The sensory origins of human position sense.

KEY POINTS: Position sense at the human forearm can be measured in blindfolded subjects by matching positions of the arms or by a subject pointing to the perceived position of an unseen arm. Effects on position sense tested were: elbow muscle conditioning with a voluntary contraction, muscle vibration, loading the arm and elbow skin stretch. Conditioning contractions and vibration produced errors in a matching task, consistent with the action of muscle spindles as position sensors. Position errors in a pointing task were not consistent with the action of muscle spindles. Loading the arm or skin stretch had no effect in either matching or pointing tasks. It is proposed that there are two kinds of position sense: (i) indicating positions of different body parts relative to one another, using signals from muscle spindles; and (ii) indicating position of the body in extrapersonal space, using signals from exteroceptors, vision, touch and hearing. ABSTRACT: Human limb position sense can be measured in two ways: in a blindfolded matching task, position of one limb is indicated with the other limb. Alternatively, position of a limb, hidden from view, is indicated with a pointer, moved by pressing a lever. These experiments examined the sensory basis of position sense measured in these two ways. Position errors were measured in 14 subjects after elbow flexors or extensors had been conditioned with a half-maximum voluntary contraction. In agreement with previous studies, in the matching trials, position errors were distributed according to a pattern consistent with the action of muscle spindles as the position sensors. In the pointing trials, all errors lay in the direction of extension of the true position of the hidden arm and their distribution was inconsistent with influences arising in muscle spindles. Vibration of elbow muscles produced an illusion of muscle lengthening during a matching task, while during the pointing task no illusion was present. Finally, the matching-pointing error difference was preserved, even when one arm was loaded with a weight or skin over the elbow was stretched. It is proposed that there are two kinds of position sense. One is signalled by muscle spindles, indicating position of one part of the body relative to another. A second provides information about the position of the body in extrapersonal space and here we hypothesise that exteroceptors, including vision, touch and hearing, acting via a central map of the body, provide the spatial information.

Position sense at the human forearm after conditioning elbow muscles with isometric contractions.

These experiments were designed to test the idea that, in a forearm position-matching task, it is the difference in afferent signals coming from the antagonist muscles of the forearm that determines the perceived position of the arm. In one experiment, flexor and then extensor muscles of the reference arm were conditioned by isometric voluntary contractions while the arm was held at the test angle, approximately 45° from the horizontal. At the same time, indicator arm flexor muscles were contracted while the arm was flexed, or extensors were contracted while it was extended. After an indicator flexor contraction, during matching, subjects made large errors in the direction of flexion, by 9.3° relative to the reference arm and after an indicator extensor contraction by 7.4° in the direction of extension. In the second experiment, with reference muscles conditioned as before, slack was introduced in indicator muscles by a combination of muscle contraction and stretch. This was expected to lower levels of afferent activity in indicator muscles. The subsequent matching experiment yielded much smaller errors than before, 1.4° in the direction of flexion. In both experiments, signal levels coming from the reference arm remained the same and what changed was the level of indicator signal. The fact that matching errors were small when slack was introduced in indicator muscles supported the view that the signal coming from reference muscles was also small. It was concluded that the brain is concerned with the signal difference from the antagonist pair of each arm and with the total signal difference between the two arms.

The senses of active and passive forces at the human ankle joint.

The traditional view of the neural basis for the sense of muscle force is that it is generated at least in part within the brain. Recently it has been proposed that force sensations do not arise entirely centrally and that there is a contribution from peripheral receptors within the contracting muscle. Evidence comes from experiments on thumb flexor and elbow flexor muscles. Here we have studied the sense of force in plantar flexor muscles of the human ankle, looking for further evidence for such a mechanism. The active angle-torque curve was measured for muscles of both legs, and for each muscle, ankle angles were identified on the ascending and descending limbs of the curve where active forces were similar. In a plantar flexion force matching task, subjects were asked to match the force in one foot, generated on the ascending limb of the curve, with force in the other foot, generated on the descending limb. It was hypothesised that despite active forces being similar, the sensation generated in the more stretched muscle should be greater because of the contribution from its peripheral stretch receptors, leading to an overestimation of the force in the stretched muscle. It was found that provided that the comparison was between active forces, there was no difference in the forces generated by the two legs, supporting the central hypothesis for the sense of force. When total forces were matched, including a component of passive force due to muscle stretch, subjects seemed to ignore the passive component. Yet subjects had an acute sense of passive force, provided that the muscles remained relaxed. It was concluded that subjects had two senses, a sense of active force, generated centrally, and a sense of passive force, or perhaps muscle stretch, generated within the muscle itself.

