Emotion recognition deficits as predictors of transition in individuals at clinical high risk for schizophrenia: a neurodevelopmental perspective.

BACKGROUND: Schizophrenia is characterized by profound and disabling deficits in the ability to recognize emotion in facial expression and tone of voice. Although these deficits are well documented in established schizophrenia using recently validated tasks, their predictive utility in at-risk populations has not been formally evaluated. METHOD: The Penn Emotion Recognition and Discrimination tasks, and recently developed measures of auditory emotion recognition, were administered to 49 clinical high-risk subjects prospectively followed for 2 years for schizophrenia outcome, and 31 healthy controls, and a developmental cohort of 43 individuals aged 7-26 years. Deficit in emotion recognition in at-risk subjects was compared with deficit in established schizophrenia, and with normal neurocognitive growth curves from childhood to early adulthood. RESULTS: Deficits in emotion recognition significantly distinguished at-risk patients who transitioned to schizophrenia. By contrast, more general neurocognitive measures, such as attention vigilance or processing speed, were non-predictive. The best classification model for schizophrenia onset included both face emotion processing and negative symptoms, with accuracy of 96%, and area under the receiver-operating characteristic curve of 0.99. In a parallel developmental study, emotion recognition abilities were found to reach maturity prior to traditional age of risk for schizophrenia, suggesting they may serve as objective markers of early developmental insult. CONCLUSIONS: Profound deficits in emotion recognition exist in at-risk patients prior to schizophrenia onset. They may serve as an index of early developmental insult, and represent an effective target for early identification and remediation. Future studies investigating emotion recognition deficits at both mechanistic and predictive levels are strongly encouraged.

Noninvasive neutron scattering measurements reveal slower cholesterol transport in model lipid membranes.

Proper cholesterol transport is essential to healthy cellular activity and any abnormality can lead to several fatal diseases. However, complete understandings of cholesterol homeostasis in the cell remains elusive, partly due to the wide variability in reported values for intra- and intermembrane cholesterol transport rates. Here, we used time-resolved small-angle neutron scattering to measure cholesterol intermembrane exchange and intramembrane flipping rates, in situ, without recourse to any external fields or compounds. We found significantly slower transport kinetics than reported by previous studies, particularly for intramembrane flipping where our measured rates are several orders of magnitude slower. We unambiguously demonstrate that the presence of chemical tags and extraneous compounds employed in traditional kinetic measurements dramatically affect the system thermodynamics, accelerating cholesterol transport rates by an order of magnitude. To our knowledge, this work provides new insights into cholesterol transport process disorders, and challenges many of the underlying assumptions used in most cholesterol transport studies to date.

Pursing a career in academic surgery among African American medical students.

BACKGROUND: There are few African American students in medical school, and even fewer are choosing academic surgical careers. The objective of this study is to provide insight into what barriers URM students perceive when considering a career in academic surgery. METHODS: This qualitative, descriptive study was conducted at the University of Pennsylvania. Sixteen African American students with an interest in surgery were recruited to participate in the study. The outcomes reported are themes of how participants perceive the challenges of pursuing an academic surgical career. RESULTS: Barriers to pursuing a career in academic surgery cited by students included lifestyle concerns, financial pressures, having to work in a predominantly white environment, lack of mentorship, feelings of having to prove oneself, stressful environments and concerns of being a minority female in surgery. CONCLUSIONS: These study findings indicate that the persistent dearth of African-Americans in academic surgery is likely multi-factorial. Some ways surgical leadership can begin addressing these issues is through establishment of formal mentorship programs, ensuring non-discriminatory recruiting processes, having explicit goals of improving diversity and supporting pipeline programs.

Dysfunction of early-stage visual processing in schizophrenia.

OBJECTIVE: Schizophrenia is associated with deficits in higher-order processing of visual information. This study evaluated the integrity of early visual processing in order to evaluate the overall pattern of visual dysfunction in schizophrenia. METHOD: Steady-state visual-evoked potential responses were recorded over the occipital cortex in patients with schizophrenia and in age- and sex-matched comparison volunteers. Visual-evoked potentials were obtained for stimuli composed of isolated squares that were modulated sinusoidally in luminance contrast, number of squares, or chromatic contrast in order to emphasize magnocellular or parvocellular visual pathway activity. RESULTS: Responses of patients to magnocellular-biased stimuli were significantly lower than those of comparison volunteers. These lower response levels were observed in conditions using both low luminance contrast and large squares that biased processing toward the magnocellular pathway. In contrast, responses to stimuli that biased processing toward the parvocellular pathway were not significantly different between schizophrenia patients and comparison volunteers. A significant interaction of group and stimulus type was observed in the condition using low luminance contrast. CONCLUSIONS: These findings suggest a dysfunction of lower-level visual pathways, which was more prominent for magnocellular than parvocellular biased stimuli. The magnocellular pathway helps in orienting toward salient stimuli. A magnocellular pathway deficit could contribute to higher-level visual cognitive deficits in schizophrenia.

