Disease activity and cognition in rheumatoid arthritis : an open label pilot study

Acknowledgements This work was supported in part by NIHR Newcastle Biomedical Research Centre. Funding for this study was provided by Abbott Laboratories. Abbott Laboratories were not involved in study design; in the collection, analysis and interpretation of data; or in the writing of the report.Peer reviewedPublisher PD

Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay

Objectives: Lead antituberculosis (anti-TB) molecules with novel mechanisms of action are urgently required to fuel the anti-TB drug discovery pipeline. The aim of this study was to validate the use of the high-throughput spot culture growth inhibition (HT-SPOTi) assay for screening libraries of compounds against Mycobacterium tuberculosis and to study the inhibitory effect of ibuprofen (IBP) and the other 2-arylpropanoic acids on the growth inhibition of M tuberculosis and other mycobacterial species. Methods: The HT-SPOTi method was validated not only with known drugs but also with a library of 47 confirmed anti-TB active compounds published in the ChEMBL database. Three over-the-counter non-steroidal anti-inflammatory drugs were also included in the screening. The 2-arylpropanoic acids, including IBP, were comprehensively evaluated against phenotypically and physiologically different strains of mycobacteria, and their cytotoxicity was determined against murine RAW264.7 macrophages. Furthermore, a comparative bioinformatic analysis was employed to propose a potential mycobacterial target. Results: IBP showed antitubercular properties while carprofen was the most potent among the 2-arylpropanoic class. A 3,5-dinitro-IBP derivative was found to be more potent than IBP but equally selective. Other synthetic derivatives of IBP were less active, and the free carboxylic acid of IBP seems to be essential for its anti-TB activity. IBP, carprofen and the 3,5-dinitro-IBP derivative exhibited activity against multidrug-resistant isolates and stationary phase bacilli. On the basis of the human targets of the 2-arylpropanoic analgesics, the protein initiation factor infB (Rv2839c) of M tuberculosis was proposed as a potential molecular target. Conclusions: The HT-SPOTi method can be employed reliably and reproducibly to screen the antimicrobial potency of different compounds. IBP demonstrated specific antitubercular activity, while carprofen was the most selective agent among the 2-arylpropanoic class. Activity against stationary phase bacilli and multidrug-resistant isolates permits us to speculate a novel mechanism of antimycobacterial action. Further medicinal chemistry and target elucidation studies could potentially lead to new therapies against TB

Irremediable impacts and unaccountable contributors: the possibility of a trust fund for victims to remedy large-scale human rights impacts

Corporate actions often adversely impact human rights in ways that are not easily justiciable. Such actions include the production and use of fossil fuels, contributing to climate change and its impacts, and actions that deny or retrogress access to the global food, housing and pharmaceutical markets. This paper terms the impacts caused by these actions ‘large-scale impacts’. Large-scale impacts feature multiple contributors, disparate victims, and no clear line of causation for establishing individual liability, and they often stem from legally permitted economic activity. This paper argues that the corporate responsibility to respect human rights – pillar two of the UN Guiding Principles on Business and Human Rights (UNGPs) – provides a useful framework for: (1) capturing the harm that such impacts cause, and (2) holding a wide range of businesses accountable for their contribution. However, the remedial mechanisms under pillar three of the UNGPs, as currently constituted, are ill-suited to such impacts. To correct this gap, this paper proposes the establishment of a Trust Fund for Victims, into which all corporate contributors to large-scale impacts would pay and against which victims could claim. Such a mechanism could significantly improve corporate accountability in the context of economic globalisation

Challenging the Commodification of Human Rights: The Case of the Right to Housing

The profitability of commodified housing is driving extreme levels of corporate investment. To boost profits investors are exploiting “undervalued” low-income housing, evicting vulnerable individuals, hoarding land and charging exploitative fees. This is causing severe harm to individuals’ right to housing across the globe, including, inter alia, rapidly increasing prices and debt, increasing evictions, homelessness, and increased recourse to substandard accommodation. The harm is endemic, but the human rights response has been tepid. This paper argues that both state obligations and the content of the right to housing under the International Covenant on Economic, Social and Cultural Rights (ICESCR) can usefully address the problem. However, in communications with State Parties the Committee on Economic, Social and Cultural Rights (CESCR) addresses issues of commodification and affordability in vague terms that fail to generate meaningful obligations. The paper grounds the CESCR’s approach in theories of enforceability which argue that enforcement is more practicable when “clear violations” can be established. The CESCR offers clear statements of breach only when identifying explicitly wrongful practices, such as discriminatory laws. This approach, however, almost entirely occludes harm caused by the marketization of human rights. It skeletonizes the “protect” limb of state obligations, permits the long-term retrogression of affordability and enables the serious subsequent effects. The paper proposes that “clear violations” can be constructed from the results of, and laws constituting, harmful marketization. A three-stage process of identification of breach, standard-setting, and policy suggestions is recommended that can turn the long-term retrogression of access to housing into specific, measurable statements of violations and recommendations. This same approach is advocated for business responsibilities under the UN Guiding Principles on Business and Human Rights, with the content of these responsibilities also evaluated

