Custom-made total ankle arthroplasty for the salvage of major talar bone loss.

AIMS: A failed total ankle arthroplasty (TAA) is often associated with much bone loss. As an alternative to arthrodesis, the surgeon may consider a custom-made talar component to compensate for the bone loss. Our aim in this study was to assess the functional and radiological outcome after the use of such a component at mid- to long-term follow-up. PATIENTS AND METHODS: A total of 12 patients (five women and seven men, mean age 53 years; 36 to77) with a failed TAA and a large talar defect underwent a revision procedure using a custom-made talar component. The design of the custom-made components was based on CT scans and standard radiographs, when compared with the contralateral ankle. After the anterior talocalcaneal joint was fused, the talar component was introduced and fixed to the body of the calcaneum. RESULTS: At a mean follow-up of 6.9 years (1 to 13), 11 ankles were stable with no radiological evidence of loosening. Only one was lost to follow-up. The mean arc of movement was 21° (10° to 35°). A total of nine patients (75%) were satisfied or very satisfied with the outcome, two (17%) were satisfied but with reservations and one (8%) was not satisfied. All but one patient had an improvement in the American Orthopaedic Foot and Ankle Society hindfoot score (p = 0.01). Just one patient developed deep infection, leading to arthrodesis. CONCLUSION: A custom-made talar component yielded satisfactory results with regard to function, stability and satisfaction. This should encourage the use of such components as an alternative to arthrodesis of the ankle in patients with a failed TAA. Cite this article: Bone Joint J 2017;99-B:231-6.

Oscillatory entrainment of subthalamic nucleus neurons and behavioural consequences in rodents and primates.

We investigated the functional role of oscillatory activity in the local field potential (LFP) of the subthalamic nucleus (STN) in the pathophysiology of Parkinson's disease (PD). It has been postulated that beta (15-30 Hz) oscillatory activity in the basal ganglia induces PD motor symptoms. To assess this hypothesis, an LFP showing significant power in the beta frequency range (23 Hz) was used as a stimulus both in vitro and in vivo. We first demonstrated in rat brain slices that STN neuronal activity was driven by the LFP stimulation. We then applied beta stimulation to the STN of 16 rats and two monkeys while quantifying motor behaviour. Although stimulation-induced behavioural effects were observed, stimulation of the STN at 23 Hz induced no significant decrease in motor performance in either rodents or primates. This study is the first to show LFP-induced behaviour in both rats and primates, and highlights the complex relationship between beta power and parkinsonian symptoms.

Differential behavioral effects of partial bilateral lesions of ventral tegmental area or substantia nigra pars compacta in rats.

Akinesia (or absence of movement) is a prominent feature of Parkinson's disease. Akinetic symptoms, however, are also observed in depression and schizophrenia, which support the hypothesis that akinesia involves more than only motor behavior. A common feature of these disorders is the disruption of dopamine homeostasis in the CNS. Here we aimed at relating the respective involvement of the nigrostriatal and mesocortical dopaminergic pathways to akinesia. We investigated in the rat the relative effects of selective bilateral partial lesions of substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) which did not affect locomotion, on fine motor, motivational and cognitive behaviors. Motor impairments were measured by the evaluation of fine motor control in the stepping test and in the paw reaching test. Cognitive functions were assessed by various paradigms: spontaneous alternation in the Y maze and object exploration task. Motivational behavior was evaluated by the 100-pellets test. The results suggested that specific behavioral impairments are obtained following selective lesions of either SNc or VTA. SNc-lesioned rats exhibited deficits in fine motor functions as previously described in animal models of Parkinson's disease, whereas VTA-lesioned rats demonstrated traits of perseveration without significant motor impairments.

Unraveling substantia nigra sequential gene expression in a progressive MPTP-lesioned macaque model of Parkinson's disease.

Taking advantage of a progressive nonhuman primate model mimicking Parkinson's disease (PD) evolution, we monitored transcriptional fluctuations in the substantia nigra using Affymetrix microarrays in control (normal), saline-treated (normal), 6 days-treated (asymptomatic with 20% cell loss), 12 days-treated (asymptomatic with 40% cell loss) and 25 days-treated animals (fully parkinsonian with 85% cell loss). Two statistical methods were used to ascertain the regulation and real-time quantitative PCR was used to confirm their regulation. Surprisingly, the number of deregulated transcripts is limited at all time points and five clusters exhibiting different profiles were defined using a hierarchical clustering algorithm. Such profiles are likely to represent activation/deactivation of mechanisms of different nature. We briefly speculate about (i) the existence of yet unknown compensatory mechanisms is unraveled, (ii) the putative triggering of a developmental program in the mature brain in reaction to progressing degeneration and finally, (iii) the activation of mechanisms leading eventually to death in final stage. These data should help development of new therapeutic approaches either aimed at enhancing existing compensatory mechanisms or at protecting dopamine neurons.

