Burden of illness of trigeminal neuralgia among patients managed in a specialist center in England

BACKGROUND: Trigeminal neuralgia (TN) causes severe episodic, unilateral facial pain and is initially treated with antiepileptic medications. For patients not responding or intolerant to medications, surgery is an option. METHODS: In order to expand understanding of the pain-related burden of illness associated with TN, a cross-sectional survey was conducted of patients at a specialist center that utilizes a multidisciplinary care pathway. Participants provided information regarding their pain experience and treatment history, and completed several patient-reported outcome (PRO) measures. RESULTS: Of 129 respondents, 69/128 (54%; 1 missing) reported no pain in the past 4 weeks. However, 84 (65%) respondents were on medications, including 49 (38%) on monotherapy and 35 (27%) on polytherapy. A proportion of patients had discontinued at least one medication in the past, mostly due to lack of efficacy (n = 62, 48%) and side effects (n = 51, 40%). A total of 52 (40%) patients had undergone surgery, of whom 30 had microvascular decompression (MVD). Although surgery, especially MVD, provided satisfactory pain control in many patients, 29% of post-surgical patients reported complications, 19% had pain worsen or stay the same, 48% were still taking pain medications for TN, and 33% reported new and different facial pain. CONCLUSIONS: In most PRO measures, respondents with current pain interference had poorer scores than those without pain interference. In the Patient Global Impression of Change, 79% expressed improvement since beginning of treatment at this clinic. These results indicate that while the multidisciplinary approach can substantially alleviate the impact of TN, there remains an unmet medical need for additional treatment options

Measuring the impact of trigeminal neuralgia pain: the Penn Facial Pain Scale-Revised

BACKGROUND AND OBJECTIVE: The Penn Facial Pain Scale (Penn-FPS) was originally developed as a supplemental module to the Brief Pain Inventory Pain Interference Index (BPI-PII) in order to fully assess the impact of trigeminal neuralgia (TN) pain on patients’ health-related quality of life (HRQoL). The current objective is to create and establish the content validity of a new stand-alone version of the measure, the Penn-FPS-Revised (Penn-FPS-R). METHODS: Twenty participants (15 USA and 5 UK) with confirmed TN engaged in concept elicitation and cognitive debriefing interviews. These semi-structured interviews allowed participants to spontaneously describe the ways in which TN impacts on HRQoL and report on the extent to which the Penn-FPS and BPI-PII measure concepts are most relevant to them. Participants were also asked to report on the suitability of the instructions, recall period, and response options. RESULTS: Concept elicitation revealed nine themes involving TN restrictions on daily activities and HRQoL, including: “talking,” “self-care,” “eating,” “eating hard foods/chewing foods,” “daily activities,” “activities with temperature change,” “touching,” “mood,” and “relationships.” Cognitive debriefing confirmed that all of the Penn-FPS concepts and some of the BPI-PII concepts (“mood,” “general activities,” and “relations with others”) were relevant, although some items required edits to better capture individuals’ experiences. The impact of temperature and/or weather on activities was also identified as an important concept that is not captured by the Penn-FPS or BPI-PII. Participants confirmed the acceptability of recall period, instructions, and response options. Results from the interviews were applied to create the Penn-FPS-R, a new brief outcome measure that assesses the impacts of TN most important to patients. CONCLUSION:The Penn-FPS-R is a new 12-item HRQoL outcome measure with content validity that can be used to assess and monitor the impact of TN treatment interventions in both clinical practice and research

Mapping the sex determination locus in the hāpuku (Polyprion oxygeneios) using ddRAD sequencing

