Digoxin toxicity in the aged. Characterising and avoiding the problem

Digoxin is one of the most frequently prescribed drugs, particularly in the elderly population where there is an increased prevalence of atrial fibrillation and cardiac failure. The drug has a narrow therapeutic range and has gained a reputation for producing adverse effects in older patients. The more frail elderly patients with coexistent disease, often taking other treatments, are more at risk from digoxin toxicity due to inappropriate dosing, noncompliance, or increased sensitivity to digoxin resulting from pharmacokinetic or pharmacodynamic interactions. Application of basic pharmacological principles may be helpful in anticipating these problems. Elderly patients more commonly receive digoxin than younger patients, which in part accounts for the higher rates of toxicity in this group. Numerous components contribute to the development of toxicity, and diagnosis of toxicity is difficult in this age group. The measurement of serum concentrations can contribute to the clinical diagnosis. A major problem is the accurate diagnosis of digoxin toxicity which may have numerous nonspecific clinical manifestations, many of which are related to coexisting disease in elderly patients. This diagnostic imprecision is well recognised but has been helped by the introduction of serum digoxin measurement. However, reliance on serum concentrations should not replace clinical judgement, since these do not always correlate with toxicity. The apparently decreasing incidence of toxicity over recent years probably reflects several factors: the improvement in digoxin formulations, awareness of digoxin pharmacology, utilisation of serum concentrations, and the realisation that digoxin withdrawal is a viable proposition in elderly patients. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin overdose, especially in the elderly population.

“Boundary-setting as a core activity in complex public systems”

Title: Boundary-setting as a core activity in complex public systems
Authors: Joanne Murphy & Mary Lee Rhodes

The definition of the boundary of a system is at the core of any systems approach (Midgley 2000; 2003). By defining boundaries we enable – and delimit – the range of outcomes sought and the actions and resources that can be brought to bear. In complex adaptive systems (CAS) analysis, the conceptualisaion and definition of boundaries is particularly challenging as they are constantly undergoing redefinition through agent action, interaction and entry/exit. (Rhodes et al 2011). The concept of ‘boundaries’ appears regularly in a wide range of literature around public management, administration, geopolitics, regeneration and organisational development. Discussions around boundaries focus on many things from concrete physical manifestations and barriers, to virtual interfaces between one organisational unit and another, or even entirely theoretical demarcations between different schools of thought (Kaboolian, 1998, Levi-Faur, 2004, Agranoff & McGuire, 2004).

However, managing ‘beyond’ such boundaries is a routinely recurring aspiration that transcends sectors and local concerns. Unsurprisingly then, there is an increasing understanding of the need to acknowledge and manage such boundaries (whether they be physical, social or organisational) within public management as a discipline (Currie et al 2007, Fitzsimmons and White, 1997, Murtagh, 2002). This paper explores the impact of boundaries on public management strategic decision-making in the sectors of urban regeneration and healthcare. In particular, it focuses on demarcations to physical space, communal identity and within professional relationships in these sectors.

The first section describes the research that gave rise to the paper and the cases examined. Next we briefly define what we mean by boundaries. We explore issues that have emerged from our analysis of urban regeneration and health care singularly, before looking at how the concept of boundaries is a recurrent concern across the sectors. The main contribution of the paper is an exploration of how a CAS lens can bring a new insight into the concept of boundaries and decision-making in the two sets of case studies. This discussion will concentrate on initial conditions, bifurcation and adaptation as key CAS factors in relation to boundaries. We conclude with a brief discussion on the benefits of a CAS lens to an analysis of boundaries in public management decision-making.
References:

Agranoff, R. and McGuire, M. (2003) Collaborative Public Management: Strategies for Local Government. Washington, DC: Georgetown Univ. Press.

Currie, G., Lockett, A. (2007) “A critique of transformational leadership: moral, professional & contingent dimensions of leadership within public services organizations”. Human Relations 60: 341-370.

Fitzsimmons and White, (1997) "Crossing boundaries: communication between professional groups", Journal of Management in Medicine, Vol. 11 Iss: 2, pp.96 – 101

Kaboolian, L. (1998) “The New Public Management: Challenging the Boundaries of the Management vs. Administration Debate” Public Administration Review Vol. 58, No. 3 pp.189-193

Levi-Faur D. and Vigoda-Gadot Eran (eds) (2004) International Public Policy and Management: Policy Learning Beyond Regional, Cultural and Political Boundaries, Marcel Dekker,
Midgley, G. (ed) (2003) Systems Thinking. London: Sage Publications

Midgley, G. (2000) Systemic Intervention: Philosophy, Methodology and Practice. New York, NY: Kluwer.

