Clinical course, costs and predictive factors for response to treatment in carpal tunnel syndrome: The PALMS study protocol

Background Carpal tunnel syndrome (CTS) is the most common neuropathy of the upper limb and a significant contributor to hand functional impairment and disability. Effective treatment options include conservative and surgical interventions, however it is not possible at present to predict the outcome of treatment. The primary aim of this study is to identify which baseline clinical factors predict a good outcome from conservative treatment (by injection) or surgery in patients diagnosed with carpal tunnel syndrome. Secondary aims are to describe the clinical course and progression of CTS, and to describe and predict the UK cost of CTS to the individual, National Health Service (NHS) and society over a two year period. Methods/Design In this prospective observational cohort study patients presenting with clinical signs and symptoms typical of CTS and in whom the diagnosis is confirmed by nerve conduction studies are invited to participate. Data on putative predictive factors are collected at baseline and follow-up through patient questionnaires and include standardised measures of symptom severity, hand function, psychological and physical health, comorbidity and quality of life. Resource use and cost over the 2 year period such as prescribed medications, NHS and private healthcare contacts are also collected through patient self-report at 6, 12, 18 and 24 months. The primary outcome used to classify treatment success or failures will be a 5-point global assessment of change. Secondary outcomes include changes in clinical symptoms, functioning, psychological health, quality of life and resource use. A multivariable model of factors which predict outcome and cost will be developed. Discussion This prospective cohort study will provide important data on the clinical course and UK costs of CTS over a two-year period and begin to identify predictive factors for treatment success from conservative and surgical interventions

ZFNGenome: A comprehensive resource for locating zinc finger nuclease target sites in model organisms

<p>Abstract</p> <p>Background</p> <p>Zinc Finger Nucleases (ZFNs) have tremendous potential as tools to facilitate genomic modifications, such as precise gene knockouts or gene replacements by homologous recombination. ZFNs can be used to advance both basic research and clinical applications, including gene therapy. Recently, the ability to engineer ZFNs that target any desired genomic DNA sequence with high fidelity has improved significantly with the introduction of rapid, robust, and publicly available techniques for ZFN design such as the Oligomerized Pool ENgineering (OPEN) method. The motivation for this study is to make resources for genome modifications using OPEN-generated ZFNs more accessible to researchers by creating a user-friendly interface that identifies and provides quality scores for all potential ZFN target sites in the complete genomes of several model organisms.</p> <p>Description</p> <p>ZFNGenome is a GBrowse-based tool for identifying and visualizing potential target sites for OPEN-generated ZFNs. ZFNGenome currently includes a total of more than 11.6 million potential ZFN target sites, mapped within the fully sequenced genomes of seven model organisms; <it>S. cerevisiae, C. reinhardtii, A. thaliana</it>, <it>D. melanogaster, D. rerio, C. elegans</it>, and <it>H. sapiens </it>and can be visualized within the flexible GBrowse environment. Additional model organisms will be included in future updates. ZFNGenome provides information about each potential ZFN target site, including its chromosomal location and position relative to transcription initiation site(s). Users can query ZFNGenome using several different criteria (e.g., gene ID, transcript ID, target site sequence). Tracks in ZFNGenome also provide "uniqueness" and ZiFOpT (Zinc Finger OPEN Targeter) "confidence" scores that estimate the likelihood that a chosen ZFN target site will function <it>in vivo</it>. ZFNGenome is dynamically linked to ZiFDB, allowing users access to all available information about zinc finger reagents, such as the effectiveness of a given ZFN in creating double-stranded breaks.</p> <p>Conclusions</p> <p>ZFNGenome provides a user-friendly interface that allows researchers to access resources and information regarding genomic target sites for engineered ZFNs in seven model organisms. This genome-wide database of potential ZFN target sites should greatly facilitate the utilization of ZFNs in both basic and clinical research.</p> <p>ZFNGenome is freely available at: <url>http://bindr.gdcb.iastate.edu/ZFNGenome</url> or at the Zinc Finger Consortium website: <url>http://www.zincfingers.org/</url>.</p

A Blast Wave from the 1843 Eruption of Eta Carinae

Very massive stars shed much of their mass in violent precursor eruptions as luminous blue variables (LBVs) before reaching their most likely end as supernovae, but the cause of LBV eruptions is unknown. The 19th century eruption of Eta Carinae, the prototype of these events, ejected about 12 solar masses at speeds of 650 km/s, with a kinetic energy of almost 10^50 ergs. Some faster material with speeds up to 1000-2000 km/s had previously been reported but its full distribution was unknown. Here I report observations of much faster material with speeds up to 3500-6000 km/s, reaching farther from the star than the fastest material in earlier reports. This fast material roughly doubles the kinetic energy of the 19th century event, and suggests that it released a blast wave now propagating ahead of the massive ejecta. Thus, Eta Car's outer shell now mimics a low-energy supernova remnant. The eruption has usually been discussed in terms of an extreme wind driven by the star's luminosity, but fast material reported here suggests that it was powered by a deep-seated explosion rivalling a supernova, perhaps triggered by the pulsational pair instability. This may alter interpretations of similar events seen in other galaxies.Comment: 10 pages, 3 color figs, supplementary information. Accepted by Natur

