However, the persistence of cognitive impairments in individuals with schizophrenia suggests that these neuroplastic changes in GABA neurotransmission from chandelier neurons are insufficient as compensatory responses. Alternatively, it is possible that compensation at chandelier cell synapses is not effective because additional interneuron subclasses

are also functionally deficient in schizophrenia.65 Consistent with this interpretation, other findings indicate that alterations in PVcontaining GABA neurons cannot account for all of the observed findings in postmortem studies of schizophrenia. For example, the levels of GAD67 and GAT1 mRNAs are reduced to comparable Inhibitors,research,lifescience,medical degrees in Cell Cycle inhibitor layers 2-5 ,47,53 even though the density of PV neurons Inhibitors,research,lifescience,medical is much greater in layers 3 and 4 than in layers 2 and 5.66 In addition, PV mRNA expression was reduced in layers 3 and 4, but not in layers 2 and 5, in subjects with schizophrenia.57 Indeed,

other studies have found lower tissue concentrations of the mRNAs for the neuropeptides somatostatin (SST) and cholecystokinin (CCK) in the DLPFC of subjects with schizophrenia (Figure 3). 51 In the cortex, SST is expressed by GABA neurons located in layers 2 and 5 that do not express PV or CR.67 CCK is also heavily expressed in GABA neurons that do not contain either PV or SST located principally in layers Inhibitors,research,lifescience,medical 2-3 of the primate prefrontal cortex.68 Interestingly, the axon terminals of CCK-containing large basket neurons, which target selectively pyramidal neuron cell bodies, contain type I cannabinoid receptors (CB1R),69 and the mRNA and protein levels of CB1R are also lower in schizophrenia.70 Inhibitors,research,lifescience,medical Because activation of the CB1R suppresses GABA release from the terminals of CCK neurons, the downregulation of this receptor

may represent a compensatory response to reduce the ability of endogenous cannabinoids to decrease GABA Inhibitors,research,lifescience,medical release from CCK/CBlR-containing axon terminals.70 Altered GABA neurotransmission in PV-containing neurons impairs prefrontal network synchrony in schizophrenia Reduced GABA signaling from PV-containing GABA neurons to the perisomatic region of pyramidal Levetiracetam neurons in the DLPFC might contribute to the pathophysiology of working memory dysfunction via the following mechanisms. First, the activity of DLPFC GABA neurons is essential for normal working memory function in monkeys.71,72 Second, PV-positive GABA neurons and pyramidal neurons share common sources (eg, thalamic afferents) of excitatory input.55 The resulting feed-forward, disynaptic inhibition creates a time window during which the number of excitatory inputs required to evoke pyramidal neuron firing must occur.73 Third, both chandelier and basket neurons target multiple pyramidal neurons,74 enabling them to use this timing mechanism to synchronize the activity of local populations of pyramidal neurons.

At 2 years 80% of the patients are in sinus selleckchem rhythm with no class I/III antiarrhythmic drug therapy, and 91% are in sinus rhythm regardless of antiarrhythmic treatment. At 5 years the freedom from any atrial arrhythmia is 81%. All patients were followed with 24 h Holter monitoring. Video-Assisted Surgical Ablation The thoracoscopic surgical ablation procedure was first based on pulmonary vein isolation (PVI) with additional lesion sets but now includes more extensive left-sided lesions. Epicardial ablative devices have allowed for the evolution of off-pump, thoracoscopic approaches. In a landmark

finding, Haissaguerre et al. found that the pulmonary veins were the major source of atrial fibrillation ectopic Inhibitors,research,lifescience,medical foci.27 This led to the first bilateral PVI with left atrial appendage (LAA) exclusion using bilateral thoracoscopic mini-thoracotomies.26 Minimally invasive ablation via bilateral mini-thoracotomies for paroxysmal AF is associated with 80.8% freedom from AF at 1 year.25 Thoracoscopic bilateral PVI with LAA exclusion has also been described for treatment Inhibitors,research,lifescience,medical of lone AF refractory to catheter ablation.30,31 This was extended to include PVI, LAA exclusion, and ablation of ganglionic plexus (GP) and ligament of Marshall.1–6,32 Bilateral PVI, LAA, and GP ablation at 6 months was found to be more effective for paroxysmal AF; 86.7% of patients with paroxysmal Inhibitors,research,lifescience,medical fibrillations were in normal sinus rhythm and 71.7% were both in normal sinus

