Cholinergic innervation is widespread throughout the brain innervating nearly every neural zone. Many cholinergic projections do not terminate at synapses, but rather nonsynaptically where they contribute to diffuse volume transmission (Dani and Bertrand 2007). This could be the case for most hippocampal and cortical projections

(Descarries et al. 1997), and would be similar to the action of other neurotransmitters including serotonin, dopamine, and noradrenaline (Vizi et al. 2010). Inhibitors,research,lifescience,medical What differentiates cholinergic transmission from these other neurotransmitters is that movement of acetylcholine (ACh) is via diffusion that is limited by acetylcholinesterase hydrolysis and not a reuptake pump (Dani and Bertrand 2007). Differently located nAChRs appear to exert different effects. Unlike in the periphery, where nAChR SB431542 activation underpins fast neurotransmission at neuromuscular junctions, the role of fast transmission appears limited centrally although Inhibitors,research,lifescience,medical recent results suggest a possible role in hippocampal pyramidal neurons (Grybko et al. 2011). Many

studies have identified a role for nAChRs in modulating neurotransmitter concentrations, with activation of presynaptic nAChRs known to enhance release of neurotransmitters acetylcholine, dopamine, noradrenaline, serotonin, glutamate, Inhibitors,research,lifescience,medical and gamma-aminobutyric acid (GABA) (Dani and Bertrand 2007). This appears to be consequence of facilitating

increasing concentration of intracellular Ca2+ through augmenting calcium influx and altering activity of voltage-gated Ca2+ channels within the terminal. Alterations in multiple Inhibitors,research,lifescience,medical receptor regulated intracellular Ca2+ pathways are linked to mood and anxiety disorders (Plein and Berk 1999, 2001; Berk et al. 2001). Numerous investigations have explored how activation of nAChRs by nicotine can exert effects on mood and anxiety symptoms. Nicotine can lead Inhibitors,research,lifescience,medical to both anxiogenic and anxiolytic effects that appear to depend upon the animal strain, STK38 dosing regimen, and experimental paradigm utilized. Exposure to nicotine in rat models leads to upregulation of nAChRs (Slotkin 2004) that is shortly followed by desensitization as exposure is continued. Activation of nAChRs, particularly the α4β2 and α7 subtypes, appears to enhance release of serotonin in several brain regions, including the dorsal raphe nucleus (Reuben and Clarke 2000; Ma et al. 2005). Interestingly, α4β2 receptor knockout mice demonstrate an increase in basal anxiety (Ross et al. 2000), suggesting a role for these receptors in anxiety regulation. These receptors also upregulate dopamine and noradrenergic neurons (Lichtensteiger et al. 1988), with these effects likely important in mediating the anxiolytic effects of nicotine (McGranahan et al. 2011).

If it is proven to be true, Guaifenesin would be a suitable candidate as an antiepileptic courtesy of its wide margin of safety. Guaifenesin can also be used in pregnancy and breastfeeding,15,16 in contrast to other antiepileptic drugs. The aim of the present study was to determine whether Guaifenesin has an anticonvulsant effect in an animal model of seizure. Materials and Methods Chemicals Guaifenesin was purchased from Exir Pharmaceutical Company, Iran and was dissolved in 0.25% Tween 20 in normal saline. Diazepam (10 mg/ml)

was obtained from Darupakhsh Pharmaceutical Company, Iran, and Pentylenetetrazol (PTZ) was purchased from Sigma and was dissolved Inhibitors,research,lifescience,medical in normal saline. Animals Male albino mice (25-35 g) were obtained from the Animal House, Shiraz University of Medical Sciences. The animals were kept Inhibitors,research,lifescience,medical in plastic cages in groups of 4-5 with free access to food and water, 12h dark/12h light cycles, and at a temperature of 22ºC±2. The animals were treated in accordance with the guidelines of the Ethics Committee of Shiraz University of

