Feasibility and acceptability of a multiple risk factor intervention: The Step Up randomized pilot trial

<p>Abstract</p> <p>Background</p> <p>Interventions are needed which can successfully modify more than one disease risk factor at a time, but much remains to be learned about the acceptability, feasibility, and effectiveness of multiple risk factor (MRF) interventions. To address these issues and inform future intervention development, we conducted a randomized pilot trial (n = 52). This study was designed to assess the feasibility and acceptability of the Step Up program, a MRF cognitive-behavioral program designed to improve participants' mental and physical well-being by reducing depressive symptoms, promoting smoking cessation, and increasing physical activity.</p> <p>Methods</p> <p>Participants were recruited from a large health care organization and randomized to receive usual care treatment for depression, smoking, and physical activity promotion or the phone-based Step Up counseling program plus usual care. Participants were assessed at baseline, three and six months.</p> <p>Results</p> <p>The intervention was acceptable to participants and feasible to offer within a healthcare system. The pilot also offered important insights into the optimal design of a MRF program. While not powered to detect clinically significant outcomes, changes in target behaviors indicated positive trends at six month follow-up and statistically significant improvement was also observed for depression. Significantly more experimental participants reported a clinically significant improvement (50% reduction) in their baseline depression score at four months (54% vs. 26%, OR = 3.35, 95% CI [1.01- 12.10], <it>p </it>= 0.05) and 6 months (52% vs. 13%, OR = 7.27, 95% CI [1.85 - 37.30], <it>p </it>= 0.004)</p> <p>Conclusions</p> <p>Overall, results suggest the Step Up program warrants additional research, although some program enhancements may be beneficial. Key lessons learned from this research are shared to promote the understanding of others working in this field.</p> <p>Trial registration</p> <p>The trial is registered with ClinicalTrials.gov (<a href="http://www.clinicaltrials.gov/ct2/show/NCT00644995">NCT00644995</a>).</p

Structural reorganization of cylindrical nanoparticles triggered by polylactide stereocomplexation

YesCo-crystallization of polymers with different configurations/tacticities provides access to materials with enhanced performance. The stereocomplexation of isotactic poly(L-lactide) and poly(D-lactide) has led to improved properties compared with each homochiral material. Herein, we report the preparation of stereocomplex micelles from a mixture of poly(L-lactide)-b-poly(acrylic acid) and poly(D-lactide)-b-poly(acrylic acid) diblock copolymers in water via crystallization-driven self-assembly. During the formation of these stereocomplex micelles, an unexpected morphological transition results in the formation of dense crystalline spherical micelles rather than cylinders. Furthermore, mixture of cylinders with opposite homochirality in either THF/H2O mixtures or in pure water at 65 °C leads to disassembly into stereocomplexed spherical micelles. Similarly, a transition is also observed in a related PEO-b-PLLA/PEO-b-PDLA system, demonstrating wider applicability. This new mechanism for morphological reorganization, through competitive crystallization and stereocomplexation and without the requirement for an external stimulus, allows for new opportunities in controlled release and delivery applications.University of Warwick, Swiss National Science Foundation and the EPSRC. The Royal Society - an Industry Fellowship to A.P.D. The Engineering and Physical Sciences Research Council (EP/G004897/1) - funding to support postdoctoral fellowships for A.P.B. as well as funding for J.S. and M.A.D. through the Warwick Centre for Analytical Science (EP/F034210/1). The Science City Research Alliance and the HEFCE Strategic Development Fund - funding support. Some items of equipment that were used in this research were funded by Birmingham Science City, with support from Advantage West Midlands and part-funded by the European Regional Development Fund

How Phytophthora cinnamomi became associated with the death of Eucalyptus marginata – the early investigations into jarrah dieback

The name jarrah dieback was used in the 1940s to describe a serious economic problem in the jarrah forest in the south west of Western Australia. This was the sudden death of groups of jarrah (Eucalyptus marginata) trees that occurred on previously logged sites that had a tendency to become waterlogged in winter. Although the cause was not determined at the time, from symptoms recorded in early investigations the most likely explanation is that the trees died as the result of waterlogging damage. In the 1960s it was shown that many of these sites were infested by the introduced oomycete Phytophthora cinnamomi and tree deaths, together with the deaths of many mid- and under-storey plants, were attributed to this pathogen. A chronology of the research, based on contemporary unpublished documents, shows that in 1968 the conclusion that P. cinnamomi caused jarrah deaths was not supported by the available evidence, because the work did not satisfy the first and fourth of Koch’s postulates. The evidence that P. cinnamomi killed many mid- and under-storey plants was much stronger. There are two problems that have been confused: the death of groups of jarrah trees (jarrah dieback) that is caused by waterlogging and the death of many mid- and under-storey plants (Phytophthora dieback) caused by P. cinnamomi infection