Sensing the body in chronic pain: a review of psychophysical studies implicating altered body representation.

There is growing evidence that chronic pain conditions can have an associated central pathology, involving both cortical reorganisation and an incongruence between expected and actual sensory-motor feedback. While such findings are primarily driven by the recent proliferation of neuroimaging studies, the psychophysical tasks that complement those investigations have received little attention. In this review, we discuss the literature that involves the subjective appraisal of body representation in patients with chronic pain. We do so by examining three broad sensory systems that form the foundations of the sense of physical self in patients with common chronic pain disorders: (i) reweighting of proprioceptive information; (ii) altered sensitivity to exteroceptive stimuli; and, (iii) disturbed interoceptive awareness of the state of the body. Such findings present compelling evidence for a multisensory and multimodal approach to therapies for chronic pain disorders.

Limb position sense, proprioceptive drift and muscle thixotropy at the human elbow joint.

These experiments on the human forearm are based on the hypothesis that drift in the perceived position of a limb over time can be explained by receptor adaptation. Limb position sense was measured in 39 blindfolded subjects using a forearm-matching task. A property of muscle, its thixotropy, a contraction history-dependent passive stiffness, was exploited to place muscle receptors of elbow muscles in a defined state. After the arm had been held flexed and elbow flexors contracted, we observed time-dependent changes in the perceived position of the reference arm by an average of 2.8° in the direction of elbow flexion over 30 s (Experiment 1). The direction of the drift reversed after the arm had been extended and elbow extensors contracted, with a mean shift of 3.5° over 30 s in the direction of elbow extension (Experiment 2). The time-dependent changes could be abolished by conditioning elbow flexors and extensors in the reference arm at the test angle, although this led to large position errors during matching (±10°), depending on how the indicator arm had been conditioned (Experiments 3 and 4). When slack was introduced in the elbow muscles of both arms, by shortening muscles after the conditioning contraction, matching errors became small and there was no drift in position sense (Experiments 5 and 6). These experiments argue for a receptor-based mechanism for proprioceptive drift and suggest that to align the two forearms, the brain monitors the difference between the afferent signals from the two arms.

Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes.

AIMS/HYPOTHESIS: The small, highly conserved vasoactive peptide urotensin II (UII) is upregulated in atherosclerosis. However, its effects in diabetes-associated atherosclerosis have not been assessed. METHODS: Endothelial cells were grown in normal- and high-glucose (5 and 25 mmol/l) media with and without UII (10⁻8 mol/l) and/or the UII receptor antagonist, SB-657510 (10⁻8 mol/l). Apoe knockout (KO) mice with or without streptozotocin-induced diabetes were treated with or without SB-657510 (30 mg kg⁻¹ day⁻¹; n = 20 per group) and followed for 20 weeks. Carotid endarterectomy specimens from diabetic and non-diabetic humans were also evaluated. RESULTS: In high (but not normal) glucose medium, UII significantly increased CCL2 (encodes macrophage chemoattractant protein 1 [MCP-1]) gene expression (human aortic endothelial cells) and increased monocyte adhesion (HUVECs). UII receptor antagonism in diabetic Apoe KO mice significantly attenuated diabetes-associated atherosclerosis and aortic staining for MCP-1, F4/80 (macrophage marker), cyclooxygenase-2, nitrotyrosine and UII. UII staining was significantly increased in carotid endarterectomies from diabetic compared with non-diabetic individuals, as was staining for MCP-1. CONCLUSIONS/INTERPRETATION: This is the first report to demonstrate that UII is increased in diabetes-associated atherosclerosis in humans and rodents. Diabetes-associated plaque development was attenuated by UII receptor antagonism in the experimental setting. Thus UII may represent a novel therapeutic target in the treatment of diabetes-associated atherosclerosis.

