Precision targeting of the plasminogen activator inhibitor-1 mechanism increases efficacy of fibrinolytic therapy in empyema.

Plasminogen activator inhibitor-1 (PAI-1) is an endogenous irreversible inhibitor of tissue-type (tPA) and urokinase (uPA) plasminogen activators. PAI-1-targeted fibrinolytic therapy (PAI-1-TFT) is designed to decrease the therapeutic dose of tPA and uPA, attenuating the risk of bleeding and other complications. Docking site peptide (DSP) mimics the part of the PAI-1 reactive center loop that interacts with plasminogen activators, thereby affecting the PAI-1 mechanism. We used DSP for PAI-1-TFT in two rabbit models: chemically induced pleural injury and Streptococcus pneumoniae induced empyema. These models feature different levels of inflammation and PAI-1 expression. PAI-1-TFT with DSP (2.0 mg/kg) converted ineffective doses of single chain (sc) tPA (72.5 µg/kg) and scuPA (62.5 µg/kg) into effective ones in chemically induced pleural injury. DSP (2.0 mg/kg) was ineffective in S. pneumoniae empyema, where the level of PAI-1 is an order of magnitude higher. DSP dose escalation to 8.0 mg/kg resulted in effective PAI-1-TFT with 0.25 mg/kg sctPA (1/8th of the effective dose of sctPA alone) in empyema. There was no increase in the efficacy of scuPA. PAI-1-TFT with DSP increases the efficacy of fibrinolytic therapy up to 8-fold in chemically induced (sctPA and scuPA) and infectious (sctPA) pleural injury in rabbits. PAI-1 is a valid molecular target in our model of S. pneumoniae empyema in rabbits, which closely recapitulates key characteristics of empyema in humans. Low-dose PAI-1-TFT is a novel interventional strategy that offers the potential to improve fibrinolytic therapy for empyema in clinical practice.

Students with mild intellectual disability engaging in proportions word problems.

The researchers conducted a qualitative case study to describe the experiences of two seventh grade students with mild intellectual disability as they engaged in mathematics word problems involving proportions. The researchers analyzed student performance in large group settings and with individualized instruction to gain perspective on the students' tendencies with challenging mathematics content. During the teaching sessions in this study, one of the participants initially struggled with the proportions word problems, but demonstrated success after teachers connected new information in the tasks to students' long-term memory and utilized gestures and diagrams to facilitate the students' processing of information. Another participant succeeded more easily with proportions word problems which, along with the success of the other participant, provides support that students with a mild intellectual disability can succeed with challenging topics, such as proportions word problems.

Glycogen Synthase Kinase-3ß Inhibition with 9-ING-41 Attenuates the Progression of Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a median survival of 3 years after diagnosis. Although the etiology of IPF is unknown, it is characterized by extensive alveolar epithelial cell apoptosis and proliferation of myofibroblasts in the lungs. While the origins of these myofibroblast appear to be diverse, fibroblast differentiation contributes to expansion of myofibroblasts and to disease progression. We found that agents that contribute to neomatrix formation and remodeling in pulmonary fibrosis (PF); TGF-ß, Factor Xa, thrombin, plasmin and uPA all induced fibroblast/myofibroblast differentiation. These same mediators enhanced GSK-3ß activation via phosphorylation of tyrosine-216 (p-Y216). Inhibition of GSK-3ß signaling with the novel inhibitor 9-ING-41 blocked the induction of myofibroblast markers; α-SMA and Col-1 and reduced morphological changes of myofibroblast differentiation. In in vivo studies, the progression of TGF-ß and bleomycin mediated PF was significantly attenuated by 9-ING-41 administered at 7 and 14 days respectively after the establishment of injury. Specifically, 9-ING-41 treatment significantly improved lung function (compliance and lung volumes; p < 0.05) of TGF-ß adenovirus treated mice compared to controls. Similar results were found in mice with bleomycin-induced PF. These studies clearly show that activation of the GSK-3ß signaling pathway is critical for the induction of myofibroblast differentiation in lung fibroblasts ex vivo and pulmonary fibrosis in vivo. The results offer a strong premise supporting the continued investigation of the GSK-3ß signaling pathway in the control of fibroblast-myofibroblast differentiation and fibrosing lung injury. These data provide a strong rationale for extension of clinical trials of 9-ING-41 to patients with IPF.

Increased expression of plasminogen activator inhibitor-1 (PAI-1) is associated with depression and depressive phenotype in C57Bl/6J mice.