Control of Parasitophorous Vacuole Expansion by LYST/Beige Restricts the Intracellular Growth of Leishmania amazonensis

The intracellular protozoan Leishmania replicates in parasitophorous vacuoles (PV) that share many features with late endosomes/lysosomes. L. amazonensis PVs expand markedly during infections, but the impact of PV size on parasite intracellular survival is still unknown. Here we show that host cells infected with L. amazonensis upregulate transcription of LYST/Beige, which was previously shown to regulate lysosome size. Mutations in LYST/Beige caused further PV expansion and enhanced L. amazonensis replication. In contrast, LYST/Beige overexpression led to small PVs that did not sustain parasite growth. Treatment of LYST/Beige over-expressing cells with vacuolin-1 reversed this phenotype, expanding PVs and promoting parasite growth. The opposite was seen with E-64d, which reduced PV size in LYST-Beige mutant cells and inhibited L. amazonensis replication. Enlarged PVs appear to protect parasites from oxidative damage, since inhibition of nitric oxide synthase had no effect on L. amazonensis viability within large PVs, but enhanced their growth within LYST/Beige-induced small PVs. Thus, the upregulation of LYST/Beige in infected cells functions as a host innate response to limit parasite growth, by reducing PV volume and inhibiting intracellular survival

The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in alcoholic patients – a multicenter randomized study

Background: Hepatic failure has been associated with reported therapeutic use of acetaminophen by alcoholic patients. The highest risk period for alcoholic patients is immediately after discontinuation of alcohol intake. This period exhibits the largest increase in CYP2E1 induction and lowest glutathione levels. Our hypothesis was that common liver tests would be unaffected by administration of the maximum recommended daily dosage of acetaminophen for 3 consecutive days to newly-abstinent alcoholic subjects. Methods: Adult alcoholic subjects entering two alcohol detoxification centers were enrolled in a prospective double-blind, randomized, placebo-controlled trial. Subjects were randomized to acetaminophen, 4 g/day, or placebo for 3 consecutive days. The study had 95% probability of detecting a 15 IU/L difference in serum ALT. Results: A total of 443 subjects were enrolled: 308 (258 completed) received acetaminophen and 135 subjects (114 completed) received placebo. Study groups did not differ in demographics, alcohol consumption, nutritional status or baseline laboratory assessments. The peak mean ALT activity was 57 [plus or minus] 45 IU/L and 55 [plus or minus] 48 IU/L in the acetaminophen and placebo groups, respectively. Subgroup analyses for subjects presenting with an elevated ALT, subjects fulfilling a diagnosis of alcoholic hepatitis and subjects attaining a peak ALT greater than 200 IU/L showed no statistical difference between the acetaminophen and control groups. The one participant developing an increased international normalized ratio was in the placebo group. Conclusion: Alcoholic patients treated with the maximum recommended daily dose of acetaminophen for 3 consecutive days did not develop increases in serum transaminase or other measures of liver injury. Treatment of pain or fever for 3 days with acetaminophen appears safe in newly-abstinent alcoholic patients, such as those presenting for acute medical care.Funding for this study was provided by McNeil Consumer Healthcare to the Denver Health Authority, Denver, Colorado

Phase I Evaluation of STA-1474, a Prodrug of the Novel HSP90 Inhibitor Ganetespib, in Dogs with Spontaneous Cancer

The novel water soluble compound STA-1474 is metabolized to ganetespib (formerly STA-9090), a potent HSP90 inhibitor previously shown to kill canine tumor cell lines in vitro and inhibit tumor growth in the setting of murine xenografts. The purpose of the following study was to extend these observations and investigate the safety and efficacy of STA-1474 in dogs with spontaneous tumors.This was a Phase 1 trial in which dogs with spontaneous tumors received STA-1474 under one of three different dosing schemes. Pharmacokinetics, toxicities, biomarker changes, and tumor responses were assessed. Twenty-five dogs with a variety of cancers were enrolled. Toxicities were primarily gastrointestinal in nature consisting of diarrhea, vomiting, inappetence and lethargy. Upregulation of HSP70 protein expression was noted in both tumor specimens and PBMCs within 7 hours following drug administration. Measurable objective responses were observed in dogs with malignant mast cell disease (n = 3), osteosarcoma (n = 1), melanoma (n = 1) and thyroid carcinoma (n = 1), for a response rate of 24% (6/25). Stable disease (>10 weeks) was seen in 3 dogs, for a resultant overall biological activity of 36% (9/25).This study provides evidence that STA-1474 exhibits biologic activity in a relevant large animal model of cancer. Given the similarities of canine and human cancers with respect to tumor biology and HSP90 activation, it is likely that STA-1474 and ganetespib will demonstrate comparable anti-cancer activity in human patients

