Factors associated with lack of improvement in submaximal exercise capacity of patients with heart failure

Aims Improvement in exercise capacity is the primary goal of physical activity programmes for patients with heart failure (HF). Although activity programmes are effective for some patients, others do not benefit. Identifying factors related to a lack of improvement in submaximal exercise capacity may help us interpret findings and design new interventions. The aim of this study is to identify factors contributing to a lack of improvement in submaximal exercise capacity 3 months after physical activity advice or an exergame intervention in patients with HF. Additionally, we aimed to assess differences in lack of improvement in submaximal exercise capacity of patients whose baseline exercise capacity predicted a worse compared with better prognosis of HF.Methods and results This secondary analysis of the HF-Wii study analysed baseline and 3 month data of the 6 min walk test (6MWT) from 480 patients (mean age 67 years, 72% male). Data were analysed separately in patients with a pre-defined 6 min walking distance at baseline of <300 m (n = 79) and >= 300 m (n = 401). Among patients with a baseline 6MWT of >= 300 m, 18% had deteriorated submaximal exercise capacity. In the multiple logistic regression analysis, lower baseline levels of self-reported physical activity [odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.60-0.97], lower baseline levels of cognitive function (OR = 0.87, 95%CI = 0.79-0.96) were significantly associated with lack of improvement in exercise capacity at 3 months. Not randomized to exergaming (OR = 0.63, 95%CI = 0.37-1.09) was likely (P = 0.097) to be associated with lack of improvement in exercise capacity at 3 months. Among the 79 patients with baseline 6MWT of <300 m, 41% (n = 32) did not improve 6MWT distance at 3 months. Independent predictors for the lack of improvement for 6MWT were New York Heart Association class III/IV (OR = 4.68, 95%CI = 1.08-20.35), higher levels of serum creatinine (OR = 1.02, 95%CI = 1.003-1.03), lower cognitive function (OR = 0.86, 95%CI = 0.75-0.99), and fewer anxiety symptoms (OR = 0.84, 95%CI = 0.72-0.98).Conclusions Lower self-reported physical activity and cognitive impairment predict lack of improvement in submaximal exercise capacity in HF patients. Patients who have a worse prognosis (score <300 m at the 6MWT) are often frail and gain less in exercise capacity. These patients may need a more comprehensive approach to have an effect on exercise capacity, including an individually tailored exercise programme with aerobic exercise (if tolerated) and strength exercises

Effects of exergaming on exercise capacity in patients with heart failure: results of an international multicentre randomized controlled trial

Aims Exergaming is a new tool to increase physical activity. This study aimed to determine the effects of access to a home-based exergame (Nintendo Wii) in patients with heart failure (HF) on exercise capacity, self-reported physical activity and patient-reported outcome measures.Methods and results We enrolled 605 HF patients in New York Heart Association functional class I-IV, independent of ejection fraction, in an international multicentre randomized controlled trial. Patients were randomized to exergame (intervention) or motivational support (control). The primary endpoint was change in submaximal aerobic exercise capacity as measured by the distance walked in 6 min (6MWT) between baseline and 3 months. Secondary endpoints included long-term submaximal aerobic exercise capacity, muscle function, self-reported physical activity, exercise motivation, exercise self-efficacy at 3, 6 and 12months. At baseline, patients on average walked 403142m on the 6MWT. Patients in the exergame group walked further compared to controls at 3 months (454123 vs. 420 +/- 127m, P = 0.005), at 6 months (452 +/- 123 vs. 426 +/- 133m, P = 0.015) and 12months (456 +/- 122 vs. 420 +/- 135m, P = 0.004). However, correcting for baseline 6MWT values by means of a linear mixed-effects model revealed no main effect for the intervention on 6MWT. Small significant effects on muscle function were found. Statistically significant treatment effects were found for muscle function but after correction for baseline and confounders, only the treatment effect for the heel-rise left at 6 months was significant (P<0.05). No treatment effect was found for exercise motivation, exercise self-efficacy, or self-reported physical activity.ConclusionExergaming was safe and feasible in patients with HF with different profiles in different health care systems, cultures and climates. However, it was not effective in improving outcomes on submaximal aerobic exercise capacity. Subgroup analysis did not identify specific subgroups benefiting from the intervention.Clinical Trial Registration: Identifier: NCT01785121

