(C) 2013 IBRO Published by Elsevier Ltd All rights reserved “

(C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.”

Immune based therapy has gained renewed interest in the search for treatment strategies for metastasized renal cell carcinoma. We determined whether radio frequency ablation combined with interleukin-2 would induce a tumor specific immune response and serve as an in situ vaccine against renal cell carcinoma.

Materials and Methods: Mice with orthotopic renal tumors were treated with radio frequency ablation combined with interleukin-2, radio frequency ablation only, interleukin-2 only or no treatment as the control. Immunohistochemistry was done to determine Selleck H 89 which cells were present in the tumor after treatment. In vitro tumor specific cytotoxicity assays were performed with CD8+ T and natural killer cells derived from the spleen of treated mice. To study whether treatment could prevent metastasis or affect the growth of established metastases we induced lung metastasis intravenously before or after treatment and subsequently quantified it.

Results: The number of natural killer, CD4+ and CD8+ T cells was significantly increased in the tumor tissue of radio frequency ablation/interleukin-2 treated mice (p < 0.0001). Natural killer and CD8+ T cells showed strong antitumor activity in vitro after combination treatment. Lung metastatic formation

was significantly AZD1208 molecular weight prevented in mice that received combination therapy (p < 0.0001). Lung metastases were significantly smaller after combination treatment (vs

interleukin-2 p = 0.025).

Conclusions: Radio frequency ablation of the primary tumor combined with interleukin-2 induces a systemic antitumor immune response to renal cell carcinoma, which is much stronger than that of interleukin-2 monotherapy. This effect appears to be mediated by natural killer and CD8+ T cells. It may have an important role in the development of new immunotherapy strategies for renal cell carcinoma.”
“Background. Olopatadine Response to antidepressant medication is higher in comparator versus placebo-controlled randomized controlled trials (RCTs). Patient expectancy is an important influence on clinical outcome in the treatment of depression and may explain this finding. The results are reported from a pilot RCT studying expectancy and depression outcome in placebo-controlled versus comparator treatment conditions.

Method. Out-patients aged 18-65 years with major depressive disorder (MDD) were enrolled in this 8-week RCT. Subjects were randomized to placebo-controlled (escitalopram or placebo) or comparator (escitalopram or citalopram) administration of antidepressant medication. Subjects reported their expected likelihood and magnitude of depression improvement before and after randomization using questions from the Credibility and Expectancy Scale (CES).

The present study demonstrates that GABA(A) and GABA(B) receptors

The present study demonstrates that GABA(A) and GABA(B) receptors in the globus Obeticholic pallidus and the substantina nigra pars reticulata play differential roles in the

production of turning behaviour. This study underlines the notion that the two types of turning, namely pivoting and circling, are valid tools to map out the information flow across the basal ganglia. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Pancreatic duodenal homeobox 1 (Pdx1) protein is a key transcription factor involved in the regulation of insulin gene expression that is expressed at high levels in the beta-cells of the pancreatic islets. We asked whether Pdx1 is a target of anti-islet autoimmunity in type I diabetes (T1D). Pdx1 autoantibodies (PAAs) were detected in non-obese diabetic (NOD) mice using ELISA, western blotting, and radioimmunoprecipitation of [(35)S]-labeled insulinoma cell line-derived Pdx1 protein. PAAs were detected as early as at 5 weeks of age, and generally peaked before the onset of clinically overt diabetes in diabetes-prone female NOD mice.

Levels declined substantially after the onset of diabetes. PAAs were not detected in the sera of NOD-scid, C57BL/6, or BALB/c mice. The titers of PAAs in NOD mouse sera were as high as 1/93 750 by ELISA. The fine specificity of PAAs was determined by western blotting using a series of truncated recombinant Pdx1 proteins. The immunodominant selleck chemicals epitopes were located to the C-terminus of the Pdx1 (p200-283) in NOD mice. PAAs also were detected in sera from human T1D patients, but the major epitopes were localized to amino acids 159-200 as well as the same region (p200-283) recognized by PAAs from NOD mice. Using [(3)H] thymidine incorporation, the p83 fragment of Pdx1 specifically stimulated proliferation of splenic T cells from recent-onset diabetic NOD mice. The presence of PAAs in prediabetic NOD mice and

