Alterations in ciliary neurotrophic factor signaling in rapsyn deficient mice

Rapsyn is a key molecule involved in the formation of postsynaptic specializations at the neuromuscular junction, in its absence there are both pre- and post-synaptic deficits including failure to cluster acety]choline receptors. Recently we have documented increases in both nerve-muscle branching and numbers of motoneurons, suggesting alterations in skeletal muscle derived trophic support for motoneurons. The aim of the present study was to evaluate the contribution of target derived trophic factors to increases in motoneuron branching and number, in rapsyn deficient mice that had their postsynaptic specializations disrupted, We have used reverse transcription-polymerase chain reaction and Western blot to document the expression of known trophic factors and their receptors in muscle, during the period of synapse formation in rapsyn deficient mouse embryos. We found that the mRNA levels for ciliary neurotrophic factor (CNTF) was decreased in the rapsyn deficient muscles compared with litter mate controls although those for NGF, BDNF, NT-3 and TGF-beta2 did not differ. We found that both the mRNA and the protein expression for suppressor of cytokine signaling 3 (SOCS3) decreased although janus kinase 2 (JAK2) did not change in the rapsyn deficient muscles compared with litter mate controls. These results suggest that failure to form postsynaptic specializations in rapsyn deficient mice has altered the CNTF cytokine signaling pathway within skeletal muscle, the target for motoneurons. This alteration may in part, account for the increased muscle nerve branching and motoneuron survival seen in rapsyn deficient mice. (C) 2001 Wiley-Liss, Inc.

The effect of musculoskeletal pain on motor activity and control

Aberrant movement patterns and postures are obvious to clinicians managing patients with musculoskeletal pain. However, some changes in motor function that occur in the presence of pain are less apparent. Clinical and basic science investigations have provided evidence of the effects of nociception on aspects of motor function. Both increases and decreases in muscle activity have been shown, along with alterations in neuronal control mechanisms, proprioception, and local muscle morphology. Various models have been proposed in an attempt to provide an explanation for some of these changes. These include the vicious cycle and pain adaptation models. Recent research has seen the emergence of a new model in which patterns of muscle activation and recruitment are altered in the presence of pain (neuromuscular activation model). These changes seem to particularly affect the ability of muscles to perform synergistic functions related to maintaining joint stability and control. These changes are believed to persist into the period of chronicity. This review shows current knowledge of the effect of musculoskeletal pain on the motor system and presents the various proposed models, in addition to other shown effects not covered by these models. The relevance of these models to both acute and chronic pain is considered. It is apparent that people experiencing musculoskeletal pain exhibit complex motor responses that may show some variation with the time course of the disorder. (C) 2001 by the American Pain Society.

New perspectives on the role of aldosterone excess in cardiovascular disease

1. Evidence from recent experimental and clinical studies suggests that excessive circulating levels of aldosterone can bring about adverse cardiovascular sequelae independent of the effects on blood pressure. Examples of these sequelae are the development of myocardial and vascular fibrosis in uninephrectomized, salt-loaded rats infused with mineralocorticoids and, in humans, an association of aldosterone with left ventricular hypertrophy, impaired diastolic and systolic function, salt and water retention causing aggravation of congestion in patients with established congestive cardiac failure (CCF), reduced vascular compliance and an increased risk of arrhythmias (resulting from intracardiac fibrosis, hypokalaemia, hypomagnesaemia, reduced baroreceptor sensitivity and potentiation of catecholamine effects). 2. These sequelae of aldosterone excess may contribute to the pathogenesis and worsen the prognosis of CCF and hypertension. 3. The heart and blood vessels may be capable of extra-adrenal aldosterone biosynthesis, raising the possibility that aldosterone may have paracrine or autocrine (and not just endocrine) effects on cardiovascular tissues. 4. The high prevalence of CCF, which is associated with secondary aldosteronism, and primary aldosteronism (PAL; recently recognized to be a much more common cause of hypertension than was previously thought) argue for an important role for aldosterone excess as a cause of cardiovascular injury. 5. The recognition of non-blood pressure-dependent adverse sequelae of aldosterone excess raises the question as to whether normotensive individuals with PAL, who have been detected as a result of genetic or biochemical screening among families with inherited forms of PAL, are at excess risk of cardiovascular events. 6. Provided that patients are carefully investigated in order to permit the appropriate selection of specific surgical (laparoscopic adrenalectomy for PAL that lateralizes on adrenal venous sampling) or medical (treatment with aldosterone antagonist medications) management and safety considerations for the use of aldosterone antagonists are kept in mind, the appreciation of a widening role for aldosterone in cardiovascular disease should provide a substantially better outlook for many patients with CCF and hypertension.