Murtagh, B. (2002). The Politics of Territory: Policy and Segregation in Northern Ireland. Basingstoke, Palgrave.

Rhodes, ML, Joanne Murphy, Jenny Muir, John Murray (2011) Public Management & Complexity Theory: Richer Decision Making in Irish Public Services, UK: Routledge

Clinical trials in cystic fibrosis

In patients with cystic fibrosis (CF), clinical trials are of paramount importance. Here, the current status of drug development in CF is discussed and future directions highlighted. Methods for pre-clinical testing of drugs with potential activity in CF patients including relevant animal models are described. Study design options for phase II and phase III studies involving CF patients are provided, including required patient numbers, safety issues and surrogate end point parameters for drugs, tested for different disease manifestations. Finally, regulatory issues for licensing new therapies for CF patients are discussed, including new directives of the European Union and the structure of a European clinical trial network for clinical studies involving CF patients is proposed.

Crime, justice and the legitimacy of military power in the international sphere

This article examines how a discourse of crime and justice is beginning to play a significant role in justifying international military operations. It suggests that although the coupling of war with crime and justice is not a new phenomenon, its present manifestations invite careful consideration of the connection between crime and political theory. It starts by reviewing the notion of sovereignty to look then at the history of the criminalisation of war and the emergence of new norms to constrain sovereign states. In this context, it examines the three ways in which military force has recently been authorised: in Iraq, in Libya and through drones in Yemen, Pakistan and Somalia. It argues the contemporary coupling of military technology with notions of crime and justice allows the reiteration of the perpetration of crimes by the powerful and the representation of violence as pertaining to specific dangerous populations in the space of the international. It further suggests that this authorises new architectures of authority, fundamentally based on military power as a source of social power.

Antioxidants and diabetic retinopathy

The biochemical perturbations in diabetes mellitus (DM) create the conditions for the production of free radicals, the consequence of which is increased oxidative stress. Evidence has accrued over the past 2 decades that suggests that oxidative stress is an important pathogenetic factor in the development of diabetic retinopathy (DR). Experimental data show that the use of strategies that ameliorate oxidative stress can prevent and retard the development of DR in the animal model. Clinical observations also suggest that reducing oxidative stress may help to reverse pathological manifestations of DR. The present article constitutes an examination of the role of antioxidants in the management of DR and the current state of clinically relevant knowledge. © 2013 Springer Science+Business Media New York.

The Postmodernist Critique of Evidence-Based Practice

In this paper, we examine the postmodernist argument that evidence-based practice (EBP) should be rejected by nurses because it restricts the sources of knowledge used by practitioners. Three main postmodernist criticisms are identified and discussed. First, that the notion of ‘best evidence’ implies a hierarchical and exclusivist approach to knowledge. We accept this argument, noting that such a hierarchy is accepted and justified by many of its proponents. Second, that the hierarchy embraced by the evidence-based practice movement damages health care because it excludes other forms of evidence that are needed to understand the complexity of care. We accept that some manifestations of EBP, notably the Cochrane Collaboration, have devalued qualitative evidence. Using our previous experience of conducting Cochrane reviews (McGaughey et al. 2007), we argue that this limits explanatory scope. Third, that it fails to take account of individuals or their experience. Here, we use evidence of the use by midwives of EBP policies and protocols to the detriment of including women in decision-making processes (Porter et al. 2007) to accept that there is also some merit to this critique. We conclude that, while it is not necessary to concur with the total rejection of EBP that postmodernists advocate, it is necessary to address the issues they raise in order to ensure that EBP better fits the requirements of nursing.
McGaughey, J., Alderdice, F., Fowler, R., Kapila, A., Mayhew, A., Moutray, M., 2007. Outreach and Early Warning Systems (EWS) for the prevention of Intensive Care admission and death of critically ill adult patients on general hospital wards. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD005529. DOI: 10.1002/14651858.CD005529.pub2.
Porter, S., Crozier, K., Sinclair, M., Kernohan, W., 2007. New midwifery? A qualitative analysis of midwives’ decision-making strategies. Journal of Advanced Nursing 60 (6), 525-534.

Resemblance of psychotic symptoms and syndromes in affected sibling pairs from the Irish Study of High-Density Schizophrenia Families:evidence for possible etiologic heterogeneity

The authors sought to determine whether the clinical manifestations of schizophrenia and other psychotic disorders are correlated in affected sibling pairs.

