Synthesis of beta-benzo[b]thienyldehydrophenylalanine derivatives by one pot palladium-catalyzed borylation and Suzuki coupling (BSC) and metal-assisted intramolecular cyclization: studies of fluorescence and antimicrobial activity

Palladium-catalyzed borylation and Suzuki coupling (BSC) in a one pot procedure was successfully applied to the synthesis of several beta-substituted dehydrophenylalanines in the benzo[b]thiophene series maintaining the stereochemistry of the starting materials. Bromobenzo[b]thiophenes bearing an ortho EDG (OMe or Me) were used as the components to be borylated with pinacolborane. Pure stereoisomers of beta-bromodehydrophenylalanines were used as the other Suzuki coupling component. Treatment of the methyl ester of N-(tert-butoxycarbonyl)-(Z)-beta-(2,3,5-trimethylbenzo[b]thien-6-yl)dehydrophenylalanine thus obtained, with Pd(OAc)2 and Cu(OAc)2 in DMF at 160 oC gave two indole derivatives (1:3). The major product resulting from isomerization and cyclization and the minor product resulting from direct cyclization (thienoindole). Reaction at 100 oC gave the same products in similar amounts. Using as starting material the methyl ester of N-(tert-butoxycarbonyl)-(Z)-beta-(2,3,7-trimethylbenzo[b]thien-6-yl)dehydrophenylalanine gave only one product, resulting from isomerization and cyclization at 100 oC. Two of the cyclized compounds were submitted to fluorescence studies; the thienoindole could be used as a fluorescent probe. Preliminary studies of antimicrobial activity were performed on the precursors and on the cyclized products.Fundação para a Ciência e Tecnologia - POCTI/99/QUI/32689, SFRH/BD/4709/2001

Co-construction of chronic illness narratives by older stroke survivors and their spouses

Illness narratives have mainly focused on individual patients' accounts, and particularly those of people experiencing the onset of chronic illness in mid-life. However, a growing number of older people are spending their later life with their partner, with both experiencing complex morbidities. We examine the shared creation of meanings among older stroke survivors and their spouses and the implications for individual and couple identity. Joint biographical narrative interviews were held with 13 stroke survivors aged 75-85 and their spouses. The analysis examined both narrative content and narrative style. Three main types of co-presentation of identity were identified. The 'united couple' described couples who pulled together and emphasised their accommodation of the stroke and normality as a couple, despite often considerable disability, and was strongly underpinned by collaborative interaction in interviews. Caring relationships were distinguished as 'positive', involving self-reliant couples who took pride in how they managed and 'frustrated' in couples who emphasised the difficulties of caring and hardships experienced and were characterised by a conflictual style of narrative. We argue that joint interviews provide new forms of data that extend notions of how illness is lived and demonstrates how the marital relationship can mediate the experience of chronic illness and disability and its impact on identity. © 2013 The Authors. Sociology of Health & Illness © 2013 Foundation for the Sociology of Health & Illness/JohnWiley & Sons Ltd

Subgrouping of Patients With Rheumatoid Arthritis Based on Pain, Fatigue, Inflammation, and Psychosocial Factors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108023/1/art38682.pd

The potential role of cost-utility analysis in the decision to implement major system change in acute stroke services in metropolitan areas in England

BACKGROUND: The economic implications of major system change are an important component of the decision to implement health service reconfigurations. Little is known about how best to report the results of economic evaluations of major system change to inform decision-makers. Reconfiguration of acute stroke care in two metropolitan areas in England, namely London and Greater Manchester (GM), was used to analyse the economic implications of two different implementation strategies for major system change. METHODS: A decision analytic model was used to calculate difference-in-differences in costs and outcomes before and after the implementation of two major system change strategies in stroke care in London and GM. Values in the model were based on patient level data from Hospital Episode Statistics, linked mortality data from the Office of National Statistics and data from two national stroke audits. Results were presented as net monetary benefit (NMB) and using Programme Budgeting and Marginal Analysis (PBMA) to assess the costs and benefits of a hypothetical typical region in England with approximately 4000 strokes a year. RESULTS: In London, after 90 days, there were nine fewer deaths per 1000 patients compared to the rest of England (95% CI -24 to 6) at an additional cost of £770,027 per 1000 stroke patients admitted. There were two additional deaths (95% CI -19 to 23) in GM, with a total costs saving of £156,118 per 1000 patients compared to the rest of England. At a £30,000 willingness to pay the NMB was higher in London and GM than the rest of England over the same time period. The results of the PBMA suggest that a GM style reconfiguration could result in a total greater health benefit to a region. Implementation costs were £136 per patient in London and £75 in GM. CONCLUSIONS: The implementation of major system change in acute stroke care may result in a net health benefit to a region, even one functioning within a fixed budget. The choice of what model of stroke reconfiguration to implement may depend on the relative importance of clinical versus cost outcomes

Lessons for major system change: centralization of stroke services in two metropolitan areas of England

