Immunological aspects of polymyalgia rheumatica and giant cell arteritis

Forty four patients with PMR/GCA have been followed from presentation for a period of 2-4 years. Immunological investigations have been carried out in a search for useful tests to assist in the diagnosis of PMR/GCA and in assessing disease activity. This study has confirmed that ESR and CRP are useful investigations at presentation of PMR/GCA, although even at this stage these tests may not be elevated. During relapses of PMR/GCA both ESR and CRP remain in the normal range in the majority of patients so no reliance should be placed on these investigations to confirm a clinical diagnosis of relapse. Alpha-1-antichymotrypsin (ACT) has shown an interesting pattern of response, in that the raised levels at presentation (1.0g/l) did not fall rapidly on prednisolone treatment but fell gradually over 2-4 years reaching normal levels (0.6g/l) in those patients satisfactorily off prednisolone treatment. An ACT concentration of ≤0.8g/l at 12 months and ≤0.7g/l at 18 months indicated a reduced risk of subsequent relapse. Hence this investigation may be a useful tool in tailoring prednisolone reduction for the individual patient with PMR/GCA. Measurement of the cytokines IL1B, IL6 and soluble IL2 receptor, using ELISA methods, did not add any useful information to the assessment of the individual patient. However the fact that IL1≤ levels were raised at presentation and relapse (albeit to only 4pg/ml and 5pg/ml respectively) does illustrate that this mediator of inflammation is involved in PMR/GCA. The elevation of soluble IL2 receptor at presentation (476 U/ml) compared with controls (366 U/ml) also illustrates that there is immune system activation in PMR/GCA. IL6 levels were not significantly elevated in this study. This study did not find low CD8+ cells in PMR/GCA prior to treatment. %CD8+ cells were significantly reduced after prednisolone treatment commenced, and a study in volunteers confirmed that this was an effect of the prednisolone itself, particularly in the older volunteers

Tradiciones de discurso y Santa Teresa

Para los historiadores del español un problema conocido es la evaluación filológica de la obra de Santa Teresa. Según una tradición, representa una forma espontánea del español que corresponde a su habla cotidiana, proporcionando así evidencia de un registro que remeda el lenguaje hablado de su época; otra tradición, sin embargo, recalca los rasgos cultos de su prosa, atribuyendo lo «vulgar» de su estilo a su deseo de rehuir la afectación y erudición. En este artículo intentamos situar el estilo de Santa Teresa dentro de las tradiciones discursivas del Siglo de Oro, arguyendo que mientras que determinados rasgos lingüísticos del Libro de la vida están determinados por los parámetros del registro lingüístico propuestos por Halliday, otros son propios de ella. A continuación estudiamos dos de estos, las construcciones relativas y la supresión del complementante que, a base de datos recuperados de los corpus lingüísticos y textos coetáneos.A notable problem for historians of Spanish is the philological evaluation of Santa Teresa's writings. One tradition sees her language as a spontaneous form of Spanish corresponding to her everyday speech, providing valuable evidence of a register which is more typical of the spoken language of the time, while another points to cultured and literary features of her style and attributes the «vulgar» features of her style to a deliberate avoidance of affectation and erudition. This article attempts to situate Teresa's writing within the discourse traditions of the Golden Age, arguing that while certain linguistic features of the Libro de la vida are determined by the parameters of linguistic register proposed by Halliday, others are more distinctively her own. It then draws on evidence gathered from linguistic corpora and contemporaneous texts to investigate two of these distinctive features, relative structures and the suppression of the que complementiser

Metabolomic profiling of macrophages determines the discrete metabolomic signature and metabolomic interactome triggered by polarising immune stimuli

Priming and activating immune stimuli have profound effects on macrophages, however, studies generally evaluate stimuli in isolation rather than in combination. In this study we have investigated the effects of pro-inflammatory and anti-inflammatory stimuli either alone or in combination on macrophage metabolism. These stimuli include host factors such as IFNγ and ovalbumin-immunoglobulin immune complexes, or pathogen factors such as LPS. Untargeted LC-MS based metabolomics provided an in-depth profile of the macrophage metabolome, and revealed specific changes in metabolite abundance upon either individual stimuli or combined stimuli. Here, by factoring in an interaction term in the linear model, we define the metabolome interactome. This approach allowed us to determine whether stimuli interact in a synergistic or antagonistic manner. In conclusion this study demonstrates a robust approach to interrogate immune-metabolism, especially systems that model host-pathogen interactions