Medical Sciences. PTZ-Induced Seizure The anticonvulsant effect of Guaifenesin was assessed in an animal model of PTZ-induced seizure. Sixty mice were randomly assigned into 6 groups (n=10/group) and received Inhibitors,research,lifescience,medical Guaifenesin Selleck XL184 intraperitoneally at doses of 100, 200, 300, and 400 mg/kg 30 minutes before the injection of PTZ (95 mg/kg). The control group was administered 0.25% Tween in normal saline. A group of mice received Diazepam (3 mg/kg) as a reference drug. The doses of Guaifenesin and Diazepam were selected according to previous studies.17,18 The latency Inhibitors,research,lifescience,medical time to the onset of myoclonic, clonic, and tonic-clonic convulsions was recorded after PTZ injection. PTZ initially produced myoclonic jerks, followed by facial and forelimb clonus, which then became sustained and led to generalized tonic-clonic Inhibitors,research,lifescience,medical jerking (loss of righting reflex and tonic forlimb flexion/extension, followed by whole body clonus).19 In addition, the percentage of the animals exhibiting convulsion and the percentage of mortality were recorded for each

studied group. The ED50s, median effective doses of Guaifenesin, protecting 50% of the mice about against clonic and tonic-clonic convulsions and death were determined. Neuromuscular Coordination–Rotarod The effect of Guaifenesin on coordinated motor movements was assessed using the Rotarod test. A day before the test, the mice were trained to stay on the rotating wheel (3 cm in diameter, 20 rpm) for more than one minute. On the test day, the animals were tested on the Rotarod (model 7600, UGO Basile, Italy) before and 30 minutes after the administration of 0.25% Tween20, Diazepam or different doses of Guaifenesin. The number of seconds each mouse remained on the rotating wheel was recorded for a maximum of 300 seconds. Statistical Analysis The data are presented as mean value±SEM.

From this initial experiment, the location of the two motor pools could be identified to target these MNs for examination of ultrastructure in separate material prepared for electron microscopy. Figure 1 Illustration of approaches used to identify MNs. (A and B) The TA and soleus motor pools exhibit rostral caudal overlap when identified via retrograde labeling after muscle injections of fluorescently labeled Cholera toxin B

subunit (CTB; A), but can … In separate animals prepared for electron Inhibitors,research,lifescience,medical microscopy, mice were deeply anesthetized with MK 2206 ketamine/xylazine and perfused intracardially with 100 mL of freshly made 2% glutaraldehyde, 2% paraformaldehyde in 0.13 mol/L sodium cacodylate buffer, pH 7.4, Inhibitors,research,lifescience,medical using a peristaltic pump at a flow rate of 10 mL/min. Perfused animals were kept at 4°C for 1–3 h, then spinal cords were carefully removed via dorsal laminectomy and place in fixative overnight at 4°C along with the various muscles. For VH, spinal cords were then embedded in 4% low temperature agarose cooled to 37°C, solidified on ice, cut on a vibratome at 250 μm, and collected serially. VH areas

of interest were dissected using epi-illumination. The (L3–L4) area was determined by the position along the rostral-caudal length of Inhibitors,research,lifescience,medical the spinal cord and by motor pool appearance as determined in Figure ​Figure1.1. Specimens were Inhibitors,research,lifescience,medical then embedded in Araldite 502 using a Lynx processor. One micron sections and subsequent 700 Å thin sections were cut using an LKB ultramicrotome, then counterstained with either toluidine blue for 1 μm sections, or uranyl acetate in 100% methanol and subsequently lead citrate Inhibitors,research,lifescience,medical for thin sections, which were viewed and photographed digitally using a Zeiss EM 10 electron microscope (Carl Zeiss

Microscopy, Hamburg, Germany). All analysis of ultrastructural features was performed on unaltered images that were collected directly from the electron microscope using the Orius EM high-resolution camera. Images shown Oxalosuccinic acid in the figures were adjusted only for contrast. Thin section maps were constructed using the X-Y stage controls of the electron microscope; subsequently the adjacent 1 μm section outline was superimposed onto this map using a camera lucida, and MNs marked (Fig. ​(Fig.1D).1D). Those cells meeting α-MN criteria within the VH motor pool (>600 μm2, one or more C-terminals, nucleus with prominent nucleolus, abundant cytoplasm and organelles) were found on the electron microscope and photographed to create a montage of the cell surface at 16,000× magnification. MNs <600 μm2 were classified as γ-MNs (Friese et al. 2009; Shneider et al. 2009).

