Rift-induced disruption of cratonic keels drives kimberlite volcanism.

Kimberlites are volatile-rich, occasionally diamond-bearing magmas that have erupted explosively at Earth's surface in the geologic past1-3. These enigmatic magmas, originating from depths exceeding 150 km in Earth's mantle1, occur in stable cratons and in pulses broadly synchronous with supercontinent cyclicity4. Whether their mobilization is driven by mantle plumes5 or by mechanical weakening of cratonic lithosphere4,6 remains unclear. Here we show that most kimberlites spanning the past billion years erupted about 30 million years (Myr) after continental breakup, suggesting an association with rifting processes. Our dynamical and analytical models show that physically steep lithosphere-asthenosphere boundaries (LABs) formed during rifting generate convective instabilities in the asthenosphere that slowly migrate many hundreds to thousands of kilometres inboard of rift zones. These instabilities endure many tens of millions of years after continental breakup and destabilize the basal tens of kilometres of the cratonic lithosphere, or keel. Displaced keel is replaced by a hot, upwelling mixture of asthenosphere and recycled volatile-rich keel in the return flow, causing decompressional partial melting. Our calculations show that this process can generate small-volume, low-degree, volatile-rich melts, closely matching the characteristics expected of kimberlites1-3. Together, these results provide a quantitative and mechanistic link between kimberlite episodicity and supercontinent cycles through progressive disruption of cratonic keels.

High-Dose Antibiotic Cement Spacers Independently Increase the Risk of Acute Kidney Injury in Revision for Periprosthetic Joint Infection: A Prospective Randomized Controlled Clinical Trial.

BACKGROUND: Standard treatment for periprosthetic joint infection (PJI) involves 2-stage exchange with placement of an antibiotic-impregnated cement spacer (ACS). Conflicting evidence exists on the role of ACS in development of acute kidney injury (AKI) after first-stage surgery. In this randomized clinical trial, we aimed to compare the incidence of AKI between the first-stage of a planned 2-stage exchange vs 1-stage exchange. This study design isolates the effect of the ACS in otherwise identical treatment groups. METHODS: The primary outcome variable was AKI, defined as a creatinine ≥1.5 times baseline or an increase of ≥0.3 mg/dL. Risk factors for AKI were evaluated using bivariate statistical tests and multivariable logistic regression. RESULTS: Patients who underwent the first stage of a planned 2-stage exchange were significantly more likely to develop AKI compared with the 1-stage exchange group (15 [22.7%] vs 4 [6.6%], P = .011). On multivariable regression analysis, ACS placement (odds ratio 7.48, 95% confidence limit 1.77-31.56) and chronic kidney disease (odds ratio 3.84, 95% confidence limit 1.22-12.08) were independent risk factors for AKI. CONCLUSION: Our study provides evidence that high-dose antibiotic cement spacers for treatment of PJI are an independent risk factor for AKI. Therefore, efforts to minimize nephrotoxicity should be employed in revision for PJI when possible.

Dynamic c-Fos changes in mouse brain during acute and protracted withdrawal from chronic intermittent ethanol exposure and relapse drinking.

Alcohol dependence promotes neuroadaptations in numerous brain areas, leading to escalated drinking and enhanced relapse vulnerability. We previously developed a mouse model of ethanol dependence and relapse drinking in which repeated cycles of chronic intermittent ethanol (CIE) vapor exposure drive a significant escalation of voluntary ethanol drinking. In the current study, we used this model to evaluate changes in neuronal activity (as indexed by c-Fos expression) throughout acute and protracted withdrawal from CIE (combined with or without a history of ethanol drinking). We analyzed c-Fos protein expression in 29 brain regions in mice sacrificed 2, 10, 26, and 74 hours or 7 days after withdrawal from 5 cycles of CIE. Results revealed dynamic time- and brain region-dependent changes in c-Fos activity over the time course of withdrawal from CIE exposure, as compared with nondependent air-exposed control mice, beginning with markedly low expression levels upon removal from the ethanol vapor chambers (2 hours), reflecting intoxication. c-Fos expression was enhanced during acute CIE withdrawal (10 and 26 hours), followed by widespread reductions at the beginning of protracted withdrawal (74 hours) in several brain areas. Persistent reductions in c-Fos expression were observed during prolonged withdrawal (7 days) in prelimbic cortex, nucleus accumbens shell, dorsomedial striatum, paraventricular nucleus of thalamus, and ventral subiculum. A history of ethanol drinking altered acute CIE withdrawal effects and caused widespread reductions in c-Fos that persisted during extended abstinence even without CIE exposure. These data indicate that ethanol dependence and relapse drinking drive long-lasting neuroadaptations in several brain regions.