Delayed intervention with AGE inhibitors attenuates the progression of diabetes-accelerated atherosclerosis in diabetic apolipoprotein E knockout mice.

AIMS/HYPOTHESIS: Formation of AGEs is increased in the diabetic milieu, which contributes to accelerated atherogenesis. We studied whether delayed treatment with AGE-inhibiting compounds, alagebrium chloride and pyridoxamine dihydrochloride, affected established atherosclerosis in experimental diabetes in comparison with the angiotensin-converting enzyme inhibitor, quinapril. METHODS: Streptozotocin-induced diabetic male Apoe (-/-) mice (n = 24 per group) received, by oral gavage, from week 10 to 20 of diabetes: no treatment; alagebrium (1 mg kg(-1) day(-1)); pyridoxamine (1 g/l in drinking water); or quinapril (30 mg kg(-1) day(-1)). Atherosclerotic lesion area (en face analysis) was evaluated for all groups. RESULTS: Delayed intervention with alagebrium decreased plaque area in the diabetic Apoe (-/-) mice compared with untreated mice (total plaque area: alagebrium 10.6 ± 1.6%, untreated, 15.1 ± 1.5%, p < 0.05). This anti-atherosclerotic effect was comparable with that achieved with quinapril (quinapril 8.4 ± 1.4%, vs untreated, p < 0.05). Pyridoxamine also attenuated plaque development in diabetic mice (5.7 ± 1.2% vs untreated 11.9 ± 1.1%, p < 0.05). The anti-atherosclerotic effect conferred by alagebrium and quinapril was associated with a significant reduction in vascular oxidative stress and circulating AGEs and methylglyoxal, although preformed AGEs were not removed from the vascular wall with either delayed intervention. CONCLUSIONS/INTERPRETATION: Inhibition of AGE accumulation, using a delayed intervention with alagebrium or pyridoxamine, significantly attenuated the progression of established diabetes-associated atherosclerosis, similar to results obtained with quinapril. These findings provide further evidence that blockade of AGE-mediated pathways may present a novel therapy for the prevention of atherosclerosis in diabetes.

Receptor for AGEs (RAGE) blockade may exert its renoprotective effects in patients with diabetic nephropathy via induction of the angiotensin II type 2 (AT2) receptor.

AIMS/HYPOTHESIS: The receptor for AGEs (RAGE) contributes to the development and progression of diabetic nephropathy. In this study, we examined whether the protective effects of RAGE blockade are exerted via modulation of the renal angiotensin II type 2 (AT2) receptor. METHODS: Control and streptozotocin diabetic mice, wild-type or deficient in the AT2 receptor (At2 knockout [KO]) or RAGE (Rage KO), were studied for 24 weeks. Adenoviral overexpression of full-length Rage in primary rat mesangial cells was also used to determine the effects on AT2 production. RESULTS: With diabetes, Rage-deficient mice had less albuminuria, and an attenuation of hyperfiltration and glomerulosclerosis as compared with diabetic wild-type and At2 KO mice. Renal gene and protein expression of RAGE was elevated with diabetes. Diabetic Rage KO mice had a greater increase in renal AT2 receptor protein than was seen in diabetic wild-type mice. Diabetes-induced increases in renal cytosolic and mitochondrial superoxide generation were prevented in diabetic Rage KO mice, but enhanced in all At2 KO mice. Adenoviral overexpression of RAGE or AGE treatment decreased cell surface AT2 expression, in association with increasing superoxide generation; both were reversed using antioxidants N-acetylcysteine and apocynin, and soluble RAGE in primary mesangial cells. CONCLUSIONS/INTERPRETATION: RAGE appears to be a common and key modulator of AT2 receptor expression, a finding that would implicate a newly defined RAGE-AT2 axis in the development and progression of diabetic nephropathy.

