Stakes sensitivity and credit rating: a new challenge for regulators

The ethical practices of credit rating agencies (CRAs), particularly following the 2008 financial crisis, have been subject to extensive analysis by economists, ethicists, and policymakers. We raise a novel issue facing CRAs that has to do with a problem concerning the transmission of epistemic status of ratings from CRAs to the beneficiaries of the ratings (investors, etc.), and use it to provide a new challenge for regulators. Building on recent work in philosophy, we argue that since CRAs have different stakes than the beneficiaries of the ratings in the ratings being accurate, what counts as knowledge (and as having ‘epistemic status’) concerning credit risk for a CRA may not count as knowledge (as having epistemic status) for the beneficiary. Further, as it stands, many institutional investors (pension funds, insurance companies, etc.) are bound by law to make some of their investment decisions dependent on the ratings of officially recognized CRAs. We argue that the observation that the epistemic status of ratings does not transmit from CRAs to beneficiaries makes salient a new challenge for those who think current regulation regarding the CRAs is prudentially justified, namely, to show that the harm caused by acting on a rating that does not have epistemic status for beneficiaries is compensated by the benefit from them acting on a CRA rating that does have epistemic status for the CRA. Unlike most other commentators, therefore, we offer a defeasible reason to drop references to CRAs in prudential regulation of the financial industry

Management of work-relevant upper limb disorders: a review

Background Upper limb disorders (ULDs) are clinically challenging and responsible for considerable work loss. There is a need to determine effective approaches for their management. Aim To determine evidence-based management strategies for work-relevant ULDs and explore whether a biopsychosocial approach is appropriate. Methods Literature review using a best evidence synthesis. Data from articles identified through systematic searching of electronic databases and citation tracking were extracted into evidence tables. The information was synthesized into high-level evidence statements, which were ordered into themes covering classification/diagnosis, epidemiology, associations/risks and management/treatment, focusing on return to work or work retention and taking account of distinctions between non-specific complaints and specific diagnoses. Results Neither biomedical treatment nor ergonomic workplace interventions alone offer an optimal solution; rather, multimodal interventions show considerable promise, particularly for occupational outcomes. Early return to work, or work retention, is an important goal for most cases and may be facilitated, where necessary, by transitional work arrangements. The emergent evidence indicates that successful management strategies require all the players to be onside and acting in a coordinated fashion; this requires engaging employers and workers to participate. Conclusions The biopsychosocial model applies: biological considerations should not be ignored, but psychosocial factors are more influential for occupational outcomes. Implementation of interventions that address the full range of psychosocial issues will require a cultural shift in the way the relationship between upper limb complaints and work is conceived and handled. Dissemination of evidence-based messages can contribute to the needed cultural shift

Urocortin protects chondrocytes from NO-induced apoptosis: a future therapy for osteoarthritis?

Osteoarthritis (OA) is characterized by a loss of joint mobility and pain resulting from progressive destruction and loss of articular cartilage secondary to chondrocyte death and/ or senescence. Certain stimuli including nitric oxide (NO) and the pro-inflammatory cytokine tumor necrosis factor α (TNF-α have been implicated in this chondrocyte death and the subsequent accelerated damage to cartilage. In this study, we demonstrate that a corticotrophin releasing factor (CRF) family peptide, urocortin (Ucn), is produced by a human chondrocyte cell line, C-20/A4, and acts both as an endogenous survival signal and as a cytoprotective agent reducing the induction of apoptosis by NO but not TNF-α when added exogenously. Furthermore, treatment with the NO donor S-nitroso-N-acetyl-D-L-penicillamine upregulates chondrocyte Ucn expression, whereas treatment with TNF-α does not. The chondroprotective effects of Ucn are abolished by both specific ligand depletion (with an anti-Ucn antibody) and by CRF receptor blockade with the pan-CRFR antagonist α-helical CRH(9-41). CRFR expression was confirmed by reverse transcription-PCR with subsequent amplicon sequence analysis and demonstrates that C-20/A4 cells express both CRFR1 and CRFR2, specifically CRFR1α and CRFR2β. Protein expression of these receptors was confirmed by western blotting. The presence of both Ucn and its receptors in these cells, coupled with the induction of Ucn by NO, suggests the existence of an endogenous autocrine/paracrine chondroprotective mechanism against stimuli inducing chondrocyte apoptosis via the intrinsic/mitochondrial pathway

An empirical approach towards the efficient and optimal production of influenza-neutralizing ovine polyclonal antibodies demonstrates that the novel adjuvant CoVaccine HT(TM) is functionally superior to Freund's adjuvant

