Sex dimorphic actions of rosiglitazone in generalised peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient mice.

AIMS/HYPOTHESIS: The aim of this study was to determine the dependency on peroxisome proliferator-activated receptor-gamma (PPAR-gamma) of insulin sensitisation and glucose homeostasis by thiazolidinediones using a global Ppar-gamma (also known as Pparg)-knockout mouse model. METHODS: Global Mox2-Cre-Ppar-gamma-knockout (MORE-PGKO) mice were treated with rosiglitazone and analysed for insulin sensitivity and glucose metabolism. Metabolic and hormonal variables were determined. Adipose and other tissues were measured and analysed for gene expression. RESULTS: Rosiglitazone induced regrowth of fat in female but not male MORE-PGKO mice, and only in specific depots. Insulin sensitivity increased but, surprisingly, was not associated with the typical changes in adipokines, plasma NEFA or tissue triacylglycerol. However, increases in alternatively activated macrophage markers, which have been previously associated with metabolic improvement, were observed in the regrown fat. Rosiglitazone improved glucose homeostasis but not insulin sensitivity in male MORE-PGKO mice, with further increase of insulin associated with an apparent expansion of pancreatic islets. CONCLUSIONS/INTERPRETATION: Stimulating fat growth by rosiglitazone is sufficient to improve insulin sensitivity in female mice with 95% PPAR-gamma deficiency. This increase in insulin sensitivity is not likely to be due to changes typically seen in adipokines or lipids but may involve changes in macrophage polarisation that occur independent of PPAR-gamma. In contrast, rosiglitazone improves glucose homeostasis in male mice with similar PPAR-gamma deficiency by increasing insulin production independent of changes in adiposity. Further, the insulin-sensitising effect of rosiglitazone is dependent on PPAR-gamma in this male lipodystrophic model.

PPAR-gamma knockout in pancreatic epithelial cells abolishes the inhibitory effect of rosiglitazone on caerulein-induced acute pancreatitis.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, such as the thiazolidinediones (TZDs), decrease acute inflammation in both pancreatic cell lines and mouse models of acute pancreatitis. Since PPAR-gamma agonists have been shown to exert some of their actions independent of PPAR-gamma, the role of PPAR-gamma in pancreatic inflammation has not been directly tested. Furthermore, the differential role of PPAR-gamma in endodermal derivatives (acini, ductal cells, and islets) as opposed to the endothelial or inflammatory cells is unknown. To determine whether the effects of a TZD, rosiglitazone, on caerulein-induced acute pancreatitis are dependent on PPAR-gamma in the endodermal derivatives, we created a cell-type specific knock out of PPAR-gamma in pancreatic acini, ducts, and islets. PPAR-gamma knockout animals show a greater response in some inflammatory genes after caerulein challenge. The anti-inflammatory effect of rosiglitazone on edema, macrophage infiltration, and expression of the proinflammatory cytokines is significantly decreased in pancreata of the knockout animals compared with control animals. However, rosiglitazone retains its effect in the lungs of the pancreatic-specific PPAR-gamma knockout animals, likely due to direct anti-inflammatory effect on lung parenchyma. These data show that the PPAR-gamma in the pancreatic epithelia and islets is important in suppressing inflammation and is required for the anti-inflammatory effects of TZDs in acute pancreatitis.

Maintenance of semantic information in capacity-limited item short-term memory.

We report a semantic effect in immediate free recall, which is localized at recency and is preserved under articulatory suppression but is highly reduced when recall is delayed after an intervening distractor task. These results are explained by a neurocomputational model based on a limited-capacity short-term memory (STM) store, consisting of activated long-term memory representations. The model makes additional predictions about serial position functions in semantically cued recall, indicating capacity limitations caused by a displacement type mechanism, which are confirmed in a second experiment. This suggests that in addition to the phonological component in verbal STM, there is an activation/item-limited component with semantically sensitive representations.

The time course of perceptual choice: the leaky, competing accumulator model.