Clothing and Colonialism: The Dungiven costume and the fashioning of early modern identities

The entanglement of identity and personal attire in colonial settings is explored through consideration of a tattered set of clothes from late sixteenth-early seventeenth-century Ireland incorporating elements of Irish, English, and Scots fashion. Reconsideration of the clothing, recovered from a bog, provides a rare opportunity to explore the physical manifestations of processes of hybridity and mimesis, as well as the pragmatic accommodations of impoverishment and displacement in colonial settings. In addition to considering the role of material culture in colonial identity formation and negotiation, examination of what has become known as the Dungiven costume also speaks to the ongoing legacy of early modern colonial encounters, as the cultural associations of the garments, and by extension their past wearer(s), continue to be subjected to the politically charged nature of identity politics in contemporary Northern Ireland.

Quantitative Measurement of [Na+] and [K+] in Postmortem Human Brain Tissue Indicates Disturbances in Subjects with Alzheimer's Disease and Dementia with Lewy Bodies

Alzheimer’s disease (AD) is associated with significant disturbances in the homeostasis of Na+ and K+ ions as well as reduced levels of Na+/K+ ATPase in the brain. This study used ICP-MS to accurately quantify Na+ and K+ concentrations in human postmortem brain tissue. We analyzed parietal cortex (Brodmann area 7) from 28 cognitively normal age-matched controls, 15 cases of moderate AD, 30 severe AD, and 15 dementia with Lewy bodies (DLB). Associations were investigated between [Na+] and [K+] and a number of variables including diagnosis, age, gender, Braak tangle stage, amyloid-β (Aβ) plaque load, tau load, frontal tissue pH, and APOE genotype. Brains from patients with severe AD had significantly higher (26%; p<0.001) [Na+] (mean 65.43 ± standard error 2.91 mmol/kg) than controls, but the concentration was not significantly altered in moderate AD or DLB. [Na+] correlated positively with Braak stage (r=0.45; p<0.0001), indicating association with disease severity. [K+] in tissue was 10% lower (p<0.05) in moderate AD than controls. However, [K+] in severe AD and DLB (40.97±1.31 mmol/kg) was not significantly different from controls. There was a significant positive correlation between [K+] and Aβ plaque load (r=0.46; p=0.035), and frontal tissue pH (r=0.35; p=0.008). [Na+] was not associated with [K+] across the groups, and neither ion was associated with tau load or APOE genotype. We have demonstrated disturbances of both [Na+] and [K+] in relation to the severity of AD and markers of AD pathology, although it is possible that these relate to late-stage secondary manifestations of the disease pathology.

In Vitro and In Vivo Anti-Schistosomal Activity of the Alkylphospholipid Analog Edelfosine

Background: Schistosomiasis is a parasitic disease caused by trematodes of the genus Schistosoma. Five species of Schistosoma are known to infect humans, out of which S. haematobium is the most prevalent, causing the chronic parasitic disease schistosomiasis that still represents a major problem of public health in many regions of the world and especially in tropical areas, leading to serious manifestations and mortality in developing countries. Since the 1970s, praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis, but concerns about relying on a single drug to treat millions of people, and the potential appearance of drug resistance, make identification of alternative schistosomiasis chemotherapies a high priority. Alkylphospholipid analogs (APLs), together with their prototypic molecule edelfosine (EDLF), are a family of synthetic antineoplastic compounds that show additional pharmacological actions, including antiparasitic activities against several protozoan parasites.

Methodology/Principal Findings: We found APLs ranked edelfosine> perifosine> erucylphosphocholine> miltefosine for their in vitro schistosomicidal activity against adult S. mansoni worms. Edelfosine accumulated mainly in the worm tegument, and led to tegumental alterations, membrane permeabilization, motility impairment, blockade of male-female pairing as well as induction of apoptosis-like processes in cells in the close vicinity to the tegument. Edelfosine oral treatment also showed in vivo schistosomicidal activity and decreased significantly the egg burden in the liver, a key event in schistosomiasis.

Conclusions/Significance: Our data show that edelfosine is the most potent APL in killing S. mansoni adult worms in vitro. Edelfosine schistosomicidal activity seems to depend on its action on the tegumental structure, leading to tegumental damage, membrane permeabilization and apoptosis-like cell death. Oral administration of edelfosine diminished worm and egg burdens in S. mansoni-infected CD1 mice. Here we report that edelfosine showed promising antischistosomal properties in vitro and in vivo.