human T1D patients, and Pdx1-specific T-cell proliferation in NOD mice provide a strong rationale for further investigation of the pathogenic role of immune responses against Pdx1 in T1D. Laboratory Investigation (2010) 90, 31-39; doi:10.1038/labinvest.2009.116; VE821 published online 9 November 2009″
“The perifornical-lateral hypothalamic area (PF-LHA) plays a central role in the regulation of behavioral arousal. The PF-LHA contains several neuronal types including wake-active hypocretin (HCRT) neurons that have been implicated in the promotion and/or maintenance of behavioral arousal. Adenosine is an endogenous sleep factor and recent evidence suggests that activation and blockade of adenosine A(1) receptors within the PF-LHA promote and suppress sleep, respectively.

Some of the other differentially expressed genes are involved in

Some of the other differentially expressed genes are involved in the regulation of the cell cycle, transcription, cell structure, and tumor invasiveness. Northern blot analyses of a subset of the neuronal genes, including Robo1, N-MYC, and alpha-internexin, confirmed their

strong expression in multiple Ad12 tumorigenic cell lines. In contrast, these neuronal genes displayed only minor or negligible expression in cells transformed by spacer-mutated Ad12. Significantly, stable introduction of E1A-12 into nontumorigenic Ad5-transformed cells induced neuronal gene expression. We found that the neuron-restrictive silencer factor, which serves as a master repressor of neuronal genes, was inactivated in both Ad12- and Ad5-transformed cells via cytoplasmic

retention, though only Ad12- transformed cells exhibited neuronal gene induction. Mutational analyses of the alpha-internexin buy PD0332991 XAV-939 mouse promoter demonstrated that E1A-12-mediated neuronal gene induction further required the activation of neuronal promoter E-box elements. These results indicate that the spacer is involved in mediating neuronal and tumor-related genes.”
“The small GTPase Rac regulates neuronal behavior, but whether it also functions in neural progenitor cells has not yet been explored. Here we report that Rac contributes to the regulation of nuclear migration in neocortical progenitor cells. Rac1 is expressed by progenitor cells in a unique spatiotemporal pattern. Cross-sectional immunohistochemical examination revealed Cyclosporin A purchase intense Rac1 immunoreactivity at the ventricular surface. Similar staining patterns were obtained by immunofluorescence for a Rac-activator, Tiam1, and by reactions to detect the GTP-bound (active) form of Rac. En face inspection of the ventricular surface revealed that apical Rac1 localization was most frequent in M-phase cells, and the endfeet of cells in other cell cycle phases also showed apical Rac1 distribution at lower frequencies. To ask whether progenitor cell behavior prior to and during M phase is Rac-dependent, we monitored

individual DiI-labeled progenitor cells live in the presence of a Rac inhibitor, NSC23766. We observed significantly retarded adventricular nuclear migration, as well as cytokinesis failures. Similar inhibitory effects were obtained by forced expression of a dominant-negative Rac1. These results suggest that Rac may play a role in interkinetic nuclear migration in the developing mouse brain. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.”
“We assessed differences in the character and specificity of autologous neutralizing antibodies (ANAbs) against individual viral variants of the quasispecies in a cohort of drug-naive subjects with long-term controlled human immunodeficiency virus type 1 (HIV-1) infection and moderate levels of broad heterologous neutralizing antibodies (HNAb).

d t ) antivenoms using nanostructured silica (SBA-15) as adjuvant

d.t.) antivenoms using nanostructured silica (SBA-15) as adjuvant and cobalt-60 (60Co)-detoxified venoms utilizing young sheep. Natural and 60Co-irradiated venoms were employed in four different hyperimmunization protocols. Thus, 8 groups of 60- to 90-d-old sheep were hyperimmunized, enzyme-linked immunosorbent assay (ELISA) serum titers collected every 14 d were assessed clinically daily, and individual

