Candida albicans Isolates from the Gut of Critically Ill Patients Respond to Phosphate Limitation by Expressing Filaments and a Lethal Phenotype

Candida albicans is an opportunistic pathogen that proliferates in the intestinal tract of critically ill patients where it continues to be a major cause of infectious-related mortality. The precise cues that shift intestinal C. albicans from its ubiquitous indolent colonizing yeast form to an invasive and lethal filamentous form remain unknown. We have previously shown that severe phosphate depletion develops in the intestinal tract during extreme physiologic stress and plays a major role in shifting intestinal Pseudomonas aeruginosa to express a lethal phenotype via conserved phosphosensory-phosphoregulatory systems. Here we studied whether phosphate dependent virulence expression could be similarly demonstrated for C. albicans. C. albicans isolates from the stool of critically ill patients and laboratory prototype strains (SC5314, BWP17, SN152) were evaluated for morphotype transformation and lethality against C. elegans and mice during exposure to phosphate limitation. Isolates ICU1 and ICU12 were able to filament and kill C. elegans in a phosphate dependent manner. In a mouse model of intestinal phosphate depletion (30% hepatectomy), direct intestinal inoculation of C. albicans caused mortality that was prevented by oral phosphate supplementation. Prototype strains displayed limited responses to phosphate limitation; however, the pho4Δ mutant displayed extensive filamentation during low phosphate conditions compared to its isogenic parent strain SN152, suggesting that mutation in the transcriptional factor Pho4p may sensitize C. albicans to phosphate limitation. Extensive filamentation was also observed in strain ICU12 suggesting that this strain is also sensitized to phosphate limitation. Analysis of the sequence of PHO4 in strain ICU12, its transcriptional response to phosphate limitation, and phosphatase assays confirmed that ICU12 demonstrates a profound response to phosphate limitation. The emergence of strains of C. albicans with marked responsiveness to phosphate limitation may represent a fitness adaptation to the complex and nutrient scarce environment typical of the gut of a critically ill patient

Cost-effectiveness of pregabalin versus venlafaxine in the treatment of generalized anxiety disorder: findings from a Spanish perspective

The objective of the present study was to describe a new model of the cost-effectiveness of treatment of generalized anxiety disorder (GAD) and its application to a comparison of pregabalin versus venlafaxine extended-release (XR) from a Spanish healthcare perspective. Microsimulation techniques, including Hamilton Anxiety Scale (HAM-A) score, number of weeks with minimal or no anxiety (HAM-A ≤ 9), and quality-adjusted life-years (QALYs), were used to predict treatment outcomes for patients with moderate-to-severe GAD who would be treated with pregabalin vs venlafaxine XR. Expected levels of healthcare utilization and unit cost of care are derived from Spanish published sources. We express cost-effectiveness alternatively in terms of incremental cost per additional week with minimal or no anxiety, and incremental cost per QALY gained [in 2007 Euros (€)]. Considering costs of drug treatment only, the incremental cost [mean (95% confidence interval)] of pregabalin (vs venlafaxine XR) would be €96 (€86, €107) per additional week with minimal or no anxiety, and €32,832 (€29,656, €36,308) per QALY gained. When other medical care costs are considered, cost-effectiveness ratios decline to €70 (€61, €80) per additional week with no or minimal anxiety, and €23,909 (€20,820, €27,006) per QALY gained. We conclude that, using a new microsimulation model of the treatment of GAD, pregabalin appears to be cost-effective vs venlafaxine XR in a Spanish healthcare setting

Cost-effectiveness analysis of pemetrexed versus docetaxel in the second-line treatment of non-small cell lung cancer in Spain: results for the non-squamous histology population

BackgroundThe objective of this study was to conduct a cost-effectiveness evaluation of pemetrexed compared to docetaxel in the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) for patients with predominantly non-squamous histology in the Spanish healthcare setting.MethodsA Markov model was designed consisting of stable, responsive, progressive disease and death states. Patients could also experience adverse events as long as they received chemotherapy. Clinical inputs were based on an analysis of a phase III clinical trial that identified a statistically significant improvement in overall survival for non-squamous patients treated with pemetrexed compared with docetaxel. Costs were collected from the Spanish healthcare perspective.ResultsOutcomes of the model included total costs, total quality-adjusted life years (QALYs), total life years gained (LYG) and total progression-free survival (PFS). Mean survival was 1.03 years for the pemetrexed arm and 0.89 years in the docetaxel arm; QALYs were 0.52 compared to 0.42. Per-patient lifetime costs were € 34677 and € 32343, respectively. Incremental cost-effectiveness ratios were € 23967 per QALY gained and € 17225 per LYG.ConclusionsPemetrexed as a second-line treatment option for patients with a predominantly non-squamous histology in NSCLC is a cost-effective alternative to docetaxel according to the € 30000/QALY threshold commonly accepted in Spain

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1–/– donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1–/– donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD

The case for the introduction of new chemotherapy agents in the treatment of advanced non small cell lung cancer in the wake of the findings of The National Institute of Clinical Excellence (NICE)