Prenatal nutritional deprivation as a risk factor in schizophrenia: preclinical evidence.

We will review evidence from preclinical literature that prenatal nutritional deprivation produces neurochemical, morphological, and electrophysiological effects reminiscent of those seen in clinical studies of schizophrenia. We will focus on effects of nutritional deficiency that are likely to have implications for schizophrenia. These include disruption of neurotransmitter systems such as dopamine and serotonin and dysgenesis of the hippocampal formation. Preclinical studies show enhanced release and turnover of dopamine and serotonin following prenatal and early postnatal nutritional deficiency. Morphology of the hippocampus, as well as electrophysiology and hippocampally-mediated behaviors are also altered. Although intriguing, these studies have not been conducted with schizophrenia in mind, and thus, outcome measures that may be more specifically related to schizophrenia have not been examined. We propose that further preclinical studies that examine the consequences of prenatal nutritional deficiency, which may lead to altered neuronal migration and other developmental abnormalities, may be useful in understanding the etiology of schizophrenia.

Monosodium glutamate and analgesia induced by morphine. Test-specific effects.

Neonatal administration of monosodium glutamate (MSG) destroyed perikarya in the arcuate nucleus and median eminence, including those that contain met-enkephalin and beta-endorphin and it increased the density of opiate receptors in the midbrain. Treatment with glutamate decreased the analgesic response on the jump test following a 10 mg/kg dose of morphine, yet increased the analgesic response on the hot-plate test following 1 mg/kg dose of morphine. The present study demonstrated that changes in morphine-induced analgesia induced by glutamate varied as functions of the pain test and of gender. While males treated with glutamate displayed attenuated analgesia induced by morphine (2.5-15 mg/kg) on the jump test, jump thresholds of females treated with glutamate were potentiated after a 10 mg/kg dose of morphine and attenuated after a 15 mg/kg dose of morphine, relative to controls. In contrast, analgesia on the hot-plate test was potentiated in animals of both genders treated with glutamate after all doses of morphine. Changes in tolerance to morphine induced by glutamate also depended on the pain test and gender. While the peak analgesic response on the jump test did not occur until the fifth injection of morphine in all rats treated with glutamate, tolerance on the jump test was subsequently retarded in males treated with glutamate and accelerated in glutamate-treated females. Tolerance on the hot-palate test appeared not to be consistently affected by treatment with glutamate. Morphine-induced hyperthermia was initially decreased in rats treated with glutamate, but subsequently decreased in glutamate-treated males and increased in glutamate-treated females.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase variation of lipopolysaccharide in Haemophilus influenzae.

Lipopolysaccharide (LPS) structures on Haemophilus influenzae, defined by monoclonal antibodies, can show phase variation from generation to generation. Several genetic loci are involved in LPS biosynthesis by H. influenzae. In this paper, we describe three loci which play a role in LPS phase variation: the lic loci; lic1 and lic3 have been sequenced and lic2 has been partially sequenced. Each locus consists of multiple open reading frames (ORF), and each contains a repetitive sequence within the 5' end of the first ORF which may be involved in the phase variability. Genes within lic1 and lic2 are directly involved in the expression of phase-variable epitopes, but the role of genes within lic3 is at a more complex level.

Thyrotropin-releasing hormone blocks neurally-mediated hyperglycemia through central action.

Central injection of thyrotropin-releasing hormone (TRH) potently blocked the development of, as well as rapidly reversed, 2-deoxyglucose (2-DG)-stimulated hyperglycemia in mice. The antihyperglycemic effect was dose-related, dependent upon the structural integrity of the peptide, dissociated from the peptide's hypophysiotropic action and from its interaction with TRH receptors, and mediated by the cholinergic parasympathetic system. Moreover, TRH blocked the rise in plasma glucose following central injection of corticotropin-releasing factor, enkephalin, clonidine and glucagon, as well as the hyperglycemic response to immobilization, electric foot shock or endotoxin administration. These results indicate that TRH, acting within the central nervous system, can block neurally-mediated hyperglycemia in addition to its previously reported actions to elicit systemic hypoglycemia in normoglycemic mice and to antagonize epinephrine-stimulated hyperglycemia in these animals.

Neuromodulatory effects of TRH upon swim and cholinergic analgesia.