No influenza type B was identified in this study. Agarose gel electrophoresis of RT-PCR products are shown in figure 1 and ​and2.2. The sensitivity cut-off of RT-PCR was 0.1 ng of total template RNA genome as described previously.17 Figure 1 Agarose gel electrophoresis

of RT-PCR products for influenza typing. Lane1: Negative control, Lane 2-6 & 9-14: clinical samples, Lane 7: influenza type A, Lane 15: influenza type B, Lane 1 & 10: Gene Ruler 100bp (CinnaGen, Iran). Figure 2 Agarose gel electrophoresis of RT-PCR products for influenza A virus subtyping. Lane 1: Negative control, #KU-57788 manufacturer keyword# Lane 2-9: clinical samples, Lane 10: Gene Ruler 100bp (CinnaGen, Iran), Lane 11: A/H1N1, Lane 12: A/H3N2. Sequence and Amino Acid Analysis

All 17 influenza A positive samples were sequenced. The nucleotide and deduced amino acid sequences of the HA1 from 17 isolated samples were compared with other GenBank sequences as well as with current vaccine strains. Based on nucleotide alignments, the Tehran/2008/H1N1 Inhibitors,research,lifescience,medical isolates had maximum similarity (98.5%) with New South Wales/18/99 isolates and 98% with those of Auckland/176/99, New Caledonia/20/99 and Tehran/7/2006. In the alignment generated based on the HA1 portion amino acid sequences, Tehran/2008/H1N1 isolates demonstrated 4-6 amino acid differences compared with vaccine candidate strain A/Brisbane/59/2007 (table 2). Inhibitors,research,lifescience,medical The Tehran/2008/ H3N2 Inhibitors,research,lifescience,medical isolates showed maximum similarity (100%) with the Nagasaki/N03/2005 strain and 99% with the Brisbane/10/2007. Alignment of the amino acids of the HA protein from these isolates demonstrated one amino acid change with the vaccine strain A/Brisbane/10/2007

(table 3). Table 2 Amino acid substitutions of hemagglutinin gene from Tehran/2008/H1N1 isolates compared with the vaccine strain (A/Brisbane/56/2007) Table 3 Amino acid substitutions of hemagglutinin gene from Tehran/2008/H3N2 Isolates compared with the vaccine strain (A/Brisbane/10/2007) Phylogenetic Analysis Nucleotide sequence Inhibitors,research,lifescience,medical of the HA1 region of the Tehran/2008/H1N1 and Tehran/2008/H3N2 isolates were compared with the vaccine strains and other influenza viruses, and their genetic relationships were considered by neighbor joining analysis with 1000 bootstrapped replicates. These analyses revealed that our H1N1 isolates were linked with A/Brisbane/59/2007 Terminal deoxynucleotidyl transferase vaccine strain and also with the Iranian isolates from previous years that all clustered in a distinct clade with 98% bootstrap value (figure 3a). Moreover, phylogenetic analysis showed that our H3N2 isolates and Nagasaki/N03/2005 strain branched in a unique cluster close to A/Brisbane-like vaccine virus, with a 99% bootstrap value (figure 3b). The phylogenetic tree is available at: http://ijms.sums.ac.ir/images/userfiles/Sep%202011/fig1a.jpg http://ijms.sums.ac.ir/images\userfiles\Sep 2011\fig1b.