Angiotensin II subtype 2 receptor blockade and deficiency attenuate the development of atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes.

AIMS/HYPOTHESIS: Most of the known actions of angiotensin II have been considered primarily to be the result of angiotensin II subtype 1 receptor activation. However, recent data suggest that the angiotensin II subtype 2 receptor (AT(2)R) may modulate key processes linked to atherosclerosis. The aim of this study was to investigate the role of AT(2)R in diabetes-associated atherosclerosis using pharmacological blockade and genetic deficiency. METHODS: Aortic plaque deposition was assessed in streptozotocin-induced diabetic apolipoprotein E (Apoe) knockout (KO) and At ( 2 ) r (also known as Agtr2)/Apoe double-KO (DKO) mice. Control and diabetic Apoe-KO mice received an AT(2)R antagonist PD123319 (5 mg kg(-1) day(-1)) via osmotic minipump for 20 weeks (n = 7-8 per group). RESULTS: Diabetes was associated with a sixfold increase in plaque area (diabetic Apoe-KO: 12.7 +/- 1.4% vs control Apoe-KO: 2.3 +/- 0.4%, p < 0.001) as well as a significant increase in aortic expression of the gene At ( 2 ) r (also known as Agtr2). The increase in plaque area with diabetes was attenuated in AT(2)R antagonist-treated diabetic Apoe-KO mice (7.1 +/- 0.5%, p < 0.05) and in diabetic At ( 2 ) r/Apoe DKO mice (9.2 +/- 1.3%, p < 0.05). These benefits occurred independently of glycaemic control or BP, and were associated with downregulation of a range of pro-inflammatory cytokines, adhesion molecules, chemokines and various extracellular matrix proteins. CONCLUSIONS/INTERPRETATION: This study provides evidence for AT(2)R playing a role in the development of diabetes-associated atherosclerosis. These findings suggest a potential utility of AT(2)R blockers in the prevention and treatment of diabetic macrovascular complications.

Cell division autoantigen 1 plays a profibrotic role by modulating downstream signalling of TGF-beta in a murine diabetic model of atherosclerosis.

AIMS/HYPOTHESIS: Excess accumulation of vascular extracellular matrix (ECM) is an important pathological process in cardiovascular diseases including diabetes-associated atherosclerosis. We explored how a recently identified molecule, cell division autoantigen 1 (CDA1), influences the profibrotic TGF-beta pathway leading to vascular ECM accumulation. METHODS: Expression levels of genes encoding for CDA1, TGF-beta and connective tissue growth factor (CTGF) were examined in aorta from Apoe(-/-) mice with or without diabetes. We used retroviral and adenoviral constructs to knockdown or overexpress Tspyl2, the gene encoding CDA1, in mouse vascular smooth muscle cells (VSMCs) with or without TGF-beta treatment in order to demonstrate the role of CDA1 in TGF-beta signalling. RESULTS: In vivo studies indicated that the mRNA levels of CDA1-encoding gene Tspyl2 and protein levels of CDA1 were elevated in the aorta of diabetic Apoe(-/-) mice, accompanied by increased levels of Tgf-beta (also known as Tgfb1), Ctgf and ECM accumulation. In vitro studies in vascular cells showed that TGF-beta treatment rapidly increased CDA1 protein levels, which then amplified TGF-beta signalling leading to upregulation of ECM genes. Knockdown of CDA1-encoding gene Tspyl2 to reduce cellular CDA1 level markedly attenuated TGF-beta-stimulated MAD homologue 3 (drosophila; SMAD3) phosphorylation and transcriptional activities. CDA1 overproduction increased and Tspyl2 knockdown decreased expression of TGF-beta receptor type I, TbetarI (also known as Tgfbr1), but not TGF-beta receptor type II, TbetarII (also known as Tgfbr2), providing a mechanism for CDA1's action in modulating TGF-beta signalling. Knockdown of CDA1-encoding gene Tspyl2 also blocked the profibrotic effect of TGF-beta in VSMCs. CONCLUSIONS/INTERPRETATION: CDA1 plays an important role in vascular ECM accumulation by amplifying TGF-beta signalling. This is critical for the profibrotic effect of TGF-beta in the vasculature. CDA1 is therefore a potential target for attenuating vascular ECM accumulation caused by enhanced TGF-beta action, as seen in diabetic atherosclerosis.