In addition to short-acting analgesic actions by itself and modulation of analgesic responses induced by endogenous opioids and neurotensin, central administration of thyrotropin-releasing hormone (TRH) potentiates footshock analgesia. The present study evaluated the effects of TRH upon the neurohormonally-mediated though nonopioid analgesia induced by swims in rats. Intracerebroventricular TRH (10 and 50 micrograms) dose-dependently potentiated swim (21, 15, 2 degrees C baths) analgesia on the tail-flick test, an effect which was not due to the hypothermic or basal pain threshold changes. Intravenous (8 mg/kg) TRH potentiated swim (21 degrees C) analgesia; the 600:1 difference in potency between routes strongly suggests central sites of neuromodulatory action. Intracerebroventricular diketopiperazine (50 micrograms), a TRH metabolite, and RX77368 (50 micrograms), a TRH analogue, also potentiated swim (21 degrees C) analgesia, effects also independent of hypothermia and basal reactivity to pain. Finally, given the excitatory interaction between TRH and acetylcholine as well as the cholinergic involvement in swim analgesia, intracerebroventricular TRH potentiated pilocarpine (10 mg/kg, IP) analgesia.

Potentiation of foot shock analgesia by thyrotropin releasing hormone.

Thyrotropin releasing hormone (TRH) interacts with both opioid and non-opioid systems in mediating hypothermic, hypoactive, cataleptic, respiratory and analgesic effects. While TRH neither antagonizes opioid analgesia nor alters pain thresholds itself, it blocks neurotensin analgesia. Different forms of pain-inhibition in rats can be activated by selectively altering the parameters of shock: while analgesia induced by 20 inescapable tail-shocks is not reversed by naltrexone, exposure to 60 or 80 shocks does elicit naltrexone-reversible analgesia. The first experiment examined whether intracerebroventricular administration of TRH (0, 10, or 50 micrograms) would alter the elevations in tail-flick latencies in rats induced by 20 or 80 foot shocks and found that TRH significantly lengthened the duration and magnitude of analgesia induced by 20 and 80 foot shocks in a dose-dependent manner. The second experiment extended these findings to the writhing test, a visceral pain test. While the number and duration of writhes of vehicle-treated rats exposed to 80 foot shocks failed to differ from baseline values. TRH (50 micrograms)-treated rats exposed to 80 foot shocks displayed significant decreases in the number and duration of writhes. The third experiment indicated that the differential effects of naltrexone upon analgesia induced by 20 or 80 tail shocks were not apparent when foot shocks were employed, precluding a definitive statement that TRH may be involved in the modulation of both opioid and non-opioid forms of analgesia.

Characterization of Escherichia coli 50S ribosomal protein L31.

The published C-terminal sequence of Escherichia coli 50S ribosomal protein L31, ellipsisRFNK (Brosius, J. (1978) Biochemistry 17, 501-508), differs from that predicted by the gene sequence, ellipsisRFNKRFNIPGSK (GenBank accession no. X78541). This discrepancy might be due to post-translational processing of the protein. To examine this possibility, we have isolated L31 from E. coli strain MRE600 and sequenced the C-terminal tryptic peptide. We find the sequence to be FBIPGSK. Size comparisons of L31 from several E. coli strains demonstrate that all are identical in size to the protein isolated from MRE600 and larger than the previously described protein, indicating that ellipsisRFNKRFNIPGSK represents the true C-terminus of L31. In addition, we show that the failure to identify L31 in many ribosome preparations is probably due to the protein's loose association with the ribosome and its ability to form various intramolecular disulfide bonds, leading to L31 forms with distinct mobilities in gels.

Imipramine and tetrabenazine: effects on monoamine receptor binding sites and phosphoinositide hydrolysis.

Treatment of rats for 21 days with tetrabenazine, a drug which depletes monoamines and is used behaviorally to screen for antidepressants, significantly decreased 5-HT2 receptor density, increased alpha 1-adrenoceptor density but did not alter beta-adrenoceptor density in homogenates of frontal cortices labeled with [3H]ketanserin, [3H]prazosin and [3H]dihydroalprenolol, respectively. These effects were not opposite to those of the antidepressant drug imipramine which decreased both 5-HT2 and beta-adrenoceptor density and did not alter alpha 1-adrenoceptor density. Some evidence for antagonistic interactions between the two drugs was found in that imipramine partially prevented the tetrabenazine-induced increase in alpha 1-adrenoceptor density and tetrabenazine partially prevented the imipramine-induced decrease in beta-adrenoceptor density. Neither drug altered phosphoinositide hydrolysis coupled to alpha 1-adrenoceptors. While the effects of tetrabenazine are frequently attributed to its reserpine-like action of depleting monoamines, these results provide the first indication that tetrabenazine alters 5-HT2 and beta-adrenoceptor density in a manner different from that of reserpine.