An animal model of a spontaneously reversible obstructive sleep apnea syndrome in the monkey.

The anatomies of the tongue and uvula in monkeys share many similarities with humans, such that this species has the closest approximation to the human upper airway than any other species. In this study, we investigated the feasibility of using small monkeys as experimental animals for an obstructive sleep apnea model. Monkeys received intradermal injections of liquid collagen in the uvula, tongue, and lateral pharyngeal walls every 2 weeks. Polysomnography was performed bi-monthly in order to control the impact of injections on breathing events, respiratory effort (as measured by esophageal pressure), and sleep. Before injections, the three animals showed normal breathing during sleep with a mean of 4.8 +/- 2.0 events/h. After injections, a mean of 27.9 +/- 19.7 hypopneas/h was recorded (P = 0.023). Total sleep time was significantly reduced, with a decrease of REM sleep and stage II sleep; however, stage I sleep increased. Collagen injections in monkey's upper airways can create sleep-disordered breathing and abnormal sleep, as seen in sleep apneic patients.

L-DOPA reverses the MPTP-induced elevation of the arrestin2 and GRK6 expression and enhanced ERK activation in monkey brain.

Dysregulation of dopamine receptors (DARs) is believed to contribute to Parkinson disease (PD) pathology. G protein-coupled receptors (GPCR) undergo desensitization via activation-dependent phosphorylation by G protein-coupled receptor kinases (GRKs) followed by arrestin binding. Using quantitative Western blotting, we detected profound differences in the expression of arrestin2 and GRKs among four experimental groups of nonhuman primates: (1) normal, (2) parkinsonian, (3) parkinsonian treated with levodopa without or (4) with dyskinesia. Arrestin2 and GRK6 expression was significantly elevated in the MPTP-lesioned group in most brain regions; GRK2 was increased in caudal caudate and internal globus pallidus. Neither levodopa-treated group differed significantly from control. The only dyskinesia-specific change was an elevation of GRK3 in the ventral striatum of the dyskinetic group. Changes in arrestin and GRK expression in the MPTP group were accompanied by enhanced ERK activation and elevated total ERK expression, which were also reversed by L-DOPA. The data suggest the involvement of arrestins and GRKs in Parkinson disease pathology and the effects of levodopa treatment.

[Pathophysiology and therapy of L-Dopa-induced dyskinesia]. / Physiopathologie et modalités thérapeutiques des dyskinésies induites à la L-Dopa.

Involuntary movements, or dyskinesias, represent a debilitating complication of levodopa therapy for Parkinson's disease. Dyskinesia is, ultimately, experienced by the vast majority of the patients. Despite the importance of this problem, little was known about the cause of dyskinesia, a situation that has dramatically evolved in the last few years. The present review presents: 1) the current understanding of dyskinesia pathophysiology and 2) the therapeutic modalities, mainly non-dopaminergic, available or in development. We here show that the questions raised by the dyskinesia may have a clinically-driven pharmacological answer: the symptomatic treatment of dyskinesia, the prevention of the priming and the de-priming of the neural networks.

The effect of vasodilators on aspirin-induced antagonism of t-PA thrombolysis.

Although i.v. t-PA has proven successful in reducing neurologic deficits in acute ischemic stroke, the disadvantages of a narrow therapeutic time window and the failure of thrombolysis in more than 50% of patients treated have necessitated an examination of adjuvant therapies to improve the rate of thrombolysis. Experimentally, the combination of aspirin therapy with t-PA has resulted in a paradoxical antagonism of thrombolysis. Reversal of this antagonism with nitric oxide (NO) donors suggested that aspirin may inhibit/ antagonize NO-related mechanisms. Using this rabbit model of thromboembolic stroke, this hypothesis is now expanded to compare two clinically relevant anti-hypertensive agents, atenolol (NO-dependent) and hydralazine (NO-independent), for their ability to improve t-PA-mediated clot lysis following aspirin pre-treatment. Thirty rabbits (10 per group) were pre-treated with aspirin (20mg kg(-1), i.v.) and then randomized to receive either vehicle, atenolol (20 microg kg(-1) h(-1), i.v.) or hydralazine (10 microg kg(-1) min(-1), i.v.) beginning 30 min following autologous clot embolization. All rabbits then received t-PA (6.3 mg kg(-1), i.v.) beginning 1 h after embolization, with completion of the protocol 4 h after embolization. Aspirin therapy reduced regional cerebral blood flow (rCBF) from 82.8m +/- 4.7 to 62.5 +/- 6.6 (n = 30; p = 0.0005). In the aspirin control group only 30% (3 of 10) rabbits demonstrated complete clot lysis, whereas the combined atenolol (60%) and hydralazine (70%) groups experienced a clot lysis rate of 65% (13 of 20 rabbits), similar to clot lysis rates previously observed with t-PA alone. In a separate series of experiments, all agents able to reverse aspirin antagonism of thrombolysis demonstrated an improvement in rCBF, suggesting a common mechanism for this diverse group of agents in reversing aspirin's antagonism of thrombolysis.