Hydrophilic interaction liquid chromatography (HILIC) in proteomics

In proteomics, nanoflow multidimensional chromatography is now the gold standard for the separation of complex mixtures of peptides as generated by in-solution digestion of whole-cell lysates. Ideally, the different stationary phases used in multidimensional chromatography should provide orthogonal separation characteristics. For this reason, the combination of strong cation exchange chromatography (SCX) and reversed-phase (RP) chromatography is the most widely used combination for the separation of peptides. Here, we review the potential of hydrophilic interaction liquid chromatography (HILIC) as a separation tool in the multidimensional separation of peptides in proteomics applications. Recent work has revealed that HILIC may provide an excellent alternative to SCX, possessing several advantages in the area of separation power and targeted analysis of protein post-translational modifications

Robustness analysis of discrete predictor-based controllers for input-delay systems

In this article, robustness to model uncertainties are analysed in the context of discrete predictor-based state-feedback controllers for discrete-time input-delay systems with time-varying delay, in an LMI framework. The goal is comparing robustness of predictor-based strategies with respect to other (sub)optimal state feedback ones. A numerical example illustrates that improvements in tolerance to modelling errors can be achieved by using the predictor framework.The authors are grateful for grant nos. DPI2008-06737-C02-01, DPI2008-06731-C02-01, DPI2011-27845-C02-01 and PROMETEO/2008/088 from the Spanish and Valencian governments.González Sorribes, A.; Sala, A.; García Gil, PJ.; Albertos Pérez, P. (2013). Robustness analysis of discrete predictor-based controllers for input-delay systems. International Journal of Systems Science. 44(2):232-239. https://doi.org/10.1080/00207721.2011.600469S232239442Boukas, E.-K. (2006). Discrete-time systems with time-varying time delay: Stability and stabilizability. Mathematical Problems in Engineering, 2006, 1-10. doi:10.1155/mpe/2006/42489Du, D., Jiang, B., & Zhou, S. (2008). Delay-dependent robust stabilisation of uncertain discrete-time switched systems with time-varying state delay. International Journal of Systems Science, 39(3), 305-313. doi:10.1080/00207720701805982El Ghaoui, L., Oustry, F., & AitRami, M. (1997). A cone complementarity linearization algorithm for static output-feedback and related problems. IEEE Transactions on Automatic Control, 42(8), 1171-1176. doi:10.1109/9.618250Gao, H., & Chen, T. (2007). New Results on Stability of Discrete-Time Systems With Time-Varying State Delay. IEEE Transactions on Automatic Control, 52(2), 328-334. doi:10.1109/tac.2006.890320Gao, H., Wang, C., Lam, J., & Wang, Y. (2004). Delay-dependent output-feedback stabilisation of discrete-time systems with time-varying state delay. 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(2008), ‘Robust Stabilization of Discrete-time Systems with Time-varying Delay: An LMI Approach’,Mathematical Problems in Engineering, 2008, 15 pages (doi:10.1155/2008/875609)Liu, X. G., Tang, M. L., Martin, R. R., & Wu, M. (2006). Delay-dependent robust stabilisation of discrete-time systems with time-varying delay. IEE Proceedings - Control Theory and Applications, 153(6), 689-702. doi:10.1049/ip-cta:20050223Lozano, R., Castillo, P., Garcia, P., & Dzul, A. (2004). Robust prediction-based control for unstable delay systems: Application to the yaw control of a mini-helicopter. Automatica, 40(4), 603-612. doi:10.1016/j.automatica.2003.10.007Manitius, A., & Olbrot, A. (1979). Finite spectrum assignment problem for systems with delays. IEEE Transactions on Automatic Control, 24(4), 541-552. doi:10.1109/tac.1979.1102124Michiels, W., & Niculescu, S.-I. (2003). On the delay sensitivity of Smith Predictors. International Journal of Systems Science, 34(8-9), 543-551. doi:10.1080/00207720310001609057Palmor, Z.J. (1996), ‘Time-delay Compensation – Smith Predictor and Its Modifications’, inThe Control Handbook, ed. W.S. Levine, Boca Raton: CRC Press, pp. 224–237Pan, Y.-J., Marquez, H. J., & Chen, T. (2006). Stabilization of remote control systems with unknown time varying delays by LMI techniques. International Journal of Control, 79(7), 752-763. doi:10.1080/00207170600654554Richard, J.-P. (2003). Time-delay systems: an overview of some recent advances and open problems. Automatica, 39(10), 1667-1694. doi:10.1016/s0005-1098(03)00167-5Wang, Q.-G., Lee, T. H., & Tan, K. K. (1999). Finite-Spectrum Assignment for Time-Delay Systems. Lecture Notes in Control and Information Sciences. doi:10.1007/978-1-84628-531-8He, Y., Wu, M., Han, Q.-L., & She, J.-H. (2008). Delay-dependentH∞control of linear discrete-time systems with an interval-like time-varying delay. 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Health service utilization patterns of primary care patients with osteoarthritis