Regional central serotonin-2 receptor binding and phosphoinositide turnover in rats with 5,7-dihydroxytryptamine lesions.

"Denervation supersensitivity" of serotonin (5-HT) receptors has been proposed to explain the behavioral supersensitivity to 5-hydroxytryptophan (5-HTP) which develops after lesions of indoleamine neurons with 5,7-dihydroxytryptamine (5,7-DHT). To examine the possible role of receptor recognition sites and second messenger activity in supersensitivity, we measured regional 5-HT2 receptor ligand binding and 5-HT-stimulated phosphoinositide turnover in adult rats with 5,7-DHT lesions made by intracisternal injection and their saline-treated controls. In [3H]ketanserin binding studies of fresh brain tissue two weeks after 5,7-DHT injection, there were no significant changes in frontal cortex, brainstem, or spinal cord in Bmax, Kd, or nH of 5-HT2 receptors, 5,7-DHT lesions did not affect basal levels of [3H]inositol phosphate (IP) accumulation but significantly increased 5-HT-stimulated [3H]IP accumulation in the brainstem (+27%) and cortex (+23%). Because brainstem rather than cortex is involved in 5-HTP-evoked myoclonus, increased 5-HT-stimulated phosphoinositide hydrolysis in brainstem following 5,7-DHT lesions in the rat may be relevant to serotonergic behavioral supersensitivity.

Depression and anxiety: role of the locus coeruleus and corticotropin-releasing factor.

Based on studies of depression and anxiety using animal (rat) models, it is suggested that, contrary to a widely accepted theory, increased activity of locus coeruleus (LC) neurons does not appear to potentiate anxiety; instead, the influence of LC activity may be opposite to this. First, studies are described that indicate that behavioral changes resembling what is seen in human clinical depression occur in rats exposed to highly stressful conditions, and the research is then traced, which links this stress-induced depression to disturbance of normal noradrenergic regulation of LC activity. Second, the potential role of corticotrophin releasing factor (CRF) in stress-induced behavioral depression is explored. CRF infused into the LC did not produce behavioral depression in the swim test but did increase anxiety; by comparison, CRF infused into the parabrachial nucleus lateral to LC increased both depression and anxiety. Finally, to further explore the relationship between LC activity and anxiety, drugs were infused into LC region to attempt to specifically activate or depress firing of LC neurons. In contrast to expectations, infusion to decrease firing of LC cells increased anxious behavior, while infusion to increase firing decreased anxious behavior. Several other studies are discussed that point to a similar conclusion. It is suggested that, at least in rats, the capacity of stress-inducing or aversive stimuli to activate LC neurons does not potentiate anxiety under environmental conditions that elicit this response, but, rather, the increased activity of the LC/dorsal noradrenergic system under such conditions may exert a counterbalancing, antianxiety influence.

Adsorbed layer structure of cationic surfactants on quartz.

Recent atomic force microscopy (AFM) surface images of surfactant adsorbed at solid and solution interfaces have shown apparent micellar aggregates familiar from bulk self-assembly. This contradicts the classical picture of laterally unstructured bilayers within which neutron reflectometry (NR) measurements have previously been analyzed. Applying both techniques to surfactant adsorption on quartz, we show that film thickness and coverage parameters derived from NR results are generally consistent with those from AFM and bulk self-assembly. NR by itself allows us to distinguish between actual bilayer and probable aggregate adsorption, which will be of particular importance when a solution's rheology makes AFM imaging impractical.

Agonist-stimulation of cerebral phosphoinositide turnover following long-term treatment with antidepressants.