Fluctuations around Bjorken Flow and the onset of turbulent phenomena

We study how fluctuations in fluid dynamic fields can be dissipated or amplified within the characteristic spatio-temporal structure of a heavy ion collision. The initial conditions for a fluid dynamic evolution of heavy ion collisions may contain significant fluctuations in all fluid dynamical fields, including the velocity field and its vorticity components. We formulate and analyze the theory of local fluctuations around average fluid fields described by Bjorken's model. For conditions of laminar flow, when a linearized treatment of the dynamic evolution applies, we discuss explicitly how fluctuations of large wave number get dissipated while modes of sufficiently long wave-length pass almost unattenuated or can even be amplified. In the opposite case of large Reynold's numbers (which is inverse to viscosity), we establish that (after suitable coordinate transformations) the dynamics is governed by an evolution equation of non-relativistic Navier-Stokes type that becomes essentially two-dimensional at late times. One can then use the theory of Kolmogorov and Kraichnan for an explicit characterization of turbulent phenomena in terms of the wave-mode dependence of correlations of fluid dynamic fields. We note in particular that fluid dynamic correlations introduce characteristic power-law dependences in two-particle correlation functions.Comment: 40 pages, 5 figures, published versio

Transcriptome and Proteome Exploration to Model Translation Efficiency and Protein Stability in Lactococcus lactis

This genome-scale study analysed the various parameters influencing protein levels in cells. To achieve this goal, the model bacterium Lactococcus lactis was grown at steady state in continuous cultures at different growth rates, and proteomic and transcriptomic data were thoroughly compared. Ratios of mRNA to protein were highly variable among proteins but also, for a given gene, between the different growth conditions. The modeling of cellular processes combined with a data fitting modeling approach allowed both translation efficiencies and degradation rates to be estimated for each protein in each growth condition. Estimated translational efficiencies and degradation rates strongly differed between proteins and were tested for their biological significance through statistical correlations with relevant parameters such as codon or amino acid bias. These efficiencies and degradation rates were not constant in all growth conditions and were inversely proportional to the growth rate, indicating a more efficient translation at low growth rate but an antagonistic higher rate of protein degradation. Estimated protein median half-lives ranged from 23 to 224 min, underlying the importance of protein degradation notably at low growth rates. The regulation of intracellular protein level was analysed through regulatory coefficient calculations, revealing a complex control depending on protein and growth conditions. The modeling approach enabled translational efficiencies and protein degradation rates to be estimated, two biological parameters extremely difficult to determine experimentally and generally lacking in bacteria. This method is generic and can now be extended to other environments and/or other micro-organisms

Identification of Leishmania Proteins Preferentially Released in Infected Cells Using Change Mediated Antigen Technology (CMAT)

Although Leishmania parasites have been shown to modulate their host cell's responses to multiple stimuli, there is limited evidence that parasite molecules are released into infected cells. In this study, we present an implementation of the change mediated antigen technology (CMAT) to identify parasite molecules that are preferentially expressed in infected cells. Sera from mice immunized with cell lysates prepared from L. donovani or L. pifanoi-infected macrophages were adsorbed with lysates of axenically grown amastigotes of L. donovani or L. pifanoi, respectively, as well as uninfected macrophages. The sera were then used to screen inducible parasite expression libraries constructed with genomic DNA. Eleven clones from the L. pifanoi and the L. donovani screen were selected to evaluate the characteristics of the molecules identified by this approach. The CMAT screen identified genes whose homologs encode molecules with unknown function as well as genes that had previously been shown to be preferentially expressed in the amastigote form of the parasite. In addition a variant of Tryparedoxin peroxidase that is preferentially expressed within infected cells was identified. Antisera that were then raised to recombinant products of the clones were used to validate that the endogenous molecules are preferentially expressed in infected cells. Evaluation of the distribution of the endogenous molecules in infected cells showed that some of these molecules are secreted into parasitophorous vacuoles (PVs) and that they then traffic out of PVs in vesicles with distinct morphologies. This study is a proof of concept study that the CMAT approach can be applied to identify putative Leishmania parasite effectors molecules that are preferentially expressed in infected cells. In addition we provide evidence that Leishmania molecules traffic out of the PV into the host cell cytosol and nucleus