Fasciolicides: Efficacy, actions, resistance and its management

The modes of action of fasciolicides are described. Closantel and other salicylanilides interfere with energy metabolism by uncoupling oxidative phosphorylation in the fluke. Other fasciolicides are believed to have a metabolic action-halogenated phenols (via uncoupling) and clorsulon (via inhibition of glycolysis)-but direct evidence is lacking. Benzimidazoles (in particular, riclabendazole) bind to fluke tubulin and disrupt microtubule-based processes. Diamphenethide inhibits protein synthesis in the fluke. Other potential drug actions may contribute to overall drug efficacy. In particular, a number of fasciolicides-salicylanilides, phenols, diamphenethide-induce a rapid paralysis of the fluke, so their action may have a neuromuscular basis, although the actions remain ill-defined. Resistance to salicylanilides and triclabendazole has been detected in the field, although drug resistance does not appear to be a major problem yet. Strategies to minimize the development of resistance include the use of synergistic drug combinations, together with the design of integrated management programmes and the search for alternatives to drugs, in particular, vaccines. (C) 1999 Harcourt Publishers Ltd.

Cardiovascular actions of trout urotensin II in the conscious trout, Oncorhynchus mykiss

The central and peripheral cardiovascular effects of synthetic trout urotensin II (UII) were investigated in the conscious rainbow trout. Intracerebroventricular injection of 50 pmol UII produced a slight (3%) but significant (P < 0.05) increase in heart rate but had no effect on mean arterial blood pressure. Injection of 500 pmol UII icy produced a significant (P < 0.05) rise (8%) in blood pressure with no change in heart rate. In contrast to the weak presser effect of centrally administered UII, intra-arterial injection of UII produced a dose-dependent increase in arterial blood pressure and decrease in heart rate with significant (P < 0.05) effects on both parameters observed at a dose of 25 pmol. Higher doses of the peptide produced a sustained decrease in cardiac output that accompanied the bradycardia and rise in arterial blood pressure. The UII-induced bradycardia, but not the increase in pressure, was abolished by pretreatment with phentolamine. Trout UII produced a sustained and dose-dependent contraction of isolated vascular rings prepared from trout efferent branchial [-log 50% of the concentration producing maximal contraction (pD(2)) = 8.30] and celiacomesenteric (pD(2) = 8.22) arteries but was without effects on vascular rings from the anterior cardinal vein. The data indicate that the presser effect of UII in trout is mediated predominantly, if not exclusively, by an increase in systemic vascular resistance. The UII-induced hypertensive response does not seem to involve release of catecholamines, but the bradycardia may arise from adrenergic-mediated activation of cardioinhibitory baroreflexes.

Modelling the control of interceptive actions

In recent years, several phenomenological dynamical models have been formulated that describe how perceptual variables are incorporated in the control of motor variables. We call these short-route models as they do not address how perception-action patterns might be constrained by the dynamical properties of the sensory, neural and musculoskeletal subsystems of the human action system. As an alternative, we advocate a long-route modelling approach in which the dynamics of these subsystems are explicitly addressed and integrated to reproduce interceptive actions. The approach is exemplified through a discussion of a recently developed model for interceptive actions consisting of a neural network architecture for the online generation of motor outflow commands, based on time-to-contact information and information about the relative positions and velocities of hand and ball. This network is shown to be consistent with both behavioural and neurophysiological data. Finally, some problems are discussed with regard to the question of how the motor outflow commands (i.e. the intended movement) might be modulated in view of the musculoskeletal dynamics.

Prospective control of manual interceptive actions:comparative simulations of extant and new model constructs

Two prospective controllers of hand movements in catching-both based on required velocity control-were simulated. Under certain conditions, this required velocity control led to overshoots of the future interception point. These overshoots were absent in pertinent experiments. To remedy this shortcoming, the required velocity model was reformulated in terms of a neural network, the Vector Integration To Endpoint model, to create a Required Velocity Integration To Endpoint model. Addition of a parallel relative velocity channel, resulting in the Relative and Required Velocity Integration To Endpoint model, provided a better account for the experimentally observed kinematics than the existing, purely behavioral models. Simulations of reaching to intercept decelerating and accelerating objects in the presence of background motion were performed to make distinct predictions for future experiments.

Bogeymen, lunatics and fanatics: collective actions and the private enforcement of European competition law

The European desire to ensure that bearers of EU rights are adequately compensated for any infringement of these rights, particularly in cases where the harm is widely diffused, and perhaps not even noticed by those affected by it, collides with another desire: to avoid the perceived excesses of an American-style system of class actions. The excesses of these American class actions are in European discourse presented as a sort of bogeyman, which is a source of irrational fear, often presented by parental or other authority figures. But when looked at critically, the bogeyman disappears. In this paper, I examine the European (and UK) proposals for collective action. I compare them to the American regime. The flaws and purported excesses of the American regime, I argue, are exaggerated. A close, objective examination of the American regime shows this. I conclude that it is not the mythical bogeyman of a US class action that is the barrier to effective collective redress; rather, the barriers to effective, wide-ranging group actions lie within European legal culture and traditions, particularly those mandating individual control over litigation.