Kinematic Performance of Gradually Variable Radius Posterior-Stabilized Primary TKA During Various Activities: An In Vivo Study Using Fluoroscopy.

BACKGROUND: Posterior-stabilized total knee arthroplasty (TKA) with gradually variable radii (G-curve) femoral condylar geometry is now available. It is believed that a G-curve design would lead to more mid-flexion stability leading to reduced incidence of paradoxical anterior slide. The objective of this study was to assess the in vivo kinematics for subjects implanted with this type of TKA under various conditions of daily living. METHODS: Tibiofemoral kinematics of 35 patients having posterior-stabilized TKA with G-curve design were analyzed using fluoroscopy while performing three activities: weight-bearing deep knee bend, gait, and walking down a ramp. The subjects were assessed for range of motion, condylar translation, axial rotation, cam-spine engagement, and condylar lift-off. RESULTS: The average weight-bearing flexion during deep knee bend was 111.4°. On average, the subjects exhibited 5.4 mm of posterior rollback of the lateral condyle and 2.0 mm of the medial condyle from full extension to maximum knee flexion. The femur consistently rotated externally with flexion, and the average axial rotation was 5.2°. Overall movement of the condyles during gait and ramp-down activity was small. No incidence of condylar lift-off was observed. CONCLUSION: Subjects in this study experienced consistent magnitudes of posterior femoral rollback and external rotation of the femur with weight-bearing flexion. The variation is similar to that previously reported for normal knee where the lateral condyle moves consistently posterior compared to the medial condyle. Subjects experienced low overall mid-flexion paradoxical anterior sliding and no incidence of condylar lift-off leading to mid-flexion stability.

Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking.

Distinct populations of D1- and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs) comprise the nucleus accumbens, and activity in D1-MSNs promotes, whereas activity in D2-MSNs inhibits, motivated behaviors. We used chemogenetics to extend D1-/D2-MSN cell specific regulation to cue-reinstated cocaine seeking in a mouse model of self-administration and relapse, and found that either increasing activity in D1-MSNs or decreasing activity in D2-MSNs augmented cue-induced reinstatement. Both D1- and D2-MSNs provide substantial GABAergic innervation to the ventral pallidum, and chemogenetic inhibition of ventral pallidal neurons blocked the augmented reinstatement elicited by chemogenetic regulation of either D1- or D2-MSNs. Because D1- and D2-MSNs innervate overlapping populations of ventral pallidal neurons, we next used optogenetics to examine whether changes in synaptic plasticity in D1- versus D2-MSN GABAergic synapses in the ventral pallidum could explain the differential regulation of VP activity. In mice trained to self-administer cocaine, GABAergic LTD was abolished in D2-, but not in D1-MSN synapses. A µ opioid receptor antagonist restored GABA currents in D2-, but not D1-MSN synapses of cocaine-trained mice, indicating that increased enkephalin tone on presynaptic µ opioid receptors was responsible for occluding the LTD. These results identify a behavioral function for D1-MSN innervation of the ventral pallidum, and suggest that losing LTDGABA in D2-MSN, but not D1-MSN input to ventral pallidum may promote cue-induced reinstatement of cocaine-seeking. SIGNIFICANCE STATEMENT: More than 90% of ventral striatum is composed of two cell types, those expressing dopamine D1 or D2 receptors, which exert opposing roles on motivated behavior. Both cell types send GABAergic projections to the ventral pallidum and were found to differentially promote cue-induced reinstatement of cocaine seeking via the ventral pallidum. Furthermore, after cocaine self-administration, synaptic plasticity was selectively lost in D2, but not D1 inputs to the ventral pallidum. The selective impairment in D2 afferents may promote the influence of D1 inputs to drive relapse to cocaine seeking.