Human rights on the altar of the market: the Blackstone letters and the financialisation of housing

This article analyses the recent exchange of letters between two UN human rights mandate-holders and the Blackstone Group LP, a private equity firm with significant investments in the rental housing market in multiple jurisdictions. The mandate-holders argue that Blackstone’s investments are causing serious harm to the right to housing, including retrogressing affordability, and increasing evictions, homelessness and housing-related poverty. The scale of investment displaces communities and reshapes the housing landscape for the next generation. Blackstone’s rebuttal was, in part, predicated on their subservience to market forces and their obeying the law in all jurisdictions. This is largely accurate, indicating that markets and their constitutive rules permit and incentivise retrogressive housing outcomes. The paper therefore argues that promoting socio-economic rights under financialised globalisation requires challenging the engrained norms of marketisation. International human rights law provides an entry point for this project

Human Rights and Political Economy: Addressing the Legal Construction of Poverty and Rights Deprivation

There has been a recent resurgence in scholarly work concerned with the economics of human rights. This article builds on this work to develop a conceptual framework of human rights and political economy. It provides a theoretical basis for the turn to human rights and economics, rooted in the increasing micro-management of the economy by liberal states that can constitute the state planning of material distribution within the state. It demonstrates that human rights principles do apply to economic questions and elaborates methods and practices to realize the potential of rights in this arena. The article applies these methods and conceptualizations to state obligations and business responsibilities to excavate current limits and potentials of rights and contextualizes the project within left critiques of rights and “claim right” perspectives

Climate Litigation Unleashed: Catalysing Action against States and Corporations

This report follows the discussions at the one-day workshop ‘Climate Litigation Unleashed: Catalysing Action against States and Corporations’ held on 22 November 2023 at the Bonavero Institute of Human Rights in Oxford

Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents

Iron oxide nanoparticles (IONPs) of low polydispersity were obtained through a simple polyol synthesis in high pressure and high temperature conditions. The control of the size and morphology of the nanoparticles was studied by varying the solvent used, the amount of iron precursor and the reaction time. Compared with conventional synthesis methods such as thermal decomposition or co-precipitation, this process yields nanoparticles with a narrow particle size distribution in a simple, reproducible and cost effective manner without the need for an inert atmosphere. For example, IONPs with a diameter of ca. 8 nm could be made in a reproducible manner and with good crystallinity as evidenced by X-ray diffraction analysis and high saturation magnetization value (84.5 emu g(-1)). The surface of the IONPs could be tailored post synthesis with two different ligands which provided functionality and stability in water and phosphate buffer saline (PBS). Their potential as a magnetic resonance imaging (MRI) contrast agent was confirmed as they exhibited high r1 and r2 relaxivities of 7.95 mM(-1) s(-1) and 185.58 mM(-1) s(-1) respectively at 1.4 T. Biocompatibility and viability of IONPs in primary human mesenchymal stem cells (hMSCs) was studied and confirmed

Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy.

OBJECTIVE: To identify the cause of isolated distal weakness in a family with both neuropathic and myopathic features on EMG and muscle histology. METHODS: Case study with exome sequencing in 2 affected individuals, bioinformatic prioritization of genetic variants, and segregation analysis of the likely causal mutation. Functional studies included Western blot analysis of the candidate protein before and after heat shock treatment of primary skin fibroblasts. RESULTS: A novel HSPB1 variant (c.387C>G, p.Asp129Glu) segregated with the phenotype and was predicted to alter the conserved α-crystallin domain common to small heat shock proteins. At baseline, there was no difference in HSPB1 protein levels nor its binding partner αB-crystallin. Heat shock treatment increased HSPB1 protein levels in both patient-derived and control fibroblasts, but the associated increase in αB-crystallin expression was greater in patient-derived than control fibroblasts. CONCLUSIONS: The HSPB1 variant (c.387C>G, p.Asp129Glu) is the likely cause of distal neuromyopathy in this pedigree with pathogenic effects mediated through binding to its partner heat shock protein αB-crystallin. Mutations in HSBP1 classically cause a motor axonopathy, but this family shows that the distal weakness can be both myopathic and neuropathic. The traditional clinical classification of distal weakness into "myopathic" or "neuropathic" forms may be misleading in some instances, and future treatments need to address the pathology in both tissues.This study was funded by Wellcome Trust (101876/Z/13/Z and 096919Z/11/Z), Medical Research Council (UK) (G0601943), and Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2). Funding bodies had no influence on study design or data interpretation.This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/NXG.000000000000011