Genetic variants of Anaplasma phagocytophilum from 14 equine granulocytic anaplasmosis cases

<p>Abstract</p> <p>Background</p> <p>Equine Granulocytic Anaplasmosis (EGA) is caused by <it>Anaplasma phagocytophilum</it>, a tick-transmitted, obligate intracellular bacterium. In Europe, it is transmitted by <it>Ixodes ricinus</it>. A large number of genetic variants of <it>A. phagocytophilum </it>circulate in nature and have been found in ticks and different animals. Attempts have been made to assign certain genetic variants to certain host species or pathologies, but have not been successful so far. The purpose of this study was to investigate the causing agent <it>A. phagocytophilum </it>of 14 cases of EGA in naturally infected horses with molecular methods on the basis of 4 partial genes (<it>16S rRNA</it>, <it>groEL</it>, <it>msp2</it>, and <it>msp4</it>).</p> <p>Results</p> <p>All DNA extracts of EDTA-blood samples of the horses gave bands of the correct nucleotide size in all four genotyping PCRs. Sequence analysis revealed 4 different variants in the partial <it>16S rRNA</it>, <it>groEL </it>gene and <it>msp2 </it>genes, and 3 in the <it>msp4 </it>gene. One <it>16S rRNA </it>gene variant involved in 11 of the 14 cases was identical to the "prototype" variant causing disease in humans in the amplified part [GenBank: <ext-link ext-link-id="U02521" ext-link-type="gen">U02521</ext-link>]. Phylogenetic analysis revealed as expected for the <it>groEL </it>gene that sequences from horses clustered separately from roe deer. Sequences of the partial <it>msp2 </it>gene from this study formed a separate cluster from ruminant variants in Europe and from all US variants.</p> <p>Conclusions</p> <p>The results show that more than one variant of <it>A. phagocytophilum </it>seems to be involved in EGA in Germany. The comparative genetic analysis of the variants involved points towards different natural cycles in the epidemiology of <it>A. phagocytophilum</it>, possibly involving different reservoir hosts or host adaptation, rather than a strict species separation.</p

Nutritional correlates of koala persistence in a low-density population

It is widely postulated that nutritional factors drive bottom-up, resource-based patterns in herbivore ecology and distribution. There is, however, much controversy over the roles of different plant constituents and how these influence individual herbivores and herbivore populations. The density of koala (Phascolarctos cinereus) populations varies widely and many attribute population trends to variation in the nutritional quality of the eucalypt leaves of their diet, but there is little evidence to support this hypothesis. We used a nested design that involved sampling of trees at two spatial scales to investigate how leaf chemistry influences free-living koalas from a low-density population in south east New South Wales, Australia. Using koala faecal pellets as a proxy for koala visitation to trees, we found an interaction between toxins and nutrients in leaves at a small spatial scale, whereby koalas preferred trees with leaves of higher concentrations of available nitrogen but lower concentrations of sideroxylonals (secondary metabolites found exclusively in eucalypts) compared to neighbouring trees of the same species. We argue that taxonomic and phenotypic diversity is likely to be important when foraging in habitats of low nutritional quality in providing diet choice to tradeoff nutrients and toxins and minimise movement costs. Our findings suggest that immediate nutritional concerns are an important priority of folivores in low-quality habitats and imply that nutritional limitations play an important role in constraining folivore populations. We show that, with a careful experimental design, it is possible to make inferences about populations of herbivores that exist at extremely low densities and thus achieve a better understanding about how plant composition influences herbivore ecology and persistence.IW and WF received a grant from New South Wales (NSW) Department of Environment, Climate Change & Water

Targeted genome engineering via zinc finger nucleases

With the development of next-generation sequencing technology, ever-expanding databases of genetic information from various organisms are available to researchers. However, our ability to study the biological meaning of genetic information and to apply our genetic knowledge to produce genetically modified crops and animals is limited, largely due to the lack of molecular tools to manipulate genomes. Recently, targeted cleavage of the genome using engineered DNA scissors called zinc finger nucleases (ZFNs) has successfully supported the precise manipulation of genetic information in various cells, animals, and plants. In this review, we will discuss the development and applications of ZFN technology for genome engineering and highlight recent reports on its use in plants

