Duloxetine inhibits effects of MDMA ("ecstasy") in vitro and in humans in a randomized placebo-controlled laboratory study.

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence. TRIAL REGISTRATION: Clinicaltrials.gov NCT00990067.

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

Effects of the PPAR-beta agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination.

BACKGROUND: Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-beta seems to play an important role in the regulation of central inflammation. In addition, PPAR-beta agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-beta agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-gamma and LPS. METHODS: Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-gamma and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG). The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), inducible NO synthase (i-NOS), PPAR-beta, PPAR-gamma, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and high molecular weight neurofilament protein (NF-H). GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4) and ED1 labeling. RESULTS: GW 501516 decreased the IFN-gamma-induced up-regulation of TNF-alpha and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-beta agonist. However, it increased IL-6 m-RNA expression. In demyelinating cultures, reactivity of both microglial cells and astrocytes was observed, while the expression of the inflammatory cytokines and iNOS remained unaffected. Furthermore, GW 501516 did not protect against the demyelination-induced changes in gene expression. CONCLUSION: Although GW 501516 showed anti-inflammatory activity, it did not protect against antibody-mediated demyelination. This suggests that the protective effects of PPAR-beta agonists observed in vivo can be attributed to their anti-inflammatory properties rather than to a direct protective or trophic effect on oligodendrocytes.

Effects of strontium ranelate and alendronate on bone microstructure in women with osteoporosis. Results of a 2-year study.

A Strontium ranelate appears to influence more than alendronate distal tibia bone microstructure as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), and biomechanically relevant parameters as assessed by micro-finite element analysis (mu FEA), over 2 years, in postmenopausal osteoporotic women.Introduction Bone microstructure changes are a target in osteoporosis treatment to increase bone strength and reduce fracture risk.Methods Using HR-pQCT, we investigated the effects on distal tibia and radius microstructure of strontium ranelate (SrRan; 2 g/day) or alendronate (70 mg/week) for 2 years in postmenopausal osteoporotic women. This exploratory randomized, double-blind trial evaluated HR-pQCT and FEA parameters, areal bone mineral density (BMD), and bone turnover markers.Results In the intention-to-treat population (n = 83, age: 64 +/- 8 years; lumbar T-score: -2.8 +/- 0.8 [DXA]), distal tibia Cortical Thickness (CTh) and Density (DCort), and cancellous BV/TV increased by 6.3%, 1.4%, and 2.5%, respectively (all P < 0.005), with SrRan, but not with alendronate (0.9%, 0.4%, and 0.8%, NS) (P < 0.05 for all above between-group differences). Difference for CTh evaluated with a distance transformation method was close to significance (P = 0.06). The estimated failure load increased with SrRan (+2.1%, P < 0.005), not with alendronate (-0.6%, NS) (between-group difference, P < 0.01). Cortical stress was lower with SrRan (P < 0.05); both treatments decreased trabecular stress. At distal radius, there was no between-group difference other than DCort (P < 0.05). Bone turnover markers decreased with alendronate; bALP increased (+21%) and serum-CTX-I decreased (-1%) after 2 years of SrRan (between-group difference at each time point for both markers, P < 0.0001). Both treatments were well tolerated.Conclusions Within the constraints of HR-pQCT method, and while a possible artefactual contribution of strontium cannot be quantified, SrRan appeared to influence distal tibia bone microstructure and FEA-determined biomechanical parameters more than alendronate. However, the magnitude of the differences is unclear and requires confirmation with another method.

Effects of a 5-h hilly running on ankle plantar and dorsal flexor force and fatigability.

This study aimed to examine the effects of a 5-h hilly run on ankle plantar (PF) and dorsal flexor (DF) force and fatigability. It was hypothesised that DF fatigue/fatigability would be greater than PF fatigue/fatigability. Eight male trail long distance runners (42.5 ± 5.9 years) were tested for ankle PF and DF maximal voluntary isokinetic contraction strength and fatigue resistance tests (percent decrement score), maximal voluntary and electrically evoked isometric contraction strength before and after the run. Maximal EMG root mean square (RMS(max)) and mean power frequency (MPF) values of the tibialis anterior (TA), gastrocnemius lateralis (GL) and soleus (SOL) EMG activity were calculated. The peak torque of the potentiated high- and low-frequency doublets and the ratio of paired stimulation peak torques at 10 Hz over 100 Hz (Db10:100) were analysed for PF. Maximal voluntary isometric contraction strength of PF decreased from pre- to post-run (-17.0 ± 6.2%; P < 0.05), but no significant decrease was evident for DF (-7.9 ± 6.2%). Maximal voluntary isokinetic contraction strength and fatigue resistance remained unchanged for both PF and DF. RMS(max) SOL during maximal voluntary isometric contraction and RMS(max) TA during maximal voluntary isokinetic contraction were decreased (P < 0.05) after the run. For MPF, a significant decrease for TA (P < 0.05) was found and the ratio Db10:100 decreased for PF (-6.5 ± 6.0%; P < 0.05). In conclusion, significant isometric strength loss was only detected for PF after a 5-h hilly run and was partly due to low-frequency fatigue. This study contradicted the hypothesis that neuromuscular alterations due to prolonged hilly running are predominant for DF.

