Advances that further elucidate the mechanism(s) of action of granins, coupled with improvements in biomarker technology and direct clinical application, should increase the translational

effectiveness of this family of proteins in disease diagnosis and drug discovery. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Orexins are neuropeptides produced in the lateral hypothalamus and implicated in regulation of sleep-wake cycle. Selective loss of orexin neurons is found in the brain of patients with narcolepsy, but the mechanisms of this pathological change are unclear. A previous study showed that excessive stimulation of N-methyl-D-aspartate (NMDA) receptors by quinolinic acid (QA) caused selective loss of orexin neurons in rat hypothalamic slice culture. Here we examined QA toxicity on orexin neurons and melanin-concentrating www.selleckchem.com/products/pi3k-hdac-inhibitor-i.html hormone (MCH) neurons in vivo. Contrary to the expectation, injection of QA (60 and 120 nmol) into the lateral hypothalamus of male C57BL/6 mice caused selective loss of MCH neurons rather than orexin neurons, and this toxicity of QA was attenuated by MK-801, an NMDA receptor antagonist. Selective loss of MCH

neurons with preserved orexin neurons was observed even when GABA(A) receptor antagonists such as bicuculline and picrotoxin were injected with QA. A significant decrease in the number of orexin neurons was induced when QA injection was performed in the dark phase of diurnal cycle, but the degree of the decrease was still lower than that in the number of MCH neurons. Finally, https://www.selleckchem.com/products/sn-38.html QA (60 nmol) induced selective loss of MCH neurons also in young rats at 3-4 weeks of age. These results do not support the hypothesis that acute excitotoxicity mediated by NMDA receptors is responsible for the pathogenesis of narcolepsy. (C) 2010 IBRO. Published AICAR price by Elsevier Ltd. All rights reserved.”
“Pleiotrophin (PTN) is a neurotrophic factor with important effects in survival and differentiation of dopaminergic neurons that has been suggested to

play important roles in drug of abuse-induced neurotoxicity. To test this hypothesis, we have studied the effects of amphetamine (10 mg/kg, four times, every 2 h) on the nigrostriatal pathway of PTN genetically deficient (PTN-/-) mice. We found that amphetamine causes a significantly enhanced loss of dopaminergic terminals in the striatum of PTN-/- mice compared to wild type (WT+/+) mice. In addition, we found a significant decrease (similar to 20%) of tyrosine hydroxylase (TH)-positive neurons only in the substantia nigra of amphetamine-treated PTN-/- mice, whereas this area of WT+/+ animals remained unaffected after amphetamine treatment. This effect was accompanied by enhanced amphetamine-induced astrocytosis in the substantia nigra of PTN-/- mice.

Haloperidol decreased locomotion both in saline and MK-801-treated animals, and this effect was not evident in the latter group receiving the higher dose of tandospirone. Tandospirone (5 mg/kg)-induced disruption of sensorimotor gating in saline or MK-801-treated animals was reversed by WAY-100635, but not by haloperidol.

These findings suggest that behavioural changes induced by tandospirone

are not fully blocked by 5-HT1A antagonists and that tandospirone (5 mg/kg) potentiates the effect of MK-801. Overall, these findings point to an interaction between NMDA and 5-HT(1A) receptors. Part of the effect of tandospirone on locomotor activity may be mediated by the actions of its active metabolites on other neurotransmitter systems.”
“Purpose: Inguinoscrotal testicular descent has been proposed to occur via

sensory fibers of the sexually dimorphic genitofemoral nerve, which release a neurotransmitter, calcitonin Tozasertib concentration gene related peptide, to guide the migrating gubernaculum into the scrotum. We hypothesize that androgen mediated regression of the genitofemoral nerve mammary branch is necessary for inguinoscrotal descent in rats. We compared the spatiotemporal development of the genitofemoral nerve in control and antiandrogen treated Veliparib rats.

Materials and Methods: A total of 29 Sprague-Dawley (R) rats were collected (animal ethics committee approval A644) in control and antiandrogen treated groups (flutamide, embryonic days 16 to 19, 75 mg/kg body weight/5% ethanol + oil) on embryonic days 17 and 19, and on postnatal day 2. Sagittal sections of the gubernaculum and its surrounding progestogen antagonist structures were processed for standard histology and immunohistochemistry for androgen receptor, nerves (Tuj1), calcitonin gene related peptide (marker for genitofemoral nerve) and cell nuclei (DAPI).