Hepatitis B screening in the Turkish-Dutch population in Rotterdam, the Netherlands; qualitative assessment of socio-cultural determinants

Background. Hepatitis B is an important health problem in the Turkish community in the Netherlands. Increased voluntary screening is necessary in this community, to detect individuals eligible for treatment and to prevent further transmission of the disease. Methods. We investigated socio-cultural determinants associated with hepatitis B screening in male and female, first and second generation Turkish migrants, by means of Focus Group Discussions. Results. Socio-cultural themes related to hepatitis B screening were identified; these were social norm, social support, sensitivity regarding sexuality, reputation, responsiveness to authority, religious responsibility, cleanliness and religious doctrine regarding health and disease, and the perceived efficacy of Dutch health care services. Motivating factors were the (religious) responsibility for one's health, the perceived obligation when being invited for screening, and social support to get tested for hepatitis B. Perceived barriers were the association of hepatitis B screening with STDs or sexual activity, the perception of low control over one's health, and the perceived low efficacy of the Dutch health care services. Reputation could act as either a motivator or barrier. Conclusion. This study identified relevant socio-cultural themes related to hepatitis B screening, which may serve to customize interventions aimed at the promotion of voluntary hepatitis B screening in the Turkish-Dutch population in the Netherlands

Activating KIR and HLA Bw4 Ligands Are Associated to Decreased Susceptibility to Pemphigus Foliaceus, an Autoimmune Blistering Skin Disease

The KIR genes and their HLA class I ligands have thus far not been investigated in pemphigus foliaceus (PF) and related autoimmune diseases, such as pemphigus vulgaris. We genotyped 233 patients and 204 controls for KIR by PCR-SSP. HLA typing was performed by LABType SSO reagent kits. We estimated the odds ratio, 95% confidence interval and performed logistic regression analyses to test the hypothesis that KIR genes and their known ligands influence susceptibility to PF. We found significant negative association between activating genes and PF. The activating KIR genes may have an overlapping effect in the PF susceptibility and the presence of more than three activating genes was protective (OR = 0.49, p = 0.003). A strong protective association was found for higher ratios activating/inhibitory KIR (OR = 0.44, p = 0.001). KIR3DS1 and HLA-Bw4 were negatively associated to PF either isolated or combined, but higher significance was found for the presence of both together (OR = 0.34, p<10−3) suggesting that the activating function is the major factor to interfere in the PF pathogenesis. HLA-Bw4 (80I and 80T) was decreased in patients. There is evidence that HLA-Bw4(80T) may also be important as KIR3DS1 ligand, being the association of this pair (OR = 0.07, p = 0.001) stronger than KIR3DS1-Bw4(80I) (OR = 0.31, p = 0.002). Higher levels of activating KIR signals appeared protective to PF. The activating KIR genes have been commonly reported to increase the risk for autoimmunity, but particularities of endemic PF, like the well documented influence the environmental exposure in the pathogenesis of this disease, may be the reason why activated NK cells probably protect against pemphigus foliaceus

p53 Gene Repair with Zinc Finger Nucleases Optimised by Yeast 1-Hybrid and Validated by Solexa Sequencing

The tumor suppressor gene p53 is mutated or deleted in over 50% of human tumors. As functional p53 plays a pivotal role in protecting against cancer development, several strategies for restoring wild-type (wt) p53 function have been investigated. In this study, we applied an approach using gene repair with zinc finger nucleases (ZFNs). We adapted a commercially-available yeast one-hybrid (Y1H) selection kit to allow rapid building and optimization of 4-finger constructs from randomized PCR libraries. We thus generated novel functional zinc finger nucleases against two DNA sites in the human p53 gene, near cancer mutation ‘hotspots’. The ZFNs were first validated using in vitro cleavage assays and in vivo episomal gene repair assays in HEK293T cells. Subsequently, the ZFNs were used to restore wt-p53 status in the SF268 human cancer cell line, via ZFN-induced homologous recombination. The frequency of gene repair and mutation by non-homologous end-joining was then ascertained in several cancer cell lines, using a deep sequencing strategy. Our Y1H system facilitates the generation and optimisation of novel, sequence-specific four- to six-finger peptides, and the p53-specific ZFN described here can be used to mutate or repair p53 in genomic loci

The interaction of bacterial pathogens with platelets.

In recent years, the frequency of serious cardiovascular infections such as endocarditis has increased, particularly in association with nosocomially acquired antibiotic-resistant pathogens. Growing evidence suggests a crucial role for the interaction of bacteria with human platelets in the pathogenesis of cardiovascular infections. Here, we review the nature of the interactions between platelets and bacteria, and the role of these interactions in the pathogenesis of endocarditis and other cardiovascular diseases