The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice.

AIMS/HYPOTHESIS: There is convincing evidence that the endothelin system contributes to diabetic nephropathy and cardiovascular disease. This study aimed to assess the effects of the non-peptidergic endothelin receptor A (ETA) antagonist avosentan in a mouse model of accelerated diabetic nephropathy and atherosclerosis in comparison with the ACE inhibitor, quinapril. METHODS: Apolipoprotein E (Apoe) knockout (KO) mice (n = 20 per group, five groups) were randomised to the following groups: non-diabetic controls and streptozotocin-induced diabetic animals gavaged daily for 20 weeks with placebo, avosentan (high dose: 30 mg/kg, or low dose: 10 mg/kg) or quinapril (given in drinking water, 30 mg/kg). RESULTS: BP was unchanged by avosentan treatment but decreased with quinapril treatment. Diabetes-associated albuminuria was significantly attenuated by high-dose avosentan after 10 and 20 weeks of treatment. Diabetic animals showed a decreased creatinine clearance, which was normalised by avosentan treatment. In diabetic mice, high-dose avosentan treatment significantly attenuated the glomerulosclerosis index, mesangial matrix accumulation, glomerular accumulation of the matrix proteins collagen IV, and renal expression of genes encoding connective tissue growth factor, vascular endothelial growth factor, transforming growth factor beta and nuclear factor kappaB (p65 subunit). Furthermore, high-dose avosentan treatment was also associated with reduced expression of the genes for ETA, ETB and angiotensin receptor 1. The renoprotective effects of avosentan were comparable or superior to those observed with quinapril. High-dose avosentan also significantly attenuated diabetes-associated aortic atherosclerosis in Apoe KO mice and reduced macrophage infiltration and aortic nitrotyrosine expression. CONCLUSIONS/INTERPRETATION: This study demonstrates that ETA blockade with avosentan may provide an alternate therapeutic strategy for the treatment of diabetic micro- and macrovascular complications.

PPARs and diabetes-associated atherosclerosis.

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors affecting the regulation of various genes relevant to the pathogenesis of diabetic complications. A number of drugs have been developed to act as agonists of the three PPARs. To date, PPAR isoforms that have been identified are the alpha, beta/delta, and gamma isosforms. Fenofibrate and gemfibrozil are two drugs that act as PPARalpha agonists and are currently in use in the clinical setting. Rosiglitazone is a PPARgamma agonist also in clinical use. These drugs have proved very useful in regulation of either glucose or lipid metabolism and consequently are used in patients with type 2 diabetes. Here, we will review the anti-atherosclerotic potential of PPAR agonists with particular emphasis on recent studies in an animal model of diabetes-associated atherosclerosis, the streptozotocin diabetic apolipoprotein E deficient mouse. These studies have shown both PPARalpha agonists, gemfibrozil and fenofibrate, confer anti-atherosclerotic effects, partly independent of their metabolic effects. Similar positive findings have also been detected in a dose-dependent manner with the PPARgamma agonist, rosiglitazone. The potential clinical implications of these findings are also discussed in view of the recently reported results of the PROACTIVE and FIELD clinical trials with the PPAR agonists rosiglitazone and fenofibrate respectively.

The shift in muscle's length-tension relation after exercise attributed to increased series compliance.