Peripheral nerve involvement probably accounts for the distal muscular atrophy and the “mixed” myogenic and neurogenic EMG pattern shown by patients with GSD III (debrancher deficiency). Another explanation often proposed is that muscle selleck chemical glycogen accumulation is much greater in glycogenoses characterized by fixed weakness than in those dominated by recurrent cramps and myoglobinuria, and this may mechanically disrupt the contractile apparatus. However, both mechanisms leave unanswered questions: for example,

why Inhibitors,research,lifescience,medical are adult patients with GSD II weak, although glycogen accumulation is usually modest and confined to skeletal muscle? Figure 2 The two major syndromes associated with defects of muscle substrate utilization. Glycogen is a highly ramified polymer of glucose in which linear chains of glucosyl units “stranded” together by α-1,4-bonds sprout – at regular intervals – side chains through α-1,6-glucosidic Inhibitors,research,lifescience,medical bonds: the resulting highly symmetrical spherical structure of each glycogen molecule makes it spatially efficient and hydrophilic: these are the osmiophilic β-particles shown by electron microscopy Inhibitors,research,lifescience,medical under the sarcolemma and – to a lesser extent – between myofibrils. For many years, it was unclear

what was the primer of glycogen synthesis, i.e. which enzyme stranded together the first glucosyl units. This starter enzyme – called glycogenin – is now known (5): the subsequent growth of glycogen into a spherical polymer is catalyzed by the sequential and – as we shall see – highly coordinated actions of two enzymes: (i) glycogen Inhibitors,research,lifescience,medical synthetase, which attaches glucosyl units in α-1,4-glucosidic

bonds from Inhibitors,research,lifescience,medical UDP-glucose to nascent linear chains of glycogen until a length of approximately 10 glucosyl units is reached; and (ii) the branching enzyme, which removes a short linear chain of approximately 4 glucosyl units and attaches it to a longer chain in an α-1,6-glucosidic bond, thus starting a new chain. It is not the purpose of first this article to review in detail the muscle glycogenoses, for which the reader is referred to recent comprehensive articles (6, 7). However, Figure ​Figure33 highlights those enzyme defects that have been associated with muscle glycogenoses within a schematic metabolic pathway of glycogen metabolism, showing by italic Roman numerals the GSD causing exercise intolerance and myoglobinuria, and by plain text Roman numerals those causing fixed weakness. In the rest of this article, I will consider a few comparative aspects between GSD V and GSD VII and provide a general framework for the more specific presentations that will follow. Figure 3 Scheme of muscle glycogen metabolism and glycolysis designating the glycogen storage diseases (GSD) affecting muscle with Roman numerals.

Pre-publication history The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-227X/10/4/prepub Supplementary Material Additional file 1: Web www.selleckchem.com/products/ldn193189.html survey for patients and caregivers of

patients with CVS. Original web survey used to gather data from patients with CVS. Click here for file(79K, PDF) Acknowledgements We would like to thank Dr Marc Gorelick for his critical review and drafting of the manuscript.
The nature and Inhibitors,research,lifescience,medical incidence of alcohol intoxications are race, sex, culture and geographical localization dependent in a lot of cases [1-3]. Since methanol is not readily available and since there’s no culture of distilling alcohol at home, severe methanol intoxications are extremely rare in the Netherlands. A foreign sailor visiting the Netherlands accidentally caused himself severe Inhibitors,research,lifescience,medical methanol intoxication by drinking unregistered illegally bought industrial

