Age at presentation with initial fistulas after hypospadias repai

Age at presentation with initial fistulas after hypospadias repair was 0 to 12 months in 5 patients, 12 to 24 in 6, 24 to 36 in 6, 36 to 48 in 2 and more than 48 in 7. Mean followup was 5.5 months (range 0 to 69).

Conclusions: While many

urethrocutaneous fistulas develop immediately following hypospadias repair, almost a quarter present well beyond the typical followup of many urologists. These findings suggest that reported learn more rates of urethrocutaneous fistula may be underestimated and longer followup may be warranted. Late recurrence of urethrocutaneous fistula is rare with 5.2% seen at more than 1 year, suggesting that more limited followup may be appropriate in these patients.”
“Background: The accuracy of multidetector computed tomographic (CT) angiography involving 64 detectors has not been well established.

Methods: We conducted a multicenter study to examine the

accuracy of 64-row, 0.5-mm multidetector CT angiography as compared with conventional coronary angiography in patients with suspected coronary artery disease. Nine centers enrolled patients who underwent calcium scoring and multidetector CT angiography before conventional coronary angiography. In 291 patients with calcium scores of 600 or less, segments 1.5 mm or more in diameter were analyzed by means of CT and conventional angiography at independent core laboratories. Stenoses of 50% or more were considered obstructive. S63845 research buy The area under the receiver-operating-characteristic curve (AUC) was used to evaluate

diagnostic accuracy relative to that of conventional angiography and subsequent revascularization status, whereas disease severity was assessed with the use of the modified Duke Coronary Artery Disease AZD4547 price Index.

Results: A total of 56% of patients had obstructive coronary artery disease. The patient-based diagnostic accuracy of quantitative CT angiography for detecting or ruling out stenoses of 50% or more according to conventional angiography revealed an AUC of 0.93 (95% confidence interval [CI], 0.90 to 0.96), with a sensitivity of 85% (95% CI, 79 to 90), a specificity of 90% (95% CI, 83 to 94), a positive predictive value of 91% (95% CI, 86 to 95), and a negative predictive value of 83% (95% CI, 75 to 89). CT angiography was similar to conventional angiography in its ability to identify patients who subsequently underwent revascularization: the AUC was 0.84 (95% CI, 0.79 to 0.88) for multidetector CT angiography and 0.82 (95% CI, 0.77 to 0.86) for conventional angiography. A per-vessel analysis of 866 vessels yielded an AUC of 0.91 (95% CI, 0.88 to 0.93). Disease severity ascertained by CT and conventional angiography was well correlated (r=0.81; 95% CI, 0.76 to 0.84). Two patients had important reactions to contrast medium after CT angiography.

Conclusions: Multidetector CT angiography accurately identifies the presence and severity of obstructive coronary artery disease and subsequent revascularization in symptomatic patients.

Latency analyses further suggest that intra-hemispheric processin

Latency analyses further suggest that intra-hemispheric processing mediates the influence of S-hand correspondence”
“We aimed to evaluate predictors and mediators of enhancing effect of adjunctive mirtazapine on cognition in schizophrenia. Patients with difficult-to-treat schizophrenia received Anlotinib in vitro either mirtazapine (n = 19) or placebo (n = 18) in a double-blind fashion for six weeks. Mirtazapine outperformed placebo on the Block Design and Stroop Dots. In the present subsidiary study, factors underlying this difference were explored with Path Analysis. Add-on mirtazapine had an independent

enhancing effect on the Block Design-measured visuo-spatial functioning. Further, this effect was mediated via changes in positive, Danusertib depressive and parkinsonism symptoms, but not in negative symptoms. This effect was predicted by higher doses of FGAs, longer duration of illness and lower initial Block Design scores. Path Analysis model fit was good. Mirtazapine may

have direct and indirect favorable effects on visuo-spatial functioning, but further research is needed. Path analysis may be a feasible statistical method for further research of neurocognition in psychopharmacological interventions in schizophrenia.

