Systematic review of antiepileptic drugs’ safety and effectiveness in feline epilepsy

Understanding the efficacy and safety profile of antiepileptic drugs (AEDs) in feline epilepsy is a crucial consideration for managing this important brain disease. However, there is a lack of information about the treatment of feline epilepsy and therefore a systematic review was constructed to assess current evidence for the AEDs’ efficacy and tolerability in cats. The methods and materials of our former systematic reviews in canine epilepsy were mostly mirrored for the current systematic review in cats. Databases of PubMed, CAB Direct and Google scholar were searched to detect peer-reviewed studies reporting efficacy and/or adverse effects of AEDs in cats. The studies were assessed with regards to their quality of evidence, i.e. study design, study population, diagnostic criteria and overall risk of bias and the outcome measures reported, i.e. prevalence and 95% confidence interval of the successful and affected population in each study and in total

One Net Fits All: A unifying semantics of Dynamic Fault Trees using GSPNs

Dynamic Fault Trees (DFTs) are a prominent model in reliability engineering. They are strictly more expressive than static fault trees, but this comes at a price: their interpretation is non-trivial and leaves quite some freedom. This paper presents a GSPN semantics for DFTs. This semantics is rather simple and compositional. The key feature is that this GSPN semantics unifies all existing DFT semantics from the literature. All semantic variants can be obtained by choosing appropriate priorities and treatment of non-determinism.Comment: Accepted at Petri Nets 201

Decreased expression of breast cancer resistance protein in the duodenum in patients with obstructive cholestasis

Background/Aims: The expression of transporters involved in bile acid homeostasis is differentially regulated during obstructive cholestasis. Since the drug efflux transporter breast cancer resistance protein (BCRP) is known to transport bile acids, we investigated whether duodenal BCRP expression could be altered during cholestasis. Methods: Using real-time RT-PCR analysis we determined mRNA expression levels in duodenal tissue of 19 cholestatic patients. Expression levels were compared to 14 healthy subjects. BCRP protein staining was determined in biopsies of 6 cholestatic and 6 healthy subjects by immunohistochemistry. Results: We found that in patients with obstructive cholestasis mean duodenal BCRP mRNA levels were significantly reduced to 53% and mean protein staining was reduced to 57%. Conclusions: BCRP, a transporter for bile acids and numerous drugs, appears to be down-regulated in the human duodenum during cholestasis. The clinical impact of these results has to be investigated in further studies. Copyright (c) 2006 S. Karger AG, Basel

International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy

Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered

Planar and van der Waals heterostructures for vertical tunnelling single electron transistors

Despite a rich choice of two-dimensional materials, which exists these days, heterostructures, both vertical (van der Waals) and in-plane, offer an unprecedented control over the properties and functionalities of the resulted structures. Thus, planar heterostructures allow p-n junctions between different two-dimensional semiconductors and graphene nanoribbons with well-defined edges; and vertical heterostructures resulted in the observation of superconductivity in purely carbon-based systems and realisation of vertical tunnelling transistors. Here we demonstrate simultaneous use of in-plane and van der Waals heterostructures to build vertical single electron tunnelling transistors. We grow graphene quantum dots inside the matrix of hexagonal boron nitride, which allows a dramatic reduction of the number of localised states along the perimeter of the quantum dots. The use of hexagonal boron nitride tunnel barriers as contacts to the graphene quantum dots make our transistors reproducible and not dependent on the localised states, opening even larger flexibility when designing future devices

A VLP-based vaccine targeting domain III of the West Nile virus E protein protects from lethal infection in mice

Background. Since its first appearance in the USA in 1999, West Nile virus (WNV) has spread in the Western hemisphere and continues to represent an important public health concern. In the absence of effective treatment, there is a medical need for the development of a safe and efficient vaccine. Live attenuated WNV vaccines have shown promise in preclinical and clinical studies but might carry inherent risks due to the possibility of reversion to more virulent forms. Subunit vaccines based on the large envelope (E) glycoprotein of WNV have therefore been explored as an alternative approach. Although these vaccines were shown to protect from disease in animal models, multiple injections and/or strong adjuvants were required to reach efficacy, underscoring the need for more immunogenic, yet safe DIII-based vaccines. Results. We produced a conjugate vaccine against WNV consisting of recombinantly expressed domain III (DIII) of the E glycoprotein chemically cross-linked to virus-like particles derived from the recently discovered bacteriophage AP205. In contrast to isolated DIII protein, which required three administrations to induce detectable antibody titers in mice, high titers of DIII-specific antibodies were induced after a single injection of the conjugate vaccine. These antibodies were able to neutralize the virus in vitro and provided partial protection from a challenge with a lethal dose of WNV. Three injections of the vaccine induced high titers of virus-neutralizing antibodies, and completely protected mice from WNV infection. Conclusions. The immunogenicity of DIII can be strongly enhanced by conjugation to virus-like particles of the bacteriophage AP205. The superior immunogenicity of the conjugate vaccine with respect to other DIII-based subunit vaccines, its anticipated favourable safety profile and low production costs highlight its potential as an efficacious and cost-effective prophylaxis against WNV

