Protein disulphide isomerase-assisted functionalization of keratin-based matrices

In living systems, protein disulphide isomerase (PDI, EC 5.3.4.1) regulates the formation of new disulphide bonds in proteins (oxidase activity) and catalyzes the rearrangement of non-native disulphide bonds (isomerase activity), leading proteins towards their native configuration. In this study, PDI was used to attach cysteine-containing compounds (CCCs) onto hair, to enhance compound migration within hair fibre and to trigger protein release. A fluorescent (5(6)-TAMRA)-labelled keratin peptide was incorporated into hair by using PDI. Similarly, PDI promoted the grafting of a cysteine-functionalized dye onto wool, as suggested by matrix-assisted laser desorption and ionization time-of-flight results. These reactions were thought to involve oxidation of disulphide bonds between CCCs and wool or hair cysteine residues, catalyzed by the oxidized PDI active site. On the other hand, PDI was demonstrated to enhance the migration of a disulphide bondfunctionalized dye within the keratin matrix and trigger the release of RNase A from wool fibres’ surface. These observations may indicate that an isomerisation reaction occurred, catalyzed by the reduced PDI active site, to achieve the thiol-disulphide exchange, i.e. the rearrangement of disulphide bonds between CCCs and keratin. The present communication aims to highlight promising biotechnological applications of PDI, derived from its almost unique properties within the isomerase family.We thank to FCT "Fundacao para a Ciencia e Tecnologia" (scholarship SFRH/BD/38363/2007) for providing Margarida Fernandes the grant for PhD studies

Troubling meanings of family and competing moral imperatives in the family lives of young people with a parent who is at the end of life

This article draws on a narrative study of young people with a parent who is at the end of life to examine how family lives are troubled by life-limiting parental illness. Young people struggled to reconcile the physical and emotional absence of family members with meanings of ‘family’; the extent to which young people could rely on family to ‘be there’ in these troubling circumstances was of practical, emotional and moral significance. Our discussion is situated in the context of an English end of life care policy predicated on the ideal of a good death as one that takes place at home accompanied by family members. We explore how the shift away from family as a site for nurturing children towards family as a space to care for the dying is experienced by young people, and consider how these competing moral imperatives are negotiated through relational practices of care

Trends in anemia management in US hemodialysis patients 2004-2010.

BACKGROUND: There have been major changes in the management of anemia in US hemodialysis patients in recent years. We sought to determine the influence of clinical trial results, safety regulations, and changes in reimbursement policy on practice. METHODS: We examined indicators of anemia management among incident and prevalent hemodialysis patients from a medium-sized dialysis provider over three time periods: (1) 2004 to 2006 (2) 2007 to 2009, and (3) 2010. Trends across the three time periods were compared using generalized estimating equations. RESULTS: Prior to 2007, the median proportion of patients with monthly hemoglobin >12 g/dL for patients on dialysis 0 to 3, 4 to 6 and 7 to 18 months, respectively, was 42%, 55% and 46% declined to 41%, 54%, and 40% after 2007, and declined more sharply in 2010 to 34%, 41%, and 30%. Median weekly Epoeitin alpha doses over the same periods were 18,000, 12,400, and 9,100 units before 2007; remained relatively unchanged from 2007 to 2009; and decreased sharply in the patients 3-6 and 6-18 months on dialysis to 10,200 and 7,800 units, respectively in 2010. Iron doses, serum ferritin, and transferrin saturation levels increased over time with more pronounced increases in 2010. CONCLUSION: Modest changes in anemia management occurred between 2007 and 2009, followed by more dramatic changes in 2010. Studies are needed to examine the effects of declining erythropoietin use and hemoglobin levels and increasing intravenous iron use on quality of life, transplantation rates, infection rates and survival

Patterns in blood pressure medication use in US incident dialysis patients over the first 6 months.

BACKGROUND: Several observational studies have evaluated the effect of a single exposure window with blood pressure (BP) medications on outcomes in incident dialysis patients, but whether BP medication prescription patterns remain stable or a single exposure window design is adequate to evaluate effect on outcomes is unclear. METHODS: We described patterns of BP medication prescription over 6 months after dialysis initiation in hemodialysis and peritoneal dialysis patients, stratified by cardiovascular comorbidity, diabetes, and other patient characteristics. The cohort included 13,072 adult patients (12,159 hemodialysis, 913 peritoneal dialysis) who initiated dialysis in Dialysis Clinic, Inc., facilities January 1, 2003-June 30, 2008, and remained on the original modality for at least 6 months. We evaluated monthly patterns in BP medication prescription over 6 months and at 12 and 24 months after initiation. RESULTS: Prescription patterns varied by dialysis modality over the first 6 months; substantial proportions of patients with prescriptions for beta-blockers, renin angiotensin system agents, and dihydropyridine calcium channel blockers in month 6 no longer had prescriptions for these medications by month 24. Prescription of specific medication classes varied by comorbidity, race/ethnicity, and age, but little by sex. The mean number of medications was 2.5 at month 6 in hemodialysis and peritoneal dialysis cohorts. CONCLUSIONS: This study evaluates BP medication patterns in both hemodialysis and peritoneal dialysis patients over the first 6 months of dialysis. Our findings highlight the challenges of assessing comparative effectiveness of a single BP medication class in dialysis patients. Longitudinal designs should be used to account for changes in BP medication management over time, and designs that incorporate common combinations should be considered

Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)

BACKGROUND: Multiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T cell activation, measurement of effects on T cell function was also pursued. METHODS: A 3-stage trial design was developed with a maximum of 40 patients and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included performance status of 0–1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to biopsy. R115777 was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST. Blood and tumor were analyzed pre-treatment and during week 7. RESULTS: Fourteen patients were enrolled. Two patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses. All patients analyzed showed potent inhibition of FT activity (85-98%) in tumor tissue; inhibition of phosphorylated ERK and Akt was also observed. T cells showed evidence of FT inhibition and diminished IFN-γ production. CONCLUSIONS: Despite potent target inhibition, R115777 showed no evidence of clinical activity in this cohort of melanoma patients. Inhibition of T cell function by FTIs has potential clinical implications. Clinicaltrials.gov number NCT0006012

Applying Market Shaping Approaches to Increase Access to Assistive Technology: Summary of the Wheelchair Product Narrative

To accelerate access to assistive technology (AT), we need to leverage the capabilities and resources of the public, private, and non-profit sectors to harness innovation and break down barriers to access. Market shaping interventions can play a role in enhancing market efficiencies, coordinating and incentivizing the number of stakeholders involved in demand and supply-side activities. Across health sectors, market shaping has demonstrated its potential to enhance national governments’ or donors’ value-for-money, diversify the supply base, and increase reliability – ultimately increasing product and service delivery access for end users. These market shaping successes in other health areas have led practitioners to hypothesize that market shaping could also be applied to assistive technology markets. ATscale, the Global Partnership for AT, aims to mobilise global stakeholders to shape markets in line with a unified strategy. To inform this strategy, it is critical to identify specific interventions required to shape markets and overcome barriers. The first product undergoing analysis by ATscale is wheelchairs. The market for appropriate wheelchairs in low-and middle income countries (LMICs) is highly fragmented and characterized by limited government interest, investment, and a low willingness-to-pay. Moreover, the market is dominated by cheaper, low quality wheelchairs which fail to meet the needs of end-users. Non-profit organizations have attempted to fill the need for context-appropriate wheelchairs, but market uptake is limited. These initial findings led ATscale to believe that market shaping could support increased access to appropriate wheelchairs. This paper outlines what market shaping is, and how it can be applied to assistive technology at large -- using the aforementioned wheelchair product narrative as an illustrative case study and presents the proposed market shaping strategy for wheelchairs. ATscale will develop a framework to evaluate short-term interventions identified to achieve a healthy market and increase access. This paper provides an opportunity to obtain feedback from interested stakeholders on the market shaping strategy for wheelchairs, as well as the product narrative process to be undertaken for other priority AT

A Social Identity Approach to Sport Psychology: Principles, Practice, and Prospects.

Drawing on social identity theory and self-categorization theory, we outline an approach to sport psychology that understands groups not simply as features of sporting contexts but rather as elements that can be, and often are, incorporated into a person's sense of self and, through this, become powerful determinants of their sport-related behavior. The underpinnings of this social identity approach are outlined, and four key lessons for sport that are indicative of the analytical and practical power of the approach are presented. These suggest that social identity is the basis for sports group (1) behavior, (2) formation and development, (3) support and stress appraisal, and (4) leadership. Building on recent developments within sport science, we outline an agenda for future research by identifying a range of topics to which the social identity approach could fruitfully contribute

Honor-Based Abuse in England and Wales: Who Does What to Whom?

Key findings are presented from an empirical study profiling 1,474 cases of honor-based abuse (HBA) known to police and victim services in England and Wales. Thematic and quantitative (regression) analyses were used to investigate whether and how HBA differed from other forms of domestic abuse and forced marriage. A new typology of HBA is proposed, based principally on the relationship(s) between victim and perpetrator(s). Interpreted within an overarching lens of gender-based violence, it is argued that Type 1 (partner abuse) and Type 3 (partner plus family abuse) are culturally specific forms of domestic abuse, whereas Type 2 (family abuse) is distinct

'Surf's up!':A call to take english soccer fan interactions on the internet more seriously

Soccer fandom practices in England have been significantly impacted by globalization. The creation of the Premier League in 1992, and the way in which satellite television company BSkyB dominated coverage of this, together with other developments, have led to changes in how fans consume top-level English soccer. Whilst such global transformations are well documented in the sociology of soccer literature, the implications of the rise of the most advanced global form of communication - the Internet - on the practices of fans of English soccer clubs, have not been fully taken into account by academics. As such, the significance of the Internet as a site for fans to interact remains under-investigated. This article argues that online interactions between fans of English clubs need to be taken more seriously by academics if they are to more fully understand how soccer contributes to the maintenance of social identities in contemporary England