This article is part of a Special Issue entitled ‘Cognitive Enhancers’. (C) 2012 Elsevier Ltd. All rights reserved.”
“Preparing for a cited, speeded response induces a set of physiological changes A review of the psychophysiology of preparation suggested that inhibition of action was an Important process among the constellation of changes constituting attentive preparation The current

experiment combined event-related functional magnetic resonance Imaging CRT0066101 cell line and cardiac inter-beat interval measures in an experiment that compared preparing for a response, watching stimuli without responding. and responding in the absence of preparation. Ten college-aged participants were tested in an initial psychophysiological experiment followed by two scanning sessions during which reverse spiral imaging was performed concurrent with inter-beat interval measurement. Two analytic approaches were used to confirm blood oxygenation level dependent responses during preparation. and these converged to show Inferior prefrontal and related subthalamic nuclei activity in the context of other known changes related to brain attentional networks. Subthalamic nuclei changes were related to the depth of preparatory Cardiac deceleration.

These results also suggest a recruitment of CRF-regulated nocicep

These results also suggest a recruitment of CRF-regulated nociceptive pathways associated with escalation of intake and dependence. A greater understanding of

relationships MLN2238 datasheet between chronic drug exposure and pain-related states may provide insight into mechanisms underlying the transition to drug addiction, as well as reveal new treatment opportunities.

This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’. (C) 2011 Elsevier Ltd. All rights reserved.”
“We determine the density profile and velocity of invasion fronts in one-dimensional infinite habitats in the presence of environmental fluctuations. The population dynamics is reformulated in terms of a stochastic reaction-diffusion equation and is reduced to a deterministic equation that incorporates the systematic contributions of the noise. We obtain analytical expressions for the front profile and velocity by constructing a variational principle. The effect of the noise differs, depending on whether it affects the density-independent growth rate, the intraspecific competition term or the Allee threshold. Fluctuations in the density-independent growth

rate increase the invasion velocity and the population density of the invaded area. Fluctuations in the competition term also change the population density of the invaded area, but modify the invasion velocity only for certain initial conditions. Fluctuations in the Allee threshold can induce pulled or pushed invasion fronts as well as invasion failure. We compare https://www.selleckchem.com/products/PHA-739358(Danusertib).html our analytical results with numerical solutions of the stochastic partial differential equations and show that our procedure proves

useful in dealing with reaction-diffusion equations with multiplicative noise. (C) 2011 Elsevier Ltd. All rights reserved.”
“Saporin, a ribosome inactivating protein is widely used for immunotoxin construction. Here we describe a mutation of saporin (sap)-3 DNA by introducing a cysteine residue, followed by protein expression and purification by ion exchange chromatography. The purified Cys255sap-3, sap-3 isomer and commercially purchased saporin, were tested for toxicity using assays measuring inhibition for protein synthesis. The IC50 values showed that the VX-661 mouse toxicity of the Cys255sap-3 is equivalent to the sap-3 isomer and commercial saporin. Reactivity of Cys255sap-3 was confirmed by labeling with a thio-specific fluorescent probe as well as conjugation with a nonspecific mouse JgG. We have found that a single cysteine within saporin provides a method for antibody conjugation that ensures a uniform and reproducible modification of a saporin variant retaining high activity. (C) 2007 Elsevier Inc. All rights reserved.”
“Type 2 diabetes is a prototypical complex systems disease that has a strong hereditary component and etiologic links with a sedentary lifestyle, overeating and obesity.

We consider several interpretations

of this discrepancy,

We consider several interpretations

of this discrepancy, including differences in research methodology and cross-species differences in functional neuroanatomy. PLX 4720 New directions for future research are outlined, emphasizing the importance of distinguishing illusory cross-species differences from the true evolutionary differences that make our species unique.”
“We describe a rapid and effective procedure for purifying recombinant eukaryotic TATA binding protein (TBP) from Escherichia coli. The method employs an affinity ligand comprising glutathione-S-transferase fused to the carboxyl-terminal activation domain of the transcriptional activator VP16 and an amino-terminal domain (TAND2) of the yeast TBP-associated factor TAF1. TBP can be purified without the need for extrinsic affinity tags, subsequent proteolysis, or downstream clean-up steps. This TBP