The parkin gene S/N167 polymorphism in Australian Parkinson's disease patients and controls

This study determined the frequencies of a G-to-A transition (S/N167) polymorphism in exon 4 of the parkin gene in Australian Parkinson's disease patients and control subjects. The genotype of each subject was determined using the polymerase chain reaction and restriction-fragment-length-polymorphism analysis. Overall, the A allele was significantly less common in the Parkinson's disease group (1.7%) compared with the control group (3.8%, OR = 0.43, 95% CI = 0.19-1.00, P < 0.05), although the frequency in the young onset Parkinson's disease group (6.6%) was not significantly different to controls. The A allele is less common in Australian Caucasian subjects compared to Japanese Parkinson's disease patients and appears to be under-represented in older-onset Parkinson's disease. <(c)> 2001 Elsevier Science Ltd. All rights reserved.

Can anticonvulsant drug therapy 'cure' epilepsy?

There is now evidence to show that, as time passes, epilepsy, even if untreated, tends to undergo spontaneous remission in a significant proportion of patients. The question therefore arises as to whether anticonvulsant drug therapy increases this chance of the patient with epilepsy ultimately entering a terminal remission which continues after the treatment is withdrawn, Le. whether anticonvulsant drug therapy itself may sometimes cure epilepsy. There are no well-designed studies available in the literature that provide a clear answer to this question. However, data from a number of investigations carried out for other purposes can be used to see whether contemporary anticonvulsant drug therapy is associated with higher rates of expected untreated terminal remission than those that apply for never-treated patients with epilepsy, or for those whose anticonvulsant treatment has probably been inadequate for various social or historical reasons. Despite the admitted uncertainties inherent in drawing conclusions from such material, there appears to be a reasonably consistent tendency for contemporary anticonvulsant drug treatment to be associated with a greater chance of achieving probable cure of epilepsy. Therefore it would appear premature to take the view that contemporary anticonvulsant drug therapy does no more than suppress epileptic seizures until epilepsy remits spontaneously, or fails to remit, with the passing of time.

Haptic information stabilizes and destabilizes coordination dynamics

Goal-directed, coordinated movements in humans emerge from a variety of constraints that range from 'high-level' cognitive strategies based oil perception of the task to 'low-level' neuromuscular-skeletal factors such as differential contributions to coordination from flexor and extensor muscles. There has been a tendency in the literature to dichotomize these sources of constraint, favouring one or the other rather than recognizing and understanding their mutual interplay. In this experiment, subjects were required to coordinate rhythmic flexion and extension movements with an auditory metronome, the rate of which was systematically increased. When subjects started in extension on the beat of the metronome, there was a small tendency to switch to flexion at higher rates, but not vice versa. When subjects: were asked to contact a physical stop, the location of which was either coincident with or counterphase to the auditor) stimulus, two effects occurred. When haptic contact was coincident with sound, coordination was stabilized for both flexion and extension. When haptic contact was counterphase to the metronome, coordination was actually destabilized, with transitions occurring from both extension to flexion on the beat and from flexion to extension on the beat. These results reveal the complementary nature of strategic and neuromuscular factors in sensorimotor coordination. They also suggest the presence of a multimodal neural integration process-which is parametrizable by rate and context - in which intentional movement, touch and sound are bound into a single, coherent unit.