Drug resistance and treatment failure in leishmaniasis: A 21st century challenge

Reevaluation of treatment guidelines for Old and New World leishmaniasis is urgently needed on a global basis because treatment failure is an increasing problem. Drug resistance is a fundamental determinant of treatment failure, although other factors also contribute to this phenomenon, including the global HIV/AIDS epidemic with its accompanying impact on the immune system. Pentavalent antimonials have been used successfully worldwide for the treatment of leishmaniasis since the first half of the 20th century, but the last 10 to 20 years have witnessed an increase in clinical resistance, e.g., in North Bihar in India. In this review, we discuss the meaning of “resistance” related to leishmaniasis and discuss its molecular epidemiology, particularly for Leishmania donovani that causes visceral leishmaniasis. We also discuss how resistance can affect drug combination therapies. Molecular mechanisms known to contribute to resistance to antimonials, amphotericin B, and miltefosine are also outlined

Global communication part 1: the use of apparel CAD technology

Trends needed for improved communication systems, through the development of future computer-aided design technology (CAD) applications, is a theme that has received attention due to its perceived benefits in improving global supply chain efficiencies. This article discusses the developments of both 2D and 3D computer-aided design capabilities, found within global fashion supply chain relationships and environments. Major characteristics identified within the data suggest that CAD/CAM technology appears to be improving; however, evidence also suggest a plateau effect, which is accrediting forced profits towards information technology manufactures, and arguably compromising the industry's competitive advantage. Nevertheless, 2D CAD increases communication speed; whereas 3D human interaction technology is seen to be evolving slowly and questionably with limited success. The article discusses the findings and also presents the issues regarding human interaction; technology education; and individual communication enhancements using technology processes. These are still prevalent topics for the future developments of global strategy and cultural communication amalgamation

Untargeted metabolomics to understand the basis of phenotypic differences in amphotericin B-resistant

Background: Protozoan Leishmania parasites are responsible for a range of clinical infections that represent a substantial challenge for global health. Amphotericin B (AmB) is increasingly used to treat Leishmania infection, so understanding the potential for resistance to this drug is an important priority. Previously we described four independently-derived AmB-resistant L. mexicana lines that exhibited resistance-associated genetic lesions resulting in altered sterol content. However, substantial phenotypic variation between these lines, including differences in virulence attributes, were not fully explained by these changes. Methods: To identify alterations in cellular metabolism potentially related to phenotypic differences between wild-type and AmB-resistant lines, we extracted metabolites and performed untargeted metabolomics by liquid chromatography-mass spectrometry. Results: We observed substantial differences in metabolite abundance between lines, arising in an apparently stochastic manner. Concerted remodeling of central carbon metabolism was not observed; however, in three lines, decreased abundance of several oligohexoses was observed. Given that the oligomannose mannogen is an important virulence factor in Leishmania, this could relate to loss of virulence in these lines. Increased abundance of the reduced forms of the oxidative stress-protective thiols trypanothione and glutathione was also observed in multiple lines. Conclusions: This dataset will provide a useful resource for understanding the molecular basis of drug resistance in Leishmania, and suggests a role for metabolic changes separate from the primary mechanism of drug resistance in determining the phenotypic profile of parasite lines subjected to experimental selection of resistance

Cognitive and behavioural strategies employed to overcome "lapses" and prevent "relapse" among weight-loss maintainers and regainers: A qualitative study.

While many behavioural weight management programmes are effective in the short-term, post-programme weight regain is common. Overcoming "lapses" and preventing "relapse" has been highlighted as important in weight-loss maintenance, but little is known on how this is achieved. This study aimed to compare the cognitive and behavioural strategies employed to overcome "lapses" and prevent "relapse" by people who had regained weight or maintained weight-loss after participating in a weight management programme. By investigating differences between groups, we intended to identify strategies associated with better weight-loss maintenance. Semi-structured interviews were conducted with 26 participants (58% female) recruited from the 5-year follow-up of the Weight Loss Referrals for Adults in Primary Care (WRAP) trial (evaluation of a commercial weight-loss programme). Participants who had lost ≥5% baseline weight during the active intervention were purposively sampled according to 5-year weight trajectories (n = 16 'Regainers', n = 10 'Maintainers'). Interviews were audio-recorded, transcribed verbatim, and analysed thematically. Key differences in strategies were that Maintainers continued to pay attention to their dietary intake, anticipated and planned for potential lapses in high-risk situations, and managed impulses using distraction techniques. Regainers did not report making plans, used relaxed dietary monitoring, found distraction techniques to be ineffective and appeared to have difficulty navigating food within interpersonal relationships. This study is one of the longest qualitative follow-ups of a weight loss trial to date, offering unique insights into long-term maintenance. Future programmes should emphasize strategies focusing on self-monitoring, planning and managing interpersonal relationships to help participants successfully maintain weight-loss in the longer-term.This study is funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research RP-PG-0216-20010. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. ALA and SJG are supported by the Medical Research Council (MC_UU_12015/4). SJG is an NIHR senior investigator. The University of Cambridge has received salary support in respect of SJG from the National Health Service in the East of England through the Clinical Academic Reserve

