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Limitations of a polythetic-categorical classification system has sparked ongoing quantitative efforts to establish a valid and reliable method for diagnosing mental illness. Dimensional methods of classification, such as the Hierarchical Taxonomy of Psychopathology (HiTOP), have been found to ameliorate the limitations of a categorical approach - despite the provisional placement of a Somatoform spectrum. The current investigation sought to elucidate the placement of the Somatoform spectrum within the HiTOP model, and to further corroborate discriminant and convergent validity of the Somatoform spectrum. Using a sample of patients seeking chronic low-back pain treatment (n = 200), superior model fit suggested Somatoform fits better as a separate spectrum from Internalizing and placing Somatoform as a subfactor of Internalizing did not improve model fit. Discriminant and convergent validity with an external criteria demonstrated distinctiveness of the Somatoform spectrum from the Internalizing spectrum in the HiTOP model.

Background Bariatric surgery usually results in substantial weight loss and a reduction in medical comorbidities. Many patients, as a consequence of the weight loss, subsequently evidence loose, redundant skin. Objectives This investigation seeks to examine the prevalence of body contouring surgery (BCS) by patients approximately 4 to 5 years after Roux-en-Y gastric bypass surgery. Demographics, change in BMI, and psychosocial variables were also used to predict body dissatisfaction, desire for BCS, and patients who reported obtaining BCS. Setting The clinical sites involved in the Longitudinal Assessment of Bariatric Surgery project, which included 10 hospitals across the United States. Methods The sample comprised 1159 patients who underwent Roux-en-Y gastric bypass and were enrolled in the Longitudinal Assessment of Bariatric Surgery-2 study. Participants were surveyed using the Excessive Skin Survey and other psychosocial measures at their 4- or 5-year postoperative outcome. The participants were predominately women (80.5%), Caucasian (88.3%), and middle-aged (mean = 46.1 yr, standard deviation = 11.11 yr). Results Participants reported modest degrees of being bothered by excessive skin, primarily in their waist/abdomen, thighs, and chest/breasts body areas. Only 11.2% of the sample had undergone any BCS procedure, and a majority of those participants paid "out of pocket" for BCS. Desire for BCS and body dissatisfaction 4 to 5 years postsurgery was associated with higher depression scores and poorer quality of life scores. Conclusions Excessive skin is associated with poorer psychosocial functioning. Despite reporting modest levels of being bothered by excessive skin and body dissatisfaction, only a small fraction of participants underwent BCS. Cost of BCS was reported to be a primary barrier for not obtaining BCS. All rights reserved.

Background The current investigation aims to predict 3-year postoperative percent total weight loss among a sample of bariatric surgery patients with super-super obesity. Objective Previous research implies that persons with presurgical super-super obesity (body mass index [BMI] ≥60 kg/m2) tend to have poorer loss outcomes compared with those with a lower presurgical BMI after bariatric surgery. Setting Cleveland Clinic, Bariatric & Metabolic Institute, Cleveland, OH. Methods Bariatric surgery candidates (N = 1231; 71.9% female; 65.8% Caucasian) completed a presurgical psychological evaluation and the Minnesota Multiphasic Personality Inventory–2–Restructured Form. Participants with a baseline BMI ≥60 (n = 164) were compared with BMI Results Patients with a BMI ≥60 were younger, less educated, and more likely to be male compared with lower BMI patients. Patients with a BMI ≥60 had greater psychosocial sequelae as evidenced by being more likely to have a history of sexual abuse, history of psychiatric hospitalization, more binge eating episodes, and higher prevalence of major depression disorder and binge eating disorder. On the Minnesota Multiphasic Personality Inventory–2–Restructured Form, those with BMI ≥60 reported greater demoralization, low positive emotions, ideas of persecution, and dysfunctional negative emotions. After controlling for surgery type, weight loss for individuals with BMI ≥60 did not greatly differ from weight loss in patients with BMI Conclusion Although patients with BMI ≥60 evidenced more psychopathology before surgery, findings suggest that the relationship between higher BMI and poorer outcome may better be explained by other co-morbid factors.

Background Thirty-day readmissions occur in 5% or more of bariatric surgery patients. Some readmissions relate directly to surgical risks, whereas others relate to more nonspecific complaints or nonadherence and may reflect risks outside of the surgical procedure. Objective To investigate whether presurgical psychosocial factors are related to readmission. Setting Tertiary/quaternary academic referral center. Methods Bariatric surgery patients readmitted within 30 days of surgery during 2012–2015 were identified (n = 102). Patients were matched (2:1) on body mass index, age, sex, and race to 204 nonreadmitted patients. Psychiatric variables and psychological testing (Minnesota Multiphasic Personality Inventory-2-Restructured Form) at intake were compared between the 2 groups. Among those readmitted, the indication for readmission was investigated. Those with specific complications (n = 61) were delineated from those with nonspecific indications (n = 33). Results Those with nonspecific readmissions were younger and more likely to be female. These patients were also less likely to be in outpatient psychiatric care than nonreadmitted patients. Significant differences were found on the Uncommon Virtues scale of the Minnesota Multiphasic Personality Inventory-2-Restructured Form, which reflects a tendency to underreport disinhibited behaviors. Those with nonspecific readmissions had significantly higher underreporting scores compared to those with specific indications or those not readmitted. Conclusions Readmitted patients, particularly those with nonspecific indications, were more likely to presurgically present themselves in an overly positive manner. The tendency to underreport may affect the team's ability to identify risk factors that could be ameliorated before surgery. Readmitted patients were also less likely to be receiving mental health care. Such ongoing treatment may increase monitoring and/or adherence after surgery.

