Current Developments in Intraspinal Agents for Cancer and Noncancer Pain

Since the late 1980s, intrathecal (IT) analgesic therapy has improved, and implantable IT drug delivery devices have become increasingly sophisticated. Physicians and patients now have myriad more options for agents and their combination, as well as for refining their delivery. As recently as 2007, The Polyanalgesic Consensus Conference of expert panelists updated its algorithm for drug selection in IT polyanalgesia. We review this algorithm and the emerging therapy included. This article provides an update on newly approved as well as emerging IT agents and the advances in technology for their delivery

Scale without Conformal Invariance at Three Loops

We carry out a three-loop computation that establishes the existence of scale without conformal invariance in dimensional regularization with the MS scheme in d=4-epsilon spacetime dimensions. We also comment on the effects of scheme changes in theories with many couplings, as well as in theories that live on non-conformal scale-invariant renormalization group trajectories. Stability properties of such trajectories are analyzed, revealing both attractive and repulsive directions in a specific example. We explain how our results are in accord with those of Jack & Osborn on a c-theorem in d=4 (and d=4-epsilon) dimensions. Finally, we point out that limit cycles with turning points are unlike limit cycles with continuous scale invariance.Comment: 21 pages, 3 figures, Erratum adde

DNA barcoding reveals the coral “laboratory-rat”, Stylophora pistillata encompasses multiple identities

Stylophora pistillata is a widely used coral “lab-rat” species with highly variable morphology and a broad biogeographic range (Red Sea to western central Pacific). Here we show, by analysing Cytochorme Oxidase I sequences, from 241 samples across this range, that this taxon in fact comprises four deeply divergent clades corresponding to the Pacific-Western Australia, Chagos-Madagascar-South Africa, Gulf of Aden-Zanzibar-Madagascar, and Red Sea-Persian/Arabian Gulf-Kenya. On the basis of the fossil record of Stylophora, these four clades diverged from one another 51.5-29.6 Mya, i.e., long before the closure of the Tethyan connection between the tropical Indo-West Pacific and Atlantic in the early Miocene (16–24 Mya) and should be recognised as four distinct species. These findings have implications for comparative ecological and/or physiological studies carried out using Stylophora pistillata as a model species, and highlight the fact that phenotypic plasticity, thought to be common in scleractinian corals, can mask significant genetic variation

Intercomparison of the northern hemisphere winter mid-latitude atmospheric variability of the IPCC models

We compare, for the overlapping time frame 1962-2000, the estimate of the northern hemisphere (NH) mid-latitude winter atmospheric variability within the XX century simulations of 17 global climate models (GCMs) included in the IPCC-4AR with the NCEP and ECMWF reanalyses. We compute the Hayashi spectra of the 500hPa geopotential height fields and introduce an integral measure of the variability observed in the NH on different spectral sub-domains. Only two high-resolution GCMs have a good agreement with reanalyses. Large biases, in most cases larger than 20%, are found between the wave climatologies of most GCMs and the reanalyses, with a relative span of around 50%. The travelling baroclinic waves are usually overestimated, while the planetary waves are usually underestimated, in agreement with previous studies performed on global weather forecasting models. When comparing the results of various versions of similar GCMs, it is clear that in some cases the vertical resolution of the atmosphere and, somewhat unexpectedly, of the adopted ocean model seem to be critical in determining the agreement with the reanalyses. The GCMs ensemble is biased with respect to the reanalyses but is comparable to the best 5 GCMs. This study suggests serious caveats with respect to the ability of most of the presently available GCMs in representing the statistics of the global scale atmospheric dynamics of the present climate and, a fortiori, in the perspective of modelling climate change.Comment: 39 pages, 8 figures, 2 table

Mitochondrial and nuclear genes suggest that stony corals are monophyletic but most families of stony corals are not (Order Scleractinia, Class Anthozoa, Phylum Cnidaria)

Modern hard corals (Class Hexacorallia; Order Scleractinia) are widely studied because of their fundamental role in reef building and their superb fossil record extending back to the Triassic. Nevertheless, interpretations of their evolutionary relationships have been in flux for over a decade. Recent analyses undermine the legitimacy of traditional suborders, families and genera, and suggest that a non-skeletal sister clade (Order Corallimorpharia) might be imbedded within the stony corals. However, these studies either sampled a relatively limited array of taxa or assembled trees from heterogeneous data sets. Here we provide a more comprehensive analysis of Scleractinia (127 species, 75 genera, 17 families) and various outgroups, based on two mitochondrial genes (cytochrome oxidase I, cytochrome b), with analyses of nuclear genes (ßtubulin, ribosomal DNA) of a subset of taxa to test unexpected relationships. Eleven of 16 families were found to be polyphyletic. Strikingly, over one third of all families as conventionally defined contain representatives from the highly divergent "robust" and "complex" clades. However, the recent suggestion that corallimorpharians are true corals that have lost their skeletons was not upheld. Relationships were supported not only by mitochondrial and nuclear genes, but also often by morphological characters which had been ignored or never noted previously. The concordance of molecular characters and more carefully examined morphological characters suggests a future of greater taxonomic stability, as well as the potential to trace the evolutionary history of this ecologically important group using fossils