rhythm and off antiarrhythmic drugs (AADs).28 Less so was observed for the patients with persistent atrial fibrillation, of whom 56.3% were in normal sinus rhythm and 46.9% both in normal sinus rhythm and off AADs.28 As to long-standing persistent cases, 50% were in normal sinus rhythm Inhibitors,research,lifescience,medical and 31.9% were also off AADs.28 The “Dallas Inhibitors,research,lifescience,medical lesion” added further left atrial linear ablation lines.29 Clinical and experimental electrophysiological studies have found ectopic impulses originating from the autonomic ganglionic

plexus in epicardial fat adjacent to the atrial pulmonary vein interface to be a source of arrhythmias.33–36 To address this, GP ablation may be performed as an adjunct to surgical ablation procedures. A prospective randomized trial of 67 patients demonstrated improved freedom from AF with the addition of ganglion plexus ablation to PVI (85.3% versus 60.6% freedom from AF) at 4.3-month follow-up.37 Similarly, comparison of patients with GP ablation with maze versus a case-matched control cohort found significantly Cediranib (AZD2171) higher freedom from AF at 1 year (90% versus 50%).38 At mid-term follow-up, among patients with long-standing persistent AF undergoing thoracoscopic PVI and GP ablation, 92.7% of patients treated with irbesartan were in sinus rhythm compared with 67.5% in a control group.39 These results suggest that the efficacy of minimally invasive surgical ablation may be augmented using adjunctive medical treatments.39 Most recently, Weimer et al.

Besides, CHAT-labeled processes were sharper and shorter from 2 months of age (data not shown). We performed Western blot analysis and quantitative PCR to

analyze the expression level of ChAT protein and transcript, respectively, in lumbar sections from 1 and 3 month of age animals. We observed no significant differences at protein level at any time point between transgenic and Inhibitors,research,lifescience,medical control littermate animals; however, it was a marked reduction in the Selleckchem INK 128 transcript of ChAT in the 1-month-age SOD1G93A mice (Fig. 1D and E). Figure 1 Early transient ChAT reduction in spinal MNs of transgenic SOD1 mice. (A) Immunofluorescent microphotographs showing ChAT content in MNs at the L4–L5 spinal cord ventral horn of nontransgenic wild-type (WT) littermates or transgenic SOD1 mice … In order to investigate whether it was a general effect affecting the production of ChAT independently of the type of neuron or it was specific for MNs, we analyzed also the cholinergic interneurons present in Inhibitors,research,lifescience,medical lamina X that innervate MNs at the lumbar level. We observed that cholinergic interneurons presented also a reduction in ChAT content within their soma (61 ± 8%, n = 13) at 1 month of age, which increased at 2 months but it was still significantly lower than in WT mice (Fig.

Inhibitors,research,lifescience,medical 2). Figure 2 Cholinergic interneurons have early decrease of ChAT in the ALS mouse model. (A) Representative immunofluorescent microphotographs showing ChAT labeling in cholinergic interneurons (green) contrasted with cellular Inhibitors,research,lifescience,medical nuclear staining with DAPI (blue), near … These results indicated that there is a generalized, early, and transient reduction in ChAT

content in the soma and Inhibitors,research,lifescience,medical processes of cholinergic neurons, both MNs and interneurons of the spinal cord, in SOD1G93A mice at 30 days of age. This decline persists in the processes but not in the soma of MNs in older transgenic mice. Quantitation of ChAT-positive boutons As mentioned, ChAT was also observed in cholinergic terminals that contact onto spinal GBA3 MNs, which belong to either recurrent axonal collaterals of interconnections between MNs (Cullheim et al. 1977) (Lagerback et al. 1981) or innervation by cholinergic interneurons. These inputs influence the MN excitatory and inhibitory balance, which is altered in ALS. Those terminals apposing MN somata are named C-boutons and represent one of the largest terminals around their perimeter (3–7 μm in cat) (Arvidsson et al. 1997). In order to analyze the ChAT content in these terminals, we counted ChAT-labeled boutons apposed to MNs at L4–L5 in WT and SOD1G93A mice at 1 and 2 months of age. We found a marked decrease (76%) in SOD1G93A mice already from 1 month of age (Fig. 3). No statistical differences were found between nontransgenic animals of 1 or 2 months of age.