Receptor-mediated stimulation of the formation of inositol phosphates (IP) in cerebral tissue may serve as a useful tool for studying long-term changes in the function of serotonin-2 (5-HT2), alpha-1-adrenergic (al), and muscarinic-cholinergic (musc) receptors. In this study we have evaluated the effects of chronic treatment with various antidepressants on receptor-mediated formation of IP in rat brain. Imipramine (IMI: 10 mg/kg/day; 14 days), Bupropion (BUPR: 40 mg/kg/day; 14 days), Lithium (Li: 0.5% in diet; 7 days) and electroshock treatment (EST: 20-30 mA/day; 7 days) were investigated. Cross-chopped slices of cerebral cortex from control and treated rats were prelabelled with myo-3H-inositol in HEPES buffer containing 11.1 mM LiCl. Accumulation of IP was measured in the presence and absence of serotonin (5-HT, 10 uM), norepinepherine (NE, 5 uM), and carbamylcholine (CCH, 100 uM). Values for agonist-stimulated IP formation in control rats were: 5-HT = 123 +/- 5%; NE = 268 +/- 16%; CCh = 205 +/- 21% of the basal level. The IP response to 5-HT was significantly lower following BUPR and higher following EST. Responses to NE and CCH were significantly lower following BUPR treatment but were not affected by the other antidepressant treatments. These observations are consistent with results of receptor-binding studies indicating up-regulation of 5-HT2 receptors by EST but are not consistent with studies showing down-regulation of 5-HT2 receptors by IMI and a lack of effect on 5-HT2 receptors by BUPR. Our results are not supportive of the notion, based mainly on [3H]prazosin binding studies, that al receptors are up-regulated by EST as well as by different antidepressant drugs.

Forming first impressions of others in schizophrenia: impairments in fast processing and in use of spatial frequency information.

Individuals form first impressions of others all the time, which affects their social functioning. Typical adults form threat impressions in faces with neutral expressions quickly, requiring less than 40 ms. These impressions appear to be mediated by low spatial frequency (LSF) content in the images. Little is known, however, about mechanisms of first impression formation in schizophrenia. The current study investigated how quickly individuals with schizophrenia can form consistent impressions of threat compared with controls and explored the mechanisms involved. Patients and controls were presented intact, LSF- or high spatial frequency (HSF)-filtered faces with durations that varied from 39 to 1703 ms and were asked to rate how threatening each face was on a scale from 1 to 5. In order to assess the speed of impression formation for intact faces, correlations were calculated for ratings made at each duration compared to a reference duration of 1703 ms for each group. Controls demonstrated a significant relation for intact faces presented for 39 ms, whereas patients required 390 ms to demonstrate a significant relation with the reference duration. For controls, LSFs primarily contributed to the formation of consistent threat impressions at 39 ms, whereas patients showed a trend for utilizing both LSF and HSF information to form consistent threat impressions at 390 ms. Results indicate that individuals with schizophrenia require a greater integration time to form a stable "first impression" of threat, which may be related to the need to utilize compensatory mechanisms such as HSF, as well as LSF, information.

Rheo-small-angle neutron scattering at the National Institute of Standards and Technology Center for Neutron Research.

We describe the design and operation of a modified commercial rheometer to simultaneously perform rheological measurements and structural studies by small angle neutron scattering (SANS). The apparatus uses a Couette geometry shear cell allowing two of the three scattering planes to be observed by performing experiments in either the radial or tangential geometries. The device enables small angle neutron scattering patterns to be obtained simultaneously with a wide variety of rheological measurements such as stress/strain flow curves, oscillatory deformations, and creep, recovery and relaxation tests, from -20 °C to 150 °C, for samples with viscosities varying by several orders of magnitude. We give a brief report of recent experiments performed on a dispersion of acicular nanoparticles and biopolymer network under stress demonstrating the utility of such measurements. This device has been developed at the National Institute of Standards and Technology's Center for Neutron Research (NCNR) and made available to the complex fluids community as part of the standard sample environment equipment.

Schizophrenia patients show task switching deficits consistent with N-methyl-d-aspartate system dysfunction but not global executive deficits: implications for pathophysiology of executive dysfunction in schizophrenia.

Schizophrenia is associated with cognitive processing deficits, including deficits in executive processing, that represent a core component of the disorder. In the Task Switching Test, subjects view ambiguous stimuli and must alternate between competing rules to generate correct responses. Subjects show worse performance (prolonged response time and/or increased error rates) on the first response after a switch than on subsequent responses ("switch costs"), as well as performing worse when stimuli are incongruent as opposed to congruent ("congruence costs"). Finally, subjects show worse performance in the dual vs single task condition ("mixing costs"). In monkeys, the N-methyl-D-aspartate (NMDA) antagonist ketamine has been shown to increase congruence but not switch costs. Here, subjects viewed colored letters and had to respond alternately based upon letter (X vs O) or color (red vs blue). Switch, congruence and mixing costs were calculated. Patients with schizophrenia (n = 16) and controls (n = 17) showed similar switch costs, consistent with prior literature. Patients nevertheless showed increased congruence and mixing costs. In addition, relative to controls, patients showed worse performance across conditions in the letter vs color tasks, suggesting deficits in form vs color processing. Overall, while confirming executive dysfunction in schizophrenia, this study indicates that not all aspects of executive control are impaired and that the task switching paradigm may be useful for evaluating neurochemical vs neuroanatomic hypotheses of schizophrenia.