Negative and positive effects of trade on health.

Comment on: Blouin C, Chopra M, van der Hoeven R.Trade and social determinants of health. Lancet. 2009;373(9662):502-7. PMID: 19167058.

Circadian and wake-dependent effects on the pupil light reflex in response to narrow-bandwidth light pulses.

PURPOSE: Nonvisual light-dependent functions in humans are conveyed mainly by intrinsically photosensitive retinal ganglion cells, which express melanopsin as photopigment. We aimed to identify the effects of circadian phase and sleepiness across 24 hours on various aspects of the pupil response to light stimulation. METHODS: We tested 10 healthy adults hourly in two 12-hour sessions covering a 24-hour period. Pupil responses to narrow bandwidth red (635 ± 18 nm) and blue (463 ± 24 nm) light (duration of 1 and 30 seconds) at equal photon fluxes were recorded, and correlated with salivary melatonin concentrations at the same circadian phases and to subjective sleepiness ratings. The magnitude of pupil constriction was determined from minimal pupil size. The post-stimulus pupil response was assessed from the pupil size at 6 seconds following light offset, the area within the redilation curve, and the exponential rate of redilation. RESULTS: Among the measured parameters, the pupil size 6 seconds after light offset correlated with melatonin concentrations (P < 0.05) and showed a significant modulation over 24 hours with maximal values after the nocturnal peak of melatonin secretion. In contrast, the post-stimulus pupil response following red light stimulation correlated with subjective sleepiness (P < 0.05) without significant changes over 24 hours. CONCLUSIONS: The post-stimulus pupil response to blue light as a marker of intrinsic melanopsin activity demonstrated a circadian modulation. In contrast, the effect of sleepiness was more apparent in the cone contribution to the pupil response. Thus, pupillary responsiveness to light is under influence of the endogenous circadian clock and subjective sleepiness.

Effects of endotoxin on lactate metabolism in humans.

ABSTRACT: INTRODUCTION: Hyperlactatemia represents one prominent component of the metabolic response to sepsis. In critically ill patients, hyperlactatemia is related to the severity of the underlying condition. Both an increased production and a decreased utilization and clearance might be involved in this process, but their relative contribution remains unknown. The present study aimed at assessing systemic and muscle lactate production and systemic lactate clearance in healthy human volunteers, using intravenous endotoxin (LPS) challenge. METHODS: Fourteen healthy male volunteers were enrolled in 2 consecutive studies (n = 6 in trial 1 and n = 8 in trial 2). Each subject took part in one of two investigation days (LPS-day with endotoxin injection and placebo-day with saline injection) separated by one week at least and in a random order. In trial 1, their muscle lactate metabolism was monitored using microdialysis. In trial 2, their systemic lactate metabolism was monitored by means of a constant infusion of exogenous lactate. Energy metabolism was monitored by indirect calorimetry and glucose kinetics was measured with 6,6-H2 glucose. RESULTS: In both trials, LPS increased energy expenditure (p = 0.011), lipid oxidation (p<0.0001), and plasma lactate concentration (p = 0.016). In trial 1, lactate concentration in the muscle microdialysate was higher than in blood, indicating lactate production by muscles. This was, however, similar with and without LPS. In trial 2, calculated systemic lactate production increased after LPS (p = 0.031), while lactate clearance remained unchanged. CONCLUSIONS: LPS administration increases lactatemia by increasing lactate production rather than by decreasing lactate clearance. Muscle is, however, unlikely to be a major contributor to this increase in lactate production. TRIAL REGISTRATION: ClinicalTrials.gov NCT01647997.

α₁-Adrenergic receptors contribute to the acute effects of 3,4-methylenedioxymethamphetamine in humans.