Results: The inguinal mammary bud, its adjacent androgen receptor and genitofemoral nerve mammary branch (containing calcitonin gene related peptide) persisted from embryonic day 17 to postnatal day 2 in all antiandrogen treated males, yet regressed in all control males by postnatal day 2.

Conclusions: Antiandrogens

resulted in the persistence of the mammary branch and inguinal mammary bud. Persistent genitofemoral nerve mammary branches may arrest or slow down gubernacular migration by releasing calcitonin gene related peptide in the mammary inguinal fat pad, thus reducing the chemotactic gradient to calcitonin gene related peptide from genitofemoral nerve branches in the distal scrotum. We hypothesize that this process may be related to antiandrogen induced cryptorchidism in the rodent.”
“Ca2+-permeable AMPA receptors (CP-AMPARs) accumulate in the nucleus accumbens (NAc) after similar to 1 month of withdrawal from a long-access cocaine self-administration regimen (6 h/d, 10d). This is functionally significant because CP-AMPARs mediate the ‘incubated’ cue-induced cocaine craving produced by this regimen.

On multivariate analysis age, no history of diabetes mellitus and AZD5153 nerve sparing were independent predictors of the preservation of potency.

Conclusions: We identified many factors that were predictors of the preservation of potency after open radical retropubic prostatectomy. Only age, no history of diabetes mellitus and neurovascular bundle preservation were independent predictors. These parameters should be considered when counseling surgical candidates so that erectile

function expectations are realistic.”
“The neural plasticity mechanisms that underlie learning and memory may also be engaged when drug addiction occurs. It was reported that long-lasting neuroadaptations induced by cocaine use and withdrawal require the participation of hippocampus. However, the role of corticotrophin-releasing factor receptors in this process remains unclear. In the present study, the effects of chronic cocaine treatment WZB117 clinical trial (a 14-day cocaine administration, 20 mg/kg i.p., daily) and short-term cocaine withdrawal (a 3-day cocaine extinction following a 14-day cocaine administration) on long-term potentiation (LTP), one prominent cellular mechanism for learning and memory, were assessed in the CA1 region of the rat hippocampal slices. We found that cocaine withdrawal, but not the chronic cocaine administration itself, significantly enhanced the magnitude of LTP in hippocampal slices, as compared with

that in saline controls. Selective blockade of corticotrophin-releasing Tideglusib factor receptor subtype 1 (CRF(1)) with the specific antagonist NBI 27914 (100 nM in vitro) attenuated the magnitude of LTP in hippocampal slices from cocaine withdrawal

rats, and intriguingly, also from saline control rats, while specific blockade of corticotrophin-releasing factor receptor subtype 2 (CRF(2)) with astressin2-B (100 nM in vitro) selectively attenuated the magnitude of LTP in hippocampal slices from cocaine withdrawal rats. Our data suggest that short-term cocaine withdrawal treatment may cause synaptic plasticity in hippocampus partially via changing the activity of CRF(2) in the hippocampus. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Purpose: After properly staged renal injury many children will undergo radiological reevaluation with computerized tomography, the modality frequently favored for its widespread availability and anatomical detail. The ALARA (as low as reasonably achievable) concept attempts to balance the potential future risk of radiation induced malignancy with the added information obtained by the study. At our institution ultrasound has been increasingly adopted as the followup imaging technique of choice. We sought to evaluate this practice in pediatric blunt renal trauma management.

Materials and Methods: We retrospectively analyzed the trauma database of a pediatric referral center for patients treated between 1997 and 2007.

We believe that the contents of this issue represent the 2012 state of the art in computational modeling of classical conditioning and provide a way to find promising avenues for future model development.”
“A growing body of evidence suggests that crack cocaine misuse has widespread systemic and cognitive consequences,

but little attention has been given to its systemic pathophysiology. We report Z-IETD-FMK here changes in inflammation markers, oxidative damage and brain derived neurotrophic factor in a sample of outpatients with crack cocaine use disorders. Fifty-three outpatients were recruited for this cross-sectional study and matched with fifty control subjects. The focus of this report is in between group this website differences in cytokines, oxidative damage and brain-derived neurotrophic factor (BDNF). Crack cocaine use was associated with higher BDNF levels when compared to controls, present only in those who used crack cocaine in the last month. Patients also had higher circulating levels of IL-1 beta, TNF-alpha and IL-10 when compared to controls.