The time course of perceptual choice is discussed in a model of gradual, leaky, stochastic, and competitive information accumulation in nonlinear decision units. Special cases of the model match a classical diffusion process, but leakage and competition work together to address several challenges to existing diffusion, random walk, and accumulator models. The model accounts for data from choice tasks using both time-controlled (e.g., response signal) and standard reaction time paradigms and its adequacy compares favorably with other approaches. A new paradigm that controls the time of arrival of information supporting different choice alternatives provides further support. The model captures choice behavior regardless of the number of alternatives, accounting for the log-linear relation between reaction time and number of alternatives (Hick's law) and explains a complex pattern of visual and contextual priming in visual word identification.

Stochastic resonance in the speed of memory retrieval.

The stochastic resonance (SR) phenomenon in human cognition (memory retrieval speed for arithmetical multiplication rules) is addressed in a behavioral and neurocomputational study. The results of an experiment in which performance was monitored for various magnitudes of acoustic noise are presented. The average response time was found to be minimal for some optimal noise level. Moreover, it was shown that the optimal noise level and the magnitude of the SR effect depend on the difficulty of the task. A computational framework based on leaky accumulators that integrate noisy information and provide the output upon reaching a threshold criterion is used to illustrate the observed phenomena.

Mechanisms for spatial integration in visual detection: a model based on lateral interactions.

Recent studies of visual detection show a configuration dependent weak improvement of thresholds with the number of targets, which corresponds to a fourth-root power law. We find this result to be inconsistent with probability summation models, and account for it by a model of 'physiological' integration that is based on excitatory lateral interactions in the visual cortex. The model explains several phenomena which are confirmed by the experimental data, such as the absence of spatial and temporal uncertainty effects, temporal summation curves, and facilitation by a pedestal in 2AFC tasks. The summation exponents are dependent on the strength of the lateral interactions, and on the distance and orientation relationship between the elements.

The role of locus coeruleus in the regulation of cognitive performance.

Noradrenergic locus coeruleus (LC) neurons were recorded in monkeys performing a visual discrimination task, and a computational model was developed addressing the role of the LC brain system in cognitive performance. Changes in spontaneous and stimulus-induced patterns of LC activity correlated closely with fluctuations in behavioral performance. The model explains these fluctuations in terms of changes in electrotonic coupling among LC neurons and predicts improved performance during epochs of high coupling and synchronized LC firing. Cross correlations of simultaneously recorded LC neurons confirmed this prediction, indicating that electrotonic coupling in LC may play an important role in attentional modulation and the regulation of goal-directed versus exploratory behaviors.

The "benefits" of distractibility: mechanisms underlying increased Stroop effects in schizophrenia.

Recent studies of selective attention in schizophrenia patients suggest a particular pattern of single-trial Stroop performance: increased facilitation but not interference in reaction times (RTs), combined with increased error interference. Our Stroop task analysis suggests that this pattern can be explained by a selective attention deficit if one accounts for (1) performance in the congruent condition; (2) the nature of the neutral stimulus; (3) the relationship between accuracy and RT; and (4) response set effects. To test these hypotheses, we examined Stroop performance in 40 DSM-IV schizophrenia patients and 20 healthy control subjects, using a range of neutral stimuli (color patches, noncolor words, color words not in the response set). The findings confirmed several of our predictions and the results were consistent with the hypothesis that abnormal Stroop performance in schizophrenia reflects a failure to adequately attend to the task-appropriate stimulus dimension (color). This inattention affects both the congruent and incongruent conditions and multiple points in the information processing pathway.

Visual synchrony affects binding and segmentation in perception.