alcohol. The background of the patient combined with the particular chemical derangements was indicative of potential methanol intoxication [4,5]. Hemodialysis in combination with ethanol or fomipezole, a costly but powerful alcohol dehydrogenase (ADH) blocker is the first choice treatment in case of a severe intoxication [6,7]. Due to severe hemodynamical instability hemodialysis was not an option Inhibitors,research,lifescience,medical and fomipezole was not available. Therefore the patient was treated with CVVH-DF and ethanol infusions to block the ADH. In the literature just a few cases using CVVH-DF for the treatment of methanol intoxication have been published so far [8,9]. Despite the fact that CVVH-DF is a second choice treatment, the metabolic derangements and the hemodynamic parameters improved rapidly after Inhibitors,research,lifescience,medical fluid resuscitation and initiation of CVVH-DF. Unfortunately the patient developed signs of cerebral herniation after all parameters had normalized. The CT scan showed instead of bleeding in the putamen massive cerebral edema followed by brain death of the patient. In case of hemodynamical instability in a patient with methanol induced metabolic derangements, CVVH-DF Inhibitors,research,lifescience,medical in combination with ethanol infusion is a relatively cheap, save all and effective alternative for hemodialysis

and fomipezole. Case Presentation A 26-year-old foreign sailor was admitted to our emergency department because of hypothermia and low Glascow Coma Scale (GCS). The patient was found unconscious in his cabin by the ship’s captain, after not appearing on deck for his shift. One of his colleagues confessed they had been celebrating together about 8-12 hours ago at the end of their shift, with alcohol they bought illegally in a small harbor store the day before. On the emergency department we saw an unconscious Caucasian male, bodyweight 68 kg’s with a maximum GCS of 3 and a body temperature of 35°Celsius. Pupils were reactive to light on both sides. Initial blood pressure was 80/40 mm/Hg with a regular heartbeat of 126 beats/min. Respiration rate was 30, but shallow.

27 In this trial, participants meeting criteria for MDD after the loss of a loved one were treated for 12 weeks with a mean final dose of 13.1 mg/day of escitalopram. Of the 29 individuals studied, 14 were diagnosed with complicated grief in addition to MDD, whereas 15 of the subjects met criteria for MDD but not for CG. When the results of treatment were analyzed by CG diagnosis, mean ICG scores SRT1720 ic50 improved by 21% in the CG group, and by 39% in the uncomplicated grief group. Given the small sample size, however, this difference was not statistically significant. Defining treatment response as “very much improved” and

or “much improved” on the CGI-I scale, 45% of the whole Inhibitors,research,lifescience,medical sample were responders in terms of grief symptoms, and 83% in terms of depressive symptoms. Another open-label trial28 was conducted in 17 participants Inhibitors,research,lifescience,medical with CG (scoring ≥30 on the ICG, more than 6 months after a loss) as a primary disorder. Participants received escitalopram 10 mg/day, with an option to increase the dose to 20 mg/day, at week 4. At 16 weeks, the response rate was of 38% with a decrease in mean

ICG score of only 24% in the intention-to-treat sample (those who attended at least Inhibitors,research,lifescience,medical one session). The main results from these studies are reported in Table I. Other medications To the best of our knowledge, there is no report on the primary efficacy of benzodiazepines for the treatment of CG. However, an earlier randomized controlled trial has

investigated the use of diazepam vs placebo in the medical management of recent grief.29 In this study,30 recently bereaved individuals were randomized to receive a bottle containing 20 tablets of Inhibitors,research,lifescience,medical either diazepam (2 mg) or placebo for PRN use during the following 6 weeks. At the 7-month follow-up, analyses failed to show any significant differences between the two groups in terms of grief symptom severity as measured by the Bereavement Phenomenology Questionnaire (BPQ30). Interestingly, those receiving diazepam had more sleep problems than Inhibitors,research,lifescience,medical those assigned to placebo. This is consistent with research on PTSD suggesting that benzodiazepines might actually increase the severity of PTSD.31-33 Furthermore, recent data suggests that the use Carnitine dehydrogenase of benzodiazepines in the after-math of a loss might also lead to long-term prescription dependence in elderly individuals.34 Combining pharmacological and psychological interventions In their 2001 publication, Zisook et al reported that during their trial, several patients specifically stated that the treatment of depressive symptoms allowed them “to grieve more intensely“ and ”confront situations that they had been avoiding when more depressed.“22 This suggests that a concurrently prescribed antidepressant might improve outcomes with psychological grief specific interventions based on behavioral techniques.