Prospective data are needed to ascertain the impact of iron chelation therapy in patients with myelodysplastic syndromes. The present 5-year prospective registry analysis was conducted to compare clinical outcomes between chelated and nonchelated patients with lower-risk myelodysplastic syndromes and transfusional iron overload. In an interim analysis at 24 months, we previously reported that chelation therapy was associated with longer median overall survival and a tendency toward longer leukemia-free survival and fewer cardiac events. In the present report, we detail findings from the final analysis at 5 years. We confirm, at the conclusion of this 5-year, prospective, non-interventional study, that overall survival was significantly longer in patients who received iron chelation therapy vs those who did not. Causes of death in the overall population were predominantly myelodysplastic syndromes/acute myeloid leukemia followed by cardiac disease. Time to progression to acute myeloid leukemia was also significantly longer in patients receiving chelation therapy, and significantly fewer patients progressed to leukemia vs those not receiving chelation therapy. Limitations of the study include a potential for clinical bias, as patients with longer predicted survival may have been chosen for chelation therapy, the differences present in concomitant conditions at baseline, and the possibility that some high-risk patients were not identified due to limited cytogenetic classification.

Background The reasons why some patients who begin the presurgical process for bariatric surgery fail to complete the procedure are understudied. Previous research implies that psychological factors play a role. Objectives To examine whether scores from baseline psychological testing incrementally predict failure to proceed with bariatric surgery beyond demographic information in patients' medical charts and data derived from a clinical interview. Setting Cleveland Clinic Bariatric and Metabolic Institute. Methods The sample (n = 1160) was mainly female (72.41%), middle aged (mean age=46.07 yr, SD=11.70) and of Caucasian descent (65.76%). Hierarchical logistic regressions were conducted to test the incremental validity of baseline Minnesota Multiphasic Personality Inventory-2 Restructured Form scores after controlling for information gathered from the psychological interview and medical charts. Relative risk ratios were calculated to reflect the clinical utility of the results. Results In total, 27.16% of patients failed to proceed with bariatric surgery after 1 year or more after a recommendation for surgery from their psychological evaluations. Psychological test scores were substantially associated with failure to proceed with surgery and significantly accounted for up to 6% of additional variance after controlling for psychological interview variables and medical chart data. Elevated scores on Minnesota Multiphasic Personality Inventory-2 Restructured Form scales, such as anxiety and substance use, identify patients at up to 2.5 times greater risk for failing to proceed with bariatric surgery. Conclusions Objective psychological test data—notably, scale scores assessing for substance abuse, anxiety, and demoralization—add to information obtained from a clinical interview and medical records in identifying patients at risk for failing to proceed with bariatric surgery.

Background Since the UN Human Rights Council's recognition on the subject in 2011, the right to access the Internet and information is now considered one of the most basic human rights of global citizens [1,2]. Despite this, an information gap between developed and resource-limited countries remains, and there is scant research on actual information needs of workers themselves. The Republic of Botswana represents a fertile ground to address existing gaps in research, policy, and practice, due to its demonstrated gap in access to information and specialists among rural health care workers (HCWs), burgeoning mHealth capacity, and a timely offer from Orange Telecommunications to access Wikipedia for free on mobile platforms for Botswana subscribers. Objectives In this study, we sought to identify clinical information needs of HCWs of Botswana and their perception of Wikipedia as a clinical tool. Methods Twenty-eight facilitated focus groups, consisting of 113 HCWs of various cadres based at district hospitals, clinics, and health posts around Botswana, were employed. Transcription and thematic analysis were performed for those groups. Results Access to the Internet is limited at most facilities. Most HCWs placed high importance upon using Botswana Ministry of Health (MoH) resources for obtaining credible clinical information. However, the clinical applicability of these materials was limited due to discrepancies amongst sources, potentially outdated information, and poor optimization for time-sensitive circumstances. As a result, HCWs faced challenges, such as loss of patient trust and compromises in patient care. Potential solutions posed by HCWs to address these issues included: multifaceted improvements in Internet infrastructure, access to up-to-date information, transfer of knowledge from MoH to HCW, and improving content and applicability of currently available information. Topics of clinical information needs were broad and encompassed: HIV, TB (Tuberculosis), OB/GYN (Obstetrics and Gynecology), and Pediatrics. HCW attitudes towards Wikipedia were variable; some trusted Wikipedia as a reliable point of care information resource whereas others thought that its use should be restricted and monitored by the MoH. Conclusions There is a demonstrated need for accessible, reliable, and up-to-date information to aid clinical practice in Botswana. Attitudes towards Wikipedia as an open information resource tool are at best, split. Therefore, future studies are necessary to determine the accuracy, currency, and relevancy of Wikipedia articles on the health topics identified by health care workers as areas of information need. More broadly speaking, future efforts should be dedicated to configure a quality-controlled, readily accessible mobile platform based clinical information application tool fitting for Botswana.

Background Graze eating is defined as repetitive, unplanned eating of small amounts of food throughout the day. Little consensuses exist regarding whether graze eating, like binge eating disorder (BED), is characterized by feelings of loss of control (LOC). Furthermore, little is known about how patients who graze eat with and without LOC differ psychologically. Objectives The present study seeks to better characterize graze eating by examining differences between graze eating with LOC (+LOC) and without LOC (–LOC) among presurgical bariatric patients. Setting A large, Midwestern academic medical center. Methods The sample consisted of 288 adult bariatric surgery candidates (mean age 45.8, standard deviation [SD] 12.57) who underwent a presurgical psychological evaluation. Graze eating, BED, and other mental health diagnoses were evaluated using a semistructured interview. Participants were also administered the Minnesota Multiphasic Personality Inventory–2–Restructured Form (MMPI-2-RF) and binge eating scale (BES). Data were collected using a retrospective chart review. Results Among the 33% (n = 95) of the sample who reported preoperative graze eating, 32% (n = 30) also endorsed LOC. Graze eating, particularly with LOC, was associated with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnoses of anxiety disorders and BED, and multiple measures of internalizing dysfunction on the MMPI-2-RF. Conclusions Bariatric surgery candidates who graze eat experience a greater degree of overall distress and psychopathology including anxiety and depression. The minority who experience grazing+LOC appear to have even greater risk of psychopathology. Moreover, there appears to be significant overlap with BED. Future research should explore whether these 2 maladaptive eating patterns benefit from similar treatment.