There were no significant differences in oxidative damage between patients and controls. These results represent a first demonstration that crack cocaine use disorders entail an activation of the reward, immune and inflammatory systems. (c) 2013 Elsevier Ireland Ltd. All rights reserved.”
“Patients with depression (n = 20) or bipolar disorder (n = 21) completed computerized ambulatory monitoring for three consecutive days. Results indicate Y-27632 mw satisfactory rates of acceptance and

compliance, with no salient fatigue effects. However, some evidence for reactive effects was found. The findings provide support for this approach in the study of mood disorders. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“A formal account of the relationship between attention and associative learning is presented within the framework of a configural theory of discrimination learning. The account is based on a connectionist network in which the entire pattern of stimulation presented on a trial activates a configural unit that then enters into an association with the trial outcome. Attention is assumed to have two roles within this network. First, the salience of the stimuli at the input to the network can be increased if they are relevant to the occurrence of reinforcement and decreased if they are irrelevant. Second, the associability of configural units can increase on trials when the outcome is surprising and decrease when the outcome is not surprising.”
“It has been suggested that minor alkaloids in plants play a role in the biological and neuronal actions of nicotine.

However, a heptamer peptide composed of a scrambled sequence of the seven amino acids in HBHP failed to bind HMGB1 and had no protective effect. Furthermore, Alvespimycin clinical trial HBHP (300 ng) delivered intranasally at 30 min before MCAO significantly suppressed infarct volume in the postischemic rat brain (maximal reduction by 41.8 +/- 5.4%) and ameliorated neurological and behavioral deficits. In contrast, scrambled heptamer peptide had no protective effect at the same dose. Together these results suggest that intranasal HBHP ameliorates neuronal damage in the ischemic brain by binding HMGB1, which might inhibit the function of HMGB1 as an endogenous danger signal molecule. (C) 2012 Elsevier

Ireland Ltd. All rights reserved.”
“Background: We chose to study polymorphisms of vitamin D receptor gene (VDR) and parathyroid hormone genes (PTH), whose protein products significantly affect calcium-phosphate metabolism in kidneys and are implicated in the pathogenesis of diabetes, which may also involve kidney damage. Methods: Distribution of genotypes of four polymorphisms in VDR gene i.e TaqI (rs731236), BsmI (rs1544410) ApaI (rs7975232), FokI (rs2228570) and two polymorphisms of PTH gene, i.e. DraII (rs6256), BstBI (rs6264), were studied using 4SC-202 cost PCR-RFLP. Examined groups consisted of 147 patients with diabetes (DM), 47 patients with non-diabetic renal disease (NDRD), 132 patients with

diabetic nephropathy (DN) and 118 healthy subjects. Conclusion: Comparison of DN group and healthy subjects identified statistically significant difference for the FokI polymorphism in VDR gene (P<10-4) and also for the BstBI polymorphism in PTH gene (P=0,023). Differences in DraII polymorphism Dehydratase distribution in PTH gene were statistically significant in each group of patients compared to healthy

subjects. In DN patients, the BBFFAATt combination of VDR gene was more frequent than in healthy subjects (P=0,046), and the BbFFAaTt variant was more frequent than in DM2 patients (P=0,018). The BBDD haplotype of PTH gene seems to be a predisposing factor for diabetes itself (P=0,019). Copyright (C) 2012 S. Karger AG, Basel”
“Development of new biomarkers is a constantly evolving field of research endeavor in psychoneuroendocrinology. Salivary biomarkers have received special attention since they are readily accessible and easily obtained. Salivary alpha-amylase (sAA) has been proposed as a sensitive biomarker for stress-related changes in the body that reflect the activity of the sympathetic nervous system (SNS), and a growing body of research is accumulating to support the validity and reliability of this parameter. However, questions remain to be answered before sAA can be accepted as an index of SNS activity. This review describes sAA as an emerging biomarker for stress and provides an overview of the current literature on stress-related alterations in sAA.