Accumbens nNOS Interneurons Regulate Cocaine Relapse.

Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relapse is correlated with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses on medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) and requires spillover of glutamate from prefrontal cortical afferents. We used a rodent self-administration/reinstatement model of relapse to show that cue-induced t-SP and reinstated cocaine seeking result from glutamate spillover, initiating a metabotropic glutamate receptor 5 (mGluR5)-dependent increase in nitric oxide (NO) production. Pharmacological stimulation of mGluR5 in NAcore recapitulated cue-induced reinstatement in the absence of drug-associated cues. Using NO-sensitive electrodes, mGluR5 activation by glutamate was shown to stimulate NO production that depended on activation of neuronal nitric oxide synthase (nNOS). nNOS is expressed in ∼1% of NAcore neurons. Using a transgene strategy to express and stimulate designer receptors that mimicked mGluR5 signaling through Gq in nNOS interneurons, we recapitulated cue-induced reinstatement in the absence of cues. Conversely, using a transgenic caspase strategy, the intensity of cue-induced reinstatement was correlated with the extent of selective elimination of nNOS interneurons. The induction of t-SP during cued reinstatement depends on activating matrix metalloproteinases (MMPs) and selective chemogenetic stimulation of nNOS interneurons recapitulated MMP activation and t-SP induction (increase in AMPA currents in MSNs). These data demonstrate critical involvement of a sparse population of nNOS-expressing interneurons in cue-induced cocaine seeking, revealing a bottleneck in brain processing of drug-associated cues where therapeutic interventions could be effective in treating drug addiction. SIGNIFICANCE STATEMENT: Relapse to cocaine use in a rat model is associated with transient increases in synaptic strength at prefrontal cortex synapses in the nucleus accumbens. We demonstrate the sequence of events that mediates synaptic potentiation and reinstated cocaine seeking induced by cocaine-conditioned cues. Activation of prefrontal inputs to the accumbens by cues initiates spillover of synaptic glutamate, which stimulates metabotropic glutamate receptor 5 (mGluR5) on a small population of interneurons (∼1%) expressing neuronal nitric oxide synthase. Stimulating these glutamate receptors increases nitric oxide (NO) production, which stimulates matrix metalloprotease-2 (MMP-2) and MMP-9 activity in the extracellular space. Manipulating the interaction between mGluR5, NO production, or MMP-2 and MMP-9 pharmacologically or genetically is sufficient to recapitulate transient synaptic potentiation and reinstate cocaine seeking.

GZ7 and GZ8 - Two Zircon Reference Materials for SIMS U-Pb Geochronology.

Here, we document a detailed characterisation of two zircon gemstones, GZ7 and GZ8. Both stones had the same mass at 19.2 carats (3.84 g) each; both came from placer deposits in the Ratnapura district, Sri Lanka. The U-Pb data are in both cases concordant within the uncertainties of decay constants and yield weighted mean 206Pb/238U ages (95% confidence uncertainty) of 530.26 Ma ± 0.05 Ma (GZ7) and 543.92 Ma ± 0.06 Ma (GZ8). Neither GZ7 nor GZ8 have been subjected to any gem enhancement by heating. Structure-related parameters correspond well with the calculated alpha doses of 1.48 × 1018 g-1 (GZ7) and 2.53 × 1018 g-1 (GZ8), respectively, and the (U-Th)/He ages of 438 Ma ± 3 Ma (2s) for GZ7 and 426 Ma ± 9 Ma (2s) for GZ8 are typical of unheated zircon from Sri Lanka. The mean U mass fractions are 680 µg g-1 (GZ7) and 1305 µg g-1 (GZ8). The two zircon samples are proposed as reference materials for SIMS (secondary ion mass spectrometry) U-Pb geochronology. In addition, GZ7 (Ti mass fractions 25.08 µg g-1 ± 0.18 µg g-1; 95% confidence uncertainty) may prove useful as reference material for Ti-in-zircon temperature estimates.