Passive immunotherapies utilising polyclonal antibodies could have a valuable role in preventing and treating infectious diseases such as influenza, particularly in pandemic situations but also in immunocompromised populations such as the elderly, the chronically immunosuppressed, pregnant women, infants and those with chronic diseases. The aim of this study was to optimise current methods used to generate ovine polyclonal antibodies. Polyclonal antibodies to baculovirus-expressed recombinant influenza haemagglutinin from A/Puerto Rico/8/1934 H1N1 (PR8) were elicited in sheep using various immunisation regimens designed to investigate the priming immunisation route, adjuvant formulation, sheep age, and antigen dose, and to empirically ascertain which combination maximised antibody output. The novel adjuvant CoVaccine HT™ was compared to Freund’s adjuvant which is currently the adjuvant of choice for commercial production of ovine polyclonal Fab therapies. CoVaccine HT™ induced significantly higher titres of functional ovine anti-haemagglutinin IgG than Freund’s adjuvant but with fewer side effects, including reduced site reactions. Polyclonal hyperimmune sheep sera effectively neutralised influenza virus in vitro and, when given before or after influenza virus challenge, prevented the death of infected mice. Neither the age of the sheep nor the route of antigen administration appeared to influence antibody titre. Moreover, reducing the administrated dose of haemagglutinin antigen minimally affected antibody titre. Together, these results suggest a cost effective way of producing high and sustained yields of functional ovine polyclonal antibodies specifically for the prevention and treatment of globally significant diseases.Natalie E. Stevens, Cara K. Fraser, Mohammed Alsharifi, Michael P. Brown, Kerrilyn R. Diener, John D. Haybal

Investigation of the biomechanical effect of variable stiffness shoe on external knee adduction moment in various dynamic exercises

10.1186/1757-1146-6-39Journal of Foot and Ankle Research61

Chitosan particles agglomerated scaffolds for cartilage and osteochondral tissue engineering approaches with adipose tissue derived stem cells

It is well accepted that natural tissue regeneration is unlikely to occur if the cells are not supplied with an extracellular matrix (ECM) substitute. With this goal, several different methodologies have been used to produce a variety of 3D scaffolds as artificial ECM substitutes suitable for bone and cartilage tissue engineering. Furthermore, osteochondral tissue engineering presents new challenges since the combination of scaffolding and co-culture requirements from both bone and cartilage applications is required in order to achieve a successful osteochondral construct. In this paper, an innovative processing route based on a chitosan particles aggregation methodology for the production of cartilage and osteochondral tissue engineering scaffolds is reported. An extensive characterization is presented including a morphological evaluation using Micro-Computed Tomography (μCT) and 3D virtual models built with an image processing software. Mechanical and water uptake characterizations were also carried out, evidencing the potential of the developed scaffolds for the proposed applications. Cytotoxicity tests show that the developed chitosan particles agglomerated scaffolds do not exert toxic effects on cells. Furthermore, osteochondral bilayered scaffolds could also be developed. Preliminary seeding of mesenchymal stem cells isolated from human adipose tissue was performed aiming at developing solutions for chondrogenic and osteogenic differentiation for osteochondral tissue engineering applications.Fundação para a Ciência e a Tecnologia (FCT)European NoE EXPERTISSUES (NMP3-CT-2004-500283)European STREP Project HIPPOCRATES (NMP3-CT-2003-505758

Biomimetic self-assembling copolymer-hydroxyapatite nanocomposites with the nanocrystal size controlled by citrate

Citrate binds strongly to the surface of calcium phosphate (apatite) nanocrystals in bone and is thought to prevent crystal thickening. In this work, citrate added as a regulatory element enabled molecular control of the size and stability of hydroxyapatite (HAp) nanocrystals in synthetic nanocomposites, fabricated with self-assembling block copolymer templates. The decrease of the HAp crystal size within the polymer matrix with increasing citrate concentration was documented by solid-state nuclear magnetic resonance (NMR) techniques and wide-angle X-ray diffraction (XRD), while the shapes of HAp nanocrystals were determined by transmission electron microscopy (TEM). Advanced NMR techniques were used to characterize the interfacial species and reveal enhanced interactions between mineral and organic matrix, concomitant with the size effects. The surface-to-volume ratios determined by NMR spectroscopy and long-range 31P{1H} dipolar dephasing show that 2, 10, and 40 mM citrate changes the thicknesses of the HAp crystals from 4 nm without citrate to 2.9, 2.8, and 2.3 nm, respectively. With citrate concentrations comparable to those in body fluids, HAp nanocrystals of sizes and morphologies similar to those in avian and bovine bones have been produced