Background  Hāpuku (Polyprion oxygeneios) is a member of the wreckfish family (Polyprionidae) and is highly regarded as a food fish. Although adults grow relatively slowly, juveniles exhibit low feed conversion ratios and can reach market size in 1–2 years, makingP. oxygeneiosa strong candidate for aquaculture. However, they can take over 5years to reach sexual maturity in captivity and are not externally sexually dimorphic, complicating many aspects of broodstock management. Understanding the sex determination system ofP. oxygeneiosand developing accurate assays to assign genetic sex will contribute significantly towards its full-scale commercialisation.  Results  DNA from parents and sexed offspring (n = 57) from a single family of captive bredP. oxygeneioswas used as a template for double digestion Restriction-site Associated DNA (ddRAD) sequencing. Two libraries were constructed usingSbfI–SphI andSbfI –NcoI restriction enzyme combinations, respectively. Two runs on an Illumina MiSeq platform generated 70,266,464 raw reads, identifying 19,669 RAD loci. A combined sex linkage map (1367cM) was constructed based on 1575 Single Nucleotide Polymorphism (SNP) markers that resolved into 35 linkage groups. Sex-specific linkage maps were of similar size (1132 and 1168cM for male and female maps respectively). A single major sex-determining locus, found to be heterogametic in males, was mapped to linkage group 14. Several markers were found to be in strong linkage disequilibrium with the sex-determining locus. Allele-specific PCR assays were developed for two of these markers, SphI6331 and SphI8298, and demonstrated to accurately differentiate sex in progeny within the same pedigree. Comparative genomic analyses indicated that many of the linkage groups within theP. oxygeneiosmap share a relatively high degree of homology with those published for the European seabass (Dicentrarchus labrax).  Conclusion  P. oxygeneioshas an XX/XY sex determination system. Evaluation of allele-specific PCR assays, based on the two SNP markers most closely associated with phenotypic sex, indicates that a simple molecular assay for sexingP. oxygeneiosshould be readily attainable. The high degree of synteny observed withD. labraxshould aid further molecular genetic study and exploitation of hāpuku as a food fish

Knockout and transgenic mice of Trp53: what have we learned about p53 in breast cancer?

The human p53 tumor suppressor gene TP53 is mutated at a high frequency in sporadic breast cancer, and Li-Fraumeni syndrome patients who carry germline mutations in one TP53 allele have a high incidence of breast cancer. In the 10 years since the first knockout of the mouse p53 tumor suppressor gene (designated Trp53) was published, much has been learned about the contribution of p53 to biology and tumor suppression in the breast through the use of p53 transgenic and knockout mice. The original mice deficient in p53 showed no mammary gland phenotype. However, studies using BALB/c-Trp53-deficient mice have demonstrated a delayed involution phenotype and a mammary tumor phenotype. Together with other studies of mutant p53 transgenes and p53 bitransgenics, a greater understanding has been gained of the role of p53 in involution, of the regulation of p53 activity by hormones, of the effect of mouse strain and modifier genes on tumor phenotype, and of the cooperation between p53 and other oncogenic pathways, chemical carcinogens and hormonal stimulation in mammary tumorigenesis. Both p53 transgenic and knockout mice are important in vivo tools for understanding breast cancer, and are yet to be exploited for developing therapeutic strategies in breast cancer

Are Trp53 rescue of Brca1 embryonic lethality and Trp53/Brca1 breast cancer association related?

Brca1 is involved in multiple biological pathways including DNA damage repair, transcriptional regulation, and cell-cycle progression. A complex pattern of interactions of Brca1 with Trp53 has also emerged. Xu and coworkers found that haploid loss of Trp53 significantly reduces the embryonic lethality observed in mice with a homozygous in-frame deletion of Brca1 exon 11. They report that widespread apoptosis correlates with the embryonic lethality resulting from this homozygous Δ11 Brca1 mutation. A mechanism responsible for Brca1-associated carcinogenesis is proposed. These experiments extend our knowledge of a complex Brca1/Trp53 relationship. However, the precise mechanisms through which Brca1 interacts with Trp53 to suppress mammary tumor formation have yet to be elucidated

Mu Insertions Are Repaired by the Double-Strand Break Repair Pathway of Escherichia coli