Preclinical studies implicate a role for α₁-noradrenergic receptors in the effects of psychostimulants, including 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). The present study evaluated the effects of the α₁-noradrenergic receptor antagonist doxazosin on the acute pharmacodynamic and pharmacokinetic response to MDMA in 16 healthy subjects. Doxazosin (8 mg/d) or placebo was administered for 3 days before MDMA (125 mg) or placebo using a randomized, double-blind, placebo-controlled, 4-session, crossover design. Doxazosin reduced MDMA-induced elevations in blood pressure, body temperature, and moderately attenuated positive mood but enhanced tachycardia associated with MDMA. The results indicate that α₁-adrenergic receptors contribute to the acute cardiostimulant and to a minor extent possibly also to the thermogenic and euphoric effects of MDMA in humans.

Physical training and hypertension have opposite effects on endothelial brain-derived neurotrophic factor expression.

AIMS: Changes in circulating brain-derived neurotrophic factor (BDNF) levels were reported in patients with or at risk for cardiovascular diseases associated with endothelial dysfunction, suggesting a link between BDNF and endothelial functionality. However, little is known on cardiovascular BDNF. Our aim was to investigate levels/localization, function, and relevance of cardiovascular BDNF. METHODS AND RESULTS: BDNF levels (western blotting) and localization (immunostaining) were assessed in the heart and aorta from rats with impaired (spontaneously hypertensive rats [SHR]), normal (Wistar Kyoto rats [WKY]), and improved (SHR and WKY subjected to physical training) endothelial function. BDNF levels were also measured in cultured endothelial cells (CECs) subjected to low and high shear stress. The cardiovascular effects of BDNF were investigated in isolated aortic rings and hearts. The results showed high BDNF levels in the heart and aorta, the expression being prominent in endothelial cells as compared with other cell types. Exogenous BDNF vasodilated aortic rings but changed neither coronary flow nor cardiac contractility. Hypertension was associated with decreased expression of BDNF in the endothelium, whereas physical training led to endothelial BDNF up-regulation not only in WKY but also in SHR. Exposure of CECs to high shear stress stimulated BDNF production and secretion. CONCLUSION: Cardiovascular BDNF is mainly localized within endothelial cells in which its expression is dependent on endothelial function. These results open new perspectives on the role of endothelial BDNF in cardiovascular health.

Oligoanalgesia in the emergency department: short-term beneficial effects of an education program on acute pain.

STUDY OBJECTIVE: Acute pain is the most frequent complaint in emergency department (ED) admissions, but its management is often neglected, placing patients at risk of oligoanalgesia. We evaluate the effect of the implementation of guidelines for pain management in ED patients with pain at admission or anytime during their stay in our ED. METHODS: This prospective pre-post intervention cohort study included data collection both before and after guideline implementation. Consecutive adult patients admitted with acute pain from any cause or with pain at any time after admission were enrolled. The quality of pain management was evaluated according to information in the ED medical records by using a standardized collection form, and its impact on patients was recorded with a questionnaire at discharge. RESULTS: Two hundred forty-nine and 192 patients were included during pre- and postintervention periods. Pain was documented in 61% and 76% of nurse and physician notes, respectively, versus 78% and 85% after the intervention (difference 17%/9%; 95% confidence interval [CI] 8% to 26%/2% to 17%, respectively). Administration of analgesia increased from 40% to 63% (difference 23%; 95% CI 13% to 32%) and of morphine from 10% to 27% (difference 17%; 95% CI 10% to 24%). Mean doses of intravenous morphine increased from 2.4 mg (95% CI 1.9 to 2.9 mg) to 4.6 mg (95% CI 3.9 to 5.3 mg); administration of nonsteroidal antiinflammatory drugs and acetaminophen increased as well. There was a greater reduction of visual analogue scale score after intervention: 2.1 cm (95% CI 1.7 to 2.4 cm) versus 2.9 cm (95% CI 2.5 to 3.3 cm), which was associated with improved patient satisfaction. CONCLUSION: Education program and guidelines implementation for pain management lead to improved pain management, analgesia, and patient satisfaction in the ED.

Autologous stem cell transplantation: leukapheresis product has anti-angiogenic effects in vivo correlating with neutrophil-derived VEGFR1.

BACKGROUND: High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) is used for the treatment of hemato-oncologic malignancies. In this study, we measured the effect of HDC/ASCT on plasma concentrations of antiangiogenic soluble vascular endothelial growth factor receptor 1 (sVEGFR1) and of leukapheresis products (LP) and patient serum on chick chorioallantoic (CAM) angiogenesis. MATERIALS AND METHODS: VEGFR1- and CD34-expressing cells of leukapheresis products were analyzed by flow cytometry. Alternatively spliced isoforms of VEGFR1 mRNA were quantified using reverse transcription PCR. RESULTS: Plasma concentrations of sVEGFR1 decreased after HDC, but significantly increased after ASCT. In the CAM assay, sera of patients elicited a proangiogenic effect before and after HDC, but a strong antiangiogenic response after ASCT, comparable to that of bevacizumab at therapeutic concentrations. LP contains high concentrations of sVEGFR1, and high density of VEGFR1(+) neutrophilic granulocytes, in which mRNA expression is shifted toward the soluble VEGFR1 isoform. CONCLUSION: Neutrophil-derived antiangiogenic sVEGFR1 within the LP may contribute to the therapeutic efficacy of ASCT.