Abolition of (-)-CGP 12177-evoked cardiostimulation in double beta(1)/beta(2)-adrenoceptor knockout mice. Obligatory role of beta(1)-adrenoceptors for putative beta 4-adrenoceptor pharmacology

Some beta (1)- and beta (2)-adrenoceptor-blocking agents, such as (-)-CGP 12177, cause cardiostimulant effects at concentrations considerably higher than those that antagonise the effects of catecholamines. The cardiostimulant effects of these non-conventional partial agonists are relatively resistant to blockade by (-)-propranolol and have been proposed to be mediated through putative beta (4)-adrenoceptors or through atypical states of either beta (1)- or beta (2)-adrenoceptors. We investigated the effects of (-)-CGP 12177 on sinoatrial rate and left atrial contractile force as well as the ventricular binding of (-)-[H-3]CGP 12177 in tissues from wild-type, beta (2)-adrenoceptor knockout and beta (1)/beta (2)-adrenoceptor double knockout mice. The cardiostimulant effects of (-)-CGP 12177 were present in wildtype and beta (2)-adrenoceptor knockout mice but were absent in beta (1)/beta (2)-adrenoceptor double knockout mice. Thus, the presence of beta (1)-adrenoceptors is obligatory for the cardiostimulant effects of (-)-CGP 12177. It appears therefore that an atypical state of the beta (1)-adrenoceptor contributes to the mediation of the cardiostimulant effects induced by non-conventional partial agonists. Ventricular beta (1)- and beta (2)-adrenoceptors, labelled in wild-type with a K(D)similar to0.5 nmol/l (similar to 16 fmol/mg protein), were absent in beta (1)/beta (2)-adrenoceptor double knockout mice. However, a high density binding site (similar to 154-391 fmol/mg protein) that did not saturate completely (K(D)similar to 80-200 nM) was labelled by (-)-[H-3]CGP 12177 in the three groups of mice, being distinct from beta (1)- and beta (2)-adrenoceptors, as well as from the site mediating the agonist effects of(-)-CGP 12177.

Changes in muscle recruitment patterns during skill acquisition

The control of movement is predicated upon a system of constraints of musculoskeletal and neural origin. The focus of the present study was upon the manner in which such constraints are adapted or superseded during the acquisition of motor skill. Individuals participated in five experimental sessions, ill which they attempted to produce abduction-adduction movements of the index finger in time with an auditory metronome. During each trial, the metronome frequency was increased in eight steps from an individually determined base frequency. Electromyographic (EMC) activity was recorded from first dorsal interosseous (FDI), first volar interosseous (FVI), flexor digitorum superficialis (FDS), and extensor digitorum communis (EDC) muscles. The movements produced on the final day of acquisition more accurately matched the required profile, and exhibited greater spatial and temporal stability, than those generated during initial performance. Tn the early stages of skill acquisition, an alternating pattern of activation in FDI and FVI was maintained, even at the highest frequencies. Tn contrast, as the frequency of movement was increased, activity in FDS and EDC was either tonic or intermittent. As learning proceeded, alterations in recruitment patterns were expressed primarily in the extrinsic muscles (EDC and FDS). These changes took the form of increases in the postural role of these muscles, shifts to phasic patterns of activation, or selective disengagement of these muscles. These findings suggest that there is considerable flexibility in the composition of muscle synergies, which is exploited by individuals during the acquisition of coordination.

Quantum measurement of coherent tunnelling between quantum dots

We describe the conditional and unconditional dynamics of two coupled quantum dots when one dot is subjected to a measurement of its occupation number by coupling it to a third readout dot via the Coulomb interaction. The readout dot is coupled to source and drain leads under weak bias, and a tunnel current flows through a single bound state when energetically allowed. The occupation of the quantum dot near the readout dot shifts the bound state of the readout dot from a low conducting state to a high conducting state. The measurement is made by continuously monitoring the tunnel current through the readout dot. We show that there is a difference between the time scale for the measurement-induced decoherence between the localized states of the dots, and the time scale on which the system becomes localized due to the measurement.

