Live fast, die young: Behavioural and physiological impacts of light pollution on a marine fish during larval recruitment.

Artificial light at night (ALAN) is a recently acknowledged form of anthropogenic pollution of growing concern to the biology and ecology of exposed organisms. Though ALAN can have detrimental effects on physiology and behaviour, we have little understanding of how marine organisms in coastal areas may be impacted. Here, we investigated the effects of ALAN exposure on coral reef fish larvae during the critical recruitment stage, encompassing settlement, metamorphosis, and post-settlement survival. We found that larvae avoided illuminated settlement habitats, however those living under ALAN conditions for 10 days post-settlement experienced changes in swimming behaviour and higher susceptibility to nocturnal predation. Although ALAN-exposed fish grew faster and heavier than control fish, they also experienced significantly higher mortality rates by the end of the experimental period. This is the first study on the ecological impacts of ALAN during the early life history of marine fish.

Effects of a combination of 3,4-methylenedioxymeth amphetamine and caffeine on real time stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry.

It is well documented that caffeine exacerbates the hyperthermia associated with acute exposure to 3,4-methylenedioxymethamphetamine (MDMA) in rats. Previous reports have also indicated that MDMA-related enhancement of dopamine release is exacerbated in the presence of caffeine. In the present study we have examined whether the effects of MDMA on real-time stimulated dopamine release, in the absence of uptake inhibition, are accentuated in the presence of caffeine. Isolated striatal slices from adult male Wistar rats were treated acutely with MDMA, caffeine, or a combination, and their effects on single and 5pulse stimulated dopamine release monitored using the technique of fast cyclic voltammetry. Caffeine at 10 or 100µM had no significant effect on single pulse stimulated dopamine release. However 100µM caffeine caused a significant peak increase in 5pulse stimulated dopamine release. Both 1 and 30µM MDMA gave rise to a significant increase in both single and 5-pulse dopamine release and reuptake. A combination of 100µM caffeine and 1 or 30µM MDMA did not significantly enhance the effects of MDMA on single or 5pulse dopamine release and reuptake when compared to that applied alone. Utilizing single action potential dependent dopamine release, these results do not demonstrate a caffeine-enhanced MDMA-induced dopamine release.

Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum.

Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D1 receptor (D1R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D1R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500 nM) induced a decrease in dopamine efflux at low frequency (single pulse or five pulses at 10 Hz) and an increase at high frequency (100 Hz) electrical field stimulation. The D1R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D1R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D1R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release.

Influence of consciousness, muscle action and activity on medial condyle translation after Oxford unicompartmental knee replacement.

BACKGROUND: Quantification of the in vivo position of the medial condyle throughout flexion is important for knee replacement design, and understanding knee pathology. The influence of consciousness, muscle action, and activity type on condyle translation was examined in patients who had undergone medial unicompartmental knee replacement (UKR) using lateral video fluoroscopy. METHODS: The position of the centre of the femoral component relative to the tibial component was measured for nine patients under different conditions. The following activities were assessed; passive flexion and extension when anaesthetised, passive flexion and extension when conscious, and active flexion, extension and step-up. RESULTS: The position of the centre of the femoral component relative to the tibial component was highly patient dependent. The greatest average translation range (14.9 mm) was observed in anaesthetised patients, and the condyle was significantly more anterior near to extension. Furthermore, when conscious but being moved passively, the femoral condyle translated a greater range (8.9 mm) than when moving actively (5.2mm). When ascending stairs, the femoral condyle was more posterior at 20-30° of flexion than during flexion/extension. CONCLUSIONS: The similarity between these results and published data suggest that knee kinematics following mobile-bearing UKR is relatively normal. The results show that in the normal knee and after UKR, knee kinematics is variable and is influenced by the patient, consciousness, muscle action, and activity type. CLINICAL RELEVANCE: It is therefore essential that all these factors are considered during knee replacement design, if the aim is to achieve more normal knee kinematics.

The effect of nicotine induced behavioral sensitization on dopamine D1 receptor pharmacology: An in vivo and ex vivo study in the rat.