Differential effects of sodium oxybate and baclofen on EEG, sleep, neurobehavioral performance, and memory.

STUDY OBJECTIVES: Sodium oxybate (SO) is a GABA(B) agonist used to treat the sleep disorder narcolepsy. SO was shown to increase slow wave sleep (SWS) and EEG delta power (0.75-4.5 Hz), both indexes of NREM sleep (NREMS) intensity and depth, suggesting that SO enhances recuperative function of NREM. We investigated whether SO induces physiological deep sleep. DESIGN: SO was administered before an afternoon nap or before the subsequent experimental night in 13 healthy volunteers. The effects of SO were compared to baclofen (BAC), another GABA(B) receptor agonist, to assess the role of GABA(B) receptors in the SO response. MEASUREMENTS AND RESULTS: As expected, a nap significantly decreased sleep need and intensity the subsequent night. Both drugs reversed this nap effect on the subsequent night by decreasing sleep latency and increasing total sleep time, SWS during the first NREMS episode, and EEG delta and theta (0.75-7.25 Hz) power during NREMS. The SO-induced increase in EEG delta and theta power was, however, not specific to NREMS and was also observed during REM sleep (REMS) and wakefulness. Moreover, the high levels of delta power during a nap following SO administration did not affect delta power the following night. SO and BAC taken before the nap did not improve subsequent psychomotor performance and subjective alertness, or memory consolidation. Finally, SO and BAC strongly promoted the appearance of sleep onset REM periods. CONCLUSIONS: The SO-induced EEG slow waves seem not to be functionally similar to physiological slow waves. Our findings also suggest a role for GABA(B) receptors in REMS generation. CITATION: Vienne J; Lecciso G; Constantinescu I; Schwartz S; Franken P; Heinzer R; Tafti M. Differential effects of sodium oxybate and baclofen on EEG, sleep, neurobehavioral performance, and memory. SLEEP 2012;35(8):1071-1084.

Inferring landscape effects on dispersal from genetic distances: how far can we go?

Functional connectivity affects demography and gene dynamics in fragmented populations. Besides species-specific dispersal ability, the connectivity between local populations is affected by the landscape elements encountered during dispersal. Documenting these effects is thus a central issue for the conservation and management of fragmented populations. In this study, we compare the power and accuracy of three methods (partial correlations, regressions and Approximate Bayesian Computations) that use genetic distances to infer the effect of landscape upon dispersal. We use stochastic individual-based simulations of fragmented populations surrounded by landscape elements that differ in their permeability to dispersal. The power and accuracy of all three methods are good when there is a strong contrast between the permeability of different landscape elements. The power and accuracy can be further improved by restricting analyses to adjacent pairs of populations. Landscape elements that strongly impede dispersal are the easiest to identify. However, power and accuracy decrease drastically when landscape complexity increases and the contrast between the permeability of landscape elements decreases. We provide guidelines for future studies and underline the needs to evaluate or develop approaches that are more powerful.

Effects of a fire response trait on diversification in replicated radiations.

Fire has been proposed as a factor explaining the exceptional plant species richness found in Mediterranean regions. A fire response trait that allows plants to cope with frequent fire by either reseeding or resprouting could differentially affect rates of species diversification. However, little is known about the generality of the effects of differing fire response on species evolution. We study this question in the Restionaceae, a family that radiated in Southern Africa and Australia. These radiations occurred independently and represent evolutionary replicates. We apply Bayesian approaches to estimate trait-specific diversification rates and patterns of climatic niche evolution. We also compare the climatic heterogeneity of South Africa and Australia. Reseeders diversify faster than resprouters in South Africa, but not in Australia. We show that climatic preferences evolve more rapidly in reseeder lineages than in resprouters and that the optima of these climatic preferences differ between the two strategies. We find that South Africa is more climatically heterogeneous than Australia, independent of the spatial scale we consider. We propose that rapid shifts between states of the fire response trait promote speciation by separating species ecologically, but this only happens when the landscape is sufficiently heterogeneous.