Background The Binge Eating Scale (BES) is a widely-used self-report measure of binge eating severity. Hood et al. [1] reported a 2-factor structure for the BES in a sample of bariatric surgery candidates, with factors labeled feelings/cognitions and behavioral manifestations. The present study aims to replicate and extend the factor structure obtained by Hood et al. [1] by testing the utility of a bifactor model that removes binge eating severity variance, which the total BES score purports to assess, in another sample of bariatric surgery candidates. Methods Bariatric surgery candidates (n = 517; 71.2% women; mean body mass index=49.50 kg/m 2 ; SD=10.17) were sampled. Twenty-four percent met DSM-IV-TR diagnostic criteria for binge eating disorder. Results Consistent with previous research, a 2-factor structure for the BES was supported; however, the 2 factors were substantially correlated ( r = .89). A bifactor model significantly improved model fit, supporting the presence of a higher-order severity factor accounting for a significant amount of variance. This factor was primarily marked by binge eating severity as demonstrated by associations with number of objective binge eating episodes and DSM-IV-TR diagnosis. In the bifactor model, the feelings/cognitions factor was modestly associated with self-reported mood psychopathology. However, contrary to expectations, the behavioral manifestation factor was not associated with empirically derived behavioral problems. Conclusions The current findings partially converge with those of Hood et al. [1] However, the use of the BES as a 2-factor measure is not recommended at this point because of lack of incremental validity demonstrated by the behavioral manifestation factor. Continued use of the BES as a unidimensional measure of binge eating severity, in conjunction with a comprehensive clinical interview, can provide useful guidance for presurgical treatment recommendations.

Background Presurgical psychological screening is used to identify factors that may impact postoperative adherence and surgical outcomes in bariatric surgery candidates. Minnesota Multiphasic Personality Inventory – 2 Restructured Form (MMPI-2-RF) findings have demonstrated utility for this task. Objectives To explore whether there are clinically meaningful gender, ethnicity, or age differences in presurgical MMPI-2-RF scores and the validity of these scores in bariatric surgery candidates. Methods The sample was composed of 872 men and 2337 women. Ethnicity/race groups included 2,204 Caucasian, 744 African American, and 96 Hispanic individuals. A sample of 165 were not included in the ethnicity/race analyses because they were of another descent. Ages groups included 18–35 year olds (n = 454), 36–49 year olds (n = 1154), 50–64 year olds, (n = 1246), and 65 years old or older (n = 355). Validity data, obtained via a retrospective chart review, were available for a subset patients (n = 1,268) who were similarly distributed. Step-down hierarchical regression analyses were conducted to assess for differential validity. Results Bariatric surgery candidates produced comparable MMPI-2-RF scores in all subsamples, indicating that the test norms generalize across demographic groups. Validity findings were also generally comparable, indicating that MMPI-2-RF scores have the same interpretive implications in demographically diverse subgroups of bariatric surgery candidates. Conclusions The MMPI-2-RF can assist in presurgical psychological screening of demographically diverse bariatric surgery candidates.

This 5-year, prospective registry enrolled 600 lower-risk MDS patients (pts) with transfusional iron overload. Clinical outcomes were compared between chelated and nonchelated pts. At baseline, cardiovascular comorbidities were more common in non-chelated pts, and MDS therapy was more common in chelated pts. At 24 months, chelation was associated with longer median overall survival (52.2 months vs. 104.4 months; p

Important functional interactions between the metabotropic glutamate 2 (mGlu2) and 5-hydroxytryptamine2A (5-HT₂A) neurotransmitter receptors have been established based on electrophysiological, biochemical and behavioral evidence. Over the last several years, dimerization between 5-HT₂A and mGlu2 receptors has been proposed to account for the functional cross-talk between these two receptors in the prefrontal cortex. The pros and cons for the existence of a heteromeric complex between 5-HT₂A and mGlu2 receptors will be reviewed here. First, the fundamental criteria needing to establish evidence for heteromeric complexes will be reviewed. Then, the in vitro evidence for and against heteromeric complexes between 5-HT₂A and mGlu2 receptors will be discussed in regard to physical and functional interactions. Finally, the data with native in situ mGlu2 and 5-HT₂A receptors will be discussed with respect to whether heteromeric complexes or a simple functional interaction between two distinct GPCRs based on brain network activity is the more simple explanation for a range of in vivo data.

Group II metabotropic glutamate (mGlu) receptor agonists were efficacious in randomized clinical research trials for schizophrenia and generalized anxiety disorder. The regional quantification of mGlu(2) and mGlu(3) receptors remains unknown. A selective and structurally novel mGlu(2/3) receptor agonist, 2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY459477) was tritiated and the distribution of mGlu(2) and mGlu(3) receptors was studied in transgenic mice lacking either mGlu(2), mGlu(3) or both receptors. LY459477 is an agonist with 1-2 nM potency for rodent and human mGlu(2) and mGlu(3) receptors. The functional selectivity of LY459477 was demonstrated by over 640-fold selectivity and the displacement binding selectivity was greater than 320-fold for all glutamate receptors except mGlu(6) (∼230-fold). More than 1000-fold selectivity was demonstrated for all non-glutamate receptors known to be targeted by antipsychotic drugs. Like atypical antipsychotic drugs, LY459477 reversed in vitro electrophysiological effects of a serotonergic hallucinogen and behavioral effects of phencyclidine or amphetamine. There was virtually no binding of [(3)H]LY459477 to any brain region in mice with a deletion of both mGlu(2) and mGlu(3) receptors. Regions enriched in mGlu(2) receptors included the medial prefrontal cortex, select hippocampal regions, the medial mammillary nucleus, the medial habenula, and the cerebellar granular cell layer. Regions enriched in mGlu(3) receptors were the dorsolateral entorhinal cortex, the hippocampal CA1 field, the piriform cortex, the substantia nigra, the thalamic reticular nucleus, and primary sensory thalamic nuclei. These findings suggest [(3)H]LY459477 should be a useful tool to further define the role of mGlu(2) and mGlu(3) receptors throughout the brain with respect to major neuropsychiatric syndromes. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Dopamine, serotonin and glutamate play a role in the pathophysiology of schizophrenia. In the brain a functional crosstalk between the serotonin receptor 5-HT(2A) and the metabotropic glutamate receptor mGlu(2) has been demonstrated. Such a crosstalk may be mediated indirectly through neuronal networks or directly by receptor oligomerization. A direct link of the 5-HT(2A)-mGlu(2) heterocomplex formation to receptor function, i.e. to intracellular signaling, has not been fully demonstrated yet. Here we confirm the formation of 5-HT(2A)-mGlu(2) heterocomplexes using quantitative Snap/Clip-tag based HTRF methods. Additionally, mGlu(2) formed complexes with 5-HT(2B) and mGlu(5) but not 5-HT(2C) indicating that complex formation is not specific to the 5-HT(2A)-mGlu(2) pair. We studied the functional consequences of the 5-HT(2A)-mGlu(2) heterocomplex addressing cellular signaling pathways. Co-expression of receptors in HEK-293 cells had no relevant effects on signaling mediated by the individual receptors when mGlu(2) agonists, antagonists and PAMs, or 5-HT(2A) hallucinogenic and non-hallucinogenic agonists and antagonists were used. Hallucinogenic 5-HT(2A) agonists induced signaling through G(q/11), but not G(i) and thus did not lead to modulation of intracellular cAMP levels. In membranes of the medial prefrontal cortex [(3)H]-LY341495 binding competition of mGlu(2/3) agonist LY354740 was not influenced by 2,5-dimethoxy-4-iodoamphetamine (DOI). Taken together, the formation of GPCR heterocomplexes does not necessarily translate into second messenger effects. These results do not put into question the well-documented functional cross-talk of the two receptors in the brain, but do challenge the biological relevance of the 5-HT(2A)-mGlu(2) heterocomplex.