Private rule-making and European governance - issues of legitimacy

Private rule-making is widely discussed as supporting institutional policy making and legislation at EU level. The following argues for a different perspective on private actor rule-making, focusing on the autonomy of social realms within which self-governance may be possible. From this perspective, private actor rule-making is considered as a potential gain in self-determination. Substantive autonomy and enhanced self-determination of all those affected are considered as prerequisites for accepting rules made by private actors. Opening the field for discussion, some manifestations of (envisaged) private rule-making at EU level are explored and discussed as to whether they should be accepted as legitimate forms of self-governance.

Investigation of physiological properties of nerves and muscles using electromyography.

The measurement and representation of the electrical activity of muscles [electromyography (EMG)] have a long history from the Victorian Era until today. Currently, EMG has uses both as a research tool, in noninvasively recording muscle activation, and clinically in the diagnosis and assessment of nerve and muscle disease and injury as well as in assessing the recovery of neuromuscular function after nerve damage. In the present report, we describe the use of a basic EMG setup in our teaching laboratories to demonstrate some of these current applications. Our practical also illustrates some fundamental physiological and structural properties of nerves and muscles. Learning activities include 1) displaying the recruitment of muscle fibers with increasing force development; 2) the measurement of conduction velocity of motor nerves; 3) the assessment of reflex delay and demonstration of Jendrassik's maneuver; and 4) a Hoffman reflex experiment that illustrates the composition of mixed nerves and the differential excitability thresholds of fibers within the same nerve, thus aiding an understanding of the reflex nature of muscle control. We can set up the classes at various levels of inquiry depending on the needs/professional requirements of the class. The results can then provide an ideal platform for a discovery learning session/tutorial on how the central nervous system controls muscles, giving insights on how supraspinal control interacts with reflexes to give smooth, precise muscular activation.

The Quest for Fictionality: Prostitution and Metatextuality in Rachilde’s Monsieur Vénus

This article considers the theme of prostitution in the decadent writings of the fin-de-siecle French author, Rachilde. It proposes that an analysis of this critically-neglected trope of her work reveals new connections between the erotics and aesthetics of her fiction. As a vector for considering tensions between fantasy and truth, and illusion and reality, prostitution, in Rachilde's texts, invites us to reflect on two of the most common cultural manifestations of decadence: sexual non-conformism and the cult of artifice. The article focuses in particular on the (male) prostitute-body of Monsieur Venus, arguing that, in its transcendence of nature, reality and utilitarian purpose, it is elevated to the status of art in Rachilde's fictional world.

Presentation of a plasmablastic lymphoma in a human immunodeficiency virus-positive patient after administration of an inferior alveolar dental block

Human immunodeficiency virus (HIV) is a serious worldwide healthcare problem with implications for all healthcare workers. The reported oral manifestations of the disease are numerous and have been categorised according to the strength of their association with HIV infection. Oral non-Hodgkin's lymphoma is strongly associated with HIV infection, and an increased incidence of such neoplasms is widely reported. This case report details the presentation of a rare subcategory of plasmablastic lymphoma in an HIV-positive patient after administration of an inferior alveolar dental block to facilitate extraction of mandibular teeth. This highly aggressive neoplasm is a large B-cell lymphoma with a predilection for the oral cavity. Unfortunately, the prognosis for such a tumour is poor as detailed in this case.

New insights into the causes of human illness due to consumption of azaspiracid contaminated shellfish

Azaspiracid (AZA) poisoning was unknown until 1995 when shellfish harvested in Ireland caused illness manifesting by vomiting and diarrhoea. Further in vivo/vitro studies showed neurotoxicity linked with AZA exposure. However, the biological target of the toxin which will help explain such potent neurological activity is still unknown. A region of Irish coastline was selected and shellfish were sampled and tested for AZA using mass spectrometry. An outbreak was identified in 2010 and samples collected before and after the contamination episode were compared for their metabolite profile using high resolution mass spectrometry. Twenty eight ions were identified at higher concentration in the contaminated samples. Stringent bioinformatic analysis revealed putative identifications for seven compounds including, glutarylcarnitine, a glutaric acid metabolite. Glutaric acid, the parent compound linked with human neurological manifestations was subjected to toxicological investigations but was found to have no specific effect on the sodium channel (as was the case with AZA). However in combination, glutaric acid (1mM) and azaspiracid (50nM) inhibited the activity of the sodium channel by over 50%. Glutaric acid was subsequently detected in all shellfish employed in the study. For the first time a viable mechanism for how AZA manifests itself as a toxin is presented.