Duration-dependent effects of the BDNF Val66Met polymorphism on anodal tDCS induced motor cortex plasticity in older adults: a group and individual perspective

The brain derived neurotrophic factor (BDNF) Val66Met polymorphism and stimulation duration are thought to play an important role in modulating motor cortex plasticity induced by non-invasive brain stimulation (NBS). In the present study we sought to determine whether these factors interact or exert independent effects in older adults. Fifty-four healthy older adults (mean age = 66.85 years) underwent two counterbalanced sessions of 1.5 mA anodal transcranial direct current stimulation (atDCS), applied over left M1 for either 10 or 20 min. Single pulse transcranial magnetic stimulation (TMS) was used to assess corticospinal excitability (CSE) before and every 5 min for 30 min following atDCS. On a group level, there was an interaction between stimulation duration and BDNF genotype, with Met carriers (n = 13) showing greater post-intervention potentiation of CSE compared to Val66Val homozygotes homozygotes (n = 37) following 20 min (p = 0.002) but not 10 min (p = 0.219) of stimulation. Moreover, Met carriers, but not Val/Val homozygotes, exhibited larger responses to TMS (p = 0.046) after 20 min atDCS, than following 10 min atDCS. On an individual level, two-step cluster analysis revealed a considerable degree of inter-individual variability, with under half of the total sample (42%) showing the expected potentiation of CSE in response to atDCS across both sessions. Intra-individual variability in response to different durations of atDCS was also apparent, with one-third of the total sample (34%) exhibiting LTP-like effects in one session but LTD-like effects in the other session. Both the inter-individual (p = 0.027) and intra-individual (p = 0.04) variability was associated with BDNF genotype. In older adults, the BDNF Val66Met polymorphism along with stimulation duration appears to play a role in modulating tDCS-induced motor cortex plasticity. The results may have implications for the design of NBS protocols for healthy and diseased aged populations.

Potentiation of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica following its co-administration with the metabolic inhibitor, ketoconazole

An in vivo study in the laboratory rat model has been carried out to monitor morphological changes in adult Fasciola hepatica over a 4-day period resulting from co-treatment with triclabendazole (TCBZ) and ketoconazole (KTZ), a cytochrome P450 inhibitor. Rats were infected with the triclabendazole-resistant Oberon isolate of F. hepatica, dosed orally with triclabendazole at a dosage of 10mg/kg live weight and ketoconazole at a dosage of 10mg/kg live weight. Flukes were recovered at 24, 48, 72 and 96 h post-treatment (p.t.) and changes to fluke ultrastructure were assessed using transmission electron microscopy (TEM). Results showed an increase in the severity of changes to the fluke ultrastructure with time p.t. Swelling of the basal infolds and the associated mucopolysaccharide masses became more severe with time. Golgi complexes, if present, were greatly reduced in size and number by 96 h p.t., and sub-tegumental flooding was seen from the 72 h time-period onwards. Some sloughing of the tegumental covering over the spines was observed at 96 h p.t. The results demonstrated that the Oberon isolate is more sensitive to TCBZ action in the presence of KTZ than to TCBZ alone, reinforcing the idea that altered drug metabolism is involved in the resistance mechanism. Moreover, they support the concept that TCBZ+inhibitor combinations (aimed at altering drug pharmacokinetics and potentiating the action of TCBZ) could be used in the treatment of TCBZ-R populations of F. hepatica.

Metabolically-inactive glucagon-like peptide-1(9-36)amide confers selective protective actions against post-myocardial infarction remodelling

BACKGROUND: Glucagon-like peptide-1 (GLP-1) therapies are routinely used for glycaemic control in diabetes and their emerging cardiovascular actions have been a major recent research focus. In addition to GLP-1 receptor activation, the metabolically-inactive breakdown product, GLP-1(9-36)amide, also appears to exert notable cardiovascular effects, including protection against acute cardiac ischaemia. Here, we specifically studied the influence of GLP-1(9-36)amide on chronic post-myocardial infarction (MI) remodelling, which is a major driver of heart failure progression.

METHODS: Adult female C57BL/6 J mice were subjected to permanent coronary artery ligation or sham surgery prior to continuous infusion with GLP-1(9-36)amide or vehicle control for 4 weeks.