Plasminogen activator inhibitor 1 (PAI-1), which is elevated in numerous disease states, has been implicated as a stress-related protein involved in the pathogenesis of depression. We measured PAI-1 in the plasma of healthy and depressed individuals and assessed plasminogen activator (PA) expression and regulation by PAI-1 in cultured normal human astrocytes (NHA). Elevated plasma PAI-1 levels were found in depressed patients. Brain tissues from depressed individuals also showed stronger expression of hippocampal PAI-1 by confocal imaging in comparison to healthy individuals. Using a lipopolysaccharide-induced inflammatory model of depression in mice, we measured PAI-1 in murine plasma and brain, by ELISA and immunohistochemistry, respectively. Similar elevations were seen in plasma but not in brain homogenates of mice exposed to LPS. We further correlated the findings with depressive behavior. Ex vivo experiments with NHA treated with proinflammatory cytokines implicated in the pathogenesis of depression showed increased PAI-1 expression. Furthermore, these studies suggest that urokinase-type plasminogen activator may serve as an astrocyte PA reservoir, able to promote cleavage of brain-derived neurotrophic factor (BDNF) during stress or inflammation. In summary, our findings confirm that derangements of PAI-1 variably occur in the brain in association with the depressive phenotype. These derangements may impede the availability of active, mature (m)BDNF and thereby promote a depressive phenotype.

Lack of durable protection against cotton smoke-induced acute lung injury in sheep by nebulized single chain urokinase plasminogen activator or tissue plasminogen activator.

BACKGROUND: Airway fibrin casts are clinically important complications of severe inhalational smoke-induced acute lung injury (ISIALI) for which reliable evidence-based therapy is lacking. Nebulized anticoagulants or a tissue plasminogen activator; tPA, has been advocated, but airway bleeding is a known and lethal potential complication. We posited that nebulized delivery of single chain urokinase plasminogen activator, scuPA, is well-tolerated and improves physiologic outcomes in ISIALI. To test this hypothesis, we nebulized scuPA or tPA and delivered these agents every 4 h to sheep with cotton smoke induced ISIALI that were ventilated by either adaptive pressure ventilation/controlled mandatory ventilation (APVcmv; Group 1, n = 14) or synchronized controlled mandatory ventilation (SCMV)/limited suctioning; Group 2, n = 32). Physiologic readouts of acute lung injury included arterial blood gas analyses, PaO2/FiO2 ratios, peak and plateau airway pressures, lung resistance and static lung compliance. Lung injury was further assessed by histologic scoring. Biochemical analyses included determination of antigenic and enzymographic uPA and tPA levels, plasminogen activator and plasminogen activator inhibitor-1 activities and D-dimer in bronchoalveolar lavage (BAL). Plasma levels of uPA, tPA antigens, D-dimers and α-macroglobulin-uPA complex levels were also assessed. RESULTS: In Group 1, tPA at the 2 mg dose was ineffective, but at 4 mg tPA or scuPA, the PaO2/FiO2 ratios, peak/plateau pressures improved during evolving injury (p < 0.01) without significant differences at 48 h. To improve delivery of the interventions, the experiments were repeated in Group 2 with limited suctioning/SCMV, which generally increased PAs in (BAL). In Group 2, tPA was ineffective, but scuPA (4 or 8 mg) improved physiologic outcomes (p < 0.01) and plateau pressures remained lower at 48 h. Airway bleeding occurred at 8 mg tPA. BAL plasminogen activator (PA) levels positively correlated with physiologic outcomes at 48 h. CONCLUSIONS: Physiologic outcomes improved in sheep in which better delivery of the PAs occurred. The benefits of nebulized scuPA were achieved without airway bleeding associated with tPA, but were transient and largely abrogated at 48 h, in part attributable to the progression and severity of ISIALI.

Inhibition of Glycogen Synthase Kinase 3ß Blocks Mesomesenchymal Transition and Attenuates Streptococcus pneumonia-Mediated Pleural Injury in Mice.

Pleural loculation affects about 30,000 patients annually in the United States and in severe cases can resolve with restrictive lung disease and pleural fibrosis. Pleural mesothelial cells contribute to pleural rind formation by undergoing mesothelial mesenchymal transition (MesoMT), whereby they acquire a profibrotic phenotype characterized by increased expression of α-smooth muscle actin and collagen 1. Components of the fibrinolytic pathway (urokinase plasminogen activator and plasmin) are elaborated in pleural injury and strongly induce MesoMT in vitro. These same stimuli enhance glycogen synthase kinase (GSK)-3ß activity through increased phosphorylation of Tyr-216 in pleural mesothelial cells and GSK-3ß mobilization from the cytoplasm to the nucleus. GSK-3ß down-regulation blocked induction of MesoMT. Likewise, GSK-3ß inhibitor 9ING41 blocked induction of MesoMT and reversed established MesoMT. Similar results were demonstrated in a mouse model of Streptococcus pneumoniae-induced empyema. Intraperitoneal administration of 9ING41, after the induction of pleural injury, attenuated injury progression and improved lung function (lung volume and compliance; P < 0.05 compared with untreated and vehicle controls). MesoMT marker α-smooth muscle actin was reduced in 9ING41-treated mice. Pleural thickening was also notably reduced in 9ING41-treated mice (P < 0.05). Collectively, these studies identify GSK-3ß as a newly identified target for amelioration of empyema-related pleural fibrosis and provide a strong rationale for further investigation of GSK-3ß signaling in the control of MesoMT and pleural injury.