Continental crust beneath southeast Iceland.

The magmatic activity (0-16 Ma) in Iceland is linked to a deep mantle plume that has been active for the past 62 My. Icelandic and northeast Atlantic basalts contain variable proportions of two enriched components, interpreted as recycled oceanic crust supplied by the plume, and subcontinental lithospheric mantle derived from the nearby continental margins. A restricted area in southeast Iceland--and especially the Öræfajökull volcano--is characterized by a unique enriched-mantle component (EM2-like) with elevated (87)Sr/(86)Sr and (207)Pb/(204)Pb. Here, we demonstrate through modeling of Sr-Nd-Pb abundances and isotope ratios that the primitive Öræfajökull melts could have assimilated 2-6% of underlying continental crust before differentiating to more evolved melts. From inversion of gravity anomaly data (crustal thickness), analysis of regional magnetic data, and plate reconstructions, we propose that continental crust beneath southeast Iceland is part of ∼350-km-long and 70-km-wide extension of the Jan Mayen Microcontinent (JMM). The extended JMM was marginal to East Greenland but detached in the Early Eocene (between 52 and 47 Mya); by the Oligocene (27 Mya), all parts of the JMM permanently became part of the Eurasian plate following a westward ridge jump in the direction of the Iceland plume.

Inferomedial Hip Center Decreases Failure Rates in Cementless Total Hip Arthroplasty for Crowe II and III Hip Dysplasia.

BACKGROUND: We sought to evaluate the outcomes of cementless acetabular components used in patients with Crowe II and III dysplasia, and to compare outcomes between cups placed within vs outside of an "anatomic" zone. Our specific aims were to (1) plot hip centers in these patients at our institution to characterize "anatomic" vs "nonanatomic" positions, (2) evaluate the association between hip center and radiographic loosening, (3) determine whether hip center was associated with acetabular component revision, and (4) compare patient-reported outcome scores between groups. METHODS: We retrospectively reviewed 88 primary cementless total hip arthroplasties at a mean follow-up of 10 years (range 2-26 years). Patients were 85% female, with a mean age of 44 years (range 28-61 years) and a body mass index of 27 kg/m2 (range 19-42 kg/m2). Medical records and radiographs were reviewed, and a survey was conducted for all patients. Anatomic hip center was defined using the 4-zone system, wherein centers are "anatomic" if they are <1 cm superior and <1 cm lateral to the approximate femoral head center. Cox proportional analyses were used to compare outcomes between groups. RESULTS: Seventy hips (80%) had an anatomic hip center. Anatomic hips had a lower incidence of radiographic acetabular loosening (0% vs 17%, P = .007) and cup revision (0% vs 28%, P = .0002). There were no differences in Hip Disability and Osteoarthritis Outcome and Joint Replacement Scores (96.2 ± 5 vs 91.9 ± 12, P = .7). CONCLUSION: The incidence of aseptic loosening and cup revision were lower when hip center was <1 cm superior and 1 cm lateral to the approximate femoral head center.

Oxytocin Reduces Ethanol Self-Administration in Mice.

BACKGROUND: Excessive ethanol (EtOH) consumption remains an important health concern and effective treatments are lacking. The central oxytocin system has emerged as a potentially important therapeutic target for alcohol and drug addiction. These studies tested the hypothesis that oxytocin reduces EtOH consumption. METHODS: Male C57BL/6J mice were given access to EtOH (20% v/v) using a model of binge-like drinking ("drinking in the dark") that also included the use of lickometer circuits to evaluate the temporal pattern of intake as well as 2-bottle choice drinking in the home cage. In addition, EtOH (12% v/v) and sucrose (5% w/v) self-administration on fixed- and progressive-ratio schedules were also evaluated. A wide range of systemically administered oxytocin doses were tested (0 to 10 mg/kg) in these models. RESULTS: Oxytocin (0, 0.3, 1, 3, or 10 mg/kg) dose dependently reduced EtOH consumption (maximal 45% reduction) in the binge drinking model, with lower effective doses having minimal effects on general locomotor activity. Oxytocin's effect was blocked by pretreatment with an oxytocin receptor antagonist, and the pattern of contacts (licks) at the EtOH bottle suggested a reduction in motivation to drink EtOH. Oxytocin decreased 2-bottle choice drinking without altering general fluid intake. Oxytocin also reduced operant responding for EtOH and sucrose in a dose-related manner. However, oxytocin decreased responding and motivation (breakpoint values) for EtOH at doses that did not alter responding for sucrose. CONCLUSIONS: These results indicate that oxytocin reduces EtOH consumption in different models of self-administration. The effects are not likely due to a general sedative effect of the neuropeptide. Further, oxytocin reduces motivation for EtOH at doses that do not alter responding for a natural reward (sucrose). While some evidence supports a role for oxytocin receptors in mediating these effects, additional studies are needed to further elucidate underlying mechanisms. Nevertheless, these results support the therapeutic potential of oxytocin as a treatment for alcohol use disorder.