purification process is rapid (requiring about 4 h after bacterial harvest) and does not require sophisticated chromatographic equipment. The resulting material is monodisperse, structured, and functionally active. We demonstrate the FG4592 efficacy of this method for purifying recombinant full-length or TBP core fragments encoded by yeast, humans and Arabidopsis. (C) 2008 Elsevier Inc. All rights reserved.”
“Animals will acquire an operant task using sensory stimuli as a primary reinforcer. Many operant tasks use sensory stimuli as cues that are paired with other primary FGFR inhibitor reinforcers. Recent studies have called attention to this potential confound, but there has not been a parametric assessment of the effect of stimulus variability on operant responding. We found that stimulus variability increased the amount of operant responding exhibited by mice, a phenomenon observed

under both fixed- and progressive-ratio schedules. (C) 2012 Elsevier Ireland Ltd. All rights reserved.”
“Routine administration of erythropoietin (EPO)-stimulating agents (ESAs) for the control of anemia has improved the quality of life of subjects with chronic kidney disease (CKD). However, a wide variation in individual response to ESA is often observed. The reasons for EPO resistance include demographic variables such as age and gender distribution, morbidity pattern, and modality of dialysis. Despite suggestions by observational data, there is no biological characteristic that puts children at a disadvantage for adequate response to ESA. On the contrary, children possess a superior capacity for red cell production, including extramedullary erythropoiesis. The reasons for larger requirement of ESA in children (than in adults) are greater inflammatory burden, disproportionate blood loss, and greater EPO dosing by pediatric physicians.

Conclusions Changes in the brain, which include changes in the en

Conclusions Changes in the brain, which include changes in the endocannabinoid system, prompt it to use different strategies (spatial and procedural, or others not evaluated in this study) to cope with the environmental demands. These cerebral changes are adaptive responses to the light-dark cycle.”
“Disulfide bonds reportedly stabilize the capsids of several viruses, including papillomavirus, polyomavirus, and simian virus 40, and have been detected in herpes simplex virus (HSV) capsids. In this study, we show that in mature HSV-1

virions, capsid proteins VP5, VP23, VP19C, UL17, and UL25 participate in covalent cross-links, and that these are susceptible OTX015 nmr to dithiothreitol (DTT). In addition, several tegument proteins were found in high-molecular-weight complexes, including VP22, UL36, 4-Hydroxytamoxifen and UL37. Cross-linked capsid complexes can be detected in virions isolated in the presence and absence of N-ethylmaleimide (NEM), a chemical that reacts irreversibly

with free cysteines to block disulfide formation. Intracellular capsids isolated in the absence of NEM contain disulfide cross-linked species; however, intracellular capsids isolated from cells pretreated with NEM did not. Thus, the free cysteines in intracellular capsids appear to be positioned such that disulfide bond formation can occur readily if they are exposed to an oxidizing environment. These results indicate that disulfide cross-links are normally present in extracellular virions but not in intracellular capsids. Interestingly, intracellular capsids isolated in the presence of NEM are unstable; B and C capsids are converted to a novel form that resembles A capsids, indicating that scaffold and DNA are lost. Furthermore, these capsids also have lost pentons and peripentonal triplexes as visualized by cryoelectron microscopy. These data indicate that capsid stability, and especially the retention of pentons, is regulated by the

formation of disulfide bonds in the capsid.”
“Predictive processing of information IWR-1 in vivo is essential for goal-directed behavior. We offer an account of auditory perception suggesting that representations of predictable patterns, or ‘regularities’, extracted from the incoming sounds serve as auditory perceptual objects. The auditory system continuously searches for regularities within the acoustic signal. Primitive regularities may be encoded by neurons adapting their response to specific sounds. Such neurons have been observed in many parts of the auditory system. Representations of the detected regularities produce predictions of upcoming sounds as well as alternative solutions for parsing the composite input into coherent sequences potentially emitted by putative sound sources. Accuracy of the predictions can be utilized for selecting the most likely interpretation of the auditory input.

The potentiating effect of orexin A (2 mu g) on the dopaminergic

The potentiating effect of orexin A (2 mu g) on the dopaminergic pivoting was not significantly inhibited by SB 334867 (10 and 20 ng) injected into the nucleus accumbens shell. The contraversive pivoting induced by a mixture of SKF 38393 (1 mu g) and quinpirole (10 mu g) injected into the nucleus accumbens shell was also potentiated by the orexin 2 receptor agonist orexin B (0.5, 1 and

2 mu g), which alone did not elicit turning behaviour. These results suggest that orexin 2 receptors in the nucleus accumbens shell play a modulatory role in rat turning behaviour. (c) 2007 Elsevier Ltd. All rights reserved.”
“Objective: Spinal cord injury can occur not only during extensive thoracoabdominal aneurysm Entospletinib supplier repair but also postoperatively, causing delayed-onset paraplegia.