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Introduction Mechanical injury can greatly influence articular cartilage, propagating inflammation, cell injury and death – risk factors for the development of osteoarthritis. Melanocortin peptides and their receptors mediate anti-inflammatory and pro-resolving mechanisms in chondrocytes. This study aimed to investigate the potential chondroprotective properties of α-MSH and [DTRP8]-γ-MSH in mechanically injured cartilage explants, their ability to inhibit pro-inflammatory and stimulate anti-inflammatory cytokines in in situ and in freshly isolated articular chondrocytes. Methods The effect of melanocortins on in situ chondrocyte viability was investigated using confocal laser scanning microscopy of bovine articular cartilage explants, subjected to a single blunt impact (1.14 N, 6.47 kPa) delivered by a drop tower. Chondroprotective effects of α-MSH, [DTRP8]-γ-MSH and dexamethasone on cytokine release by TNF-α-activated freshly isolated articular chondrocytes/mechanically injured cartilage explants were investigated by ELISA. Results A single impact to cartilage caused discreet areas of chondrocyte death, accompanied by pro-inflammatory cytokine release; both parameters were modulated by α-MSH, [DTRP8]-γ-MSH and dexamethasone. Melanocortin pre-treatment of TNF-α-stimulated freshly isolated chondrocytes resulted in a bell-shaped inhibition in IL-1β, IL-6 and IL-8, and elevation of IL-10 production. The MC3/4 antagonist, SHU9119, abrogated the effect of [DTRP8]-γ-MSH but not α-MSH on cytokine release. Conclusion Melanocortin peptide pre-treatment prevented chondrocyte death following mechanical impact to cartilage and led to a marked reduction of pro-inflammatory cytokines, whilst prompting the production of anti-inflammatory/pro-resolving cytokine IL-10. Development of small molecule agonists towards melanocortin receptors could thus be a viable approach for preventing chondrocyte inflammation and death within cartilage and represent an alternative approach for the treatment of osteoarthritis

Screening for Diabetes and Hypertension in a Rural Low Income Setting in Western Kenya Utilizing Home-Based and Community-Based Strategies

BACKGROUND: The burdens of hypertension and diabetes are increasing in low- and middle-income countries (LMICs). It is important to identify patients with these conditions early in the disease process. The goal of this study, therefore, is to compare community- versus home-based screening for hypertension and diabetes in Kenya. METHODS: This was a feasibility study conducted by the Academic Model Providing Access to Healthcare (AMPATH) program in Webuye, a town in western Kenya. Home-based (door-to-door) screening occurred in March 2010 and community-based screening in November 2011. HIV counselors were trained to screen for diabetes and hypertension in the home-based screening with local district hospital based staff conducting the community-based screening. Participants \u3e18 years old qualified for screening in both groups. Counselors referred all participants with a systolic blood pressure (SBP) ≥ 160 mmHg and/or a random blood glucose ≥ 7 mmol/L (126 mg/dL) to a local clinic for follow-up. Differences in likelihood of screening positive between the two strategies were compared using Fischer\u27s Exact Test. Logistic regression models were used to identify factors associated with the likelihood of following-up after a positive screening. RESULTS: There were 236 participants in home-based screening: 13 (6%) had a SBP ≥ 160 mmHg, and 54 (23%) had a random glucose ≥ 7 mmol/L. There were 346 participants in community-based screening: 35 (10%) had a SBP ≥ 160 mmHg, and 27 (8%) had a random glucose ≥ 7 mmol/L. Participants in community-based screening were twice as likely to screen positive for hypertension compared to home-based screening (OR=1.93, P=0.06). In contrast, participants were 3.5 times more likely to screen positive for a random blood glucose ≥ 7 mmol/L with home-based screening (OR=3.51, P CONCLUSION: Community- or home-based screening for diabetes and hypertension in LMICs is feasible. Due to low rates of follow-up, screening efforts in rural settings should focus on linking cases to care

Seaweed polysaccharide-based hydrogels used for the regeneration of articular cartilage

This manuscript provides an overview of the in vitro and in vivo studies reported in the literature focusing on seaweed polysaccharides based hydrogels that have been proposed for applications in regenerative medicine, particularly, in the field of cartilage tissue engineering. For a better understanding of the main requisites for these specific applications, the main aspects of the native cartilage structure, as well as recognized diseases that affect this tissue are briefly described. Current available treatments are also presented to emphasize the need for alternative techniques. The following part of this review is centered on the description of the general characteristics of algae polysaccharides, as well as relevant properties required for designing hydrogels for cartilage tissue engineering purposes. An in-depth overview of the most well known seaweed polysaccharide, namely agarose, alginate, carrageenan and ulvan biopolymeric gels, that have been proposed for engineering cartilage is also provided. Finally, this review describes and summarizes the translational aspect for the clinical application of alternative systems emphasizing the importance of cryopreservation and the commercial products currently available for cartilage treatment.Authors report no declarations of interest. Authors thank the Portuguese Foundation for Science and Technology (FCT) for the PhD fellowship of Elena G. Popa (SFRH/BD/64070/2009) and research project (MIT/ECE/0047/2009). The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no REGPOT-CT2012-316331-POLARIS