Sequential Adaptive Mutations Enhance Efficient Vector Switching by Chikungunya Virus and Its Epidemic Emergence

The adaptation of Chikungunya virus (CHIKV) to a new vector, the Aedes albopictus mosquito, is a major factor contributing to its ongoing re-emergence in a series of large-scale epidemics of arthritic disease in many parts of the world since 2004. Although the initial step of CHIKV adaptation to A. albopictus was determined to involve an A226V amino acid substitution in the E1 envelope glycoprotein that first arose in 2005, little attention has been paid to subsequent CHIKV evolution after this adaptive mutation was convergently selected in several geographic locations. To determine whether selection of second-step adaptive mutations in CHIKV or other arthropod-borne viruses occurs in nature, we tested the effect of an additional envelope glycoprotein amino acid change identified in Kerala, India in 2009. This substitution, E2-L210Q, caused a significant increase in the ability of CHIKV to develop a disseminated infection in A. albopictus, but had no effect on CHIKV fitness in the alternative mosquito vector, A. aegypti, or in vertebrate cell lines. Using infectious viruses or virus-like replicon particles expressing the E2-210Q and E2-210L residues, we determined that E2-L210Q acts primarily at the level of infection of A. albopictus midgut epithelial cells. In addition, we observed that the initial adaptive substitution, E1-A226V, had a significantly stronger effect on CHIKV fitness in A. albopictus than E2-L210Q, thus explaining the observed time differences required for selective sweeps of these mutations in nature. These results indicate that the continuous CHIKV circulation in an A. albopictus-human cycle since 2005 has resulted in the selection of an additional, second-step mutation that may facilitate even more efficient virus circulation and persistence in endemic areas, further increasing the risk of more severe and expanded CHIK epidemics

Wealth and sexual behaviour among men in Cameroon

BACKGROUND: The 2004 Demographic and Health Survey (DHS) in Cameroon revealed a higher prevalence of HIV in richest and most educated people than their poorest and least educated compatriots. It is not certain whether the higher prevalence results partly or wholly from wealthier people adopting more unsafe sexual behaviours, surviving longer due to greater access to treatment and care, or being exposed to unsafe injections or other HIV risk factors. As unsafe sex is currently believed to be the main driver of the HIV epidemic in sub-Saharan Africa, we designed this study to examine the association between wealth and sexual behaviour in Cameroon. METHODS: We analysed data from 4409 sexually active men aged 15–59 years who participated in the Cameroon DHS using logistic regression models, and have reported odds ratios (OR) with confidence intervals (CI). RESULTS: When we controlled for the potential confounding effects of marital status, place of residence, religion and age, men in the richest third of the population were less likely to have used a condom in the last sex with a non-spousal non-cohabiting partner (OR 0.43, 95% CI 0.32–0.56) and more likely to have had at least two concurrent sex partners in the last 12 months (OR 1.38, 95% CI 1.12–1.19) and more than five lifetime sex partners (OR 1.97, 95% CI 1.60–2.43). However, there was no difference between the richest and poorest men in the purchase of sexual services. Regarding education, men with secondary or higher education were less likely to have used a condom in the last sex with a non-spousal non-cohabiting partner (OR 0.24, 95% CI 0.16–0.38) and more likely to have started sexual activity at age 17 years or less (OR 2.73, 95% CI 2.10–3.56) and had more than five lifetime sexual partners (OR 2.59, 95% CI 2.02–3.31). There was no significant association between education and multiple concurrent sexual partnerships in the last 12 months or purchase of sexual services. CONCLUSION: Wealthy men in Cameroon are more likely to start sexual activity early and have both multiple concurrent and lifetime sex partners, and are less likely to (consistently) use a condom in sex with a non-spousal non-cohabiting partner. These unsafe sexual behaviours may explain the higher HIV prevalence among wealthier men in the country. While these findings do not suggest a redirection of HIV prevention efforts from the poor to the wealthy, they do call for efforts to ensure that HIV prevention messages get across all strata of society