Methods: A series of 858 thoracoabdominal aneurysm repairs (June 1990-June 2006) with an overall paraplegia rate of 2.7% was analyzed retrospectively. Serial segmental artery sacrifice was monitored by using somatosensory evoked potentials; segmental arteries were not reimplanted. Of a total of 20 cases of paraplegia, 3 occurred intraoperatively and 7 occurred late postoperatively: these will not be analyzed further.

In 10 cases (the paraplegia group) spinal cord injury occurred within 48 hours after thoracoabdominal selleck screening library aneurysm repair, despite intact somatosensory evoked potentials at the end of the procedure. These patients with early postoperative delayed paraplegia were compared with 10 matched control subjects

selleck compound who recovered without spinal cord injury.

Results: In the paraplegia group a median of 9 segmental arteries (range, 5-12 segmental arteries) were sacrificed. There were 9 male subjects: median age was 63 years (range, 40-79 years), and 4 of 10 had cerebrospinal fluid drainage. A median of 9 segmental arteries (range, 2-12 segmental arteries) were also sacrificed in the matched recovery group. There were 4 male subjects; median age was 66 years (range, 40-78 years), and 8 of 10 had cerebrospinal fluid drainage. During the first 48 hours postoperatively, there were no significant differences in arterial and mixed venous oxygen saturation, partial arterial O-2 and CO2 pressures, body temperature, glucose, hematocrit, or pH. The mean central venous pressures, however, were significantly higher in the paraplegic patients from 1 to 5 hours postoperatively (P = .03). In addition, although absolute mean aortic pressures did not differ between matched pairs postoperatively, when pressures were considered as a percentage of individual antecedent preoperative mean aortic pressure, paraplegic patients had significantly lower values during the first 5 hours postoperatively (P = .03).

A plenary session organized by the Publications Committee of the

A plenary session organized by the Publications Committee of the Human Proteome Organisation at the 7(th) HUPO congress [Orchard, S., Ping, P., Proteomics 2009, 9, 502-503] highlighted lack of commonality between the different journals in their reporting requirements as an issue for potential authors and it had been agreed at that event to organise a subsequent, open meeting to discuss this further. As the authors of a set of independent reporting requirements, the MIAPE documents [Taylor, C. F., Paton, N. W., Lilley, K. S., Binz, P.-A. et al., Nat. Biotechnol. 2007, 25, 887-893], the PD0332991 price HUPO Proteomics Standards Initiative (HUPO-PSI) agreed to act as co-hosts and hold this meeting

adjacent to their annual workshop in Turku, Finland, April 25-27(th) 2009. Most of the specialist journals publishing in this field were represented at the event as well as data providers, databases and the authors of the HUPO-PSI standards documents.”
“The aim of the present selleck chemical study was to investigate the thermoregulatory effects of neuronal activation with sodium L-glutamate (glutamate) in the preoptic area (POA) of the hypothalamus and to examine its possible interaction with the thermogenic effects of GABA and prostaglandin

E-2 (PGE(2)). Unilateral microinjection of glutamate (5 nmol) into the lateral POA or its vicinity elicited a prompt increase in tail skin temperature and simultaneous decreases in the O-2 consumption rate (VO2), heart rate, and colonic temperature in urethane-chloralose-anesthetized rats. A central subpopulation of these sites at around the level of bregma was also responsive to the thermogenic and tachycardic effects of GABA (30 nmol). Although the microinjection of GABA into nearby sites elicited no direct effect, it greatly attenuated the hypothermic effects of glutamate subsequently administered to the same site. These results suggest that activation of the lateral POA elicited heat-loss responses and that its central part provided a tonic inhibitory drive toward heat production and tail vasoconstriction. On the other hand, the microinjection of glutamate elicited initial small

decreases and subsequent large increases in VO2 and heart rate in the rostromedial POA. However, no thermoregulatory response was elicited by the microinjection Cyclosporin A mw of glutamate at sites where the microinjection of PGE(2) (35 fmol) elicited thermogenic, tachycardic and hyperthermic responses. These results may suggest that the rostromedial POA contained two glutamate-responsive cell groups that had opposite influences on thermoregulation and that the locus that was highly sensitive to the thermogenic effect of PGE(2) was unreactive to glutamate. Collectively, activation of neurons in the lateral POA and rostromedial POA evoked distinct thermoregulatory responses. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.”
“This study aimed to provide a tool for selecting the best approach to virological testing of bottled waters.