biomedcentral.com/1472-684X/11/3/prepub Acknowledgements This research was supported by the Health Research Board and Irish Hospice Foundation through the Palliative Care Fellowship awarded to Dr Stone (HSR/2008/17). Additional funding was received from The Atlantic Philanthropies, The Irish Cancer Society, Irish Hospice

Foundation and a gift from a donor.
Palliative care has become an important public health issue since the past decade [1]. The ageing of the population and the rising life expectancy are contributing to this development. Also, the pattern of diseases people suffer and die from has changed from acute illnesses Inhibitors,research,lifescience,medical towards chronic illnesses [1-3]. In addition to advances in medical knowledge and technology that increase treatment possibilities at the end of life, these epidemiological transitions have led to a growing need of palliative care Inhibitors,research,lifescience,medical in the last phase of life [4]. The primary goal of palliative care is to ensure the best possible quality of life of patients and their families facing a life threatening illness [1,5]. Most people in their

end-stage of life, regardless of their initial disease, want to be cared for and to die at home [6,7]. Therefore, place of death is considered an indicator of quality of end-of-life Inhibitors,research,lifescience,medical care [8]. DAPT secretase cost However, research in Belgium and in the Netherlands has shown that 30-40% of palliative patients are transferred from home to a hospital or health care institution in the last week of life [9,10]. Inhibitors,research,lifescience,medical This trend is also seen internationally [11]. Transitions in the location of care are often extremely stressful for patient and caregivers [11] and can pose a challenge for the continuity of care [11,12]. Place of death has also become a topic of wider interest Inhibitors,research,lifescience,medical for public health policy, due to the focus in health care on cutting costs in acute care settings [13]. Many European countries have implemented policy measures to reduce the number of acute care hospital beds as a means to restrict

hospital expenditure [5]. With this shift in location of care for the seriously ill from hospital to home, the reliance on family caregivers to support patients with terminal illness at home is growing [13]. These family caregivers are of vital importance (-)-p-Bromotetramisole Oxalate for those wanting to die at home. Without them, remaining at home in the last phase of life would be impossible for many patients [14,15]. However, caregiving for terminally ill patients can be burdensome for informal caregivers, possibly leading to burn-out [16,17]. Due to a growing number of palliative patients and the desire for less institutionalized care, community-based palliative care will become a big challenge [18]. The development of innovative approaches to deliver good quality of care at home is therefore necessary. One such approach is the use of telemedicine.

Although there have never been as many recognized potential targets for drug therapy in psychiatric disease

as at present, there has been no major progress in terms of marketed agents revolutionizing therapy. The partial cloning of the human genome now allows us to define the total number of receptors in the human genome (for example, about, 48 nuclear receptors, about 750 receptors coupled to G proteins). This is a definitive statement defining the future, and perhaps eventually the limits, of drug discovery. One of us (M. Spedding) is chairman of the Nomenclature Committee for the International Union of Inhibitors,research,lifescience,medical Pharmacology (NC-IUPHAR), which has the mission of classifying Inhibitors,research,lifescience,medical these receptors. Hie sequences of the receptors coupled to G proteins (GPCRs) have now been defined, and the olfactory receptors and pseudogenes separated, leaving several hundred known or orphan receptors that may be drug targets. However, screening for agonists and antagonists, and then proceeding to clinical trials to test whether a certain hypothesis works,

is one of the most expensive experiments known to man! Furthermore, the main reason for Inhibitors,research,lifescience,medical the failure of new drugs when they get into clinical trials is not pharmacokinetics or toxic side effects, but lack of efficacy (Figure 1.) Figure 1. Reasons for stopping clinical development of 121 compounds from 7 British companies (B. Cox, personal communication). Reproduced

from reference 21: Sebban C, Tesolin-Decros S, Ciprian-Ollivier J, Perret L, Spedding M. Effects of phencydidine (PCP) Inhibitors,research,lifescience,medical and … This lack of efficacy means that either the original hypothesis of why the drug should work in man was wrong or – and this is more likely – that the tests performed in animals where the drug was active did not measure the same parameters as the tests in phase 1 or 2 clinical trials Inhibitors,research,lifescience,medical (which, in turn, may not reflect, the disease situation). As there are now hundreds of potential targets from the human genome, and most compounds going into man appear not, to be effective, what can be done? MTMR9 The response by much of the pharmaceutical industry is to push up screening of new targets by high-throughput testing of chemical libraries on new receptors (or other potential targets), eliminating targets that do not yield active results in disease models (frequently based on transgenic animals), and then taking promising compounds into the clinic for abbreviated “proof of concept” testing in man. However, it is not Rapamycin molecular weight always possible to have proof of concept, testing that reflects the situation in diverse patient populations. An alternative approach is to benefit from the breakthroughs made in basic research in brain function over the last few years to study the pathology in man, and then construct new animal models which better mimic the disease state.