The association of health literacy with adherence in older 2 adults, and its role in interventions: a systematic meta-review

Background: Low health literacy is a common problem among older adults. It is often suggested to be associated with poor adherence. This suggested association implies a need for effective adherence interventions in low health literate people. However, previous reviews show mixed results on the association between low health literacy and poor adherence. A systematic meta-review of systematic reviews was conducted to study the association between health literacy and adherence in adults above the age of 50. Evidence for the effectiveness of adherence interventions among adults in this older age group with low health literacy was also explored. Methods: Eight electronic databases (MEDLINE, ERIC, EMBASE, PsycINFO, CINAHL, DARE, the Cochrane Library, and Web of Knowledge) were searched using a variety of keywords regarding health literacy and adherence. Additionally, references of identified articles were checked. Systematic reviews were included if they assessed the association between health literacy and adherence or evaluated the effectiveness of interventions to improve adherence in adults with low health literacy. The AMSTAR tool was used to assess the quality of the included reviews. The selection procedure, data-extraction, and quality assessment were performed by two independent reviewers. Seventeen reviews were selected for inclusion. Results: Reviews varied widely in quality. Both reviews of high and low quality found only weak or mixed associations between health literacy and adherence among older adults. Reviews report on seven studies that assess the effectiveness of adherence interventions among low health literate older adults. The results suggest that some adherence interventions are effective for this group. The interventions described in the reviews focused mainly on education and on lowering the health literacy demands of adherence instructions. No conclusions could be drawn about which type of intervention could be most beneficial for this population. Conclusions: Evidence on the association between health literacy and adherence in older adults is relatively weak. Adherence interventions are potentially effective for the vulnerable population of older adults with low levels of health literacy, but the evidence on this topic is limited. Further research is needed on the association between health literacy and general health behavior, and on the effectiveness of interventions

Modeling recursive RNA interference.

An important application of the RNA interference (RNAi) pathway is its use as a small RNA-based regulatory system commonly exploited to suppress expression of target genes to test their function in vivo. In several published experiments, RNAi has been used to inactivate components of the RNAi pathway itself, a procedure termed recursive RNAi in this report. The theoretical basis of recursive RNAi is unclear since the procedure could potentially be self-defeating, and in practice the effectiveness of recursive RNAi in published experiments is highly variable. A mathematical model for recursive RNAi was developed and used to investigate the range of conditions under which the procedure should be effective. The model predicts that the effectiveness of recursive RNAi is strongly dependent on the efficacy of RNAi at knocking down target gene expression. This efficacy is known to vary highly between different cell types, and comparison of the model predictions to published experimental data suggests that variation in RNAi efficacy may be the main cause of discrepancies between published recursive RNAi experiments in different organisms. The model suggests potential ways to optimize the effectiveness of recursive RNAi both for screening of RNAi components as well as for improved temporal control of gene expression in switch off-switch on experiments

Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema

Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al

Why is it difficult to implement e-health initiatives? A qualitative study

<b>Background</b> The use of information and communication technologies in healthcare is seen as essential for high quality and cost-effective healthcare. However, implementation of e-health initiatives has often been problematic, with many failing to demonstrate predicted benefits. This study aimed to explore and understand the experiences of implementers - the senior managers and other staff charged with implementing e-health initiatives and their assessment of factors which promote or inhibit the successful implementation, embedding, and integration of e-health initiatives.<p></p> <b>Methods</b> We used a case study methodology, using semi-structured interviews with implementers for data collection. Case studies were selected to provide a range of healthcare contexts (primary, secondary, community care), e-health initiatives, and degrees of normalization. The initiatives studied were Picture Archiving and Communication System (PACS) in secondary care, a Community Nurse Information System (CNIS) in community care, and Choose and Book (C&B) across the primary-secondary care interface. Implementers were selected to provide a range of seniority, including chief executive officers, middle managers, and staff with 'on the ground' experience. Interview data were analyzed using a framework derived from Normalization Process Theory (NPT).<p></p> <b>Results</b> Twenty-three interviews were completed across the three case studies. There were wide differences in experiences of implementation and embedding across these case studies; these differences were well explained by collective action components of NPT. New technology was most likely to 'normalize' where implementers perceived that it had a positive impact on interactions between professionals and patients and between different professional groups, and fit well with the organisational goals and skill sets of existing staff. However, where implementers perceived problems in one or more of these areas, they also perceived a lower level of normalization.<p></p> <b>Conclusions</b> Implementers had rich understandings of barriers and facilitators to successful implementation of e-health initiatives, and their views should continue to be sought in future research. NPT can be used to explain observed variations in implementation processes, and may be useful in drawing planners' attention to potential problems with a view to addressing them during implementation planning

Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms

<p>Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.</p> <p>Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.</p> <p>Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.</p&gt