Behavioral sensitization is a phenomenon which can develop following repeated intermittent administration of a range of psychostimulants, and other compounds, and may model neuroplastic changes seen in addictive processes and neuropsychiatric disease. The aim of the present study was to investigate the effect of dopamine D1 receptor (D1R) ligands on nicotine-induced behavioral sensitization and their molecular consequences in the striatum. Wistar rats were chronically treated (5 days) with vehicle or nicotine (0.4 mg/kg; s.c.) and locomotor activity was measured. Following a 5 day withdrawal period, rats were pretreated with vehicle or the D1R antagonist SCH-23390 (0.03 mg/kg; i.p.) and challenged with nicotine. Either 45 min or 24h post-challenge, the striatum was isolated and ex vivo receptor binding and cAMP accumulation (using LC-MS/MS) were assessed. It was shown that chronic nicotine administration induced the development and expression of locomotor sensitization, of which the latter was blocked by SCH-23390. Nicotine-induced sensitization had no effect on forskolin stimulated cAMP accumulation but increased the efficacy of dopamine for the D1R and decreased the potency of D1R agonists. These effects were antagonized by in vivo pre-challenge with SCH-23390. No effect on D1 receptor binding was observed. Moreover, time dependent effects were observed between tissue taken 45 min and 24h post-challenge. The present findings provide a connection between behavioral sensitization and intracellular cAMP accumulation through the D1R. Together these data suggest that changes in D1R signaling in the dorsal striatum may play an important role in the underlying mechanisms of nicotine-induced behavioral sensitization.

The shape of the distal femur: a geometrical study using MRI.

We scanned 25 left knees in healthy human subjects using MRI. Multiplanar reconstruction software was used to take measurements of the inferior and posterior facets of the femoral condyles and the trochlea. A 'basic circle' can be defined which, in the sagittal plane, fits the posterior and inferior facets of the lateral condyle, the posterior facet of the medial condyle and the floor of the groove of the trochlea. It also approximately fits both condyles in the coronal plane (inferior facets) and the axial plane (posterior facets). The circle fitting the inferior facet of the medial condyle in the sagittal plane was consistently 35% larger than the other circles and was termed the 'medial inferior circle'. There were strong correlations between the radii of the circles, the relative positions of the centres of the condyles, the width of the condyles, the total knee width and skeletal measurements including height. There was poor correlation between the radii of the circles and the position of the trochlea relative to the condyles. In summary, the condyles are approximately spherical except for the inferior facet medially, which has a larger radius in the sagittal plane. The size and position of the condyles are consistent and change with the size of the person. However, the position of the trochlea is variable even though its radius is similar to that of the condyles. This information has implications for understanding anterior knee pain and for the design of knee replacements.

Hypoxia-inducible factor signalling mechanisms in the central nervous system.

In the CNS, neurones are highly sensitive to the availability of oxygen. In conditions where oxygen availability is decreased, neuronal function can be altered, leading to injury and cell death. Hypoxia has been implicated in a number of central nervous system pathologies including stroke, head trauma and neurodegenerative diseases. Cellular responses to oxygen deprivation are complex and result in activation of short- and long-term mechanisms to conserve energy and protect cells. Failure of synaptic transmission can be observed within minutes following this hypoxia. The acute effects of hypoxia on synaptic transmission are primarily mediated by altering ion fluxes across membranes, pre-synaptic effects of adenosine and other actions at glutamatergic receptors. A more long-term feature of the response of neurones to hypoxia is the activation of transcription factors such as hypoxia-inducible factor. The activation of hypoxia-inducible factor is governed by a family of dioxygenases called hypoxia-inducible factor prolyl 4 hydroxylases (PHDs). Under hypoxic conditions, PHD activity is inhibited, thereby allowing hypoxia-inducible factor to accumulate and translocate to the nucleus, where it binds to the hypoxia-responsive element sequences of target gene promoters. Inhibition of PHD activity stabilizes hypoxia-inducible factor and other proteins thus acting as a neuroprotective agent. This review will focus on the response of neuronal cells to hypoxia-inducible factor and its targets, including the prolyl hydroxylases. We also present evidence for acute effects of PHD inhibition on synaptic transmission and plasticity in the hippocampus.

Targeting tumour necrosis factor-α in hypoxia and synaptic signalling.

Tumour necrosis factor (TNF)-α is a pro-inflammatory cytokine, which is synthesised and released in the brain by astrocytes, microglia and neurons in response to numerous internal and external stimuli. It is involved in many physiological and pathophysiological processes such as gene transcription, cell proliferation, apoptosis, synaptic signalling and neuroprotection. The complex actions of TNF-α in the brain are under intense investigation. TNF-α has the ability to induce selective necrosis of some cells whilst sparing others and this has led researchers to discover multiple activated signalling cascades. In many human diseases including acute stroke and inflammation and those involving hypoxia, levels of TNF-α are increased throughout different brain regions. TNF-α signalling may also have several positive and negative effects on neuronal function including glutamatergic synaptic transmission and plasticity. Exogenous TNF-α may also exacerbate the neuronal response to hypoxia. This review will summarise the actions of TNF-α in the central nervous system on synaptic signalling and its effects during hypoxia.