Contains fulltext : 53455.pdf ( ) (Open Access)BACKGROUND: To assess factors associated with visits to GPs, orthopaedists, and non-physician practitioners of complementary medicine (alternative practitioners) by primary care patients with osteoarthritis (OA). METHODS: Cross-sectional survey among 1250 consecutively addressed patients from 75 primary care practices in Germany. All patients suffered from OA of the knee or hip according to ACR criteria. They received questionnaires collecting sociodemographic data, data about health service utilisation, prescriptions, comorbidities. They also included established instruments as the Arthritis Impact Measurement Scale (AIMS2-SF) to assess disease-specific quality of life and the Patient Health Questionnaire (PHQ-9) to assess depression. Hierarchical stepwise multiple linear regression models were used to reveal significant factors influencing health service utilization. RESULTS: 1021 of 1250 (81.6%) questionnaires were returned. Nonrespondents did not differ from participants. Factors associated with health service use (HSU) varied between providers of care. Not being in a partnership, achieving a high score on the PHQ-9, increased pain severity reflected in the "symptom" scale of the AIMS2-SF, and an increased number of drug prescriptions predicted a high frequency of GP visits. The PHQ-9 score was also a predictor for visits to orthopaedists, as were previous GP contacts, a high score in the "symptom" scale as well as a high score in the "lower limb scale" of the AIMS2-SF. Regarding visits to alternative practitioners, a high score in the AIMS -"social" scale was a positive predictor as older people were less likely to visit them. CONCLUSION: Our results emphasize the need for awareness of psychological factors contributing to the use of health care providers. Addressing the revealed factors associated with HSU appropriately may lead to decreased health care utilization. But further research is needed to assess how this can be done successfully

Proteomic Profile of Reversible Protein Oxidation Using PROP, Purification of Reversibly Oxidized Proteins

Signal transduction pathways that are modulated by thiol oxidation events are beginning to be uncovered, but these discoveries are limited by the availability of relatively few analytical methods to examine protein oxidation compared to other signaling events such as protein phosphorylation. We report here the coupling of PROP, a method to purify reversibly oxidized proteins, with the proteomic identification of the purified mixture using mass spectrometry. A gene ontology (GO), KEGG enrichment and Wikipathways analysis of the identified proteins indicated a significant enrichment in proteins associated with both translation and mRNA splicing. This methodology also enabled the identification of some of the specific cysteine residue targets within identified proteins that are reversibly oxidized by hydrogen peroxide treatment of intact cells. From these identifications, we determined a potential consensus sequence motif associated with oxidized cysteine residues. Furthermore, because we identified proteins and specific sites of oxidation from both abundant proteins and from far less abundant signaling proteins (e.g. hepatoma derived growth factor, prostaglandin E synthase 3), the results suggest that the PROP procedure was efficient. Thus, this PROP-proteomics methodology offers a sensitive means to identify biologically relevant redox signaling events that occur within intact cells

Expression of Trichoderma reesei β-Mannanase in Tobacco Chloroplasts and Its Utilization in Lignocellulosic Woody Biomass Hydrolysis

Lignocellulosic ethanol offers a promising alternative to conventional fossil fuels. One among the major limitations in the lignocellulosic biomass hydrolysis is unavailability of efficient and environmentally biomass degrading technologies. Plant-based production of these enzymes on large scale offers a cost-effective solution. Cellulases, hemicellulases including mannanases and other accessory enzymes are required for conversion of lignocellulosic biomass into fermentable sugars. β-mannanase catalyzes endo-hydrolysis of the mannan backbone, a major constituent of woody biomass. In this study, the man1 gene encoding β-mannanase was isolated from Trichoderma reesei and expressed via the chloroplast genome. PCR and Southern hybridization analysis confirmed site-specific transgene integration into the tobacco chloroplast genomes and homoplasmy. Transplastomic plants were fertile and set viable seeds. Germination of seeds in the selection medium showed inheritance of transgenes into the progeny without any Mendelian segregation. Expression of endo-β-mannanase for the first time in plants facilitated its characterization for use in enhanced lignocellulosic biomass hydrolysis. Gel diffusion assay for endo-β-mannanase showed the zone of clearance confirming functionality of chloroplast-derived mannanase. Endo-β-mannanase expression levels reached up to 25 units per gram of leaf (fresh weight). Chloroplast-derived mannanase had higher temperature stability (40°C to 70°C) and wider pH optima (pH 3.0 to 7.0) than E.coli enzyme extracts. Plant crude extracts showed 6–7 fold higher enzyme activity than E.coli extracts due to the formation of disulfide bonds in chloroplasts, thereby facilitating their direct utilization in enzyme cocktails without any purification. Chloroplast-derived mannanase when added to the enzyme cocktail containing a combination of different plant-derived enzymes yielded 20% more glucose equivalents from pinewood than the cocktail without mannanase. Our results demonstrate that chloroplast-derived mannanase is an important component of enzymatic cocktail for woody biomass hydrolysis and should provide a cost-effective solution for its diverse applications in the biofuel, paper, oil, pharmaceutical, coffee and detergent industries

Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases : updated guidelines and recommendations from the EBMT autoimmune diseases working party (ADWP) and the joint accreditation committee of EBMT and ISCT (JACIE)

These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials

Disruption of PML Nuclear Bodies Is Mediated by ORF61 SUMO-Interacting Motifs and Required for Varicella-Zoster Virus Pathogenesis in Skin

Promyelocytic leukemia protein (PML) has antiviral functions and many viruses encode gene products that disrupt PML nuclear bodies (PML NBs). However, evidence of the relevance of PML NB modification for viral pathogenesis is limited and little is known about viral gene functions required for PML NB disruption in infected cells in vivo. Varicella-zoster virus (VZV) is a human alphaherpesvirus that causes cutaneous lesions during primary and recurrent infection. Here we show that VZV disrupts PML NBs in infected cells in human skin xenografts in SCID mice and that the disruption is achieved by open reading frame 61 (ORF61) protein via its SUMO-interacting motifs (SIMs). Three conserved SIMs mediated ORF61 binding to SUMO1 and were required for ORF61 association with and disruption of PML NBs. Mutation of the ORF61 SIMs in the VZV genome showed that these motifs were necessary for PML NB dispersal in VZV-infected cells in vitro. In vivo, PML NBs were highly abundant, especially in basal layer cells of uninfected skin, whereas their frequency was significantly decreased in VZV-infected cells. In contrast, mutation of the ORF61 SIMs reduced ORF61 association with PML NBs, most PML NBs remained intact and importantly, viral replication in skin was severely impaired. The ORF61 SIM mutant virus failed to cause the typical VZV lesions that penetrate across the basement membrane into the dermis and viral spread in the epidermis was limited. These experiments indicate that VZV pathogenesis in skin depends upon the ORF61-mediated disruption of PML NBs and that the ORF61 SUMO-binding function is necessary for this effect. More broadly, our study elucidates the importance of PML NBs for the innate control of a viral pathogen during infection of differentiated cells within their tissue microenvironment in vivo and the requirement for a viral protein with SUMO-binding capacity to counteract this intrinsic barrier

Human Flt3L Generates Dendritic Cells from Canine Peripheral Blood Precursors: Implications for a Dog Glioma Clinical Trial

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and carries a dismal prognosis. We have developed a conditional cytotoxic/immunotherapeutic approach using adenoviral vectors (Ads) encoding the immunostimulatory cytokine, human soluble fms-like tyrosine kinase 3 ligand (hsFlt3L) and the conditional cytotoxic molecule, i.e., Herpes Simplex Type 1- thymide kinase (TK). This therapy triggers an anti-tumor immune response that leads to tumor regression and anti-tumor immunological memory in intracranial rodent cancer models. We aim to test the efficacy of this immunotherapy in dogs bearing spontaneous GBM. In view of the controversy regarding the effect of human cytokines on dog immune cells, and considering that the efficacy of this treatment depends on hsFlt3L-stimulated dendritic cells (DCs), in the present work we tested the ability of Ad-encoded hsFlt3L to generate DCs from dog peripheral blood and compared its effects with canine IL-4 and GM-CSF.Our results demonstrate that hsFlT3L expressed form an Ad vector, generated DCs from peripheral blood cultures with very similar morphological and phenotypic characteristics to canine IL-4 and GM-CSF-cultured DCs. These include phagocytic activity and expression of CD11c, MHCII, CD80 and CD14. Maturation of DCs cultured under both conditions resulted in increased secretion of IL-6, TNF-alpha and IFN-gamma. Importantly, hsFlt3L-derived antigen presenting cells showed allostimulatory potential highlighting their ability to present antigen to T cells and elicit their proliferation.These results demonstrate that hsFlt3L induces the proliferation of canine DCs and support its use in upcoming clinical trials for canine GBM. Our data further support the translation of hsFlt3L to be used for dendritic cells' vaccination and gene therapeutic approaches from rodent models to canine patients and its future implementation in human clinical trials