Her work epitomizes one perspective on the developmental trajectory of schizophrenia;

as a child psychiatrist, she emphasizes the role of maturational processes occurring early in development, a view that has sometimes been called “doomed from the womb.” Another remarkably prescient hypothesis concerning neurodevelopmental factors and schizophrenia was advanced by Irwin Feinberg, who in 1983 proposed Inhibitors,research,lifescience,medical that schizophrenia might be “caused by a fault in programmed synaptic elimination during adolescence.”6 While Fish emphasized the importance of genetic vulnerability and markers that appeared during early childhood, Feinberg Inhibitors,research,lifescience,medical argued that the crucial period for the development of schizophrenia occurred during the

teens and 20s, when brain maturation is occurring rapidly and when the disorder has its most characteristic age of onset. Working as a sleep researcher, he had noted that normal adolescents exhibit striking changes in sleep architecture and event-related potentials, as measured by electroencephalography (EEG). He also Inhibitors,research,lifescience,medical drew on early observations that brain metabolic rate, measured using the nitrous oxide method, declines during LY2157299 nmr adolescence and inferred that this might reflect the occurrence of a major Inhibitors,research,lifescience,medical change in brain organization.7 Drawing on Huttenlocher’s studies showing that synaptic density decreases during adolescence,8 presumably due to pruning back of gray matter (GM), he inferred that the brain’s decreased metabolic needs during normal adolescence were due to a paradoxical process that eliminated synapses and Inhibitors,research,lifescience,medical yet also increased efficiency of cognitive processing. He then proceeded to suggest that schizophrenia occurs as a consequence of a defect in a gene/protein that regulates neurodevelopmental

processes such as synaptic pruning, and nerve growth factor (NGF) is cited as a possible example: The control [over synaptic elimination] may be exercised by determining TCL the availability of, or the requirements for, the trophic factor that maintains synaptic connections…. As a result of some abnormality in this process, too many, too few or the wrong synapses are eliminated. (Regrettably, we have no basis to choose among these possibilities.) As a consequence of this “bug” in the genetic program, defects of neuronal integration develop, producing the symptomatology of schizophrenia. (p 331) This seminal paper thus laid the groundwork for an alternative view: schizophrenia is a neurodevelopmental disorder that arises during adolescence or young adulthood because of an aberration in the genetic regulation of brain maturation.

Alexa

488 donkey anti-goat (1:2000; Jackson Immunoresearch Labs, West Grove, PA) and Alexa 568 donkey anti-rabbit (1:2000; Invitrogen, Grand Island, NY) were used as secondary antibodies. For Nissl staining, Alexa Fluor FITC-conjugated Nissl (1:5000; Invitrogen) was applied to sections (10 min), and thereafter, sections were again rinsed in PBS. Survival and neurological function Animals (n = 12 per genotype) remained in the study until they lost the ability to right themselves within 3 sec after being placed on their back, at which point they were removed from study, and categorized as “CDK inhibitor drugs expired.” For disease progression, function was rated from score 4 (no Inhibitors,research,lifescience,medical sign of disease Inhibitors,research,lifescience,medical on any functional test) to 0 as adapted from Rouaux et al. (2007), where 3 = reduced limb extension and/or tremors upon suspension by the tail, but otherwise appears normal, 2 = deficits on functional tests (tail suspension, grip, activity, or rotarod), but no visually obvious abnormalities, 1 = visually obvious uni- or bilateral paralysis in addition to abnormalities on functional Inhibitors,research,lifescience,medical tests, 0 = loss of righting reflex, visually obvious uni- or bilateral paralysis and abnormalities

on functional tests. Functional tests were as follows: (i) Grip strength: animals were held so that their hind limbs grasped the pull bar of a grip strength meter (Columbus instruments, Columbus, OH) and were pulled forward until their grip was broken. Data from five trials were normalized to