Mu is both a transposable element and a temperate bacteriophage. During lytic growth, it amplifies its genome by replicative transposition. During infection, it integrates into the Escherichia coli chromosome through a mechanism not requiring extensive DNA replication. In the latter pathway, the transposition intermediate is repaired by transposase-mediated resecting of the 5′ flaps attached to the ends of the incoming Mu genome, followed by filling the remaining 5 bp gaps at each end of the Mu insertion. It is widely assumed that the gaps are repaired by a gap-filling host polymerase. Using the E. coli Keio Collection to screen for mutants defective in recovery of stable Mu insertions, we show in this study that the gaps are repaired by the machinery responsible for the repair of double-strand breaks in E. coli—the replication restart proteins PriA-DnaT and homologous recombination proteins RecABC. We discuss alternate models for recombinational repair of the Mu gaps

Collaboration and knowledge exchange between scholars in Britain and the empire, 1830–1914

In recent years there has been a growing interest among historians in the British Empire as a space of knowledge production and circulation. Much of this work assumes that scholarly cooperation and collaboration between individuals and institutions within the Empire had the effect (and often also the aim) of strengthening both imperial ties and the idea of empire. This chapter argues, however, that many examples of scholarly travel, exchange, and collaboration were undertaken with very different goals in mind. In particular, it highlights the continuing importance of an ideal of scientific internationalism, which stressed the benefits of scholarship for the whole of humanity and prioritized the needs and goals of individual academic and scientific disciplines. As the chapter shows, some scholars even went on to develop nuanced critiques of the imperial project while using the very structures of empire to further their own individual, disciplinary and institutional goals

In silico modeling indicates the development of HIV-1 resistance to multiple shRNA gene therapy differs to standard antiretroviral therapy

<p>Abstract</p> <p>Background</p> <p>Gene therapy has the potential to counter problems that still hamper standard HIV antiretroviral therapy, such as toxicity, patient adherence and the development of resistance. RNA interference can suppress HIV replication as a gene therapeutic via expressed short hairpin RNAs (shRNAs). It is now clear that multiple shRNAs will likely be required to suppress infection and prevent the emergence of resistant virus.</p> <p>Results</p> <p>We have developed the first biologically relevant stochastic model in which multiple shRNAs are introduced into CD34+ hematopoietic stem cells. This model has been used to track the production of gene-containing CD4+ T cells, the degree of HIV infection, and the development of HIV resistance in lymphoid tissue for 13 years. In this model, we found that at least four active shRNAs were required to suppress HIV infection/replication effectively and prevent the development of resistance. The inhibition of incoming virus was shown to be critical for effective treatment. The low potential for resistance development that we found is largely due to a pool of replicating wild-type HIV that is maintained in non-gene containing CD4+ T cells. This wild-type HIV effectively out-competes emerging viral strains, maintaining the viral <it>status quo</it>.</p> <p>Conclusions</p> <p>The presence of a group of cells that lack the gene therapeutic and is available for infection by wild-type virus appears to mitigate the development of resistance observed with systemic antiretroviral therapy.</p

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Environmental factors shaping the distribution of common wintering waterbirds in a lake ecosystem with developed shoreline

In this study, we tested whether the spatial distribution of waterbirds is influenced by shoreline urbanization or other habitat characteristics. We conducted monthly censuses along shoreline sections of a continental lake (Lake Balaton, Hungary) to assess the abundance of 11 common species that use this lake as a feeding and staging area during migration and winter. We estimated the degree of urbanization of the same shoreline sections and also measured other habitat characteristics (water depth, extent of reed cover, biomass of zebra mussels, distances to waste dumps and to other wetlands). We applied linear models and model averaging to identify habitat variables with high relative importance for predicting bird distributions. Bird abundance and urbanization were strongly related only in one species. Other habitat variables exhibited stronger relationships with bird distribution: (1) diving ducks and coots preferred shoreline sections with high zebra mussel biomass, (2) gulls preferred sites close to waste dumps, and (3) the abundances of several species were higher on shoreline sections close to other wetlands. Our findings suggest that the distribution of waterbirds on Lake Balaton is largely independent of shoreline urbanization and influenced by food availability and connectivity between wetlands