These results identified syntenin-2 as the first PDZ domain protein controlled by HPV8 and HPV16 at the mRNA level.”
“This study investigates whether figurative comprehension in schizophrenia is influenced by the salience of idiomatic meaning, and whether it is affected by clinical and demographic factors and IQ Twenty-seven schizophrenic patients and 25 healthy participants performed a semantic relatedness judgement task which required the comprehension of idioms with two plausible meanings (literal and figurative). The study also used

literal expressions. The figurative meaning of the idioms was less salient (ILS), more salient (IFS), or equally salient (IES) compared selleck chemicals to the literal meaning. The results showed “”a salience effect”" (i.e., all participants understood the salient meanings better than the less salient meanings). There was also a “”figurativeness effect”" (i.e., healthy individuals understood the figurative meaning of IES better than the

literal meaning but not schizophrenic patients). In patients, JPH203 mouse their thought disorder influenced the figurative comprehension of IFS. The verbal IQ influenced the figurative comprehension of ILS. The thought disorder, the verbal IQ and the educational level influenced the figurative comprehension of IES. The patients’ clinically evaluated concretism was associated with a reduced figurative comprehension of IFS and IES evaluated at a cognitive level. The results are discussed in relation to cognitive mechanisms which underscore figurative comprehension in schizophrenia. (C) 2010 Dichloromethane dehalogenase Elsevier Ireland Ltd. All rights reserved.”
“BACKGROUND: Enrollment in the Stenting and Aggressive Medical Management for the Prevention

of stroke in Intracranial Stenosis (SAMMPRIS) trial was halted owing to higher-than-expected 30-day stroke rates in the stenting arm. Improvement in periprocedural stroke rates from angioplasty and stenting for intracranial atherosclerotic disease (ICAD) requires an understanding of the mechanisms of these events.

OBJECTIVE: To identify the types and mechanisms of periprocedural stroke after angioplasty and stenting for ICAD.

METHODS: Patients who experienced a hemorrhagic or ischemic stroke or a cerebral infarct with temporary signs within 30 days of attempted angioplasty and stenting in SAMMPRIS were identified. Study records, including case report forms, procedure notes, and imaging were reviewed. Strokes were categorized as ischemic or hemorrhagic. Ischemic strokes were categorized as perforator territory, distal embolic, or delayed stent thrombosis. Hemorrhagic strokes were categorized as subarachnoid or intra-parenchymal. Causes of hemorrhage (wire perforation, vessel rupture) were recorded.

RESULTS: Three patients had an ischemic stroke after diagnostic angiography. Two of these strokes were unrelated to the procedure.

In the present study, transcranial magnetic stimulation (TMS) was used to investigate the causal involvement of frontal and parietal areas in different stages of the PM process (in particular, target checking and intention retrieval), and to determine the specific contribution of these regions to PM performance.

Our results demonstrate that repetitive TMS (rTMS) interferes with prospective memory performance when applied at 150-350 ms to the right dorsolateral prefrontal cortex (DLPFC), and at 400-600 ms when applied to the left posterior parietal cortex (PPC).

The present study provides clear evidence that the right DLPFC plays

a crucial role in early components of the PM process (target checking), while the left PPC seems to be mainly involved in later processes, such as the retrieval BV-6 manufacturer of the intended action. (C) 2011 Elsevier Ltd. All rights reserved.”
“Objectives: This study evaluated early and long-term results of endovascular treatment of iliac artery occlusions and compared these outcomes with those in patients treated for stenotic lesions.

Methods: During a 10-year period ending in January 2010, 223 endovascular

procedures to treat aortoiliac occlusive disease (PAD) were performed. All patients were prospectively enrolled in a dedicated database. The intervention was performed for iliac occlusion in 109 patients (group 1) and for iliac stenosis in 114 (group 2). Early results were analyzed and compared by eFT-508 chi(2) and Fisher exact tests. Follow-up consisted of clinical examination and duplex scanning at discharge, <= 3 months, at 6 and 12 months, and yearly thereafter. Follow-up results were analyzed with

Kaplan-Meier curves and compared with the log-rank test.