After years of nihilism towards the use of chemotherapy for non small cell lung cancer in the UK it would appear that we have now reached the point where the use of chemotherapy to relieve symptoms, maintain quality of life, and prolong life, are now accepted for informed patients with good performance status willing to accept short-term toxicities. The use of the new agents vinorelbine, gemcitabine and paclitaxel in combination with cisplatin or carboplatin are all active regimens which offer small but real advantages over standard UK triple therapies (MVP, MIC) in terms of resource use, toxicity profiles and response rates. Overall survival could be increased by as much as 10% at one year on indirect comparisons. The use of docetaxel as second line therapy now offers lung cancer patients a second bite of the cherry, and should overall also prolong survival. It is only in embracing these small gains that we can currently make progress in the treatment of NSCLC

Cost-effectiveness analysis of antimuscarinics in the treatment of patients with overactive bladder in Spain: A decision-tree model

<p>Abstract</p> <p>Background</p> <p>Fesoterodine, a new once daily antimuscarinic, has proven to be an effective, safe, and well-tolerated treatment in patients with overactive bladder (OAB). To date, no analysis has evaluated the economic costs and benefits associated with fesoterodine, compared to antimuscarinics in Spain. The purpose of this analysis was to assess the economic value of OAB treatment with fesoterodine relative to extended release tolterodine and solifenacin, from the societal perspective.</p> <p>Methods</p> <p>The economic model was based on data from two 12-week, randomized, double-blind, and multicenter trials comparing fesoterodine and tolterodine extended released (ER). Treatment response rates for solifenacin were extracted from the published literature. Discontinuation and efficacy were based on the results of a 12-week multinational randomized clinical trial extrapolated to 52 weeks. Changes in health related quality of life were assessed with the King's Health Questionnaire, which was transformed into preference-based utility values. Medical costs included (expressed in € 2010) were antimuscarinics, physician visits, laboratory tests, incontinence pads and the costs of OAB-related comorbidities, fractures, skin infections, urinary tract infections, depression, and nursing home admissions associated with incontinence. Time lost from work was also considered. Univariate sensitivity analyses were also performed.</p> <p>Results</p> <p>At week 12, continents accounted for 50.6%, 40.6% and 47.2% of patients in the fesoterodine, tolterodine, and solifenacin groups, respectively. By week 52, the projected proportions of patients remaining on therapy were 33.1%, 26.5% and 30.8%, respectively. The projected quality- adjusted life years (QALY) gain (compared to baseline) over the 52-week simulation period were 0.01014, 0.00846 and 0.00957, respectively. The overall treatment cost was estimated at €1,937, €2,089 and €1,960 for fesoterodine, tolterodine and solifenacin, respectively. Therefore, treatment with fesoterodine resulted in similar overall costs and greater QALY gain than treatment with either tolterodine or solifenacin. Sensitivity analysis showed that these results were robust to all changes performed.</p> <p>Conclusions</p> <p>The results of this economic analysis suggest that fesoterodine is a cost-effective alternative to tolterodine and solifenacin for the treatment of patients with OAB in Spain. Fesoterodine provides additional health benefits while maintain a similar level of costs being a cost-effective treatment strategy from a societal perspective.</p

Comparison of crystallization characteristics and mechanical properties of polypropylene processed by ultrasound and conventional micro injection molding

YesUltrasound injection molding has emerged as an alternative production route for the manufacturing of micro-scale polymeric components, where it offers significant benefits over the conventional micro-injection molding process. In this work, the effects of ultrasound melting on the mechanical and morphological properties of micro-polypropylene parts were characterized. The ultrasound injection molding process was experimentally compared to the conventional micro-injection molding process using a novel mold, which allows mounting on both machines and visualization of the melt flow for both molding processes. Direct measurements of the flow front speed and temperature distributions were performed using both conventional and thermal high-speed imaging techniques. The manufacturing of micro-tensile specimens allowed the comparison of the mechanical properties of the parts obtained with the different processes. The results indicated that the ultrasound injection molding process could be an efficient alternative to the conventional process

Neue linguistische Methoden und arbeitstechnische Verfahren in der Erschliessung der ägyptischen Grammatik

15 páginas, 1 tabla, 6 figuras.Does diversity beget diversity? Diversity includes a diversity of concepts because it is linked to variability in and of life and can be applied to multiple levels. The connections between multiple levels of diversity are poorly understood. Here, we investigated the relationships between genetic, bacterial, and chemical diversity of the endangered Atlanto-Mediterranean sponge Spongia lamella. These levels of diversity are intrinsically related to sponge evolution and could have strong conservation implications. We used microsatellite markers, denaturing gel gradient electrophoresis and quantitative polymerase chain reaction, and high performance liquid chromatography to quantify genetic, bacterial, and chemical diversity of nine sponge populations. We then used correlations to test whether these diversity levels covaried. We found that sponge populations differed significantly in genetic, bacterial, and chemical diversity. We also found a strong geographic pattern of increasing genetic, bacterial, and chemical dissimilarity with increasing geographic distance between populations. However, we failed to detect significant correlations between the three levels of diversity investigated in our study. Our results suggest that diversity fails to beget diversity within a single species and indicates that a diversity of factors regulates a diversity of diversities, which highlights the complex nature of the mechanisms behind diversityResearch funded by grants from the Agence Nationale de la Recherche (ECIMAR), from the Spanish Ministry of Science and Technology SOLID (CTM2010-17755) and Benthomics (CTM2010-22218-C02-01) and the BIOCAPITAL project (MRTN-CT-2004-512301) of the European Union. This is a contribution of the Consolidated Research Group ‘‘Grupo de Ecologı´a Bento´nica,’’ SGR2009-655.Peer reviewe