OBJECTIVES: Our aim was to identify the factors influencing the selection of a model of acute stroke service centralization to create fewer high-volume specialist units in two metropolitan areas of England (London and Greater Manchester). It considers the reasons why services were more fully centralized in London than in Greater Manchester. METHODS: In both areas, we analysed 316 documents and conducted 45 interviews with people leading transformation, service user organizations, providers and commissioners. Inductive and deductive analyses were used to compare the processes underpinning change in each area, with reference to propositions for achieving major system change taken from a realist review of the existing literature (the Best framework), which we critique and develop further. RESULTS: In London, system leadership was used to overcome resistance to centralization and align stakeholders to implement a centralized service model. In Greater Manchester, programme leaders relied on achieving change by consensus and, lacking decision-making authority over providers, accommodated rather than challenged resistance by implementing a less radical transformation of services. CONCLUSIONS: A combination of system (top-down) and distributed (bottom-up) leadership is important in enabling change. System leadership provides the political authority required to coordinate stakeholders and to capitalize on clinical leadership by aligning it with transformation goals. Policy makers should examine how the structures of system authority, with performance management and financial levers, can be employed to coordinate transformation by aligning the disparate interests of providers and commissioners

XMM-Newton and Swift observations prove GRB 090709A to be a distant, standard, long GRB

GRB 090709A is a long gamma-ray burst (GRB) discovered by Swift, featuring a bright X-ray afterglow as well as a faint infrared transient with very red and peculiar colors. The burst attracted a large interest because of a possible quasi-periodicity at P=8.1 s in the prompt emission, suggesting that it could have a different origin with respect to standard, long GRBs. In order to understand the nature of this burst, we obtained a target of opportunity observation with XMM-Newton. X-ray spectroscopy, based on XMM-Newton and Swift data, allowed us to model the significant excess in photoelectric absorption with respect to the Galactic value as due to a large column density (about 6.5E+22 cm^-2) in the GRB host, located at z=4.2. Such a picture is also consistent with the infrared transient's properties. Re-analysis of the prompt emission, based on INTEGRAL and on Swift data, excludes any significant modulation at P=8.1 s. Thus, we conclude that GRB 090709A is a distant, standard, long GRB.Comment: 7 pages, 7 figures, 2 tables; MNRAS, in press. (V3: minor changes to match the final version.

Differences in the signaling pathways of α1A- and α1B-adrenoceptors are related to different endosomal targeting

Aims: To compare the constitutive and agonist-dependent endosomal trafficking of α1A- and α1B-adrenoceptors (ARs) and to establish if the internalization pattern determines the signaling pathways of each subtype. Methods: Using CypHer5 technology and VSV-G epitope tagged α1A- and α1B-ARs stably and transiently expressed in HEK 293 cells, we analyzed by confocal microscopy the constitutive and agonist-induced internalization of each subtype, and the temporal relationship between agonist induced internalization and the increase in intracellular calcium (determined by FLUO-3 flouorescence), or the phosphorylation of ERK1/2 and p38 MAP kinases (determined by Western blot). Results and Conclusions: Constitutive as well as agonist-induced trafficking of α1A and α1B ARs maintain two different endosomal pools of receptors: one located close to the plasma membrane and the other deeper into the cytosol. Each subtype exhibited specific characteristics of internalization and distribution between these pools that determines their signaling pathways: α1A-ARs, when located in the plasma membrane, signal through calcium and ERK1/2 pathways but, when translocated to deeper endosomes, through a mechanism sensitive to β-arrestin and concanavalin A, continue signaling through ERK1/2 and also activate the p38 pathway. α1B-ARs signal through calcium and ERK1/2 only when located in the membrane and the signals disappear after endocytosis and by disruption of the membrane lipid rafts by methyl-β-cyclodextrin

Cost-effectiveness of stent-retriever thrombectomy in combination with IV t-PA compared with IV t-PA alone for acute ischemic stroke in the UK.

Objective: To evaluate the cost-effectiveness of neurothrombectomy with a stent retriever (Solitaire**Solitaire Revascularization Device is a registered trademark of Medtronic (Irvine, CA). View all notes Revascularization Device) in treating acute ischemic stroke patients from the UK healthcare provider perspective. Methods: A Markov model was developed to simulate health outcomes and costs of two therapies over a lifetime time horizon: stent-retriever thrombectomy in combination with intravenous tissue-type plasminogen activator (IV t-PA), and IV t-PA alone. The model incorporated an acute phase (0–90 days) and a rest of life phase (90+ days). Health states were defined by the modified Rankin Scale score. During the rest of life phase, patients remained in the same health state until a recurrent stroke or death. Clinical effectiveness and safety data were taken from the SWIFT PRIME study. Resource use and health state utilities were informed by published data. Results: Combined stent-retriever thrombectomy and IV t-PA led to improved quality-of-life and increased life expectancy compared to IV t-PA alone. The higher treatment costs associated with the use of stent-retriever thrombectomy were offset by long-term cost savings due to improved patient health status, leading to overall cost savings of £33 190 per patient and a net benefit of £79 402. Deterministic and probabilistic sensitivity analyses demonstrated that the results were robust to a wide range of parameter inputs. Limitations: The acute and long-term costs resource use data were taken from a study based on a patient population that was older and may have had additional comorbidities than the SWIFT PRIME population, resulting in costs that may not be representative of the cohort within this model. In addition, the estimates may not reflect stroke care today as no current evidence is available; however, the cost estimates were deemed reasonable by clinical opinion. Conclusions: Combined stent-retriever neurothrombectomy and IV t-PA is a cost-effective treatment for acute ischemic stroke compared with IV t-PA alone