weight were measured, until d 84. Incomplete Freund’s (IFA) and nanostructured silica (SBA15) adjuvants were compared. The lethal dose (LD50) for both venoms was determined following intraperitoneal (ip) administration to mice. High-performance liquid chromatography on reversed phase (HPLC-RP) was used also to Avapritinib mouse measure the 60Co irradiation effects on Apis venom. At the end of the study, sheep were killed in a slaughterhouse. Kidneys were histologically analyzed. LD50 was 5.97 mg/kg Apis and 0.07 mg/kg C.d.t. for native compared to 13.44 mg/kg Apis and 0.35 mg/kg C.d.t. Smoothened inhibitor for irradiated venoms. HPLC revealed significant differences in chromatographic profiles between native and irradiated Apis venoms. Native venom plus IFA compared with SBA-15 showed significantly higher antibody titers for both venoms. Apis-irradiated venom plus IFA or SBA-15 displayed similar

antibody titers but were significantly lower when compared with native venom plus IFA. Weight gain did not differ significantly among all groups. 60Co irradiation decreased S63845 concentration toxicity and maintained venom immunogenic capacity, while IFA produced higher antibody titers. SBA-15 was able to act as an adjuvant without producing adverse effects. Hyperimmunization did not affect sheep weight gain, which would considerably reduce the cost of antiserum production, as these sheep were still approved for human consumption even after being subjected to hyperimmunization.”
“Effects of newly synthesized nootropic and anxiolytic dipeptide Noopept on inhibitory

synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 mu M) significantly increased the frequency of spike-dependant spontaneous IPSCs whereas spike-independent mIPSCs remained unchanged. It was suggested that Noopept mediates its effect due to the activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“Myonecrosis with permanent loss of muscle mass is a relevant local toxic effect following envenomation with Bothrops jararacussu snake venom. Regeneration of adult skeletal muscle involves the activation of satellite cells, a process regulated by myogenic regulatory factors (MRF). MyoD is an MRF involved in both proliferation and differentiation of satellite cells.


and a large variety of leukocyte subpopulations


and a large variety of leukocyte subpopulations also were shown to be infectious. The use of endpoint titration in tg338 mice indicated that the infectivity in WBC (per ml of blood) was 10(6.5)-fold lower than that in 1 g of posterior brainstem sample. In both WBC and brainstem, infectivity displayed similar resistance to PK digestion. The data strongly support the concept that WBC are an accurate target for reliable TSE detection by PMCA. The presence of infectivity in short-life-span blood cellular elements raises the question of the origin of prionemia.”
“Accumulating evidence indicates that the Notch signaling pathway fulfills important roles in ischemia-stimulated neurogenesis, which may be regarded as an phosphatase inhibitor etiological factor in post-stroke depression. Here we explored Notch, signaling, hippocampal neurogenesis and behavioral responses to chronic unpredicted mild stress (CUMS) in adult ischemic rats.

Animals were CX-6258 cost treated with permanent middle cerebral artery occlusion followed by an 18 day CUMS procedure. Proliferating cells in the hippocampus and their cell fate were investigated on days 19 and 28 after ischemic surgery. Additionally, expression of the Notch, intracellular domain (NICD) and its downstream targets Hes1 and Hes5 was examined. A sucrose preference test and forced swim test were used to assess behavioral responses. CUMS produced depressive-like behaviors and decreased the number of proliferating cells on day 19 (both p<0.001), accompanied by a decreased expression of both NU7026 Hes1 and Hes5 in the hippocampus of ischemic animals (p<0.001). On day 28, CUMS resulted in a decreased number of neurogenically-differentiating cells in the subgranular zone (p<0.001) while permitting differentiation into astrocytes in the hilus

(p<0.05). Hes1 and Hes5 protein expression levels were increased. The expression of the NICD was significantly decreased at both time-points. CUMS led to expression changes in the Notch, signaling cascade in ischemic rats, most of which concerned hippocampal neurogenesis. This suggests that variation in Notch, activity and subsequent expression of its downstream targets, including Hes1 and Hes5, may, at least in part, contribute to modulation of ischemia-related hippocampal neurogenesis by CUMS. (C) 2009 Elsevier Inc. All rights reserved.”
“The orienting of attention to internal or mnemonic representations held in visual working memory (VWM) has recently become a field of increasing interest. While a number of studies support the hypothesis that attention to selected representations in VWM reduces memory load, conclusive findings are still missing.