Since most of the targets of the pineal projections of zebrafish

Since most of the targets of the pineal projections of zebrafish appear to be premotor and precerebellar centers, the neural output of the pineal organ is probably, because of its photoreceptive and circadian function, involved in photic and circadian modulation of these centers. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Objectives. People who are CFTRinh-172 concentration close to retirement age show the highest rates of weight gain and obesity. We investigate the effect of retirement oil the change in body mass index (BMI)

in diverse groups varying by wealth status and occupation type.

Methods. Six panels of the Health and Retirement Study (1992-2002) on individuals aged 50-71 were used (N = 37,807). We used fixed-effects regression

models with instrumental variables method to estimate the causal effect of retirement on change in the BMI.

Results. Retirement leads to modest weight gain. 0.24 BMI on average. Weight gain with retirement was found among people who were already overweight and those with lower wealth retiring from physically demanding occupations. The cumulative effect of aging among people in their 50s, however, outweighs the effect of retirement; the average BM I gain between ages 50 and 60 is 1.30, 5 times the effect of retirement.

Conclusions. Given the increasing number of people approaching retirement age, the population level impact of the weight gain ascribed to retirement on health outcomes

Poziotinib datasheet and health care system might be significant. Future research should evaluate programs targeted to older adults who are most likely to gain weight with retirement.”
“The basal forebrain (BF) comprises morphologisally and functionally heterogeneous cell populations, in. including cholinergic learn more and non-cholinergic corticopetal neurons that are implicated in sleep-wake modulation, learning, memory and attention. Several studies suggest that glutamate may be among inputs affecting cholinergic corticopetal neurons but such inputs have not been demonstrated unequivocally. We examined glutamatergic axon terminals in the sublenticular substantia innominata in rats using double-immunolabeling for vesicular glutamate transporters (Vglut1 and Vglut2) and choline acetyltransferase (ChAT) at the electron microscopic level. In a total surface area of 30,000 mu m(2), we classified the pre- and postsynaptic elements of 813 synaptic boutons. Vglut1 and Vglut2 boutons synapsed with cholinergic dendrites, and occasionally Vglut2 axon terminals also synapsed with cholinergic cell bodies. Vglut1 terminals formed synapses with unlabeled dendrites and spines with equal frequency, while Vglut2 boutons were mainly in synaptic contact with unlabeled dendritic shafts and occasionally with unlabeled spines. In general, Vglut1 boutons contacted more distal dendritic compartments than Vglut2 boutons.


“Human papillomavirus (HPV) E6 oncoproteins target many ce


“Human papillomavirus (HPV) E6 oncoproteins target many cellular proteins for ubiquitin-mediated proteasomal degradation. In the case of p53, this is mediated principally by the E6AP ubiquitin ligase. Several studies have reported that E6 can target certain of its substrates in an apparently E6AP-independent fashion and that several of these substrates vary in the degree to which they are degraded by E6 at different stages of malignancy. To more fully

understand the regulation of the E6AP/E6 proteolytic targeting complex, we performed a mass spectroscopic analysis of HPV type 18 (HPV-18) E6 protein complexes and identified the HECT domain-containing ubiquitin ligase EDD as a new HPV-18 E6 binding partner. www.selleckchem.com/products/bb-94.html We show that EDD can interact independently with both E6 and E6AP. Furthermore, EDD appears to regulate E6AP expression levels independently of E6, and loss of EDD stimulates the proteolytic activity of the E6/E6AP complex. Conversely, higher levels of EDD expression protect a number of substrates from E6-induced degradation, partly as a consequence of lower levels of E6 and E6AP expression. Intriguingly, reduction in EDD expression levels in HPV-18-positive HeLa cells enhances cell resistance to apoptotic and growth arrest stimuli. These studies suggest that changes in the levels of EDD expression during different stages of E7080 the viral life cycle or during malignancy could have a profound effect