45,56,57 In LGK-974 datasheet recent years, immunological

research in TS has focused on cytokines. In a recent prospective longitudinal study, increased serum levels of the cytokines interleukin (IL)-12 and tumor necrosis factor (TNF)-oc in juvenile TS patients were observed.58 During exacerbations of tics, a further increase in IL-12 and TNF-oc was observed, pointing to a relationship between tic severity and proinflammatory cytokines. In OCD, however, decreased levels of TNF-ot were described.59-61 Since OCD and TS show a high rate of comorbidity, a possibly discriminative marker – decreased in OCD and increased Inhibitors,research,lifescience,medical in TS- would be very valuable. Although the results of the kynurenine estimations in TS are divergent, depending on interfering factors,62,63 changes in the kynurenine levels in the sera of TS patients also point to the involvement of the immune system. Kynurenine is the product of activated monocytes/ macrophages; changes in kynurenine production take place during Inhibitors,research,lifescience,medical inflammatory processes. Moreover, kynurenine and other products of the tryptophan/kynureninemetabolism are neuroactive proteins, possibly themselves contributing to changes in neurotransmitter metabolism. Moreover, increased levels of the soluble adhesion molecules Inhibitors,research,lifescience,medical V-CAM-1 and E-selectin – increased in inflammatory states – were reported in children and adults suffering from TS.64 A case report of successful

Inhibitors,research,lifescience,medical treatment with a cyclo-oxygenase (COX)-2 inhibitor also promotes the view that an inflammatory process is involved in TS.65 Inflammation in TS as e result of an infectious or postinfectious process It has been described that tics appear or are exacerbated in acute Lyme disease,66 infection with Mycoplasma pneumoniae,67,68 or acute streptococcal infection.69 Moreover, an association of the common cold with tic disorders has been observed.63 Improvement or remission of the tics has been

Inhibitors,research,lifescience,medical associated with antibiotic therapy.65,66,68 These findings strongly suggest that infectious agents contribute to the pathogenesis of tics and TS. PANDAS70,71 has been extensively described during recent years. The main symptoms of PANDAS are motor and vocal tics and OC behavior like that found in TS.72 Although crossreacting antibodies against the putamen have been observed in PANDAS,73 the mechanism has not yet been established. TS is proposed to be secondly a part of PANDAS. Increased antibody titers and other features of PANDAS, however, have also been described in adult TS patients,74,75 while the PANDAS concept is restricted to children. Antibodies against certain streptococcal M proteins, ie, proteins on the surface of streptococci which are known to be responsible for the virulence and the immune properties of the particular streptococcal strain, are increased in children and adult TS patients.

19,36 For instance, the brain has a higher metabolism level than the rest of the body and utilizes

a large proportion of consumed oxygen, hence increasing the potential for producing reactive oxygen species and subsequent oxidative stress. Oxidative stress mediates specific neuronal damage, including modifications to lipids, protein, and DNA, resulting in inflammation, Inhibitors,research,lifescience,medical an increase in reactive astrocytes, and altered Ca2+- and mitochondria-mediated neuronal functions, which together may contribute to the deterioration of mental capacities with age.37,38 Further, with rare exceptions, neurons do not divide,39 and thus cellular damage tends to accumulate with increasing age. This is paralleled by a decrease in the capacity for cellular repair.36 Structurally, studies reveal a decrease in neuron volumes, a small loss or no change in cell numbers,40,41 and a progressive thinning of cortical thickness, Inhibitors,research,lifescience,medical affecting

both gray and white matter.42,43 Functionally, studies Inhibitors,research,lifescience,medical indicate a continuous decline with age in certain aspects of MM-102 ic50 cognitive functions (speed of processing, working memory, and long-term memory) beginning in the 20s.44 In contrast, verbal knowledge increases throughout the lifetime.32 This latter observation highlights the point that, while studies often demonstrate a negative conceptual bias towards aging, age-related changes can also be positive, and may represent Inhibitors,research,lifescience,medical the recruitment of protective mechanisms against known deleterious effects of aging (ie, oxidative stress) or uncharacterized and beneficial late Inhibitors,research,lifescience,medical brain-maturation processes. Based on the above observations, and supported by developments in gene array technology, our group7,8 and others45-48 have investigated the presence of age-dependent gene expression changes in the human brain, as molecular correlates of affected cellular functions. “Molecular aging” of the human brain