Eccentric exercise can produce damage to muscle fibres. Here damage indicators are measured in the medial gastrocnemius muscle of the anaesthetised cat after eccentric contractions on the descending limb of the muscle's length-tension relation, compared with eccentric contractions on the ascending limb and concentric contractions on the descending limb. One damage indicator is a shift of the optimum length for peak active tension, in the direction of longer muscle lengths. The shift has been attributed to an increase in muscle compliance. It is a corollary of a current theory for the mechanism of the damage. With the intention of seeking further support for the theory, in these experiments we test the idea that other damage indicators, specifically the fall in twitch:tetanus ratio and in muscle force are due, in part, to such an increase in compliance. This was tested in an undamaged muscle by insertion of a compliant spring (0.19 mm N(-1)) in series with the muscle. This led to a fall in tetanic tension by 17%, a shift in optimum length of 1.7 mm in the direction of longer muscle lengths and a fall in twitch tetanus ratio by 15%. The fall in tension is postulated to be due to development of non-uniform sarcomere lengths within muscle fibres. It is concluded that after a series of eccentric contractions of a muscle, the fall in force is the result of a number of interdependent factors, not all of which are a direct consequence of the damage process.

Position sense at the human forearm in the horizontal plane during loading and vibration of elbow muscles.

When blindfolded subjects match the position of their forearms in the vertical plane they rely on signals coming from the periphery as well as from the central motor command. The command signal provides a positional cue from the accompanying effort sensation required to hold the arm against gravity. Here we have asked, does a centrally generated effort signal contribute to position sense in the horizontal plane, where gravity cannot play a role? Blindfolded subjects were required to match forearm position for the unloaded arm and when flexors or extensors were bearing 10%, 25% or 40% of maximum loads. Before each match the reference arm was conditioned by contracting elbow muscles while the arm was held flexed or extended. For the unloaded arm conditioning led to a consistent pattern of errors which was attributed to signals from flexor and extensor muscle spindles. When elbow muscles were loaded the errors from conditioning converged, presumably because the spindles had become coactivated through the fusimotor system during the load-bearing contraction. However, this convergence was seen only when subjects supported a static load. When they moved the load differences in errors from conditioning persisted. Muscle vibration during load bearing or moving a load did not alter the distribution of errors. It is concluded that for position sense of an unloaded arm in the horizontal plane the brain relies on signals from muscle spindles. When the arm is loaded, an additional signal of central origin contributes, but only if the load is moved.

Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation.

AIMS/HYPOTHESIS: It is postulated that peroxisome proliferator-activated receptor alpha agonists confer cardiovascular benefits in diabetes, independently of their effects on lipid metabolism. We investigated putative mechanisms responsible for these anti-atherogenic effects in an in vivo model of diabetes-associated atherosclerosis. MATERIALS AND METHODS: Control and streptozotocin-induced diabetic apolipoprotein-deficient mice received gemfibrozil (100 mg kg(-1) day(-1)) or no treatment for 20 weeks. Aortic plaque deposition was assessed by Sudan IV staining and subsequent en face quantification. Superoxide production was measured using lucigenin-enhanced chemiluminescence. Markers of pathways including inflammation and oxidative stress were measured using real-time RT-PCR. RESULTS: No significant effect of gemfibrozil was observed on glycated haemoglobin, cholesterol or insulin in diabetic mice. Diabetes was associated with a three-fold increase in plaque area and a significant increase in NADPH-dependent superoxide compared with control mice. Gemfibrozil significantly attenuated plaque area and superoxide production in diabetic mice. In addition, gemfibrozil reduced the expression of the genes encoding the NADPH oxidase subunits p47phox, gp91phox and Rac-1. In addition, gemfibrozil reduced the expression of the genes encoding nuclear factor kappa B (NF-kappaB) subunit, p65, the NF-kappaB-dependent chemokine monocyte chemoattractant protein-1, and tissue factor. CONCLUSIONS/INTERPRETATIONS: This study demonstrates that gemfibrozil exerts anti-atherogenic actions, independently of changes in cholesterol and glucose metabolism. Such findings emphasise the possible usefulness of fibrates such as gemfibrozil in a setting of atherosclerosis even in the absence of dyslipidaemia.