We found that significant amounts of endogenous PGRN were secrete

We found that significant amounts of endogenous PGRN were secreted from isolated NPCs in cultures. To assess the bio-activities of endogenous and exogenous PGRN, we studied NPCs derived from wild-type mice (WT-NPCs) and PGRN-deficient mice (KO-NPCs). We found that proliferation of KO-NPCs was significantly enhanced by PGRN treatment; however, PGRN treatment apparently did not affect proliferation of WT-NPCs perhaps because of the high levels of

endogenous PGRN expression. NPC death and asymmetric cellular division of KO-NPCs and WT-NPCs, which results in production of neural this website stem cells, astrocytes, or oligodendrocytes, were not affected by PGRN treatment. We also investigated the signaling mechanism(s) that mediate PGRN-induced NPC proliferation and found that phosphorylation of serine 9 (S9) of glycogen synthase

kinase 3-beta (GSK3 beta), which Daporinad ic50 was dependent on phosphatidylinositol 3-kinase (PI3K) activity, was induced by PGRN treatment. In addition, a GSK3 beta-specific inhibitor enhanced NPC proliferation. Taken together, our observations indicate that PGRN enhanced NPC proliferation, at least in part, via inducing GSK3 beta phosphorylation. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Objectives. To examine antecedent consequent relations of perceived control to health and social support across adulthood and old age.

Methods. We applied (multigroup) Selleckchem ASP2215 change score models to two waves of data collected 9 years apart from 6,210 participants of the Midlife in the United States survey (MIDUS, 24-75 years at baseline). We used composite measures of perceived control (personal mastery and constraints), health (chronic conditions, acute conditions, and functional limitations), and social support (support and strain associated with spouse/partner, family, and friends).

Results. Analyses revealed evidence for direct and independent multidirectional accounts.

Greater initial control predicted weaker declines in health and stronger increases in support. In turn, increases in control were predicted by better initial health and more support. Changes in control were also accompanied by concurrent changes in the other two domains, and relations involving control were larger in size than those between health and support. We found only small sociodemographic differences across age, gender, and education group.

Discussion. We conclude that perceiving control may serve as both a precursor and an outcome of health and social support across the adult age range and suggest routes for further inquiry.”
“Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a hypoxia-inducible neuroprotective protein that also stimulates proliferation of neuronal precursor cells.

9 ml/min per 1 73 m(2) (referent) and increased

9 ml/min per 1.73 m(2) (referent) and increased selleck products at both lower and higher levels of eGFR. Specifically, the hazard ratio of death was 3.7 and 1.8 among patients

with an eGFR equal to or above 105 and 90-104.9 ml/min per 1.73 m(2), respectively, compared to the referent group. Similar results were seen when the CKD-EPI equation (sensitivity analyses) was used to assess eGFR. Higher levels of eGFR were not associated with the risk of kidney failure or myocardial infarction. Thus, the presence and severity of proteinuria was significantly associated with graded increases in the risk of clinical outcomes for both lower and higher eGFR. We do not know, however, whether the finding at higher eGFR could be due to inadequacies of the eGFR formula at low serum creatinine levels.”
“Gliomas are highly heterogeneous and therapy resistant tumors with a poor prognosis. Novel experimental therapeutic approaches have shown some promising results, but often target specific molecular mechanisms or antigens, and careful characterization of the molecular subgroup of the tumors will therefore selleck chemicals llc likely be important. Thorough

investigations of gene and protein alterations are also important to better understand the tumorigenic mechanisms. We have undertaken a proteomic approach, using 2-D DIGE and LC-MS/MS protein identification, to investigate 38 human gliomas and normal brains. We show that the proteome profile can discriminate between normal brain and BGJ398 order tumors, and between tumors of varying grade by a supervised classifier. Furthermore, an analysis of the identified proteins shows an enrichment of proteins associated to pathways known to be central in gliomas, such as MEK/Erk signaling and actin cytoskeleton. It also shows a shift between different glial fibrillary acidic protein (GFAP) representatives in different grades. In a previous study the gene expression profile was characterized in an almost identical set of tumors, which enabled a paired analysis of the gene and protein expression profiles. We show that there is often a weak correlation between the mRNA and protein level. This, together with

the ability of proteomics to identify PTMs, emphasizes the benefit of characterization on a protein level.”
“Free recall (FR) is a ubiquitous internally-driven retrieval operation that crucially affects our day-to-day life. The neural correlates of FR, however, are not sufficiently understood, partly due to the methodological challenges presented by its emerging property and endogenic nature. Using fMRI and performance measures, the neuro-behavioral correlates of FR were studied in 33 healthy participants who repeatedly encoded and retrieved word-lists. Retrieval was determined either overtly via verbal output (Experiment 1) or covertly via motor responses (Experiment 2). Brain activation during FR was characterized by two types of performance-based parametric analyses of retrieval changes over time.