Examination of ten fractured Oxford unicompartmental knee bearings.

Since the Oxford knee was first used unicompartmentally in 1982, a small number of bearings have fractured. Of 14 retrieved bearings, we examined ten samples with known durations in situ (four Phase 1, four Phase 2 and two Phase 3). Evidence of impingement and associated abnormally high wear (> 0.05 mm per year) as well as oxidation was observed in all bearings. In four samples the fracture was associated with the posterior radio-opaque wire. Fracture surfaces indicated fatigue failure, and scanning electron microscopy suggested that the crack initiated in the thinnest region. The estimated incidence of fracture was 3.20% for Phase 1, 0.74% for Phase 2, 0.35% for Phase 3, and 0% for Phase 3 without the posterior marker wire. The important aetiological factors for bearing fracture are impingement leading to high wear, oxidation, and the posterior marker wire. With improved surgical technique, impingement and high wear should be prevented and modern polyethylene may reduce the oxidation risk. A posterior marker wire is no longer used in the polyethylene meniscus. Therefore, the rate of fracture, which is now very low, should be reduced to a negligible level.

A critique of revision rate as an outcome measure: re-interpretation of knee joint registry data.

National registers compare implants by their revision rates, but the validity of the method has never been assessed. The New Zealand Joint Registry publishes clinical outcomes (Oxford knee scores, OKS) alongside revision rates, allowing comparison of the two measurements. In the two types of knee replacement, unicompartmental (UKR) had a better knee score than total replacement (TKR), but the revision rate of the former was nearly three times higher than that of the latter. This was because the sensitivity of the revision rate to clinical failure was different for the two implants. For example, of knees with a very poor outcome (OKS < 20 points), only about 12% of TKRs were revised compared with about 63% of UKRs with similar scores. Revision therefore is not an objective measurement and should not be used to compare these two types of implant. Furthermore, revision is much less sensitive than the OKS to clinical failure in both types and therefore exaggerates the success of knee replacements, particularly of TKR.

Hydroxylase inhibition reduces synaptic transmission and protects against a glutamate-induced ischemia in the CA1 region of the rat hippocampus.

The discovery of hydroxylases as oxygen sensors and key regulators of hypoxia-induced gene expression has made them a novel target for manipulating the transcriptional response to hypoxia for therapeutic benefit. In this study we have investigated the effect of prolyl hydroxylase inhibition on synaptic activity in hippocampal slices and compared this to the changes occurring following exposure to hypoxia. Furthermore, we investigated a potentially protective role for hydroxylase inhibition against a glutamate-induced ischemic insult in the CA1 region of organotypic hippocampal cultures. Application of the hydroxylase inhibitor, dimethyloxallyl glycine (DMOG), depressed synaptic transmission. Both hypoxia and DMOG induced a reversible reduction in synaptic transmission, enhanced paired pulse facilitation (P<0.05) and inhibited N-methyl d-aspartate receptor (NMDAR) activity (P<0.01). However the effects of DMOG were adenosine A(1) receptor independent. Our results also suggest a potential therapeutic application for prolyl 4-hydroxylase (PHD) inhibitors in cerebral ischemia, since DMOG protected the CA1 region in organotypic hippocampal slices against a glutamate-induced ischemic insult.

Adenosine A1 receptor-mediated inhibition of dopamine release from rat striatal slices is modulated by D1 dopamine receptors.

Dopamine release is regulated by presynaptic dopamine receptors and interactions between adenosine and dopamine receptors have been well documented. In the present study, dopamine release from isolated striatal slices from Wistar rats was measured using fast cyclic voltammetry. Single-pulse stimulation (0.1 ms, 10 V) was applied every 5 min over a 2-h period. Superfusion with the adenosine (A)(1) receptor agonist N(6)-cyclopentyladenosine (CPA), but not the A(2) receptor agonist 3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl] phenyl]propanoic acid (CGS 21680), inhibited dopamine release in a concentration-dependent manner (IC(50) 3.80 x 10(-7) m; n = 10). The dose-response curve to CPA was shifted to the right (IC(50) 6.57 x 10(-6) m; n = 6, P < 0.05 vs. control) by the A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Neither the D(1) agonist 6-chloro-APB nor the D(1) antagonist R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3- benzazepine-7-ol (SCH 23390) altered dopamine release on their own. However, SCH 23390 (3 microm) significantly attenuated the response to CPA (IC(50) 1.44 x 10(-5) m; n = 6, P < 0.01 vs. control). Furthermore, the inhibitory effect of CPA was significantly increased in the presence of 6-chloro-APB (1 microm). In radioligand binding experiments, CPA interacted with high- and low-affinity states of [(3)H]DPCPX-lableled A(1) receptors. The high-affinity agonist binding to A(1) receptors was inhibited by the stable guanosine triphosphate analogue Gpp(NH)p. In contrast, neither the proportion nor the affinity of high-affinity A(1) receptors was altered by dopamine or SCH 23390. These results provide evidence that the inhibition of dopamine release by adenosine A(1) receptors is dependent, at least in part, on the simultaneous activation of D(1) dopamine receptors. While the mechanism underlying this interaction remains to be determined, it does not appear to involve an intramembrane interaction between A(1) and D(1) receptors.