The visual system analyses information by decomposing complex objects into simple components (visual features) that are widely distributed across the cortex. When several objects are present simultaneously in the visual field, a mechanism is required to group (bind) together visual features that belong to each object and to separate (segment) them from features of other objects. An attractive scheme for binding visual features into a coherent percept consists of synchronizing the activity of their neural representations. If synchrony is important in binding, one would expect that binding and segmentation are facilitated by visual displays that are temporally manipulated to induce stimulus-dependent synchrony. Here we show that visual grouping is indeed facilitated when elements of one percept are presented at the same time as each other and are temporally separated (on a scale below the integration time of the visual system) from elements of another percept or from background elements. Our results indicate that binding is due to a global mechanism of grouping caused by synchronous neural activation, and not to a local mechanism of motion computation.

Modeling the Temporal Dynamics of IT Neurons in Visual Search: A Mechanism for Top-Down Selective Attention.

We propose a neural model for object-oriented attention in which various visual stimuli (shapes, colors, letters, etc.) are represented by competing, mutually inhibitory, cell assemblies. The model's response to a sequence of cue and target stimuli mimics the neural responses in infero temporal (IT) visual cortex of monkeys performing a visual search task: enhanced response during the display of the stimulus, which decays but remains above a spontaneous rate after the cue disappears. When, subsequently, a display consisting of the target and several distractors is presented, the activity of all stimulus-driven cells is initially enhanced. After a short period of time, however, the activity of the cell assembly representing the cue stimulus is enhanced while the activity of the distractors decays because of mutual competition and a small top-down "expectational" input. The model fits the measured delayed activity in IT-cortex, recently reported by Chelazzi, Miller, Duncan, and Desimone (1993a), and we suggest that such a process, which is largely independent of the number of distractors, may be used by the visual system for selecting an expected target (appearing at an uncertain location) among distractors.

Lateral interactions in primary visual cortex: a model bridging physiology and psychophysics.

Recent physiological studies show that the spatial context of visual stimuli enhances the response of cells in primary visual cortex to weak stimuli and suppresses the response to strong stimuli. A model of orientation-tuned neurons was constructed to explore the role of lateral cortical connections in this dual effect. The differential effect of excitatory and inhibitory current and noise conveyed by the lateral connections explains the physiological results as well as the psychophysics of pop-out and contour completion. Exploiting the model's property of stochastic resonance, the visual context changes the model's intrinsic input variability to enhance the detection of weak signals.

Phenothiazine treatment and respiratory distress syndrome in a child.

An 11-year-old boy who was treated with a relatively high dose of methotrimeprazine meleate (Levemepromazine) a phenothiazine antipsychotic drug, was admitted to the pediatric intensive care unit suffering from respiratory distress syndrome. He required intensive treatment and support for 13 days. The persistent effects of methotrimeprazine meleate on various organs are typical of the prolonged biological action of the phenothiazine metabolites. The association of phenothiazine overdose and respiratory distress syndrome merits consideration.

A neural model of the dynamic activation of memory.

We study an Attractor Neural Network that stores natural concepts, organized in semantic classes. The concepts are represented by distributed patterns over a space of attributes, and are related by both semantic and episodic associations. While semantic relations are expressed through an hierarchical coding over the attribute space, episodic links are realized via specific synaptic projections. Due to dynamic thresholds expressing neuronal fatigue, the network's behavior is characterized by convergence toward the concept patterns on a short time scale, and by transitions between the various patterns on a longer time scale. In its baseline, undamaged state, the network manifests semantic, episodic, and random transitions, and demonstrates the phenomenon of priming. Modeling possible pathological changes, we have found that increasing the 'noise' level or the rate of neuronal fatigue decreases the frequency of semantic transitions. When neurons characterized by large synaptic connectivity are deleted, semantic transitions decay before the episodic ones, in accordance with the findings in patients with Alzheimer's disease.

Human parvovirus B19 specific IgG, IgA, and IgM antibodies and DNA in serum specimens from persons with erythema infectiosum.