Results: The two groups had similar risk factors for atherosclerosis and comorbidities. Critical limb ischemia was more common in group 1 (20.5%) Fluocinolone acetonide than in group 2 (8.5%; P = .01). Intraoperative technical details were similar, except for a higher percentage of brachial and contralateral femoral access and more frequent use of nitinol stents in group 1. Two immediate technical failures occurred, one in both groups, requiring immediate conversion to surgical bypass. Four intraoperative iliac ruptures occurred, two in each group; all were successfully treated with covered stents. An additional 10 immediate complications occurred (8 in group 1; 2 in group 2), one of which required conversion to open surgical bypass. The cumulative rate of perioperative complications was 9% in group 1 and 3.5% in group 2 (P = .08). Primary patency at 30 days was 97.3% and 98.7%, respectively. Mean duration of follow-up was 28.4 months; 203 patients (91%) had a regular postoperative follow-up visit. At 60 months, primary patency in group 1 vs group 2 was 82.4% vs 77.7% (P = .9), assisted primary patency was 90.6% vs 85.5% (P = .4), and estimated secondary patency was 93.1% vs 92.8% (P = .

“
“Anti-cyclic citrullinated peptide (anti-CCP) antibodies are well-established serological markers that show high sensitivity and specificity in early rheumatoid arthritis (RA) and are associated with bone erosions of RA. However, some patients subsequently progress to RA even if there is no presence of anti-CCP antibodies in an early

stage. The aim of this study is to evaluate the diagnostic utility of matrix metalloproteinase-3 (MMP-3), high-sensitivity C-reactive protein (hsCRP) and IgM rheumatoid factor for predicting RA in anti-CCP-negative patients with recent-onset undifferentiated arthritis (UA). Baseline levels of those markers were measured at the entry of the study. A total of 99 patients with UA were included, among them 44 patients (44.4 %) had been classified as having RA by a skilled rheumatologist PCI-32765 manufacturer at some

point during 1-year follow-up. Of these 99 patients, 34 patients (34.3 %) had anti-CCP antibodies and 65 patients (65.7 %) had no anti-CCP antibodies. Eleven patients who were anti-CCP-negative developed RA. We compared sensitivity, specificity, positive predictive value and negative predictive value of serum markers of these anti-CCP-negative RA patients. The combined usage of MMP-3 with hsCRP is relatively superior to other markers as predictors of RA.”
“Our objective was Selleckchem Alpelisib to determine the prevalence juvenile idiopathic arthritis (JIA) in Sharkia Governorate, Egypt. Population-based study was performed to identify the prevalence of JIA in Sharkia Governorate, Egypt, between November 2009 and November 2010. Prevalence of JIA was 3.43 per 100,000 (95 % CI 3.1-4.3). Prevalence in boys was 2.58 per 100,000 (95 % CI 2.4-3.6) and in girls 4.33 per 100,000 (95 % CI 3.3-5.1). Uveitis presented in 19.7 % of cases, antinuclear antibody in 48.5 %, and rheumatoid factor in 27.2 %. Oligoarthritis representing 52.2 % of the total population, and enthesitis-related Axenfeld syndrome arthritis presented only in 6 patients. No cases

of undifferentiated arthritis or psoriatic arthritis were found. This is the first epidemiological study of JIA in Sharkia, Egypt. Oligoarthritis was the most common subtype.”
“Our aim was to determine whether the Fc receptor-like 3 (FCRL3) -169 C/T (rs7528684) polymorphism confers susceptibility to systemic lupus erythematosus (SLE). A meta-analysis was conducted on the associations between the FCRL3 -169 C/T polymorphism and the SLE. A total of nine sets of comparisons containing 3,628 patients and 6,490 controls were considered. The meta-analysis showed no association between the SLE and the FCRL3 -169 C allele in all study patients (odds ratio [OR] = 0.999, 95 % confidence interval [CI] = 0.925-1.080, p = 0.986).

vermiformis and N. fowleri suggesting a limited temperature growth range for this strain.

Conclusions: Identifying the presence of pathogenic legionellae may require the use of multiple host amoebae and incubation check details temperatures.