body weight and expressed as compression/g of body weight. (ii) Activity test: animals were allowed to freely ambulate in a 60 × 60 cm open chamber divided into Inhibitors,research,lifescience,medical equal Inhibitors,research,lifescience,medical quadrants for 3 min. The number of times they passed into each quadrant, or reared (vertical rise) during exploration was recorded. (iii) Rotarod: mice were acclimatized on the rotarod (UgoBasile, VA, Italy) at 10 rpm (5 min) for 5 days prior to testing. For tests, mice were placed on the rotarod, and it accelerated from 10 to 54 rpm within 5 min. The time each mouse stayed on the rotarod was expressed as ADAMTS5 the latency to fall. The score shown represents the best single score from three successive rotarod trials. All functional tests were performed weekly by an investigator blinded to genotype starting from Week 8 until the animal was classified as expired. Statistical methods Data are expressed as the mean ± standard error of the mean (SEM) for each group. Functional progression scores and survival data were assessed with the Kaplan–Meier statistical test. Other behavioral data were assessed with two-way ANOVA for the effect of time and score, followed by individual post hoc t-tests for each time point. Morphological and biochemical data were evaluated with individual t-tests.

However, these studies have been conducted in rats in whom the frontal cortex is poorly evolved, and given the marked activation produced in the prefrontal cortex and amygdala by drug-associated stimuli in LY294002 purchase psychostimulant addicts, the conclusion that compulsive relapse is entirely derived from corticostriatal habit circuitry Inhibitors,research,lifescience,medical may be an oversimplification. Indeed, it has been argued that a primary role for therapy in treating addiction is to strengthen prefrontal regulation of drug-seeking behaviors, whether through psychosocial interventions or pharmacotherapy.27,58,59 Enduring psychostimulant-induced

neuroplasticity in the prefrontal to accumbens glutamate projection Given the apparent critical role played by Inhibitors,research,lifescience,medical glutamatergic afférents to the nucleus accumbens in initiating drugseeking or craving, recent studies have identified a number of enduring cellular changes in glutamate transmission that may be critical pathological neuroadaptations to psychostimulant use, and may serve as targets for pharmcotherapeutic intervention. In general the neuroplasticity can be categorized as postsynaptic, presynaptic and nonsynaptic (ie, residing predominantly in glia). However, since these processes are intimately related to each other, it is perhaps best to consider all the adaptations Inhibitors,research,lifescience,medical as changes in glutamate homeostasis,

the end result of which is a psychostimulant-induced enduring change in the fidelity of communication between the prefrontal cortex and the nucleus accumbens, and the regulation by this projection of corticostriatal habit circuitry. It has been Inhibitors,research,lifescience,medical proposed that this loss of fidelity results

in a weakening or loss in the capacity of psychostimulant addicts to cognitively intervene in habitual behaviors, thereby making drug-seeking more difficult to control and increasing the vulnerability to relapse.27 As mentioned above, drug-seeking is associated with a large release Inhibitors,research,lifescience,medical of prefrontal glutamate into the nucleus accumbens. The large release of glutamate during drugseeking is all the more remarkable because it was discovered using microdialysis. which is not a very sensitive measure of glutamate below transmission.60 Indeed, when animals are trained to seek a biological reward, such as food, microdialysis cannot measure glutamate release.49 Thus, the large psychostimulant-induced release of glutamate has been hypothesized to be a pathological and perhaps critical mediator of relapse. This hypothesis is supported by the fact that treatments interrupting synaptic glutamate release also inhibit drug-seeking. This includes a variety of pharmacological treatments that have the potential to be developed into pharmacotherapeutic agents, as outlined below.

