Responding to the alarm caused by recent hospital scandals and accounts of unintended harm to patients, this author draws on her experience of analyzing the health care systems of over a dozen ...countries and examines whether greater regulation has increased patient safety and health care quality. It will be of key interest to government actors, health care professionals and medico-legal scholars.
Complex target SELEX Shamah, Steven M; Healy, Judith M; Cload, Sharon T
Accounts of chemical research,
01/2008, Volume:
41, Issue:
1
Journal Article
Peer reviewed
Aptamers are non-naturally occurring structured oligonucleotides that may bind to small molecules, peptides, and proteins. Typically, aptamers are generated by an in vitro selection process referred ...to as SELEX (systematic evolution of ligands by exponential enrichment). Aptamers that bind with high affinity and specificity to proteins that reside on the cell surface have potential utility as therapeutic antagonists, agonists, and diagnostic agents. When the target protein requires the presence of the cell membrane (e.g., G-protein-coupled receptors, ion channels) or a co-receptor to fold properly, it is difficult or impossible to program the SELEX experiment with purified, soluble protein target. Recent advances in which the useful range of SELEX has been extended from comparatively simple purified forms of soluble proteins to complex mixtures of proteins in membrane preparations or in situ on the surfaces of living cells offer the potential to discover aptamers against previously intractable targets. Additionally, in cases in which a cell-type specific diagnostic is sought, the most desirable target on the cell surface may not be known. Successful application of aptamer selection techniques to complex protein mixtures can be performed even in the absence of detailed target knowledge and characterization. This Account presents a review of recent work in which membrane preparations or whole cells have been utilized to generate aptamers to cell surface targets. SELEX experiments utilizing a range of target "scaffolds" are described, including cell fragments, parasites and bacteria, viruses, and a variety of human cell types including adult mesenchymal stem cells and tumor lines. Complex target SELEX can enable isolation of potent and selective aptamers directed against a variety of cell-surface proteins, including receptors and markers of cellular differentiation, as well as determinants of disease in pathogenic organisms, and as such should have wide therapeutic and diagnostic utility.
Background: Migrant health is receiving increasing international attention, reflecting recognition of the health inequities experienced among many migrant populations and the need for health systems ...to adapt to diverse migrant populations. In the Greater Mekong Subregion (GMS) there is increasing migration associated with uneven economic integration and growth, socio-economic vulnerabilities, and disparities between countries. There has been limited progress, however, in improving migrant access to health services in the Subregion. This paper examines the health needs, access barriers, and policy responses to cross-border migrants in five GMS countries.
Methods: A review of published literature and research was conducted on migrant health and health service access in Cambodia, Lao People's Democratic Republic, Myanmar, Thailand, and Viet Nam, as well as analysis of current migration trends and universal health coverage (UHC) indicators in the Subregion. The review included different migrant types: i.e. migrant workers, irregular migrants, victims of trafficking, refugees and asylum seekers, and casual cross-border migrants.
Results: There is substantial diversity in the capacity of GMS health systems to address migrant populations. Thailand has sought to enhance migrant health coverage, including development of migrant health policies/programs, bilateral migrant worker agreements, and migrant health insurance schemes; Viet Nam provides health protection for emigrant workers. Overall, however, access to good quality health care remains weak for many citizens in GMS countries let alone migrants. Migrant workers - and irregular migrants in particular - face elevated health risks yet are not adequately covered and incur high out-of-pocket (OOP) payments for health services.
Conclusions: UHC implies equity: UHC is only achieved when everyone has the opportunity to access and use good-quality health care. Efforts to achieve UHC in the GMS require deliberate policy decisions to include migrants. The emergence of the UHC agenda, and the focus on migrant health among policy makers and partners, present an opportunity to tackle barriers to health service access, extend coverage, and strengthen partnerships in order to improve migrant health. This is an opportune time for GMS countries to develop migrant-inclusive health systems.
ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets. ARC1779 is being developed as a novel antithrombotic ...agent for use in patients with acute coronary syndromes.
This was a randomized, double-blind, placebo-controlled study in 47 healthy volunteers of doses of ARC1779 from 0.05 to 1.0 mg/kg. Pharmacodynamic effects were measured by an ELISA for free vWF A1 binding sites and by a platelet function analyzer. In terms of pharmacokinetics, the concentration-time profile of ARC1779 appeared monophasic. The observed concentration and area under the curve were dose proportional. The mean apparent elimination half-life was approximately 2 hours, and mean residence time was approximately 3 hours. The mean apparent volumes of distribution (at steady state and during terminal phase) were approximately one half the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance ranged from approximately 10% to approximately 21% of the glomerular filtration rate, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. Inhibition of vWF A1 binding activity was achieved with an EC(90) value of 2.0 mug/mL (151 nmol/L) and of platelet function with an EC(90) value of 2.6 mug/mL (196 nmol/L). ARC1779 was generally well tolerated, and no bleeding was observed. Adverse events tended to be minor and not dose related.