The stroke oxygen pilot study: a randomized control trial of the effects of routine oxygen supplementation early after acute stroke--effect on key outcomes at six months

Introduction: Post-stroke hypoxia is common, and may adversely affect outcome. We have recently shown that oxygen supplementation may improve early neurological recovery. Here, we report the six-month outcomes of this pilot study. Methods: Patients with a clinical diagnosis of acute stroke were randomized within 24 h of admission to oxygen supplementation at 2 or 3 L/min for 72 h or to control treatment (room air). Outcomes (see below) were assessed by postal questionnaire at 6 months. Analysis was by intention-to-treat, and statistical significance was set at p#0.05. Results: Out of 301 patients randomized two refused/withdrew consent and 289 (148 in the oxygen and 141 in the control group) were included in the analysis: males 44%, 51%; mean (SD) age 73 (12), 71 (12); median (IQR) National Institutes of Health Stroke Scale score 6 (3, 10), 5 (3, 10) for the two groups respectively. At six months 22 (15%) patients in the oxygen group and 20 (14%) in the control group had died; mean survival in both groups was 162 days (p= 0.99). Median (IQR) scores for the primary outcome, the modified Rankin Scale, were 3 (1, 5) and 3 (1, 4) for the oxygen and control groups respectively. The covariate-adjusted odds ratio was 1.04 (95% CI 0.67, 1.60), indicating that the odds of a lower (i.e. better) score were non-significantly higher in the oxygen group (p= 0.86). The mean differences in the ability to perform basic (Barthel Index) and extended activities of daily living (NEADL), and quality of life (EuroQol) were also non-significant. Conclusions: None of the key outcomes differed at 6 months between the groups. Although not statistically significant and generally of small magnitude, the effects were predominantly in favour of the oxygen group; a larger trial, powered to show differences in longer-term functional outcomes, is now on-going. Trial Registration: Controlled-Trials.com ISRCTN12362720; Eudract.ema.europa.eu 2004-001866-4

The SOS Pilot Study: a RCT of routine oxygen supplementation early after acute stroke—effect on recovery of neurological function at one week

Mild hypoxia is common after stroke and associated with poor long-term outcome. Oxygen supplementation could prevent hypoxia and improve recovery. A previous study of routine oxygen supplementation showed no significant benefit at 7 and 12 months. This pilot study reports the effects of routine oxygen supplementation for 72 hours on oxygen saturation and neurological outcomes at 1 week after a stroke

Genomic instability at the locus of sterol C24-methyltransferase promotes amphotericin B resistance in Leishmania parasites

Amphotericin B is an increasingly important tool in efforts to reduce the global disease burden posed by Leishmania parasites. With few other chemotherapeutic options available for the treatment of leishmaniasis, the potential for emergent resistance to this drug is a considerable threat. Here we characterised four novel amphotericin B-resistant Leishmania mexicana lines. All lines exhibited altered sterol biosynthesis, and hypersensitivity to pentamidine. Whole genome sequencing demonstrated resistance-associated mutation of the sterol biosynthesis gene sterol C5-desaturase in one line. However, in three out of four lines, RNA-seq revealed loss of expression of sterol C24-methyltransferase (SMT) responsible for drug resistance and altered sterol biosynthesis. Additional loss of the miltefosine transporter was associated with one of those lines. SMT is encoded by two tandem gene copies, which we found to have very different expression levels. In all cases, reduced overall expression was associated with loss of the 3' untranslated region of the dominant gene copy, resulting from structural variations at this locus. Local regions of sequence homology, between the gene copies themselves, and also due to the presence of SIDER1 retrotransposon elements that promote multi-gene amplification, correlate to these structural variations. Moreover, in at least one case loss of SMT expression was not associated with loss of virulence in primary macrophages or in vivo. Whilst such repeat sequence-mediated instability is known in Leishmania genomes, its presence associated with resistance to a major antileishmanial drug, with no evidence of associated fitness costs, is a significant concern