RESULTS: Infarct size was similar between groups with no effect of GLP-1(9-36)amide on MI-induced cardiac hypertrophy, although modest reduction of in vitro phenylephrine-induced H9c2 cardiomyoblast hypertrophy was observed. Whilst echocardiographic systolic dysfunction post-MI remained unchanged, diastolic dysfunction (decreased mitral valve E/A ratio, increased E wave deceleration rate) was improved by GLP-1(9-36)amide treatment. This was associated with modulation of genes related to extracellular matrix turnover (MMP-2, MMP-9, TIMP-2), although interstitial fibrosis and pro-fibrotic gene expression were unaltered by GLP-1(9-36)amide. Cardiac macrophage infiltration was also reduced by GLP-1(9-36)amide together with pro-inflammatory cytokine expression (IL-1β, IL-6, MCP-1), whilst in vitro studies using RAW264.7 macrophages revealed global potentiation of basal pro-inflammatory and tissue protective cytokines (e.g. IL-1β, TNF-α, IL-10, Fizz1) in the presence of GLP-1(9-36)amide versus exendin-4.

CONCLUSIONS: These data suggest that GLP-1(9-36)amide confers selective protection against post-MI remodelling via preferential preservation of diastolic function, most likely due to modulation of infiltrating macrophages, indicating that this often overlooked GLP-1 breakdown product may exert significant actions in this setting which should be considered in the context of GLP-1 therapy in patients with cardiovascular disease.

The African National Congress and its Critics: 'Predatory Liberalism', Black Empowerment and Intra-Alliance Tensions in Post-Apartheid South Africa

Post-apartheid South Africa is characterized by centralized, neo-liberal policymaking that perpetuates, and in some cases exaggerates, socio-economic inequalities inherited from the apartheid era. The African National Congress (ANC) leadership’s alignment with powerful international and domestic market actors produces tensions within the Tripartite Alliance and between government and civil society. Consequently, several characteristics of ‘predatory liberalism’ are evident in contemporary South Africa: neo-liberal restructuring of the economy is combined with an increasing willingness by government to assert its authority, to marginalize and delegitimize those critical of its abandonment of inclusive governance. A new form of oligarch power, combining entrenched economic interests with those of a new ‘black bourgeoisie’ promoted by narrowly implemented Black Economic Empowerment policies, diminishes prospects for broad-based socio-economic transformation. Because the new policy environment is failing to resolve tensions between global market demands for increasing market liberalization and domestic popular demands for poverty-alleviation and socio-economic transformation, the ANC leadership is forced increasingly to confront ‘ultra-leftists’ who are challenging its credentials as defender of the National Democratic Revolution which was the cornerstone in the anti-apartheid struggle.

State power matters: power, the state and political struggle in the post-war American novel

This article is concerned with resituating the state at the centre of the analytical stage and, concomitantly, with drawing attention to the dangers of losing sight of the state as a locus of power. It seeks to uncover the relationship between two related lines of critical inquiry: Marxist and Foucauldian theories of the state; and the attempts by three postwar American novelist (Ken Kesey, William Burroughs and E.L. Doctorow) to determine the nature and extent of this power and to consider under what conditions political struggle might be possible. It argues that such a move is needed because recent critical analysis has been too preoccupied by corporeal micropolitics and global macropolitics, and that the postwar American novel can help us in this move because it is centrally concerned with the repressive potentiality of the US state. It maintains that the resuscitation of Marxist state theories in early 1970s and a debate between Poulantzas and Foucault is intriguingly foreshadowed and even critiqued by these novels. Consequently, it concludes that these novels constitute an unrecognized pre-history of what would become one of the key intellectual debates of the late twentieth century: an engagement between Marxist and post-structuralist conceptions of the power and resistance.

Post-trauma: Is evidence based practice a fantasy?

Trauma, bereavement, and loss are universal human experiences. Much has been written about the process that the bereaved go through following the loss of a loved one. Recent events such as 9/11, earthquakes in Turkey, genocides in Rwanda, community conflict in Northern Ireland, and the Asian Tsunami Disaster have drawn unprecedented public attention to the subject of traumatic bereavement. Increasingly, it is recognised that while most people are able to cope with loss generally by eventually restructuring their lives, those bereaved in traumatic circumstance often find it extremely difficult. As a consequence, a plethora of interventions have emerged, however, to-date, little is know about their actual effectiveness in helping the bereaved. With the emphasis of health and welfare professions on evidencebased practice (EBP) greater than ever and a raising awareness of accountability as key element of ethical practice, the call for EBP in traumatic bereavement is compelling. Using examples from work carried out in Northern Ireland, we look at the backdrop of the issues involved, describe some of the most commonly used therapeutic interventions, and explore the possibility of evidence-based practice.