The need to develop effective treatments for Alzheimer's disease has been confounded by repeated clinical failures where promising new chemical entities that have been extensively characterized in preclinical models of Alzheimer's disease have failed to show efficacy in the human disease state. This has been attributed to: the selection of drug targets that have yet to be shown as causal to the disease as distinct from being the result of the disease process, a lack of congruence in the animal models of Alzheimer's disease, wild-type and transgenic, to the human disease, and the enrollment of patients in proof of concept clinical trials who are at too advanced a stage of the disease to respond to any therapeutic. The development of validated biomarkers that can be used for disease diagnosis and progression is anticipated to improve patient enrollment in clinical trials, to develop new animal models and to identify new disease targets for drug discovery. The present review assesses the status of current efforts in developing CSF biomarkers for Alzheimer's disease and briefly discusses the status of CSF biomarker efforts in schizophrenia, depression, Parkinson's disease and multiple sclerosis.

Recently, a metabotropic glutamate(2/3) (mGlu(2/3)) receptor agonist prodrug was found to improve both the positive and negative symptoms of schizophrenic patients. Thus far, however, definitive data directly describing the effects of mGlu(2/3) receptor agonists on cognition in schizophrenic patients is lacking. In this review, we will first describe the location of mGlu(2) and mGlu(3) receptors with respect to cellular compartments in cortical circuits of both the prefrontal cortex and the hippocampal formation. We will then address the function of mGlu(2) and mGlu(3) receptors in both macrocircuits and microcircuits involving the prefrontal cortex and hippocampal formation. Imbalance within and between macrocircuits, including the re-entrant cortico-striatal-thalamic loops; the trisynaptic organization of the hippocampal formation; and the ascending reticular activating system/monoaminergic brainstem nuclei projecting throughout the neural axis, appear central to understanding both the pathophysiology and therapeutic approaches for treating the pervasive cognitive dysfunction associated with schizophrenia. Understanding the function of mGlu(2) and mGlu(3) receptors in these macrocircuits also may provide answers to currently conflicting data between some preclinical studies and the clinical studies seemingly predicting impairment and improvement in cognitive function with activation of mGlu(2) and mGlu(3) receptors.

The neurokinin-1 (NK-1) antagonist LY686017 showed activity in preclinical anxiety models. The clinical development of LY686017 included a PET study and a proof-of-concept in social anxiety disorder (SAD). [ 11 C]GR205171 was used healthy volunteers receiving 1–100 mg/d LY686017 for 28 days to determine brain receptor occupancy (RO). The mean NK-1 RO increased ranged from 25% with 1 mg to 93% with 100 mg. Subsequently, a 12-week randomized clinical trial tested LY686017 vs. paroxetine, or placebo in SAD. Pharmacokinetic (PK)/RO modeling based on the PET results predicted that once daily dosing of > 30 mg LY686017 led to sustained trough RO of over 80%. 189 outpatients 1 suffering from SAD were randomly assigned to 12-weeks treatment with 50 mg/d LY686017 ( N = 77), placebo ( N = 74), or 20 mg/d paroxetine ( N = 38). There was no significant difference between LY686017 and placebo as measured with the Liebowitz Social Anxiety scale (LSAS). The active comparator paroxetine showed positive trends on primary and secondary measures. The plasma concentrations were above the level expected to produce maximal brain NK-1 RO based on the PK/RO relationship obtained in the human PET investigation. Thus, further evaluation of LY686017 for the treatment of SAD does not seem warranted.

We have searched for correlations between the pointing directions of ultrahigh energy cosmic rays observed by the High Resolution Fly's Eye experiment and Active Galactic Nuclei (AGN) visible from its northern hemisphere location. No correlations, other than random correlations, have been found. We report our results using search parameters prescribed by the Pierre Auger collaboration. Using these parameters, the Auger collaboration concludes that a positive correlation exists for sources visible to their southern hemisphere location. We also describe results using two methods for determining the chance probability of correlations: one in which a hypothesis is formed from scanning one half of the data and tested on the second half, and another which involves a scan over the entire data set. The most significant correlation found occurred with a chance probability of 24%., 13 pages, 1 table, 5 figures