Nutritional support during this critical period is of paramount importance to ensure adequate hepatic regeneration and postoperative-recovery. A perioperative nutritional plan should be devised for each individual patient based on the nutritional status and hepatic function. Non-cirrhotic patients

with adequate preoperative nutritional status may not require Inhibitors,research,lifescience,medical any special intervention and should be started on early oral/enteral diet. On the other hand, patients who are either malnourished, with or without compromised liver function (find more cirrhosis or steatosis) and who undergo major hepatic resection will benefit from perioperative nutritional support preferably through enteral route. The benefit of early Inhibitors,research,lifescience,medical enteral nutrition has now been firmly established in a wide variety of surgical patients. Richter, et al. (11) evaluated five randomized controlled studies that compared enteral versus parenteral nutrition in the post-hepatic resection patients (12-16). Based on the results, the authors concluded that enteral nutrition resulted in significantly lower rate of wound infections and catheter related complications than parenteral

nutrition. While there was no difference in mortality, patients receiving enteral nutrition showed better post-operative Inhibitors,research,lifescience,medical immune competence as evidenced by decreased post-operative infectious complications. Hotta, et al. found that supplementation with TPN had no effect on the post-operative outcomes

(17). Current evidence strongly supports the use of enteral Inhibitors,research,lifescience,medical route for nutritional support unless otherwise contraindicated. In addition to early enteral nutrition, branched Inhibitors,research,lifescience,medical chain amino acids and other immune-enhancing agents have received recent attention and deserve special mention. Liver disease results in altered amino acid metabolism characterized by low circulating levels of branched chain amino acids (leucine, isoleucine and valine), elevated circulating levels of methionine and aromatic amino acids. Results from two large randomized controlled trials have shown that branched chain amino acids (BCAA) supplementation in patients with advanced cirrhosis was associated with improved nutritional status and decreased frequency of complications else of cirrhosis (18,19). Okabayashi et al. evaluated the impact of oral supplementation of branched chain amino acids and carbohydrates on quality of life (QOL) measures in patients undergoing hepatic resection (20). In this study QOL measures was assessed by subjective perception of functioning and physical, mental, and social well-being and were evaluated before and after surgery, up to 12 months post-operatively.

1999; Bob et al. 2010), increased TNF-α, IFN-γ, IL-1β, and decreased production of interleukin-8 (IL-8) and interleukin-2 (IL-2). More recently, increases in a number of proinflammatory cytokines and chemokines (IL-6, IL-1α, IL-1β, IL-8, monocyte chemotactic protein-1 [MCP-1], macrophage

inflammatory protein-1 α [MIP-1α], Inhibitors,research,lifescience,medical eotaxin, granulocyte macrophage CSF [GM-CSF], interferon-alpha [IFN-α]) were observed in patients with PD and PTSD (Hoge et al. 2009). A number of factors may help explain the above heterogeneous results, including differences between anxiety disorder subtypes, study design, and confounding factors. Despite these heterogeneous results, other insights suggest increased inflammation contributes to anxiety pathogenesis. For instance, Inhibitors,research,lifescience,medical cytokine-based immunotherapy can lead to increased anxiety symptoms (Maes et al. 2001). Furthermore, depressive and anxiety symptoms induced by administration of cytokines are responsive to selective SSRIs (Gupta et al. 2006; de Knegt et al. 2011). We are not aware of any studies that have assessed the impact of cigarette smoking on inflammatory mediator expression in anxiety disorders. However, there is evidence that smoking and depression act synergistically to increase inflammation (Nunes et al. 2012). Inhibitors,research,lifescience,medical Further, in a study assessing cytokine

levels in the gingival crevicular fluid in patients with periodontal disease, levels of inflammatory cytokines IL-6 and IL-8 were both positively correlated with increasing psychological stress, as measured by the Modified and Perceived Stress Scale (Linn 1986), and cigarette smoking

Inhibitors,research,lifescience,medical (Giannopoulou et al. 2003). Oxidative and nitrosative stress Free radicals are by-products of oxidative Inhibitors,research,lifescience,medical phosphorylation that, at low or moderate concentrations, participate in normal cellular processes such as signaling pathways, mitosis, apoptosis, and responses to injury or infection (Valko et al. 2007). However, damage can occur to cellular components, including proteins, nucleic acid, carbohydrates, and lipids when levels of oxidative free Isotretinoin radicals increase beyond the antioxidant capacity of cells. Increases in free radical concentrations can occur selleck chemicals llc through both increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and/or decreased expression of antioxidants (Hovatta et al. 2010). Damage to these cellular components can alter the structure and function of membrane fatty acids and proteins, and alter or damage DNA and mitochondrial function leading to cell death (Maes et al. 2011b). Increased plasma markers of O&NS have been repeatedly demonstrated in anxiety-disordered populations and animal models of anxiety (for review see Hovatta et al. 2010). In addition, increased hippocampal oxidative stress is anxiogenic (de Oliveira et al. 2007).