Pathophysiology of levodopa-induced dyskinesia: potential for new therapies.

Involuntary movements--or dyskinesias--are a debilitating complication of levodopa therapy for Parkinson's disease, and is experienced in most patients. Despite the importance of this problem, little was known about the cause of dyskinesia until recently; however, this situation has changed significantly in the past few years. Our increased understanding of levodopa-induced dyskinesia is not only valuable for improving patient care, but also in providing us with new insights into the functional organization of the basal ganglia and motor systems.

Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease.

The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease symptoms, although widely accepted, has, to date, not been determined experimentally in nonhuman primates in which a more rigorous definition of the mechanisms responsible for the threshold effect might be obtained. The present study was thus designed to determine (1) the relationship between Parkinsonian symptom appearance and level of degeneration of the nigrostriatal pathway and (2) the concomitant presynaptic and postsynaptic striatal response to the denervation, in monkeys treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that produces a progressive Parkinsonian state. The kinetics of the nigrostriatal degeneration described allow the determination of the critical thresholds associated to symptom appearance, these were a loss of 43.2% of tyrosine hydroxylase-immunopositive neurons at the nigral level and losses of 80.3 and 81.6% DA transporter binding and DA content, respectively, at the striatal level. Our data argue against the concept that an increase in DA metabolism could act as an efficient adaptive mechanism early in the disease progress. Surprisingly, the D(2)-like DA receptor binding showed a biphasic regulation in relation to the level of striatal dopaminergic denervation, i.e., an initial decrease in the presymptomatic period was followed by an upregulation of postsynaptic receptors commencing when striatal dopaminergic homeostasis is broken. Further in vivo follow-up of the kinetics of striatal denervation in this, and similar, experimental models is now needed with a view to developing early diagnosis tools and symptomatic therapies that might enhance endogenous compensatory mechanisms.

Upregulation of striatal preproenkephalin gene expression occurs before the appearance of parkinsonian signs in 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine monkeys.

GABA and enkephalin-utilizing efferents from the striatum to the external segment of the pallidal complex (GPe) are thought to be overactive in Parkinson's disease (PD). This overactivity is generally held to play a major role in the genesis of parkinsonian symptoms, which are thought to appear when dopaminergic neuronal death exceeds a critical threshold. Little is known, however, regarding the activity of this pathway during disease progression and more particularly, prior to the emergence of parkinsonian symptoms. In order to test the hypothesis that an upregulation of striatal preproenkephalin-A (PPE-A) mRNA levels occurs before the appearance of parkinsonian motor disabilities, the present study assessed PPE-A mRNA expression and striatal dopamine (DA) content following a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration protocol in monkeys that produces a progressive parkinsonian state. Groups ranged from normal to full parkinsonian through asymptomatic lesioned monkeys. The key finding of this study is that PPE-A expression is already upregulated in asymptomatic-lesioned monkeys showing a marked DA depletion (56%). Importantly, this up-regulation is restricted to motor regions of the basal ganglia circuitry. The increased PPE-A mRNA expression observed in asymptomatic, but DA-depleted animals, supports our initial hypothesis of such an upregulation occurring before the appearance of parkinsonian motor disabilities. Furthermore, when considered with recent electrophysiological and histochemical data, these findings question the functional significance of upregulated enkephalin transmission in the indirect striatopallidal pathway.

Pallidal border cells: an anatomical and electrophysiological study in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkey.