Down-regulation of 5-hydroxytryptamine 2A (5-HT 2A ) receptors has been a consistent effect induced by most antidepressant drugs. The evidence for down-regulation of 5-HT 2A receptor binding following subchronic treatment with fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) is mixed. The question of 5-HT 2A receptor sensitivity during chronic administration of antidepressants is important since activation of 5-HT 2A receptors is associated with impulsivity. Continued activation of 5-HT 2A receptors may functionally oppose activation of other non-5-HT 2A receptors in the prefrontal cortex associated with the clinical efficacy of SSRI treatment. Therefore, the effects of repeated daily administration of fluoxetine (10 mg/kg, i.p. ×3 weeks) on pharmacologically characterized electrophysiological response mediated by 5-HT 2A receptor activation, 5-HT-induced excitatory postsynaptic currents (EPSCs), in rat prefrontal cortical slices was examined. The concentration–response curve for 5-HT-induced EPSCs was unchanged following subchronic fluoxetine treatment. This subchronic fluoxetine treatment failed to modify electrophysiological responses to AMPA in layer V pyramidal cells as well. These findings would be consistent with the hypothesis that blockade of 5-HT 2A receptors may enhance the effects of SSRIs or serotonin/norepinephrine reuptake inhibitors (SNRIs).

Glutamate plays an important role in the psychotomimetic effects of both channel blocking N-methyl d -aspartate (NMDA) receptor antagonists and hallucinogenic drugs which activate 5-hydroxytryptamine2A (5-HT2A) receptors. Previous work suggested that activation of non-NMDA ionotropic glutamate receptors mediates the effects of 5-HT-induced excitatory post-synaptic potentials/currents (EPSPs/EPSCs) when recording from layer V pyramidal cells in the rat medial pre-frontal cortex (mPFC). However, those effects are mediated by either α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate receptors of the iGluk5 subtype. To test whether activation of AMPA receptors is sufficient to mediate 5-HT-induced EPSCs, a 2,3-benzodiazepine that selectively blocks AMPA receptors was assessed. This selective AMPA receptor antagonist potently suppressed 5-HT-induced EPSCs. Since phenethylamine hallucinogens induce head shakes by activating 5-HT2A receptors in the mPFC and this action is modulated by glutamate, we also examined whether selective blockade of AMPA receptors would suppress DOI-induced head shakes. As predicted, we found that selective blockade of AMPA receptors suppressed DOI-induced head shakes. Given evidence that activation of AMPA receptors is an important downstream effect for both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens, we also tested multiple doses of DOI with a sub-anesthetic dose of MK-801. Synergistic action between these two classes of psychotomimetic drugs was demonstrated by MK-801 enhancing DOI-induced head shakes and locomotor activity. These findings expand the dependence of both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens on enhancing extracellular glutamate.

We report the results of a search for point-like deviations from isotropy in the arrival directions of ultra-high energy cosmic rays in the northern hemisphere. In the monocular data set collected by the High-Resolution Fly's Eye, consisting of 1,525 events with energy exceeding 10^18.5 eV, we find no evidence for point-like excesses. We place 90% c.l. upper limits less than or equal to 0.8 cosmic rays/km^2yr on the flux from such sources as a function of position in the sky., Comment: 24 pages, 16 figures

We have studied several sources of systematic uncertainty in calculating the aperture of the High Resolution Fly's Eye experiment (HiRes) in monocular mode, primarily as they affect the HiRes-II site. The energy dependent aperture is determined with detailed Monte Carlo simulations of the air showers and the detector response. We have studied the effects of changes to the input energy spectrum and composition used in the simulation. A realistic shape of the input spectrum is used in our analysis in order to avoid biases in the aperture estimate due to the limited detector resolution. We have examined the effect of exchanging our input spectrum with a simple E^{-3} power law in the "ankle" region. Uncertainties in the input composition are shown to be significant for energies below about 10^{18} eV for data from the HiRes-II detector. Another source of uncertainties is the choice of the hadronic interaction model in the air shower generator. We compare the aperture estimate for two different models: QGSJet01 and SIBYLL 2.1. We also describe the implications of employing an atmospheric database with hourly measurements of the aerosol component, instead of using an average as has been used in our previously published measurements of the monocular spectra., Comment: 27 pages, 15 figures, revision

Increased activity level after total hip arthroplasty (THA) is considered a risk factor for early prosthetic failure in young patients. Forty-one primary total hip arthroplasties in 34 patients were evaluated. Walking activity was measured using a pedometer to record gait cycles. Patients completed a University of California, Los Angeles (UCLA) activity questionnaire. Linear wear rates were measured. Mean ages at surgery and final follow-up were 42 and 50.3 years, respectively (mean gait cycles per year, 1.2 million; mean UCLA score, 6; mean linear wear, 0.16 mm/y). Increased body mass index and age correlated with decreased gait cycles per year. Patients with systemic disease were less active than patients with localized hip conditions. Femoral head diameter was a predictor of linear wear. The average gait cycles per year and wear rate for this population do not appear accelerated relative to average values reported in older populations.

Air fluorescence detectors traditionally determine the dominant chemical composit ion of the ultrahigh energy cosmic ray flux by comparing the averaged slant depth of the shower maximum, $X_{max}$, as a function of energy to the slant depths expect ed for various hypothesized primaries. In this paper, we present a method to make a direct measurement of the expected mean number of protons and iron by comparing the shap es of the expected $X_{max}$ distributions to the distribution for data. The advantages of this method includes the use of information of the full distribution and its ability to calculate a flux for various cosmic ray compositi ons. The same method can be expanded to marginalize uncertainties due to choice of spectra, hadronic models and atmospheric parameters. We demonstrate the technique with independent simulated data samples from a parent sample of protons and iron. We accurately predict the number of protons and iron in the parent sample and show that the uncertainties are meaningful., 11 figures, 22 pages, accepted by Astroparticle Physics