Peripheral arterial disease is associated with an increased risk of atrial fibrillation in the elderly.

AIMS: To examine the relationship between peripheral arterial disease (PAD) and atrial fibrillation (AF) in a population-based cohort study of older adults. METHODS AND RESULTS: We examined the relationship between PAD and AF in 5143 participants (85% white, 43% male) in the Cardiovascular Health Study (CHS), a longitudinal, observational study of adults aged 65 years and older. Peripheral arterial disease was defined by abnormal ankle-brachial index (ABI) values (<1.0 or >1.4). Incident AF events were ascertained by self-reported history, study electrocardiograms, and hospitalization discharge records. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between PAD and AF. Over a median follow-up of 11.7 years, a total of 1521 participants developed AF. The incidence rate (per 1000 person-years) of AF was higher in those with PAD (incidence rate = 32.9, 95% CI = 29.5, 36.7) than those without PAD (incidence rate = 23.3, 95% CI = 22.0, 24.6). In a multivariate Cox regression analysis, PAD was associated with an increased risk for AF (HR = 1.52, 95% CI = 1.34, 1.72). Each 0.1 decrease in the ABI was associated with a 6% increase in the risk for AF (HR = 1.06, 95% CI = 1.02, 1.10). The associations of high (>1.4) and low (<1.0) ABI values with AF were examined separately and were in the same direction as the main result for PAD (ABI < 1.0: HR = 1.24, 95% CI = 1.08, 1.42; ABI > 1.4: HR = 1.33, 95% CI = 0.95, 1.86). CONCLUSION: The presence of PAD should alert practitioners to the increased risk of AF. Elderly patients with PAD possibly will benefit from routine electrocardiographic screening to identify AF events.

Chronic intermittent ethanol exposure and withdrawal leads to adaptations in nucleus accumbens core postsynaptic density proteome and dendritic spines.

Alcohol use disorder is a chronic relapsing brain disease characterized by the loss of ability to control alcohol (ethanol) intake despite knowledge of detrimental health or personal consequences. Clinical and pre-clinical models provide strong evidence for chronic ethanol-associated alterations in glutamatergic signaling and impaired synaptic plasticity in the nucleus accumbens (NAc). However, the neural mechanisms that contribute to aberrant glutamatergic signaling in ethanol-dependent individuals in this critical brain structure remain unknown. Using an unbiased proteomic approach, we investigated the effects of chronic intermittent ethanol (CIE) exposure on neuroadaptations in postsynaptic density (PSD)-enriched proteins in the NAc of ethanol-dependent mice. Compared with controls, CIE exposure significantly changed expression levels of 50 proteins in the PSD-enriched fraction. Systems biology and functional annotation analyses demonstrated that the dysregulated proteins are expressed at tetrapartite synapses and critically regulate cellular morphology. To confirm this latter finding, the density and morphology of dendritic spines were examined in the NAc core of ethanol-dependent mice. We found that CIE exposure and withdrawal differentially altered dendrite diameter and dendritic spine density and morphology. Through the use of quantitative proteomics and functional annotation, these series of experiments demonstrate that ethanol dependence produces neuroadaptations in proteins that modify dendritic spine morphology. In addition, these studies identified novel PSD-related proteins that contribute to the neurobiological mechanisms of ethanol dependence that drive maladaptive structural plasticity of NAc neurons.