A dopamine transporter-radioligand binding study demonstrated a dopaminergic innervation around the pallidal complex in the normal monkey (n=5), i.e. where a subpopulation of pallidal neurons known as "border cells" is classically identified. Surprisingly, this peripallidal binding persists in monkeys rendered parkinsonian (n=5) with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. The border cell electrophysiological activity was then analysed in normal and parkinsonian monkeys (n=2), either in the untreated state or following administration of levodopa. Pallidal border cell firing frequency was significantly decreased after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (8.9+/-0.7 vs 31.4+/-1.6Hz, P<0.05). This decrease was partly corrected by levodopa administration (19.2+/-1.0Hz, P<0.05 vs both normal and parkinsonian situations). The peripallidal dopaminergic innervation suggests that pallidal border cells are under a direct dopaminergic control, arising from the ventral tegmental area and/or the basal forebrain magnocellular complex, the role of which remains unknown. Moreover, the relative sparing of these dopaminergic fibers in parkinsonian monkeys suggests that they would exhibit specific adaptive properties totally different from those described in the nigrostriatal pathway.

Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey.

Despite the importance and frequency of levodopa-induced dyskinesias, little is known about their causal mechanisms. In this study, electrophysiological single-unit recordings of the neuronal activity of the globus pallidus internalis (GPi), the main basal ganglia output structure, and the globus pallidus externalis (GPe) were recorded continuously in both normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated subhuman primates before and after the administration of three dopamine agonists--apomorphine (a dopaminergic mixed agonist), SKF-38393 (a D1 partial agonist) and piribedil (a D2/D3 agonist)--at doses known to induce dyskinesias in the parkinsonian monkey. Changes in both the firing frequency and the firing pattern were analysed in relation to behavioural modifications. In both the normal and the parkinsonian monkey, the three agonists induced a decrease in the mean firing frequency of GPi neurones, although dyskinesias were induced only in the parkinsonian animals. In this situation, the improvement of parkinsonian motor abnormalities was correlated with the decrease in GPi firing frequency, whereas firing pattern changes were concomitant with the onset of dyskinesias. Moreover, firing frequency seemed to be decreased excessively during dyskinesias. The results indicate that the electrophysiological mechanism of dyskinesia involves an excessive decrease in GPi firing frequency and a modification of the firing pattern. However, the similarity between the induced decrease in firing frequency in normal and parkinsonian animals underlines the need for dopamine depletion in the induction of dyskinesias.

16(R)-hydroxyeicosatetraenoic acid, a novel cytochrome P450 product of arachidonic acid, suppresses activation of human polymorphonuclear leukocyte and reduces intracranial pressure in a rabbit model of thromboembolic stroke.

OBJECTIVE: Activated polymorphonuclear leukocytes (PMNs) have been suggested to contribute to the development of increased intracranial pressure (ICP). We recently demonstrated that human PMNs produce a novel cytochrome P450-derived arachidonic acid metabolite, 1 6(R)-hydroxyeicosatetraenoic acid [16(R)-HETE], that modulates their function. It was thus of interest to examine this novel mediator in an acute stroke model. METHODS: 16-HETE was assessed initially in a variety of human PMN and platelet in vitro assays and subsequently in an established rabbit model of thromboembolic stroke. A total of 50 rabbits completed a randomized, blinded, four-arm study, receiving 16(R)-HETE, tissue plasminogen activator, both, or neither. Experiments were completed 7 hours after autologous clot embolization. The primary end point for efficacy was the suppression of increased ICP. RESULTS: In in vitro assays, 16(R)-HETE selectively inhibited human PMN adhesion and aggregation and leukotriene B4 synthesis. In the thromboembolic stroke model, animals that received 16(R)-HETE demonstrated significant suppression of increased ICP (7.7 +/- 1.2 to 13.1 +/- 2.7 mm Hg, baseline versus final 7-h time point, mean +/- standard error), compared with either the vehicle-treated group (7.7 +/- 0.9 to 15.8 +/- 2.6 mm Hg) or the tissue plasminogen activator-treated group (7.6 +/- 0.6 to 13.7 +/- 2.1 mm Hg). The group that received the combination of 16(R)-HETE plus tissue plasminogen activator demonstrated no significant change in ICP for the duration of the protocol (8.6 +/- 0.6 to 11.1 +/- 1.2 mm Hg). CONCLUSION: 16(R)-HETE suppresses the development of increased ICP in a rabbit model of thromboembolic stroke and may serve as a novel therapeutic strategy in ischemic and inflammatory pathophysiological states.

Spontaneous long-term compensatory dopaminergic sprouting in MPTP-treated mice.