Adaptation to chronic eccentric exercise in humans: the influence of contraction velocity

We compared changes in muscle fibre composition and muscle strength indices following a 10 week isokinetic resistance training programme consisting of fast (3.14 rad(.)s(-1)) or slow (0.52 rad(.)s(-1)) velocity eccentric muscle contractions. A group of 20 non-resistance trained subjects were assigned to a FAST (n = 7), SLOW (n = 6) or non-training CONTROL (n = 7) group. A unilateral training protocol targeted the elbow flexor muscle group and consisted of 24 maximal eccentric isokinetic contractions (four sets of six repetitions) performed three times a week for 10 weeks. Muscle biopsy samples were obtained from the belly of the biceps brachii. Isometric torque and concentric and eccentric torque at 0.52 and 3.14 rad(.)s(-1) were examined at 0, 5 and 10 weeks. After 10 weeks, the FAST group demonstrated significant [mean (SEM)] increases in eccentric [29.6 (6.4)%] and concentric torque [27.4 (7.3) %] at 3.14 rad(.)s(-1), isometric torque [21.3 (4.3)%] and eccentric torque [25.2 (7.2) %] at 0.52 rad(.)s(-1). The percentage of type I fibres in the FAST group decreased from [53.8 (6.6)% to 39.1 (4.4)%] while type lib fibre percentage increased from [5.8 (1.9)% to 12.9 (3.3)%; P < 0.05]. In contrast. the SLOW group did not experience significant changes in muscle fibre type or muscle torque. We conclude that neuromuscular adaptations to eccentric training stimuli may be influenced by differences in the ability to cope with chronic exposure to relatively fast and slow eccentric contraction velocities. Possible mechanisms include greater cumulative damage to contractile tissues or stress induced by slow eccentric muscle contractions.

Stimulation of protein kinase C-dependent and -independent signaling pathways by bistratene A in intestinal epithelial cells

The marine toxin bistratene A (BisA) potently induces cytostasis and differentiation in a variety of systems. Evidence that BisA is a selective activator of protein kinase C (PKC) delta implicates PKC delta signaling in the negative growth-regulatory effects of this agent. The current study further investigates the signaling pathways activated by BisA by comparing its effects with those of the PKC agonist phorbol 12-myristate 13-acetate (PMA) in the IEC-18 intestinal crypt cell line. Both BisA and PMA induced cell cycle arrest in these cells, albeit with different kinetics. While BisA produced sustained cell cycle arrest in G(o)/G(1) and G(2)/M, the effects of PMA were transient and involved mainly a G(o)/G(1), blockade. BisA also produced apoptosis in a proportion of the population, an effect not seen with PMA. Both agents induced membrane translocation/activation of PKC, with BisA translocating only PKC delta and PMA translocating PKC alpha, delta, and epsilon in these cells. Notably, while depletion of PKC alpha, delta, and epsilon abrogated the cell cycle-specific effects of PMA in IEC-18 cells, the absence of these PKC isozymes failed to inhibit BisA-induced G(o)/G(1), and G(2)/M arrest or apoptosis. The cell cycle inhibitory and apoptotic effects of BisA, therefore, appear to be PKC-independent in IEG-18 cells. On the other hand, BisA and PMA both promoted PKC-dependent activation of Erk 1 and 2 in this system. Thus, intestinal epithelial cells respond to BisA through activation of at least two signaling pathways: a PKC delta -dependent pathway, which leads to activation of mitogen-activated protein kinase and possibly cytostasis in the appropriate context, and a PKC-independent pathway, which induces both cell cycle arrest in G(o)/G(1) and G(2)/M and apoptosis through as yet unknown mechanisms. (C) 2001 Elsevier Science Inc. All rights reserved.