Auditory observation of stepping actions can cue both spatial and temporal components of gait in Parkinson's disease patients

Objectives: A common behavioural symptom of Parkinson’s disease (PD) is reduced step length (SL). Whilst sensory cueing strategies can be effective in increasing SL and reducing gait variability, current cueing strategies conveying spatial or temporal information are generally confined to the use of either visual or auditory cue modalities, respectively. We describe a novel cueing strategy using ecologically-valid ‘action-related’ sounds (footsteps on gravel) that convey both spatial and temporal parameters of a specific action within a single cue.
Methods: The current study used a real-time imitation task to examine whether PD affects the ability to re-enact changes in spatial characteristics of stepping actions, based solely on auditory information. In a second experimental session, these procedures were repeated using synthesized sounds derived from recordings of the kinetic interactions between the foot and walking surface. A third experimental session examined whether adaptations observed when participants walked to action-sounds were preserved when participants imagined either real recorded or synthesized sounds.
Results: Whilst healthy control participants were able to re-enact significant changes in SL in all cue conditions, these adaptations, in conjunction with reduced variability of SL were only observed in the PD group when walking to, or imagining the recorded sounds.
Conclusions: The findings show that while recordings of stepping sounds convey action information to allow PD patients to re-enact and imagine spatial characteristics of gait, synthesis of sounds purely from gait kinetics is insufficient to evoke similar changes in behaviour, perhaps indicating that PD patients have a higher threshold to cue sensorimotor resonant responses.

Human parietal and primary motor cortical interactions are selectively modulated during the transport and grip formation of goal-directed hand actions

Posterior parietal cortex (PPC) constitutes a critical cortical node in the sensorimotor system in which goal-directed actions are computed. This information then must be transferred into commands suitable for hand movements to the primary motor cortex (M1). Complexity arises because reach-to-grasp actions not only require directing the hand towards the object (transport component), but also preshaping the hand according to the features of the object (grip component). Yet, the functional influence that specific PPC regions exert over ipsilateral M1 during the planning of different hand movements remains unclear in humans. Here we manipulated transport and grip components of goal-directed hand movements and exploited paired-pulse transcranial magnetic stimulation (ppTMS) to probe the functional interactions between M1 and two different PPC regions, namely superior parieto-occipital cortex (SPOC) and the anterior region of the intraparietal sulcus (aIPS), in the left hemisphere. We show that when the extension of the arm is required to contact a target object, SPOC selectively facilitates motor evoked potentials, suggesting that SPOC-M1 interactions are functionally specific to arm transport. In contrast, a different pathway, linking the aIPS and ipsilateral M1, shows enhanced functional connections during the sensorimotor planning of grip. These results support recent human neuroimaging findings arguing for specialized human parietal regions for the planning of arm transport and hand grip during goal-directed actions. Importantly, they provide new insight into the causal influences these different parietal regions exert over ipsilateral motor cortex for specific types of planned hand movements

Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix

Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically exploited for glycaemic control in diabetes, which also confers acute cardioprotection and benefits in experimental/clinical heart failure. We specifically investigated the role of the GLP-1 mimetic, exendin-4, in post-myocardial infarction (MI) remodelling, which is a key contributor to heart failure. Adult female normoglycaemic mice underwent coronary artery ligation/sham surgery prior to infusion with exendin-4/vehicle for 4 weeks. Metabolic parameters and infarct sizes were comparable between groups. Exendin-4 protected against cardiac dysfunction and chamber dilatation post-MI and improved survival. Furthermore, exendin-4 modestly decreased cardiomyocyte hypertrophy/apoptosis but markedly attenuated interstitial fibrosis and myocardial inflammation post-MI. This was associated with altered extracellular matrix (procollagen IαI/IIIαI, connective tissue growth factor, fibronectin, TGF-β3) and inflammatory (IL-10, IL-1β, IL-6) gene expression in exendin-4-treated mice, together with modulation of both Akt/GSK-3β and Smad2/3 signalling. Exendin-4 also altered macrophage response gene expression in the absence of direct actions on cardiac fibroblast differentiation, suggesting cardioprotective effects occurring secondary to modulation of inflammation. Our findings indicate that exendin-4 protects against post-MI remodelling via preferential actions on inflammation and the extracellular matrix independently of its established actions on glycaemic control, thereby suggesting that selective targeting of GLP-1 signalling may be required to realise its clear therapeutic potential for post-MI heart failure.