A role for inflammatory mediators in the IL-18 mediated attenuation of LTP in the rat dentate gyrus.

Pro-inflammatory cytokines are known to be elevated in several pathological conditions that are associated with deficits in cognition. We have previously demonstrated that interleukin-18 (IL-18) inhibits long-term potentiation (LTP) in the dentate gyrus in vitro. In this study we have examined the involvement of the inflammatory mediators COX-2 and iNOS in IL-18-mediated inhibition of LTP. The effect of an anti-inflammatory PPARgamma agonist was also investigated. We report that the impairment of LTP by IL-18 is significantly attenuated by prior application of the COX-2 inhibitor, SC-236 and the iNOS inhibitor 1400W. These agents had no effect on paired pulse depression in the dentate gyrus. Furthermore, application of the PPARgamma agonist ciglitazone also attenuated IL-18-mediated inhibition of LTP. We discuss a role for p38 MAP kinase in these effects. This study provides novel evidence for the involvement of inflammatory mediators in IL-18-mediated inhibition of LTP in the rat dentate gyrus in vitro.

Mathematical models of passive motion at the human ankle joint by equivalent spatial parallel mechanisms.

The paper presents a theoretical model of the ankle joint, i.e. tibio-talar articulation, which shows how the articular surfaces and the ligaments, acting together as a mechanism, can control the passive kinematics of the joint. The authors had previously shown that, in virtually unloaded conditions, the ankle behaves as a single degree-of-freedom system, and that two ligament fibres remain nearly isometric throughout the flexion arc. Two different equivalent spatial parallel mechanisms together with corresponding kinematic models were formulated. These assumed isometricity of fibres within the calcaneal-fibular and tibio-calcaneal ligaments and rigidity of the articulating surfaces, taken as three sphere-plane contacts in one model, and as a single spherical pair in the other. Geometry parameters for the models were obtained from three specimens. Motion predictions compare quite well with the measured motion of the specimens. The differences are accounted for by the simplifications adopted to represent the complex anatomical structures, and might be reduced by future more realistic representations of the natural articular surfaces.

Development and clinical application of meniscal unicompartmental arthroplasty.

About one-third of osteoarthritic patients requiring knee replacement have focal lesions limited mainly to the medial compartment and can achieve excellent postoperative function after medial unicompartmental replacement. However, late failures of many unicompartmental prostheses require revision at a rate about twice that of total knee replacement. The use of a fully conforming mobile-bearing meniscal unicompartmental prosthesis in the hands of experienced surgeons can reduce revision rates to levels equivalent to the best results achieved with total knee replacement. The paper argues the case for such a prosthesis and demonstrates that the usual modes of failure of unicompartmental arthroplasty, most of them biomechanical, can thereby be avoided.

Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-alpha on long-term potentiation.

Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory. We have previously demonstrated in our laboratory that the inhibition of long-term potentiation (LTP) in the dentate gyrus region of the rat hippocampus, by tumor necrosis factor (TNF)-alpha, represents a biphasic response, an early phase dependent on p38 mitogen activated protein kinase (MAPK) activation and a later phase, possible dependent on protein synthesis. Many of the factors involved in the early modulation of LTP by TNF-alpha have yet to be elucidated. This study investigated if metabotropic glutamate receptors (mGluRs) are functionally linked to the inhibitory effect of TNF-alpha on LTP in the rat dentate gyrus in vitro. We report that the impairment of early-LTP by TNF-alpha is significantly attenuated by prior application of the group I/II mGluR antagonist MCPG and more specifically the mGluR5 antagonist MPEP. Since TNF-alpha is now known to cause transient increases in intracellular Ca(2+) levels from ryanodine-sensitive stores, we explored the possibility that disruption of intracellular Ca(2+) homeostasis could be involved. Ryanodine was found to significantly reverse the inhibition of LTP by TNF-alpha. From these studies we propose that the TNF-alpha inhibition of LTP is dependent upon the activation of TNFR1 and mGlu5-receptors. Importantly this study provides the first proof of the involvement of ryanodine-sensitive intracellular Ca(2+) stores in TNF-alpha mediated inhibition of LTP.