5-Hydroxytryptamine2A (5-HT2A) receptor regulation is atypical compared to most other monoaminergic receptors in that chronic administration of both antagonists and agonists results in down-regulation of cortical 5-HT2A receptor number and the functional in vitro and in vivo effects. We have recently found that midline thalamic lesions, which appeared to block glutamate release induced by activation of 5-HT2A receptors, also increased 5-HT2A receptor binding in layers I and Va of the medial prefrontal cortex (mPFC). These layers contain the highest density of both 5-HT2A receptors and thalamocortical terminals from the midline and intralaminar thalamic nuclei. These findings suggest the hypothesis that excitatory amino acid release plays a role in regulation of postsynaptic 5-HT2A receptors, and that down-regulation of 5-HT2A receptors by 5-HT2A agonists may not be attributed only to simple occupancy of the receptor by direct agonists. Therefore, we examined the effect of a single 30 min pretreatment with the metabotropic glutamate2/3 (mGlu2/3) receptor agonist (1S,2S,5R,6S)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylate monohydrate (LY354740; 10 mg/kg, i.p.) on the second of three consecutive days of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) treatment (1.25 mg/kg, i.p.). The subchronic DOI administration significantly decreased binding of [125I]DOI to 5-HT2A receptors in layers I and Va of the mPFC by approximately 25%. In contrast, a single dose of LY354740 on Day 2 of this regimen completely blocked the DOI-induced down-regulation. Thus, a presumed hypoglutamatergic state secondary to thalamic lesions and increased glutamate release induced by a subchronic regimen of a 5-HT2A agonist (and hallucinogenic drug) differentially regulate prefrontal cortical 5-HT2A receptor binding.

Background & Aims: The activated pregnane X receptor is antifibrogenic in rodent chronic liver injury in vivo models. The aim of this study was to determine the effects of human pregnane X receptor activators on human hepatic stellate cell transdifferentiation to a profibrogenic phenotype in vitro. Methods: Hepatic stellate cells were isolated from resected human liver and cultured under conditions in which they trans-differentiate into profibrogenic myofibroblasts. Results: The pregnane X receptor was expressed in primary cultures at the level of messenger RNA and protein and was activated by the ligand rifampicin as judged by increases in binding of proteins to the pregnane X receptor ER6 DNA response element and by increases in ER6-dependent reporter gene expression. Short-term treatment of hepatic stellate cells with rifampicin inhibited the expression of selected fibrosis-related genes (transforming growth factor β1, α–smooth muscle actin), proliferation-related genes, and WNT signaling-associated genes. There was also an increase in interleukin-6 secretion and an inhibition in DNA synthesis. Long-term treatment with rifampicin over several weeks reduced the proliferation and transdifferentiation of hepatic stellate cells. Small interfering RNA knockdown of the pregnane X receptor in a hepatic stellate cell line reduced the binding of proteins to the ER6 DNA response element and abrogated pregnane X receptor activator-dependent changes in transforming growth factor β1 expression, interleukin-6 secretion, and proliferation. Conclusions: The pregnane X receptor is transcriptionally functional in human hepatic stellate cells and activators inhibit transdifferentiation and proliferation. The pregnane X receptor may therefore be an effective target for antifibrotic therapy.

Both a 5-hydroxytryptamine2A (5-HT2A) agonist and immobilization stress previously have been shown to differentially alter brain-derived neurotrophic factor (BDNF) mRNA expression in the neocortex and hippocampus. Both 5-HT2A receptor activation and immobilization stress also increase glutamate release in the rat prefrontal cortex. Given that the metabotropic glutamate2/3 receptor (mGluR2/3) agonist (1S,2S,5R,6S)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylate monohydrate (LY354740) suppressed electrophysiological, behavioral and biochemical effects of 5-HT2A receptor activation in the medial prefrontal cortex (mPFC), we assessed the efficacy of the mGluR2/3 agonist in suppressing the stress-induced increase in BDNF mRNA expression. LY35740 (10 mg/kg, i.p.) attenuated the immobilization stress-induced increase in BDNF mRNA expression in the rat mPFC. This result is consistent with the hypothesis that mGlu2/3 agonists may be an efficacious treatment for stress-induced neuropsychiatric syndromes.

We have measured the cosmic ray spectrum at energies above $10^{17}$ eV using the two air fluorescence detectors of the High Resolution Fly's Eye experiment operating in monocular mode. We describe the detector, PMT and atmospheric calibrations, and the analysis techniques for the two detectors. We fit the spectrum to models describing galactic and extragalactic sources. Our measured spectrum gives an observation of a feature known as the ``ankle'' near $3\times 10^{18}$ eV, and strong evidence for a suppression near $6\times 10^{19}$ eV., Comment: 14 pages, 9 figures. To appear in Physics Letters B. Accepted version

In the past few years, small scale anisotropy has become a primary focus in the search for source of Ultra-High Energy Cosmic Rays (UHECRs). The Akeno Giant Air Shower Array (AGASA) has reported the presence of clusters of event arrival directions in their highest energy data set. The High Resolution Fly's Eye (HiRes) has accumulated an exposure in one of its monocular eyes at energies above 10^(19.5) eV comparable to that of AGASA. However, monocular events observed with an air fluorescence detector are characterized by highly asymmetric angular resolution. A method is developed for measuring autocorrelation with asymmetric angular resolution. It is concluded that HiRes-I observations are consistent with no autocorrelation and that the sensitivity to clustering of the HiRes-I detector is comparable to that of the reported AGASA data set. Furthermore, we state with a 90% confidence level that no more than 13% of the observed HiRes-I events above 10^(19.5) eV could be sharing common arrival directions. However, because a measure of autocorrelation makes no assumption of the underlying astrophysical mechanism that results in clustering phenomena, we cannot claim that the HiRes monocular analysis and the AGASA analysis are inconsistent beyond a specified confidence level., Comment: 16 pages, 23 figures

Ultra-cold neutrons (UCN), neutrons with energies low enough to be confined by the Fermi potential in material bottles, are playing an increasing role in measurements of fundamental properties of the neutron. The ability to manipulate UCN with material guides and bottles, magnetic fields, and gravity can lead to experiments with lower systematic errors than have been obtained in experiments with cold neutron beams. The UCN densities provided by existing reactor sources limit these experiments. The promise of much higher densities from solid deuterium sources has led to proposed facilities coupled to both reactor and spallation neutron sources. In this Letter we report on the performance of a prototype spallation neutron-driven solid deuterium source. This source produced bottled UCN densities of 145±7 UCN/cm 3 , about three times greater than the largest bottled UCN densities previously reported. These results indicate that a production UCN source with substantially higher densities should be possible.