upon the ability of E6 to target various substrates for proteolytic degradation and thereby directly influence the development of HPV-induced malignancy.”
“We have investigated the adenosine-mediated presynaptic inhibition of primary afferent-evoked glutamate release in rat substantia gelatinosa neurons of the trigeminal subnucleus caudalis using a conventional whole-cell patch clamp technique. Adenosine reversibly and concentration dependently decreased the amplitude of glutamatergic excitatory postsynaptic currents and increased the paired-pulse ratio, indicating that adenosine acts presynaptically

to reduce glutamate release from primary afferents. The adenosine-induced inhibition of excitatory postsynaptic currents was occluded by a selective A(1) receptor antagonist, DPCPX, and was mimicked Selleckchem AS1842856 by a selective A(1) receptor agonist CPA. The results suggest that presynaptic A(1) receptors decrease action potential-dependent glutamate release from trigeminal primary afferents onto medullary dorsal horn neurons, and thus adenosine A(1) receptors could be a potential target for the treatment of pain of orofacial tissues. NeuroReport 22:711-715 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.”
“The targets of broadly cross-neutralizing (BCN) antibodies are of great interest in the HIV vaccine field. We have identified a subtype C HIV-1-superinfected individual, CAP256, with high-level BCN activity, and characterized the antibody specificity mediating breadth.

In addition, similar to 75% of ANDV-infected LECs became viable m

In addition, similar to 75% of ANDV-infected LECs became viable mononuclear giant cells, >4 times larger than normal, in response to VEGF-A. Giant cells are associated with constitutive mammalian target of rapamycin (mTOR) activation, and we found that both giant LECs and LEG permeability were sensitive to rapamycin, an mTOR inhibitor, and VEGF-C addition. These findings indicate that ANDY uniquely alters VEGFR2-mTOR signaling responses of LECs, resulting in giant cell and LEG permeability responses. This suggests that ANDY infection alters normal LEG and lymphatic vessel functions which may contribute to edematous fluid accumulation during HPS. Moreover, the ability of VEGF-C and

rapamycin to normalize LEG responses suggests a potential therapeutic approach for reducing pulmonary edema and the severity of HPS following ANDY infection.”
“Smaller hippocampal volume is reported in major depressive disorder (MDD). AZD6738 in vitro We hypothesize that it may Pritelivir chemical structure be related to fewer granule neurons (GN) in the dentate gyrus (DG), a defect possibly reversible with antidepressants. We studied age-, sex-, and postmortem interval-matched groups: no major psychopathology (controls); unmedicated-MDD; and MDD treated with serotonin reuptake inhibitors

(MDD*SSRI) or tricyclics (MDD*TCA). Frozen right hippocampi were fixed, sectioned (50 mu m), immunostained with neuronal nuclear marker (NeuN), and counterstained with hematoxylin. GN and glial

number, and DG and granule cell layer (GCL) volumes were stereologically estimated. Fewer GNs in the anterior DG were present in unmedicated-MDDs compared with controls (p = 0.013). Younger age of MDD onset correlated with fewer GNs (p = 0.021). Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs (p = 0.028) and controls (p = 0.032). Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicated-MDDs vs controls (p = 0.008) and larger in MDD*SSRIs vs unmedicated-MDDs (p<0.001), MDD*TCAs (p<0.001), and controls (p<0.001). find more Anterior GCL volume and GN number (r = 0.594, p = 0.001), and mid DG volume and GN number (r = 0.398, p = 0.044) were correlated. Anterior DG capillary density correlated with GN number (p = 0.027), and with GCL (p = 0.024) and DG (r = 0.400, p = 0.047) volumes. Posterior DG volume and GN number did not differ between groups. Fewer GNs in unmedicated-MDD without fewer neuronal progenitor cells, as previously reported, suggests a cell maturation or survival defect, perhaps related to MDD duration. This may contribute to a smaller hippocampus and is potentially reversed by SSRIs. Postmortem studies are correlative and animal studies are needed to test implied causal relationships. Neuropsychopharmacology (2013) 38, 1068-1077; doi:10.1038/npp.2013.