In conclusion,

we show that a learning experience involvi

In conclusion,

we show that a learning experience involving discrepancy during the particularly plastic neonatal period is able to induce long-term effects, which result in enhanced adult hippocampal dependent spatial memory. Furthermore, our data document a role of plasticity molecules like pCREB in mediating hippocampal dependent learning and detection of novelty not only in adulthood, but also more importantly in the neonatal period of the rat. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Follicular lymphoma (FL) B cells contract Selleckchem Adriamycin tight connections with their microenvironment, which governs the pathogenesis and progression of the disease. Indeed, specific immune response gene signatures, obtained from whole biopsy samples, have been associated with patient survival. In this study, we performed gene expression profiling of purified B cell and non-B cell compartments obtained from FL and reactive lymph nodes. We identified 677 non-redundant genes defining the FL interface and involving 26 FL-specific functional networks. This approach highlighted an interleukin-4 (IL-4)-centered pathway associated with an activation of signal transducer and activator of transcription 6 (STAT6), which favors overexpression of IL-4-target genes. In addition,

FL microenvironment was characterized by a strong enrichment in follicular helper T cells (T-FH), as demonstrated through transcriptomic and flow cytometry analyses. The majority of phospho-STAT6(pos) B cells were MRT67307 purchase located at the vicinity of cells expressing the programmed death 1 (PD-1) T-FH marker. Moreover, purified FL-derived T-FH, expressed IL4 at very high levels compared with purified tonsil-derived T-FH or non-T-FH microenvironment. Altogether, to our study demonstrated that tumor-infiltrating T-FH specifically express functional IL-4 in FL, creating an IL-4-dependent T-FH-B cell axis. This cross talk could sustain FL pathogenesis and represent a new potential therapeutic target. Leukemia (2010) 24, 2080-2089; doi:10.1038/leu.2010.223; published online 14 October 2010″
“I.c.v. administration of the octadecaneuropeptide (ODN),

a peptide derived from diazepam-binding inhibitor (DBI), induces anorexigenic and anxiogenic-like actions in rodents. We have recently shown that, in goldfish, i.c.v. injection of ODN also reduces food consumption via the metabotropic endozepine receptor. However, there is little information regarding the structure of DBI and the psychophysiological roles of endozepines in fish. Therefore, in the present study, we isolated and cloned a cDNA encoding goldfish DBI. The deduced sequence exhibits high similarity with non-mammalian DBIs, and we investigated the effect of homologous ODN on psychomotor activity in goldfish. i.c.v. injection of synthetic goldfish ODN at 10 pmol/g body weight (BW) stimulated locomotor activity.

Treatment with modafinil significantly attenuated the performance

Treatment with modafinil significantly attenuated the performance decrements seen for several parameters including

cognitive-psychomotor speed, visual attention and reaction times both with progressive hours awake and when working at adverse circadian phases. Subjective alertness and sleep parameters were similar between treatment groups, but modafinil-treated participants had fewer bouts of inadvertent sleep during scheduled waking. Modafinil reduced the neurobehavioral impairment associated with work, both during prolonged wakefulness SU5402 and at adverse circadian phases, without adversely affecting subjective alertness or subsequent sleep. These features suggest that modafinil might be a particularly relevant countermeasure against the deleterious