The present study sought to determine whether severe 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication elicits spontaneous long-term compensatory sprouting in mice. Animals, once treated, were kept without further treatment for 0.5, 1, 5, or 7 months. The stability of the nigral degeneration was checked by evaluation of the number of tyrosine hydroxylase immunoreactive (TH-IR) neurons, whereas sprouting was assessed using both [(3)H]-dopamine (DA) uptake by striatal synaptosomes and optical density of TH-immunolabeled fibers in the striatum as markers. At 0.5 month after MPTP intoxication (80 mg/kg, i.p.), we observed comparable decreases of 83% in DA uptake, 83.3% in TH fiber density, and 74% in the number of TH-IR neurons compared to age-matched saline-treated animals. From 5 months onwards, both DA uptake and striatal TH fiber density increased significantly (50% and 34.9% at 5 months, 65% and 67.4% at 7 months, respectively) in comparison with age-matched saline-treated animals, although the number of TH-IR neurons remained stable (73% of degeneration at 7 months). These results indicate clearly that spontaneous long-term compensatory dopaminergic sprouting is a phenomenon that is not restricted to situations of partial nigral degeneration but can, on the contrary, constitute a response even to severe stable MPTP-induced nigral degeneration.

Adaptive changes in the nigrostriatal pathway in response to increased 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration in the mouse.

Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5-day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH-immunoreactive neurons (-70.2%) and striatal dopamine content (-38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.

16(R)-hydroxy-5,8,11,14-eicosatetraenoic acid, a new arachidonate metabolite in human polymorphonuclear leukocytes.

Intact human polymorphonuclear leukocytes (PMNL) incubated with substimulatory amounts of arachidonic acid in the absence of a calcium ionophore formed four metabolites that were isolated by reverse-phase HPLC and characterized structurally by GC/MS. A major metabolite eluting as the most abundant peak of radioactivity lacked UV chromophores above 215 nm, and its formation was sensitive to 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF525A) but not 3-amino-1-[m(trifluoromethyl)phenyl]-2-pyrazoline (BW755C), suggesting that it was likely to be a product of cytochrome P450. The GC/MS analysis revealed the presence of two components: 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) and 16-hydroxy-5,8,11,14-eicosatetraenoic acid (16-HETE) in an approximate ratio of 4:1. The minor metabolites were identified as 15-HETE and 5-HETE. Although 20-HETE has been observed previously as a product of arachidonic acid metabolism in PMNL, the occurrence of 16-HETE was a novel finding. The stereochemistry of the hydroxyl group in PMNL-derived 16-HETE was established by analysis of 1-pentafluorobenzyl-16-naphthoyl derivatives on a chiral-phase chromatographic column and comparison with authentic synthetic stereoisomers. The PMNL-derived radioactive metabolite co-eluted with the synthetic 16(R)-HETE stereoisomer. Analysis of the total lipid extracts from intact PMNL followed by mild alkaline hydrolysis resulted in detectable amounts of 16-HETE (108+/-26 pg/10(8) cells) and 20-HETE (341+/-69 pg/10(8) cells), which suggested that these HETEs were formed from endogenous arachidonic acid and esterified within PMNL lipids. Thus, in contrast to calcium ionophore-stimulated neutrophils that generate large amounts of 5-lipoxygenase products, the intact PMNL generate 20-HETE and 16(R)-HETE via a cytochrome P450 omega- and omega-4 oxygenase(s).

Ratio of inhibited-to-activated pallidal neurons decreases dramatically during passive limb movement in the MPTP-treated monkey.

Mink advanced the hypothesis in 1996 that the role of the basal ganglia (BG) is primarily one of focused selection; the encouragement of motor mechanisms inducing a desired movement and the inhibition of competing mechanisms. This would imply, in normal subjects, a ratio of inhibited-to-activated (I/A) movement-related globus pallidus pars internalis (GPi) neurons <1 and a drastic decrease of this ratio in the parkinsonian state. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication should therefore decrease the specificity of the response of this neuronal population. To test this working hypothesis we studied the activity of GPi neurons in response to passive limb movement in the normal and the parkinsonian monkey. Extracellular unit recordings monitored any correlation between passive limb movements and eventual modifications of the neuronal activity of the GPi in two calm, awake, and drug naive monkeys (Macaca fascicularis) before and after MPTP intoxication. In the normal animal, arm- and leg-related neurons were located in clusters in the medial part of the GPi. The I/A ratio was 0.22. Most GPi cells were linked to a single joint. In the MPTP-treated monkey, the number of movement-related neurons increased, the I/A ratio dropped significantly to 0.03, and most responding cells were linked to several joints. These data, which cannot be explained by the classic "box" model, endorse Mink's hypothesis.