Kv7 channels in the nucleus accumbens are altered by chronic drinking and are targets for reducing alcohol consumption.

Alcohol use disorders (AUDs) are a major public health issue and produce enormous societal and economic burdens. Current Food and Drug Administration (FDA)-approved pharmacotherapies for treating AUDs suffer from deleterious side effects and are only effective in a subset of individuals. It is therefore essential to find improved medications for the management of AUDs. Emerging evidence suggests that anticonvulsants are a promising class of drugs for treating individuals with AUDs. In these studies, we used integrative functional genomics to demonstrate that genes that encode Kv7 channels (i.e. Kcnq2/3) are related to alcohol (ethanol) consumption, preference and acceptance in rodents. We then tested the ability of the FDA-approved anticonvulsant retigabine, a Kv7 channel opener, to reduce voluntary ethanol consumption of Wistar rats in a two-bottle choice intermittent alcohol access paradigm. Systemic administration and microinjections of retigabine into the nucleus accumbens significantly reduced alcohol drinking, and retigabine was more effective at reducing intake in high- versus low-drinking populations of Wistar rats. Prolonged voluntary drinking increased the sensitivity to the proconvulsant effects of pharmacological blockade of Kv7 channels and altered surface trafficking and SUMOylation patterns of Kv7.2 channels in the nucleus accumbens. These data implicate Kcnq2/3 in the regulation of ethanol drinking and demonstrate that long-term drinking produces neuroadaptations in Kv7 channels. In addition, these results have identified retigabine as a potential pharmacotherapy for treating AUDs and Kv7 channels as a novel therapeutic target for reducing heavy drinking.

Seasonal Incidence of Emergent Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Emergent coronary artery bypass grafting (CABG) surgery is often required in the case of severe coronary artery disease, which is refractory to traditional management. The objective of our study was to test the hypothesis that there is seasonal variation in the incidence of emergent CABG. METHODS: A sinusoidal logistic regression model was used to analyze operative data at our cardiovascular institute of 270 cases spanning 5939 calendar days. RESULTS: A cyclic peak risk for emergent CABG was observed for late winter (calendar day 66; P = .036). The odds ratios for the 1-, 2- and 3-month window surrounding this peak were 1.8 (95% CI = 0.94-3.5, P = .072), 1.6 (95% CI = 1.06-2.5, P = .024) and 1.4 (95% CI = 0.9-1.8, P = .066), respectively. CONCLUSION: Our results suggest that a seasonal variation may exist in the incidence of patients presenting with severe coronary artery disease requiring emergent CABG. This information is useful in the scheduling of hospital resources and staff. It also provides important etiology clues underlying coronary artery disease that may lead to future interventions or targeted therapies.

Survivorship After Periprosthetic Femur Fracture: Factors Affecting Outcome.

BACKGROUND: Data addressing risk factors predictive of mortality and reoperation after periprosthetic femur fractures (PPFxs) are lacking. This study examined survivorship and risk ratios for mortality and reoperation after surgical treatment for PPFx and associated clinical risk factors. METHODS: A retrospective review was performed for 291 patients treated surgically for PPFx between 2004 and 2013. Primary outcomes were death and reoperation. RESULTS: Mortality at 1 year was 13%, whereas the rate of reoperation was 12%. Greater span of fixation and revision arthroplasty (vs open reduction internal fixation) trended toward a lower likelihood of reoperation. CONCLUSION: After PPFx, patients have a 24% risk of either death or reoperation at 1 year. Factors contributing to increased mortality are nonmodifiable. Risk of reoperation is minimized with greater span of fixation and performance of revision arthroplasty.

Sensitization and Tolerance Following Repeated Exposure to Caffeine and Alcohol in Mice.