effects of prolonged work hours, shift work, and transmeridian travel. Neuropsychopharmacology (2010) 35, 1910-1920; doi: 10.1038/npp.2010.63; published online 26 May 2010″
“Interferon (IFN) signaling is initiated by the recognition of viral components by host pattern recognition receptors. Dengue virus (DEN) triggers IFN-beta induction through a molecular mechanism involving the cellular RIG-I/MAVS signaling pathway. Here we report that the MAVS protein level is reduced in DEN-infected cells and that caspase-1 and caspase-3 cleave MAVS at residue D429. In addition to its well-known function in IFN induction, MAVS is also a proapoptotic molecule that triggers disruption of the mitochondrial membrane potential and activation of caspases. Although different domains are required for the induction of cytotoxicity and IFN, caspase cleavage at residue 429 abolished S63845 order both functions of MAVS. The apoptotic role of MAVS in viral infection and double-stranded RNA (dsRNA) stimulation was

demonstrated in cells with reduced endogenous MAVS expression induced by RNA interference. Even though IFN-beta promoter activation was largely suppressed, DEN production was not affected greatly in MAVS knockdown cells. Instead, DEN-and dsRNA-induced cell death and caspase activation were delayed and attenuated in N-acetylglucosamine-1-phosphate transferase the cells with reduced levels of MAVS. These results reveal a new role of MAVS in the regulation of cell death beyond its well-known function of IFN induction in antiviral innate immunity.”
“There is shared genetic risk for dependence on multiple substances, and the nicotinic receptor gene cluster on chromosome 15 harbors multiple polymorphisms that associate to this risk. Here, we report the results of an association study with 21 SNPs genotyped across the CHRNA5, CHRNA3, and CHRNB4 loci on chromosome 15q25.1. The sample consists of a discovery set (N = 1858) of European-American and African-American (AA) families, ascertained on the basis of a sibling pair with cocaine and/or opioid dependence, and a case-control replication sample (N = 3388) collected for association studies of alcohol, cocaine, and opioid dependence.

75 (95% CI 0 69-0 81) Given the prespecified constraint of achie

75 (95% CI 0.69-0.81). Given the prespecified constraint of achieving at least 85% sensitivity, our model led to the clinical Selleckchem Crenolanib decision rule, for children with a first febrile urinary tract infection cystography should be performed in cases with ureteral

dilatation and serum procalcitonin level 0.17 ng/ml or higher, or without ureteral dilatation (ie ureter not visible) when serum procalcitonin level is 0.63 ng/ml or higher. The rule had 86% sensitivity (95% CI 74-93) with 47% specificity (95% CI 42-51). Internal cross-validation produced 86% sensitivity (95% CI 79-93) and 43% specificity (95% CI 39-47).

Conclusions: A clinical decision rule was derived to enable a selective approach to cystography in children with urinary tract infection. The rule predicts high grade vesicoureteral reflux with approximately 85% sensitivity and avoids half of the cystograms that do not find reflux grade III or higher. Further validation is needed before its widespread use.”
“Although established smokers have a very regular pattern of smoking behavior, converging lines of evidence suggest that the escalation of smoking behavior is a critical Emricasan ic50 factor in the development of dependence. However, the neurobiological mechanisms that underlie the escalation

of smoking are unknown, because there is no animal model of the escalation of nicotine intake. On the basis of the pattern of smoking behavior in humans and presence of monoamine oxidase inhibitors in tobacco smoke, we hypothesized that the escalation of nicotine intake may only occur when animals are given extended-access (21 h per day) self-administration sessions after repeated periods of abstinence (24-48 h), and after chronic inhibition of monoamine oxidase using phenelzine sulfate. Intermittent access (every Uroporphyrinogen III synthase 24-48 h) to extended nicotine self-administration produced a robust escalation of nicotine intake, associated with increased responding under fixed- and progressive-ratio schedules of reinforcement, and increased somatic signs of withdrawal. The escalation of nicotine intake

was not observed in rats with intermittent access to limited (1 h per day) nicotine self-administration or daily access to extended (21 h per day) nicotine self-administration. Moreover, inhibition of monoamine oxidase with daily administration of phenelzine increased nicotine intake by similar to 50%. These results demonstrate that the escalation of nicotine intake only occurs in animals given intermittent periods of abstinence with extended access to nicotine, and that inhibition of monoamine oxidase may contribute to the escalation of smoking, thus validating both an animal model of the escalation of smoking behavior and the contribution of monoamine oxidase inhibition to compulsive nicotine-seeking. Neuropsychopharmacology (2012) 37, 2153-2160; doi:10.1038/npp.2012.