This is the first-in-human evaluation of a novel aptamer antagonist of vWF. ARC1779 produced dose- and concentration-dependent inhibition of vWF activity and platelet function with duration of effect suitable for the intended clinical use in acute coronary syndromes.
Aptamers are highly selective nucleic acid-based drugs that are currently being developed for numerous therapeutic indications. Here, we determine plasma pharmacokinetics and tissue distribution in ...rat of several novel aptamer compositions, including fully 2'-O-methylated oligonucleotides and conjugates bearing high-molecular weight polyethylene glycol (PEG) polymers, cell-permeating peptides, and cholesterol.
Levels of aptamer conjugates in biological samples were quantified radiometrically and by a hybridization-based dual probe capture assay with enzyme-linked fluorescent readout. Intact aptamer in urine was detected by capillary gel electrophoresis and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF).
Aptamer compositions examined exhibited a wide range of mean residence times in circulation (0.6-16 h) and significant variation in distribution levels among organs and tissues. Among the conjugates tested, in vivo properties of aptamers were altered most profoundly by conjugation with PEG groups. Complexation with a 20 kDa PEG polymer proved nearly as effective as a 40 kDa PEG polymer in preventing renal clearance of aptamers. Conjugation with 20 kDa PEG prolonged aptamer circulatory half-life, while reducing both the extent of aptamer distribution to the kidneys and the rate of urinary elimination. In contrast, the fully 2'-O-Me aptamer composition showed rapid clearance from circulation, and elimination with intact aptamer detectable in urine at 48 h post-administration.
We find that conjugation and chemical composition can alter fundamental aspects of aptamer residence in circulation and distribution to tissues. Though the primary effect of PEGylation was on aptamer clearance, the prolonged systemic exposure afforded by presence of the 20 kDa moiety appeared to facilitate distribution of aptamer to tissues, particularly those of highly perfused organs.
Self‐regulation by the health professions, while improving, is no longer enough; external drivers for safer health care include governments, funders and consumers.
Enforced self‐regulation is often ...more promising than a “command and control” strategy.
Research evidence on the responsive regulatory pyramid and its options offers lessons for health care policy makers and managers.
Start at the base of the regulatory pyramid — try persuasion first; move up the pyramid to secure compliance, and then be willing to move back down.
Use existing capacities and structures, and if possible avoid new bureaucracies of control.
This paper explores whether middle-income Asian countries are reorienting their health services in response to non-communicable diseases (NCDs). Malaysia, Sri Lanka, and Thailand were selected as ...case studies of Asian societies experiencing rapid increases both in NCDs and an aging population. While NCD programs, especially those related to diabetes and stroke, are well-established in Thailand, health services struggle to respond to increasing numbers of people with chronic health problems. Health services at all levels must plan ahead for more patients with chronic and often multiple conditions who require better integrated health care.
Health ombudsmen (health complaints commissioners), an unusual entity internationally, exist only in England, New Zealand, and the Australian states and territories. Established to respond to ...complaints from patients, the intention is to make health services and professionals more accountable to the public. Most cases are handled around the softer base of a regulatory pyramid, such as advice to complainants and requests to providers for an explanation and/or apology. Few cases escalate to investigations and prosecutions. Although the legal powers of some health ombudsmen to redress individual grievances have been strengthened, most lack the independent power to initiate an inquiry into systemic problems. To produce quality improvements, health ombudsmen need powers to require compliance from providers and to initiate inquiries. With the advent of new health sector regulators, health ombudsmen must negotiate their role and function within expanding networks of governance.
Health ombudsmen warrant attention as unusual entities both internationally and given their statutory mandate to respond directly to patient complaints about health professionals and health services. They also act as a ‘public watchdog’ in making health institutions more accountable for making systemic improvements to their services.
Among the multitudes lured to Australia's shores in the 1850s by the glitter of gold were entrepreneurial musicians who hoped to attract audiences eager for entertainment and culture. The tours of ...nineteenth-century virtuoso musicians around Europe and the Americas are well-researched, but less so touring musicians to the Antipodean gold rush. While the 1850s gold rush had profound impacts on social, economic and political life in Australia, the impact of gold upon cultural life warrants more attention. Newspapers of the time record many visiting musicians who hoped to profit from the backwash of rivers of gold. This article opens a window onto this world by studying the concert tours around Australia from 1854 to 1858 of Miska Hauser. A European classical musician with elite violin school training, he is notable as the first world-class violinist to tour the Australian colonies. This study draws upon the digital records of colonial newspapers available online from the National Library of Australia. This article analyses the populist concert programmes that Hauser presented to diverse audiences during his indefatigable tours around Australia and explores the extent of his professional and financial success.
PDF
