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.

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.

The molecular basis of galactosemia - Past, present and future

Galactosemia, an inborn error of galactose metabolism, was first described in the 1900s by von Ruess. The subsequent 100years has seen considerable progress in understanding the underlying genetics and biochemistry of this condition. Initial studies concentrated on increasing the understanding of the clinical manifestations of the disease. However, Leloir's discovery of the pathway of galactose catabolism in the 1940s and 1950s enabled other scientists, notably Kalckar, to link the disease to a specific enzymatic step in the pathway. Kalckar's work established that defects in galactose 1-phosphate uridylyltransferase (GALT) were responsible for the majority of cases of galactosemia. However, over the next three decades it became clear that there were two other forms of galactosemia: type II resulting from deficiencies in galactokinase (GALK1) and type III where the affected enzyme is UDP-galactose 4'-epimerase (GALE). From the 1970s, molecular biology approaches were applied to galactosemia. The chromosomal locations and DNA sequences of the three genes were determined. These studies enabled modern biochemical studies. Structures of the proteins have been determined and biochemical studies have shown that enzymatic impairment often results from misfolding and consequent protein instability. Cellular and model organism studies have demonstrated that reduced GALT or GALE activity results in increased oxidative stress. Thus, after a century of progress, it is possible to conceive of improved therapies including drugs to manipulate the pathway to reduce potentially toxic intermediates, antioxidants to reduce the oxidative stress of cells or use of "pharmacological chaperones" to stabilise the affected proteins.

Topical antihistamines and mast cell stabilisers for treating seasonal and perennial allergic conjunctivitis

BACKGROUND: Seasonal/perennial allergic conjunctivitis is the most common allergic conjunctivitis, usually with acute manifestations when a person is exposed to allergens and with typical signs and symptoms including itching, redness, and tearing. The clinical signs and symptoms of allergic conjunctivitis are mediated by the release of histamine by mast cells. Histamine antagonists (also called antihistamines) inhibit the action of histamine by blocking histamine H1 receptors, antagonising the vasoconstrictor, and to a lesser extent, the vasodilator effects of histamine. Mast cell stabilisers inhibit degranulation and consequently the release of histamine by interrupting the normal chain of intracellular signals. Topical treatments include eye drops with antihistamines, mast cell stabilisers, non-steroidal anti-inflammatory drugs, combinations of the previous treatments, and corticosteroids. Standard treatment is based on topical antihistamines alone or topical mast cell stabilisers alone or a combination of treatments. There is clinical uncertainty about the relative efficacy and safety of topical treatment.

OBJECTIVES: The objective of this review was to assess the effects of topical antihistamines and mast cell stabilisers, alone or in combination, for use in treating seasonal and perennial allergic conjunctivitis.

SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2014, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2014), EMBASE (January 1980 to July 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 17 July 2014. We also searched the reference lists of review articles and relevant trial reports for details of further relevant publications.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing topical antihistamine and mast cell stabilisers, alone or in combination, with placebo, no treatment or to any other antihistamine or mast cell stabiliser, or both, that examined people with seasonal or perennial allergic conjunctivitis, or both. The primary outcome was any participant-reported evaluation (by questionnaire) of severity of four main ocular symptoms: itching, irritation, watering eye (tearing), and photophobia (dislike of light), both separately and, if possible, by an overall symptom score. We considered any follow-up time between one week and one year.

DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. Disagreements were resolved by discussion among review authors and the involvement of a third review author. We followed standard methodological approaches used by Cochrane.

MAIN RESULTS: We identified 30 trials with a total of 4344 participants randomised, with 17 different drugs or treatment comparisons. The following antihistamines and mast cell stabilisers were evaluated in at least one RCT: nedocromil sodium or sodium cromoglycate, olopatadine, ketotifen, azelastine, emedastine, levocabastine (or levocabastine), mequitazine, bepotastine besilate, combination of antazoline and tetryzoline, combination of levocabastine and pemirolast potassium. The most common comparison was azelastine versus placebo (nine studies).We observed a large variability in reporting outcomes. The quality of the studies and reporting was variable, but overall the risk of bias was low. Trials evaluated only short-term effects, with a range of treatment of one to eight weeks. Meta-analysis was only possible in one comparison (olopatadine versus ketotifen). There was some evidence to support that topical antihistamines and mast cell stabilisers reduce symptoms and signs of seasonal allergic conjunctivitis when compared with placebo. There were no reported serious adverse events related to the use of topical antihistamine and mast cell stabilisers treatment.

AUTHORS' CONCLUSIONS: It seems that all reported topical antihistamines and mast cell stabilisers reduce symptoms and signs of seasonal allergic conjunctivitis when compared with placebo in the short term. However, there is no long-term data on their efficacy. Direct comparisons of different antihistamines and mast cell stabilisers need to be interpreted with caution. Overall, topical antihistamines and mast cell stabilisers appear to be safe and well tolerated. We observed a large variability in outcomes reported. Poor quality of reporting challenged the synthesis of evidence.

Mental illness or mental distress; stigma and concealment in University students - a discussion paper

This discussion paper addresses the issue of mental distress, sometimes mis- perceived or misinterpreted as mental illness. The
focus is on positive psychology. Reflecting in part on a UK-based study with younger University students studying to health
related degrees, nursing, midwifery and medicine (N = 12), many of the students were apparently suffering dis-stress with
disordered eating at least in part being used as a coping mechanism. However notwithstanding that they were at the end of
their first year studies in health, a significant number of the students interpreted their approach to eating as a mental illness.
Consequently, many within the study felt stigmatised and were reluctant to acknowledge certainly to the University health care
authorities that there was an issue; perceiving both academic and career/professional consequences of mental health labelling. The
paper approaches the issue of mental health from a health promoting perspective, reflecting against the theory of salutogenesis
and its focus within the three dimensions of comprehensibility, manageability and meaningfulness as an approach to building
resilience and managing stressors to better facilitate a sense of coherence. Complex manifestations of distress and poor coping
mechanisms can in some cases be misinterpreted or miss perceived as mental illness. Promoting mental health and reducing the
stigma of mental illness or the misperception of mental distress as mental illness, would need to be addressed in order to more
effectively outreach certainly to younger University students who might be at risk. The focus should be on how better to promote
their sense of coherence.