BACKGROUND: Energy drinks are popular mixers with alcohol. While energy drinks contain many ingredients, caffeine is an important pharmacologically active component and is generally present in larger amounts than in other caffeinated beverages. In these studies, we investigated the hypothesis that caffeine would influence the effects of alcohol (ethanol [EtOH]) on conditioned taste aversion (CTA), ataxia, and locomotor activity (LA) after repeated exposure. METHODS: Four groups of mice were exposed by oral gavage twice daily to vehicle, EtOH (4 g/kg), caffeine (15 mg/kg), or the EtOH/caffeine combination. CTA to saccharin and ataxia in the parallel rod task was evaluated after 8 or 16 gavages, respectively, using EtOH (1 to 3 g/kg) or EtOH/caffeine (3 mg/kg + 2 g/kg) challenges. In addition, LA was evaluated initially and after repeated exposure to oral gavage of these drugs and doses. RESULTS: Repeated oral gavage of EtOH produced significant locomotor sensitization, with those mice increasing total distance traveled by 2-fold. The locomotor response to caffeine, while significantly greater than vehicle gavage, did not change with repeated exposure. On the other hand, repeated gavage of caffeine/EtOH combination produced a substantial increase in total distance traveled after repeated exposure (~4-fold increase). After repeated EtOH exposure, there was significant tolerance to EtOH in the CTA and parallel rod tests. However, neither a history of caffeine exposure nor including caffeine influenced EtOH-induced CTA. Interestingly, a history of caffeine exposure increased the ataxic response to the caffeine/EtOH combination and appeared to reduce the ataxic response to high doses of EtOH. CONCLUSIONS: The data support the general hypothesis that repeated exposure to caffeine influences the response to EtOH. Together with previously published work, these data indicate that caffeine influences some EtOH-related behaviors, notably locomotion and ataxia, but appears not to influence the expression of conditioned behaviors.

Cobalt to Chromium Ratio is Not a Key Marker for Adverse Local Tissue Reaction (ALTR) in Metal on Metal Hips.

The diagnosis of adverse local tissue reaction (ALTR) after metal-on-metal total hip arthroplasty (MoMTHA) presents a significant challenge. No single biomarker is specific for ALTR. The purpose of this study was to determine if the ratio of cobalt to chromium ions is useful for diagnosing ALTR in MoMTHA. In 89 bearing-related revision THAs, preoperative cobalt and chromium ion levels were compared to an intraoperative soft tissue damage grading scale. The average cobalt to chromium ratio was 2.96 (0-20). There was no correlation between the tissue scale and the cobalt to chromium ratio (R=0.095; P=0.41). Many variables affecting ion production/excretion mitigate the use of the ion ratio. The cobalt to chromium ratio is not a predictive biomarker for ALTR in MoMTHA.

Influence of sensitization on the discriminative stimulus effects of methylphenidate in mice.

Methylphenidate (MPH) remains an important therapy for attention-deficit hyperactivity disorder, but aspects of its pharmacology remain unclear. In the present study, we used a regimen of MPH (8 mg/kg daily×14 days) in C57BL/6J mice to determine whether establishing locomotor sensitization to MPH influenced the acquisition and the dose-response function of MPH in a classic drug discrimination procedure. MPH-sensitized mice (SENS group) showed enhanced locomotor activity to the 8 mg/kg exposure dose as well as a 2 mg/kg dose before discrimination training. However, the SENS mice did not acquire discrimination of either a low dose (2 mg/kg) or a higher dose (4 mg/kg) of MPH any more rapidly than the CTRL mice. Further, during generalization testing, the dose-response functions for the SENS and CTRL mice were identical. Therefore, we did not find that previous exposure to MPH, which produced a sensitized locomotor response, facilitated MPH discrimination.

Metal ion levels: how can they help us?

Ion levels have been shown to reliably predict abnormal function of the bearing surface with increased wear, but ion levels should not be used alone as a trigger for when to proceed with revision surgery with metal-metal articulations. Risk stratification strategies help determine which patients should be monitored more closely with serial ion levels, cross-sectional imaging with a MARS MRI, or proceed on to revision. Based on the current data available, an ion level greater than 4.5 ppb (Cr or Co) may serve as a threshold for when abnormal wear is occurring, and is suggested as a trigger for a MARS MRI scan.