measured using in an in-vitro GA model following inhibition of expression using siRNA. In all, 23 genes not previously reported in association with GA were identified. Two genes, Net1 and Myeov, were selected for further analysis and increased expression was detected in GA tissue compared to paired normal tissue using quantitative PCR. siRNA-mediated downregulation of Net1 and Myeov resulted in decreased proliferation and invasion of gastric cancer cells in vitro. These functional studies highlight a putative role for NET1 and Myeov in the development and progression of gastric cancer. These genes may provide important targets for intervention in GA, evidenced by their role in promoting invasion and proliferation, key phenotypic hallmarks of cancer cells

Identification of differentially expressed genes using an annealing control primer system in stage III serous ovarian carcinoma

<p>Abstract</p> <p>Background</p> <p>Most patients with ovarian cancer are diagnosed with advanced stage disease (<it>i.e</it>., stage III-IV), which is associated with a poor prognosis. Differentially expressed genes (DEGs) in stage III serous ovarian carcinoma compared to normal tissue were screened by a new differential display method, the annealing control primer (ACP) system. The potential targets for markers that could be used for diagnosis and prognosis, for stage III serous ovarian cancer, were found by cluster and survival analysis.</p> <p>Methods</p> <p>The ACP-based reverse transcriptase polymerase chain reaction (RT PCR) technique was used to identify DEGs in patients with stage III serous ovarian carcinoma. The DEGs identified by the ACP system were confirmed by quantitative real-time PCR. Cluster analysis was performed on the basis of the expression profile produced by quantitative real-time PCR and survival analysis was carried out by the Kaplan-Meier method and Cox proportional hazards multivariate model; the results of gene expression were compared between chemo-resistant and chemo-sensitive groups.</p> <p>Results</p> <p>A total of 114 DEGs were identified by the ACP-based RT PCR technique among patients with stage III serous ovarian carcinoma. The DEGs associated with an apoptosis inhibitory process tended to be up-regulated clones while the DEGs associated with immune response tended to be down-regulated clones. Cluster analysis of the gene expression profile obtained by quantitative real-time PCR revealed two contrasting groups of DEGs. That is, a group of genes including: <it>SSBP1</it>, <it>IFI6 DDT</it>, <it>IFI27</it>, <it>C11orf92</it>, <it>NFKBIA</it>, <it>TNXB</it>, <it>NEAT1 </it>and <it>TFG </it>were up-regulated while another group of genes consisting of: <it>LAMB2</it>, <it>XRCC6</it>, <it>MEF2C</it>, <it>RBM5</it>, <it>FOXP1</it>, <it>NUDCP2</it>, <it>LGALS3</it>, <it>TMEM185A</it>, and <it>C1S </it>were down-regulated in most patients. Survival analysis revealed that the up-regulated genes such as <it>DDAH2, RNase K and TCEAL2 </it>might be associated with a poor prognosis. Furthermore, the prognosis of patients with chemo-resistance was predicted to be very poor when genes such as <it>RNase K, FOXP1</it>, <it>LAMB2 </it>and <it>MRVI1 </it>were up-regulated.</p> <p>Conclusion</p> <p>The DEGs in patients with stage III serous ovarian cancer were successfully and reliably identified by the ACP-based RT PCR technique. The DEGs identified in this study might help predict the prognosis of patients with stage III serous ovarian cancer as well as suggest targets for the development of new treatment regimens.</p