Organizing empyema induced in mice by Streptococcus pneumoniae: effects of plasminogen activator inhibitor-1 deficiency.

BACKGROUND: Pleural infection affects about 65,000 patients annually in the US and UK. In this and other forms of pleural injury, mesothelial cells (PMCs) undergo a process called mesothelial (Meso) mesenchymal transition (MT), by which PMCs acquire a profibrogenic phenotype with increased expression of α-smooth muscle actin (α-SMA) and matrix proteins. MesoMT thereby contributes to pleural organization with fibrosis and lung restriction. Current murine empyema models are characterized by early mortality, limiting analysis of the pathogenesis of pleural organization and mechanisms that promote MesoMT after infection. METHODS: A new murine empyema model was generated in C57BL/6 J mice by intrapleural delivery of Streptococcus pneumoniae (D39, 3 × 10(7)-5 × 10(9) cfu) to enable use of genetically manipulated animals. CT-scanning and pulmonary function tests were used to characterize the physiologic consequences of organizing empyema. Histology, immunohistochemistry, and immunofluorescence were used to assess pleural injury. ELISA, cytokine array and western analyses were used to assess pleural fluid mediators and markers of MesoMT in primary PMCs. RESULTS: Induction of empyema was done through intranasal or intrapleural delivery of S. pneumoniae. Intranasal delivery impaired lung compliance (p < 0.05) and reduced lung volume (p < 0.05) by 7 days, but failed to reliably induce empyema and was characterized by unacceptable mortality. Intrapleural delivery of S. pneumoniae induced empyema by 24 h with lung restriction and development of pleural fibrosis which persisted for up to 14 days. Markers of MesoMT were increased in the visceral pleura of S. pneumoniae infected mice. KC, IL-17A, MIP-1ß, MCP-1, PGE2 and plasmin activity were increased in pleural lavage of infected mice at 7 days. PAI-1(-/-) mice died within 4 days, had increased pleural inflammation and higher PGE2 levels than WT mice. PGE2 was induced in primary PMCs by uPA and plasmin and induced markers of MesoMT. CONCLUSION: To our knowledge, this is the first murine model of subacute, organizing empyema. The model can be used to identify factors that, like PAI-1 deficiency, alter outcomes and dissect their contribution to pleural organization, rind formation and lung restriction.

Dose dependency of outcomes of intrapleural fibrinolytic therapy in new rabbit empyema models.

The incidence of empyema (EMP) is increasing worldwide; EMP generally occurs with pleural loculation and impaired drainage is often treated with intrapleural fibrinolytic therapy (IPFT) or surgery. A number of IPFT options are used clinically with empiric dosing and variable outcomes in adults. To evaluate mechanisms governing intrapleural fibrinolysis and disease outcomes, models of Pasteurella multocida and Streptococcus pneumoniae were generated in rabbits and the animals were treated with either human tissue (tPA) plasminogen activator or prourokinase (scuPA). Rabbit EMP was characterized by the development of pleural adhesions detectable by chest ultrasonography and fibrinous coating of the pleura. Similar to human EMP, rabbits with EMP accumulated sizable, 20- to 40-ml fibrinopurulent pleural effusions associated with extensive intrapleural organization, significantly increased pleural thickness, suppression of fibrinolytic and plasminogen-activating activities, and accumulation of high levels of plasminogen activator inhibitor 1, plasminogen, and extracellular DNA. IPFT with tPA (0.145 mg/kg) or scuPA (0.5 mg/kg) was ineffective in rabbit EMP (n = 9 and 3 for P. multocida and S. pneumoniae, respectively); 2 mg/kg tPA or scuPA IPFT (n = 5) effectively cleared S. pneumoniae-induced EMP collections in 24 h with no bleeding observed. Although intrapleural fibrinolytic activity for up to 40 min after IPFT was similar for effective and ineffective doses of fibrinolysin, it was lower for tPA than for scuPA treatments. These results demonstrate similarities between rabbit and human EMP, the importance of pleural fluid PAI-1 activity, and levels of plasminogen in the regulation of intrapleural fibrinolysis and illustrate the dose dependency of IPFT outcomes in EMP.