To determine the diagnostic use of different markers of acute parvovirus B19 infection, serum specimens obtained from 128 persons with erythema infectiosum were tested for specific immunoglobulin G (IgG), IgA, and IgM antibodies by capture enzyme immunoassay (EIA) using Chinese hamster ovary (CHO) cell-expressed B19 antigen, and tested for circulating B19 DNA by polymerase chain reaction (PCR). A significant rise in specific IgG and IgA antibodies was detected in 87% and 77%, respectively, of persons from whom acute- and convalescent-phase serum specimens were available. Specific IgA antibodies were detected in single serum specimens from 90% of cases and were present in 22 (18%) of 120 persons from a control group without a history of recent exposure to B19. Specific IgM antibodies were detected in 97% of cases and one person (1%) from the control group. B19 DNA was detected in 94% of cases and was absent in 20 persons from the control group positive for both IgG and IgA antibodies. Serum specimens obtained between 4 and 6 months after onset of illness from six additional persons were also tested. All had specific IgG antibodies, four (67%) had IgA, five (83%) had IgM, and none had detectable B19 DNA. Our data indicate that 1) specific IgA antibodies are too persistent to be a useful indicator of recent B19 infection; 2) specific IgM antibodies are the most sensitive indicator of acute B19 infection in immunologically normal persons but can persist up to 6 months; and 3) B19 DNA can often be detected up to 2 months after onset of illness even in immunologically normal hosts and might be a useful adjunct test for diagnosis of acute B19 infection.

Schematic and situational determinants of depressed and nondepressed students' interpretation of feedback.

We examined whether depressed persons' social skill deficits contribute to their negative cognitions and whether this contribution is independent of their negative schemata. Depressed (n = 60) and nondepressed (n = 60) subjects engaged in group discussions. We assessed subjects' social competence schemata with a questionnaire and subjects' actual level of social competence in the discussion through objective ratings made by codiscussants and outside observers. We found that independently of their negative schemata, depressed subjects' social skill deficits explained a significant portion of the variance in their more negative interpretation of feedback (relative to nondepressed subjects'). This suggests that real deficits in depressed persons' performance compound the effects of their negative schemata and further contribute to their negative cognitions. We also further explored findings by Dykman et al. (1989) and Lewinsohn et al. (1980).

Intestinal water transport in juvenile Atlantic salmon (Salmo salar L.) during smolting and following transfer to seawater.

1. The rate of mucosal to serosal water movement was measured in vitro in non-everted midgut segments in Atlantic salmon (Salmo salar L.) during parr-smolt transformation (February-July) and following transfer of smolts to seawater in May. 2. The rate increased significantly during smolting from 5.61 microliters/cm2/hr in the parr (February) to 11.03 microliters/cm2/hr in smolts in May. 3. Measured at intervals over a period of 20 days in seawater, the rate of water transport was not significantly different from that found in the freshwater-adapted smolts (11.20 microliters/cm2/hr). 4. Intestinal water transport is sodium-linked and inhibited by ouabain but is not stimulated by cortisol.

Parallel Activation of Memories in an Oscillatory Neural Network.

We describe a feedback neural network whose elements possess dynamic thresholds. This network has an oscillatory mode that we investigate by measuring the activities of memory patterns as functions of time. We observe spontaneous and induced transitions between the different oscillating memories. Moreover, the network exhibits pattern segmentation, by oscillating between different memories that are included as a mixture in a constant input. The efficiency of pattern segmentation decreases strongly as the number of the input memories is increased. Using oscillatory inputs we observe resonance behavior.

Segmentation, Binding, and Illusory Conjunctions.

We investigate binding within the framework of a model of excitatory and inhibitory cell assemblies that form an oscillating neural network. Our model is composed of two such networks that are connected through their inhibitory neurons. The excitatory cell assemblies represent memory patterns. The latter have different meanings in the two networks, representing two different attributes of an object, such as shape and color. The networks segment an input that contains mixtures of such pairs into staggered oscillations of the relevant activities. Moreover, the phases of the oscillating activities representing the two attributes in each pair lock with each other to demonstrate binding. The system works very well for two inputs, but displays faulty correlations when the number of objects is larger than two. In other words, the network conjoins attributes of different objects, thus showing the phenomenon of "illusory conjunctions," as in human vision.