It has been known for some time that robust changes in gene expression occur with aging in peripheral tissues.49 The fact that age-related changes in gene expression extend to the brain may not be surprising, given the body of knowledge about changes in structure and function of the and brain with age (described briefly above). Indeed, one might hypothesize that age-related changes in gene expression reflect a general deterioration of the brain and that a preponderance of genes would be affected. This, however, does not appear to be the case. Recent genome-wide studies demonstrate that a relatively small number of genes exhibit age-dependent gene expression changes.

2012; McGurk et al. 2004; Minzenberg et al. 2004; Pae, 2013; Tracy et al. 1998]. The effects of the muscarinergic antagonism had not been investigated thoroughly in a clinical setting at the initiation of the study.

Sertindole and olanzapine are both atypical antipsychotics [Nielsen and Nielsen, 2009], with differences in receptor affinities, especially with sertindole not showing any marked affinity for the muscarinergic receptor whereas olanzapine has a high affinity and an antagonizing effect [Correll, 2010]. In addition, Inhibitors,research,lifescience,medical sertindole does not show a tendency to induce Parkinsonism in treated patients [Seeman and Tallerico, 1998], thereby excluding the need for concomitant anticholinergic drugs. In this study we aimed to investigate the effects of sertindole and olanzapine Inhibitors,research,lifescience,medical on cognition in patients diagnosed with schizophrenia, utilizing a computerized cognitive test battery. Material and methods Design The study is a 12-week, double-blind randomized head-to-head study in which all participants are randomized to either sertindole or olanzapine. Participants were recruited in Denmark and Sweden, but due to poor recruitment in the Swedish center (one participant) only data from Denmark are reported. Primary outcome was change in cognition as measured by the CANTAB test battery (Cambridge Cognition Ltd, Inhibitors,research,lifescience,medical Bottisham, Cambridge, UK) [Lowe and Rabbitt, 1998; Sahakian and Owen, 1992].

Participants were randomized 1:1 to receive either sertindole or olanzapine. The initial dose of sertindole was 4 mg, which was increased by 4 mg every fourth day until 16 mg was reached. Treatment doses of sertindole were between Inhibitors,research,lifescience,medical 16 and 24 mg. The dose of 24 mg was only used in exceptionally cases, as the risk of QTc prolongation is dose dependent. The initial dose of olanzapine was 10 mg and the flexible dose range was between 10 and 20 mg. All participants were treated with a tablet of sertindole or an identical placebo tablet, and an Inhibitors,research,lifescience,medical encapsulated olanzapine tablet or a dummy tablet, so participants were either on sertindole or olanzapine throughout the study period. Block size randomization was conducted by the pharmacy

SPTLC1 by computer and randomization block size was variable. Disclosure of blinding was done after reporting of PANSS values to the pharmacy. Participants Men and women, between the ages of 18 and 65 years, diagnosed with an International Classification of Diseases, 10th revision diagnosis of check details schizophrenia F20.0–F20.3 and F20.9 (paranoid, hebephrenic, catatonic, undifferentiated or unspecified subtypes) were eligible for participation [World Health Organization, 1992]. Patients were excluded if an electrocardiogram showed QTc prolongation or if QT prolongation over 500 ms was shown after initiation of study drugs. Before inclusion, normal levels of potassium or magnesium were required, as well as a negative pregnancy test for women. All women were required to use a safe form of birth control.