Length-dependent changes in voluntary activation, maximum voluntary torque and twitch responses after eccentric damage in humans.

To assess the contribution of central and peripheral factors to changes in maximum voluntary force and its length dependence after eccentric muscle damage, voluntary and twitch torque were measured across a wide angular range, along with voluntary activation using twitch interpolation. Isometric torque from both maximum voluntary contractions (MVCs) and paired twitches to motor nerve stimulation were measured from 60 to 150 deg elbow flexion in 10 deg increments in eight subjects. Optimal angles were determined by curve fitting. Each subject then performed eccentric contractions until voluntary torque had decreased by approximately 40%. Measurements were repeated at 2 h, 1 day and 8 days post-exercise to follow acute and longer-term changes. Before exercise, the optimal angle was in the mid-range (93+/-10 deg; mean+/-s.d.) for MVCs, and at a more extended elbow angle for the twitch (106+/-6 deg, P < 0.05). Voluntary activation was generally high (> 94%) but depended on elbow angle, with activation being approximately 4% lower at the most flexed compared to the most extended angle. Two hours after exercise, MVCs decreased 40%, while twitch torque declined 70%. All subjects showed a shift in optimal angle to longer muscle lengths for MVCs (17+/-16 deg at 2 h, 14+/-7 deg at day 1, P < 0.05). This shift contributed minimally (approximately 3%) to the reduction in torque at 90 deg, as the torque-angle relation was relatively flat around the optimum. The twitch showed a smaller shift (approximately 4 deg) to longer lengths which was not statistically significant. Voluntary activation was significantly impaired in the early stages after exercise (2 h and day 1, P < 0.05), particularly at short muscle lengths. By 8 days after exercise, the optimal angle had returned to pre-exercise values, but MVC, twitch torque and voluntary activation had not fully recovered. Eccentric exercise causes a short-term shift in the optimal angle for MVCs and produces a length-dependent impairment in voluntary activation. Therefore, it appears that both central and peripheral factors limit muscle performance following eccentric damage, with limits to voluntary drive being especially important at short lengths.

Effect of eccentric exercise on position sense at the human forearm in different postures.

This is a study of the ability of blindfolded human subjects to match the position of their forearms before and after eccentric exercise. The hypothesis tested was that the sense of effort contributed to forearm position sense. The fall in force after the exercise was predicted to alter the relationship between effort and force and thereby induce position errors. In the arms-in-front posture, subjects had their unsupported reference arm set to one of two angles from the horizontal, 30 or 60 degrees , and they matched its position by voluntary placement of their other arm. Matching errors were compared with a task where the arms were counterweighted, so could be moved in the vertical plane with minimal effort, and where the arms were moved in the horizontal plane. In these latter two tasks, the intention was to test whether removal of an effort sensation from holding the arm against gravity influenced matching performance. It was found that, although absolute errors for counterweighted and horizontal matching were no larger than for unsupported matching, their standard deviations, 6.1 and 6.8 degrees , respectively, were significantly greater than for unsupported matching (4.6 degrees ), indicating more erratic matching. The eccentric exercise led, the next day, to a fall in maximum voluntary muscle torque of >or=15%. This was accompanied by a significant increase in matching errors for the unsupported matching task from 2.7 +/- 0.5 to 0.8 +/- 0.7 degrees but not for counterweighted (1.4 +/- 0.2 to -0.2 degrees +/- 1.1 degrees ) or horizontal matching (-1.3 +/- 0.7 degrees to -1.8 +/- 0.7 degrees ). This, it is postulated, is because the reduced voluntary torque after exercise was accompanied by a greater effort required to support the arms, leading to larger matching errors. However, effort is only able to provide positional information for unsupported matching where gravity plays a role. In gravity-neutral tasks like counterweighted or horizontal matching, a change in the effort-force relationship after exercise leaves matching accuracy unaffected.

Effect of muscle fatigue on the sense of limb position and movement.