Mechanics of the anterior drawer test at the ankle: the effects of ligament viscoelasticity.

The anterior drawer test at the human ankle joint is a routine clinical examination. The relationship between the mechanical response of this joint and the flexion angle was elucidated by a recent mathematical model, using purely elastic mechanical characteristics for the ligament fibres. The objective of the present work was to assess the effect of ligament viscoelasticity on the force response of the ankle joint for anterior displacements of the foot relative to the tibia, at different ankle flexion positions. A viscoelastic model of the ligaments from the literature was included in the recently proposed mathematical model. Drawer tests were simulated at several flexion angles and for increasing velocities of the imposed anterior displacement. The stiffness of the model ankle joint increased only modestly with velocity. The response force found for a 6mm displacement at 20 degrees plantarflexion increased by only 13% for a one hundred-fold increase in velocity from 0.1 to 10 mm/s. The flexion angle was confirmed as the most influential parameter in the mechanical response of the ankle to anterior drawer test.

A novel method for in vivo knee prosthesis wear measurement.

Wear remains an important cause of failure in knee replacement. Of the current methods of early performance assessment or prediction, simulators have been un-physiological, single X-ray film analyses remain limited by accuracy and retrieval and survival methods have a prohibitive time scale. An accurate method is needed to allow a timely assessment of polyethylene component wear in vivo, when a new design is introduced, in order to predict likely outcome. We present a new method for measuring wear in vivo that we believe will allow this prediction of long-term wear. X-ray film pairs were taken of implanted prosthetic metal components. When the X-ray system was calibrated, projections of the appropriate Computer Aided Design (CAD) model could be matched to the shapes on the scanned X-ray films to find component positions. Interpenetration of the metal femoral component into the polyethylene component could then be established and represents our estimate of "wear". This method was used to measure in vivo prosthesis wear to an accuracy of 0.11 mm.

Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogen-activated protein kinase-dependent mechanism which maps to early-but not late-phase LTP.

The pro-inflammatory cytokine tumor-necrosis factor-alpha (TNF-alpha) is elevated in several neuropathological states that are associated with learning and memory deficits. Previous work has reported that TNF-alpha inhibits the induction of LTP in areas CA1 [Neurosci Lett 146 (1992) 176] and dentate gyrus [Neurosci Lett 203 (1996) 17]. The mechanism(s) underlying this process of inhibition have not to date been addressed. Here, we show that perfusion of TNF-alpha prior to long-term potentiation (LTP) inducing stimuli inhibited LTP, and that in late-LTP (3 h post-tetanus) a depression in synaptic field recordings was observed (68 +/- 5%, n = 6 versus control 175 +/- 7%, n = 6, P < 0.001). We investigated the involvement of the mitogen-activated protein kinase (MAPK) p38 in the inhibition of LTP by TNF-alpha as p38 MAPK has previously been shown to be involved in interleukin-1beta inhibition of LTP in the dentate gyrus [Neuroscience 93 (1999b) 57]. Perfusion of TNF-alpha led to an increase in the levels of phosphorylated p38 MAPK detectable in the granule cells of the dentate gyrus. The p38 MAPK inhibitor SB 203580 (1 microM) was found by itself to have no significant effect on either early or late phase LTP in the dentate gyrus. SB 203580 was found to significantly reverse the inhibition of early LTP by TNF-alpha (SB/TNF-alpha 174 +/- 5%, n = 6 versus TNF-alpha 120 +/- 7%, n = 6, P < 0.001, 1 h post-tetanus) to values comparable to control LTP (control 175 +/- 7%, n = 6). Interestingly however, the depressive effects of TNF-alpha on late LTP (2-3 h) were clearly not attenuated by p38 MAPK inhibition (SB/TNF-alpha 132 +/- 5%, n = 6 versus control LTP 175 +/- 7%, n = 6, P < 0.001, 3 h post-tetanus). This work suggests that TNF-alpha inhibition of LTP represents a biphasic response, a p38 MAPK-dependent phase that coincides with the early phase of LTP and a p38 MAPK independent phase that temporally maps to late LTP.