Epistatic Roles of E2 Glycoprotein Mutations in Adaption of Chikungunya Virus to Aedes Albopictus and Ae. Aegypti Mosquitoes

Between 2005 and 2007 Chikungunya virus (CHIKV) caused its largest outbreak/epidemic in documented history. An unusual feature of this epidemic is the involvement of Ae. albopictus as a principal vector. Previously we have demonstrated that a single mutation E1-A226V significantly changed the ability of the virus to infect and be transmitted by this vector when expressed in the background of well characterized CHIKV strains LR2006 OPY1 and 37997. However, in the current study we demonstrate that introduction of the E1-A226V mutation into the background of an infectious clone derived from the Ag41855 strain (isolated in Uganda in 1982) does not significantly increase infectivity for Ae. albopictus. In order to elucidate the genetic determinants that affect CHIKV sensitivity to the E1-A226V mutation in Ae. albopictus, the genomes of the LR2006 OPY1 and Ag41855 strains were used for construction of chimeric viruses and viruses with a specific combination of point mutations at selected positions. Based upon the midgut infection rates of the derived viruses in Ae. albopictus and Ae. aegypti mosquitoes, a critical role of the mutations at positions E2-60 and E2-211 on vector infection was revealed. The E2-G60D mutation was an important determinant of CHIKV infectivity for both Ae. albopictus and Ae. aegypti, but only moderately modulated the effect of the E1-A226V mutation in Ae. albopictus. However, the effect of the E2-I211T mutation with respect to mosquito infections was much more specific, strongly modifying the effect of the E1-A226V mutation in Ae. albopictus. In contrast, CHIKV infectivity for Ae. aegypti was not influenced by the E2-1211T mutation. The occurrence of the E2-60G and E2-211I residues among CHIKV isolates was analyzed, revealing a high prevalence of E2-211I among strains belonging to the Eastern/Central/South African (ECSA) clade. This suggests that the E2-211I might be important for adaptation of CHIKV to some particular conditions prevalent in areas occupied by ECSA stains. These newly described determinants of CHIKV mosquito infectivity for Ae. albopictus and Ae. aegypti are of particular importance for studies aimed at the investigation of the detailed mechanisms of CHIKV adaptations to its vector species

The development of a web- and a print-based decision aid for prostate cancer screening

Background Whether early detection and treatment of prostate cancer (PCa) will reduce disease-related mortality remains uncertain. As a result, tools are needed to facilitate informed decision making. While there have been several decision aids (DAs) developed and tested, very few have included an exercise to help men clarify their values and preferences about PCa screening. Further, only one DA has utilized an interactive web-based format, which allows for an expansion and customization of the material. We describe the development of two DAs, a booklet and an interactive website, each with a values clarification component and designed for use in diverse settings. Methods We conducted two feasibility studies to assess men\u27s (45-70 years) Internet access and their willingness to use a web- vs. a print-based tool. The booklet was adapted from two previous versions evaluated in randomized controlled trials (RCTs) and the website was created to closely match the content of the revised booklet. Usability testing was conducted to obtain feedback regarding draft versions of the materials. The tools were also reviewed by a plain language expert and the interdisciplinary research team. Feedback on the content and presentation led to iterative modifications of the tools. Results The feasibility studies confirmed that the Internet was a viable medium, as the majority of men used a computer, had access to the Internet, and Internet use increased over time. Feedback from the usability testing on the length, presentation, and content of the materials was incorporated into the final versions of the booklet and website. Both the feasibility studies and the usability testing highlighted the need to address men\u27s informed decision making regarding screening. Conclusions Informed decision making for PCa screening is crucial at present and may be important for some time, particularly if a definitive recommendation either for or against screening does not emerge from ongoing prostate cancer screening trials. We have detailed our efforts at developing print- and web-based DAs to assist men in determining how to best meet their PCa screening preferences. Following completion of our ongoing RCT designed to test these materials, our goal will be to develop a dissemination project for the more effective tool