Metabotropic glutamate receptors are a family of class III G-protein-coupled receptors comprising eight members (mGluR1–8), which are an attractive target in the central nervous system because of the widespread use of glutamate as the principal excitatory amino acid transmitter. The unique pharmacology of class III G-protein coupled receptors, their forebrain localization in key limbic-related cortical/thalamic/striatal/amygdaloid circuits, and the promise of subtle modulation of glutamatergic neurotransmission make these receptors intriguing targets for a wide variety of neuropsychiatric disorders.

We investigated the effects of stepwise thermal treatment of [100]-CZ- and FZ-silicon on the crystal defects and the etching behavior in KOH solutions. The anisotropy (the quotient of the vertical etch rate and the underetching of the mask), formed crystal defects as well as the surface roughness of the exposed {100}- and {111}-planes are examined. Thermal treatment of the silicon substrate can result in a precipitation of the interstitial oxygen. The precipitated oxygen causes elastic stress in the crystal which can be relieved by a generation of defects [1] , [2] . We found out that the evolution of these defects accelerates the lateral etch rate considerably. For the reference, the samples without thermal treatment the anisotropy has a value of 120 for FZ-silicon and 70 for CZ-silicon, respectively. However, with rising temperature and process time the anisotropy decreases to 30 for FZ-silicon and 15 for CZ-silicon. At the same time, the surface quality of the {100}- and {111}-planes degrades with increasing temperature. The roughness value Ra rises from 5 nm to approximately 30 nm. Along with the variation of the etching behavior during thermal treatment, we further present a suitable model for the oxygen-dependence of the etch rate.

The serotonin (5-HT) hypothesis of schizophrenia arose from early studies on interactions between the hallucinogenic drug LSD (D-lysergic acid diethylamide) and 5-HT in peripheral systems. More recent studies have shown that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and phenethylamines (e.g. , mescaline), produce their central effects through a common action upon 5-HT(2) receptors. This review focuses on two brain regions, the locus coeruleus and the cerebral cortex, where the actions of indoleamine and the phenethylamine hallucinogens have been shown to be mediated by 5-HT(2A) receptors; in each case, the hallucinogens (via 5-HT(2A) receptors) have been found to enhance glutamatergic transmission. In the prefrontal cortex, 5-HT(2A)-receptors stimulation increases the release of glutamate, as indicated by a marked increase in the frequency of excitatory postsynaptic potentials/currents (EPSPs/EPSCs) in the apical dendritic region of layer V pyramidal cells; this effect is blocked by inhibitory group II/III metabotropic glutamate agonists acting presynaptically and by an AMPA/kainate glutamate antagonist, acting postsynaptically at non-NMDA glutamate receptors. A major alternative drug model of schizophrenia, previously believed to be entirely distinct from that of the psychedelic hallucinogens, is based on the psychotomimetic properties of antagonists of the NMDA subtype of glutamate receptor (e.g., phencylidine and ketamine). However, recently it has been found that many of the effects of the NMDA antagonists may also (1) involve 5-HT(2A) receptors and (2) be mediated through excess activity at non-NMDA (i.e., AMPA/kainate) glutamate receptors. Moreover, pharmacological manipulations of glutamate transmission (e. g., by inhibitory metabotropic glutamate agonists) provide unexpected parallels between the actions of these two classes of drugs. Given an emerging recognition of the importance of alterations in glutamatergic transmission in the actions of both psychedelic hallucinogens an NMDA antagonists, this review concludes with of implications for the pathophysiology and therapy of schizophrenia.

A prototype of a solid deuterium (SD 2 ) source of Ultra-Cold Neutrons (UCN) is currently being tested at LANSCE. The source is contained within an assembly consisting of a 4 K polyethylene moderator surrounded by a 77 K beryllium flux trap in which is embedded a spallation target. Time-of-flight measurements have been made of the cold neutron spectrum emerging directly from the flux trap assembly. A comparison is presented of these measurements with results of Monte Carlo (LAHET/MCNP) calculations of the cold neutron fluxes produced in the prototype assembly by a beam of 800 MeV protons incident on the tungsten target. A UCN detector was coupled to the assembly through a guide system with a critical velocity of 8 m/s ( 58 Ni). The rates and time-of-flight data from this detector are compared with calculated values. Measurements of UCN production as a function of SD 2 volume (thickness) are compared with predicted values. The dependence of UCN production on SD 2 temperature and proton beam intensity are also presented.

We describe the design and expected performance of the PHENIX Multiplicity and Vertex Detector (MVD) sub-system of the PHENIX detector at the Relativistic Heavy Ion Collider (RHIC).

Residual macrostresses are measured on samples having a surface layer composed of a steel substrate and a thin TiN coating. The surface of machine components can be covered by a TiN layer for the purpose of increasing hardness and wear resistance. Various methods are used for the deposition of this layer. Among them there are: physical vapour deposition (PVD), like-ion plating, sputter ion plating, magnetron sputtering (MS), and chemical vapour deposition. This article deals with the layers of TiN deposited on steel 12050 using PVD-MS. The TiN layer is studied in connection with residual stress distribution and the machining of the substrate surface. The substrate is machined by milling and then coated with a TiN layer.