Significance and Impact of the Study: Temperature conditions and species of amoeba host supported in drinking water appear to be important for the selection of human-pathogenic legionellae and point to future research required to better understand Legionella ecology.”
“We manipulated

categorical typicality and the presence of conflicting information as participants categorized multifeatured artificial animals. In Experiment 1, rule-irrelevant features were correlated with particular categories during training. In the test phase, participants applied a one-dimensional rule to stimuli with rule-irrelevant features that were category-congruent, category-incongruent, or novel. Category-incongruent and novel features delayed RT and P3 latency, but

had no effect on the N2. Experiment 2 used a two-dimensional rule to create conflict between rule-relevant features. Conflict resulted in prolonged RTs and larger amplitudes of a prefrontal www.selleckchem.com/products/nocodazole.html positive component, but had no impact on the N2. Stimuli with novel features did elicit a larger N2 than those with frequent features. These results suggest limitations on the generality of the N2′s sensitivity to conflicting information while confirming its sensitivity to attended visual novelty.”
“TRPV1 (transient receptor potential, vanilloid) channels belong to a family of ligand-gated ion channels gated not only by the binding of certain lipophilic molecules but also by extracellular protons and physical stimuli such as heat or osmotic pressure changes. These nonselective cation channels are permeable to Na(+) and K(+) and are also very Ca(2+) permeable; in fact, TRPV1 is as Ca(2+) permeable as the NMDA receptor channel and

can, thus, act as a trigger for Ca(2+)-mediated cell signaling. Although these channels are highly expressed in primary sensory afferents, accumulating evidence indicates that TRPV family channels are also present in the brain. Here, we review evidence that TRPV channels in the central nervous system might contribute to many basic neuronal functions including resting FER membrane potential, neurotransmitter release and synaptic plasticity.”
“Hypertonic solutions are mainstay of osmotherapy to cerebral edema. How hypertonic solutions affect healthy brain homeostasis, however, is not fully understood. Using rat model of cerebral edema induced by local cryoinjury, we found with immunohistochemistry that less microglial activation in healthy hemishere 24h after hypertonic saline (HS, 3% NaCl) administration, compared to mannitol (20%, the same osmotic concentration of 3% NaCl) while dehydrating the brain tissue.

On these occasions, FL’s memory was good. Thus, she was able to remember events from earlier days when memory was tested covertly. FL performed differently in a number of ways from individuals who were instructed to consciously feign her pattern of memory impairment. It was also the impression of those who worked with FL that she believed she had the memory impairment that she described and that she was not intentionally feigning amnesia. On the basis of her neuropsychological findings, together with a normal neurological exam, normal MRI findings, and psychiatric evaluation, we suggest that FL exhibits a unique form of functional

amnesia and that its characterization may have been influenced by knowledge of how amnesia was depicted in a popular film. She subsequently improved (and began retaining day-to-day memory) at Johns Hopkins University Tozasertib chemical structure where she was in a supportive in-patient environment and was shown how to take control of her condition by interrupting her sleep at 4-h intervals. Published by Elsevier Ltd.”
“This study investigated the neural basis of the effect of gaze direction

on facial expression processing in children with and without ASD, using event-related potential (ERP). Children with ASD (10-17-year olds) and typically developing (TD) children (9-16-year olds) were asked to determine the emotional expressions (anger or fearful) of a facial stimulus with a direct or averted gaze, and the PLX4032 ERPs were recorded concurrently. In TD children, faces with a congruent expression and gaze direction in approach-avoidance motivation, such as an angry face with a direct gaze pentoxifylline (i.e., approaching motivation) and a fearful face with an averted gaze (i.e., avoidant motivation), were recognized more accurately and elicited larger N170 amplitudes than motivationally incongruent facial stimuli (an angry face with an averted gaze and a fearful face with a direct gaze). These results demonstrated the neural basis and time course of integration of facial expression and gaze direction in TD children and its impairment in children

with ASD. (C) 2010 Elsevier Ltd. All rights reserved.”
“Prions can be detected and quantified currently by using either immunoassays such as Western-blot. ELISA or conformation dependent immunoassay, or an infectivity assay in laboratory animals (bioassay). While immunoassays are inexpensive and rapid, they are based on the detection of PrP(Sc), the abnormal isoform of the prion protein, a surrogate marker for prion infectivity. The bioassay is considered the gold-standard analytical method for measuring prion infectivity, but it is very costly and time-consuming, involving the destruction of large numbers of animals. The use of the transgenic MovS6 cell line is described for the development of an in vitro tissue culture infectivity assay (TCIA) for prion detection and quantitation.