We have recently shown that in an unsupported forearm-matching task blindfolded human subjects are able to achieve an accuracy of 2-3 degrees . If one arm was exercised to produce significant fatigue and the matching task was repeated, it led subjects to make position-matching errors. Here that result is confirmed using fatigue from a simple weight-lifting exercise. A 30% drop in maximum voluntary force after the exercise was accompanied by a significant matching error of 1.7 degrees in the direction of extension when the reference arm had been fatigued, and 1.9 degrees in the direction of flexion when the indicator arm had been fatigued. We also tested the effect of fatigue on a simple movement tracking task where the reference forearm was moved into extension at a range of speeds from 10 to 50 degrees s(-1). Fatigue was found not to significantly reduce the movement-tracking accuracy. In a second experiment, movement tracking was measured while one arm was vibrated. When it was the reference arm, the subject perceived the movement to be significantly faster (3.7 degrees s(-1)) than it actually was. When it was the indicator, it was perceived to be slower (4.6 degrees s(-1)). The data supports the view that muscle spindles are responsible for the sense of movement, and that this sense is not prone to the disturbance from fatigue. By contrast, the sense of position can be disturbed by muscle fatigue. It is postulated, that the sense of effort experienced by holding the arm against the force of gravity is able to provide information about the position in space of the limb and that the increased effort from fatigue produces positional errors.

Muscle spindle signals combine with the sense of effort to indicate limb position.

Experiments were carried out to test the hypothesis that, in the absence of vision, position sense at the human forearm is generated by the combined input from muscle spindles in elbow flexor muscles and signals of central origin giving rise to a sense of effort. In a forearm position-matching task, to remove a possible contribution from the sense of effort, the reference arm was held supported at the test angle. Subjects were less accurate in matching elbow position of the supported forearm than when it was unsupported. Adding a 2 kg weight to the unsupported reference arm led subjects to make matching errors consistent with an increase in the effort signal. Evidence of a contribution from muscle spindles was provided by showing that the direction of position matching errors could be systematically altered by flexion or extension conditioning of the reference arm before its placement at the test angle. Such changes in errors with conditioning could be shown to be present when the reference arm was supported, unsupported, or unsupported and weighted. It is concluded that both peripheral signals from muscle spindles and signals of central origin, associated with the motor command required to maintain arm position against the force of gravity, can provide information about forearm position.

Preventing atherosclerosis with angiotensin-converting enzyme inhibitors: emphasis on diabetic atherosclerosis.

The incidence of diabetes is increasing at an alarming rate to the point where it is becoming an epidemic. An ageing population, sedentary lifestyle and an unhealthy diet are considered to have contributed toward this. What we must now consider is not only the burden of the disease but the complications that arise from diabetes, in particular kidney and heart disease. Foremost, more than half of the diabetic population will die from cardiovascular-related causes. Whilst diabetes is most often associated with hypertension, dyslipidaemia and obesity, these factors do not fully account for the increased burden of cardiovascular disease in people with diabetes. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease, and more specifically, diabetes-associated atherosclerosis. In addition to the recognised metabolic abnormalities associated with diabetes, upregulation of putative pathological pathways such as advanced glycation endproducts, renin-angiotensin system, oxidative stress and increased expression of growth factors and cytokines have been observed in the setting of diabetes. All of these have been shown to play a causal role in atherosclerotic plaque formation and thus may explain the increased risk of macrovascular complications in those patients with diabetes. In this review the effect of inhibiting the renin-angiotensin system with angiotensin converting enzyme inhibition and a comparison to angiotensin II receptor antagonism is discussed, with the results of clinical trails reflecting the more recently discovered, non-haemodynamic, proatherogenic actions of angiotensin II. The need for experimental models of diabetes-associated atherosclerosis will be covered, with particular emphasis given to the streptozotocin-diabetic apolipoprotein E knockout mouse. Finally, growth factors, including vascular endothelial growth factor and platelet-derived growth factor are discussed in detail.