Previously, serotonin (5-HT) was found to induce a marked increase in glutamatergic spontaneous excitatory postsynaptic currents (EPSCs) in apical dendrites of layer V pyramidal cells of prefrontal cortex; this effect was mediated by 5-HT2A receptors, a proposed site of action of hallucinogenic and atypical antipsychotic drugs. Unexpectedly, although the effect of 5-HT was Ca2+-dependent and tetrodotoxin-sensitive, it did not appear to involve the activation of excitatory afferent impulse flow. This paradox prompted us to investigate (in rat brain slices) whether 5-HT was acting through an atypical mode of excitatory transmitter release. We found that the frequency of 5-HT-induced spontaneous EPSCs was fully supported by Sr2+ in the absence of added Ca2+, implicating the mechanism of asynchronous transmitter release which has been linked to the high-affinity Ca2+-sensor synaptotagmin III. Although the early, synchronous component of electrically evoked EPSCs was reduced while 5-HT was being applied, late, nonsynchronous components were enhanced during 5-HT washout and also by the 5-HT2 partial agonist 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI); the effect of DOI was blocked by a selective 5-HT2A antagonist (MDL 100,907). This late, nonsynchronous component was distinct from conventional polysynaptic EPSCs evoked in the presence of the GABAA antagonist bicuculline, but resembled asynchronous glutamatergic excitatory postsynaptic potentials (EPSPs) evoked in the presence of Sr2+. An enhancement of asynchronous EPSCs by a specific neurotransmitter receptor has not been reported previously. The possible role of excessive asynchronous transmission in the cerebral cortex in mediating the hallucinogenic effects of 5-HT2A agonists such as DOI is discussed.

We compared 5-hydroxytryptamine (5-HT), norepinephrine and dopamine for their efficacy at increasing excitatory postsynaptic current frequency in layer V pyramidal cells from rat medial prefrontal cortical slices. 5-HT, norepinephrine and dopamine increased the excitatory postsynaptic current frequency by 15.9-, 4.5- and 1.7-fold, respectively. Similar to previous results with 5-HT-induced excitatory postsynaptic currents, blockade of mu-opioid receptors, of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptors and fast Na+ channels suppressed the norepinephrine-induced excitatory postsynaptic currents. The norepinephrine-induced, and in most cases, the dopamine-induced increase in excitatory postsynaptic current frequency was blocked by the alpha1-adrenoceptor antagonist prazosin while the alpha2-adrenoceptor antagonist yohimbine did not block either the norepinephrine- or the 5-HT-induced increase in excitatory postsynaptic currents frequency. The potency of three 5-HT2 receptor antagonists with varying selectivity for 5-HT2A/2B/2C receptors tested against the 5-HT-induced increase in excitatory postsynaptic current frequency are in agreement with the affinity of these drugs for the 5-HT2A receptor. These findings suggest that 5-HT2A receptor or alpha1-adrenoceptor activation enhance neurotransmitter release from a similar subset of glutamate terminals that innervate apical dendrites of layer V pyramidal cells.

A short description of a new accelerator called KALIF–HELIA is given, that is presently under construction at the Forschungszentrum Karlsruhe. This High Energy Linear Induction Accelerator couples a self-magnetically insulated transmission line with the induction linac technology: the 1 MV pulses from 6 induction cells are added in a “magnetically insulated voltage adder” (MIVA) delivering for 50 ns a pulse of 6 MV and 400 kA to a matched load. This technology is considered in all light ion beam driven reactor concepts as a low cost alternative for the production of energy by inertial fusion (IFE). The pulses delivered by these generators are coupled to diodes that generate the intense light ion beams. Focusing of these beams is presently insufficient and requires scaling to IFE conditions. However, the available scaling laws for beam divergence are not in agreement with the few results from experiments performed at high power levels. Therefore, a verification and improvement of these scaling laws is necessary in order to extrapolate more reliably to beams needed for IFE conditions. For the start-up phase – foreseen for end 1997 – KALIF–HELIA will be operated first in negative polarity generating an electron beam. The subsequent operation of the accelerator in positive polarity will allow the verification of the voltage dependence in the divergence scaling laws for proton beams and acceleration voltages up to 6 MV. In a second step, the predicted influence of the ion mass on the beam divergence will be investigated by accelerating Li+ ions instead of protons.

A Multiplicity-Vertex Detector (MVD) has been designed, and is in construction for the PHENIX Experiment at the Relativistic Heavy Ion Collider (RHIC). The 35 000 channel silicon detector is a two-layer barrel comprised of 112 strip detectors, and two disk-shaped endcaps comprised of 24 wedge-shaped pad detectors. The support structure of the MVD is very low mass, only 0.4% of a radiation length in the central barrel. The detector front-end electronics are a custom CMOS chip set containing preamplifier, discriminator, analog memory unit, and analog-to-digital converter. The system has pipelined acquisition, performs in simultaneous read/write mode, and is clocked by the 10 MHz beam crossing rate at RHIC. These die, together with a pair of commercial FPGAs that are used for control logic, are packaged in a mutlichip-module (MCM). The MCM will be fabricated in the High-Density-Interconnect (HDI) process. The prototype MCM design layout is described.

By intracellular and whole cell recording in rat brain slices, it was found that bath-applied serotonin (5-HT) produces an increase in the frequency and amplitude of spontaneous excitatory postsynaptic potentials/currents (EPSPs/EPSCs) in layer V pyramidal cells of neocortex and transitional cortex (e.g. medial prefrontal, cigulate and frontoparietal). The EPSCs were suppressed by LY293558, an antagonist selective for the AMPA subtype of excitatory amino acid receptor, and by two selective 5-HT2A receptor antagonists, MDL 100907 and SR 46349B. In addition, the EPSCs were suppressed by the fast sodium channel blocker tetrodotoxin (TTX) and were dependent upon external calcium. However, despite being TTX-sensitive and calcium dependent, there was no evidence that the EPSPs resulted from an increase in impulse flow in excitatory neuronal afferents to layer V pyramidal cells. The EPSCs could be induced rapidly by the microiontophoresis of 5-HT directly to "hot spots" within the apical (but not basilar) dendritic field of recorded neurons, indicating that excitatory amino acids may be released by a TTX-sensitive focal action of 5-HT on a subset of glutamatergic terminals in this region. Consistent with such a presynaptic action, the inhibitory metabotropic glutamate receptor agonist (1S,3S)-aminocyclopentane-1,3-dicarboxylate markedly reduced the induction of EPSPs by 5-HT. Postsynaptically, 5-HT enhanced a subthreshold TTX-sensitive sodium current, potentially contributing to an amplification of EPSC amplitudes. These data suggest 5-HT. via 5-HT2A receptors, enhances spontaneous EPSPs/EPSCs in neocortical layer V pyramidal cells through a TTX-sensitive focal action in the apical dendritic field which may involve both pre- and postsynaptic mechanisms.