Assessment of Scientific Reasoning: the Effects of Task Context, Data, and Design on Student Reasoning in Control of Variables.

Scientific reasoning is an important component under the cognitive strand of the 21st century skills and is highly emphasized in the new science education standards. This study focuses on the assessment of student reasoning in control of variables (COV), which is a core sub-skill of scientific reasoning. The main research question is to investigate the extent to which the existence of experimental data in questions impacts student reasoning and performance. This study also explores the effects of task contexts on student reasoning as well as students' abilities to distinguish between testability and causal influences of variables in COV experiments. Data were collected with students from both USA and China. Students received randomly one of two test versions, one with experimental data and one without. The results show that students from both populations (1) perform better when experimental data are not provided, (2) perform better in physics contexts than in real-life contexts, and (3) students have a tendency to equate non-influential variables to non-testable variables. In addition, based on the analysis of both quantitative and qualitative data, a possible progression of developmental levels of student reasoning in control of variables is proposed, which can be used to inform future development of assessment and instruction.

The time course of resolution of adhesions during fibrinolytic therapy in tetracycline-induced pleural injury in rabbits.

The time required for the effective clearance of pleural adhesions/organization after intrapleural fibrinolytic therapy (IPFT) is unknown. Chest ultrasonography and computed tomography (CT) were used to assess the efficacy of IPFT in a rabbit model of tetracycline-induced pleural injury, treated with single-chain (sc) urokinase plasminogen activators (scuPAs) or tissue PAs (sctPA). IPFT with sctPA (0.145 mg/kg; n = 10) and scuPA (0.5 mg/kg; n = 12) was monitored by serial ultrasonography alone (n = 12) or alongside CT scanning (n = 10). IPFT efficacy was assessed with gross lung injury scores (GLIS) and ultrasonography scores (USS). Pleural fluids withdrawn at 0-240 min and 24 h after IPFT were assayed for PA and fibrinolytic activities, α-macroglobulin/fibrinolysin complexes, and active PA inhibitor 1 (PAI-1). scuPA and sctPA generated comparable steady-state fibrinolytic activities by 20 min. PA activity in the scuPA group decreased slower than the sctPA group (kobs = 0.016 and 0.042 min(-1)). Significant amounts of bioactive uPA/α-macroglobulin (but not tPA; P < 0.05) complexes accumulated at 0-40 min after IPFT. Despite the differences in intrapleural processing, IPFT with either fibrinolysin was effective (GLIS ≤ 10) in animals imaged with ultrasonography only. USS correlated well with postmortem GLIS (r(2) = 0.85) and confirmed relatively slow intrapleural fibrinolysis after IPFT, which coincided with effective clearance of adhesions/organization at 4-8 h. CT scanning was associated with less effective (GLIS > 10) IPFT and higher levels of active PAI-1 at 24 h following therapy. We concluded that intrapleural fibrinolysis in tetracycline-induced pleural injury in rabbits is relatively slow (4-8 h). In CT-scanned animals, elevated PAI-1 activity (possibly radiation induced) reduced the efficacy of IPFT, buttressing the major impact of active PAI-1 on IPFT outcomes.

Mesomesenchymal transition of pleural mesothelial cells is PI3K and NF-κB dependent.

Pleural organization follows acute injury and is characterized by pleural fibrosis, which may involve the visceral and parietal pleural surfaces. This process affects patients with complicated parapneumonic pleural effusions, empyema, and other pleural diseases prone to pleural fibrosis and loculation. Pleural mesothelial cells (PMCs) undergo a process called mesothelial mesenchymal transition (MesoMT), by which PMCs acquire a profibrotic phenotype characterized by cellular enlargement and elongation, increased expression of α-smooth muscle actin (α-SMA), and matrix proteins including collagen-1. Although MesoMT contributes to pleural fibrosis and lung restriction in mice with carbon black/bleomycin-induced pleural injury and procoagulants and fibrinolytic proteases strongly induce MesoMT in vitro, the mechanism by which this transition occurs remains unclear. We found that thrombin and plasmin potently induce MesoMT in vitro as does TGF-ß. Furthermore, these mediators of MesoMT activate phosphatidylinositol-3-kinase (PI3K)/Akt and NF-κB signaling pathways. Inhibition of PI3K/Akt signaling prevented TGF-ß-, thrombin-, and plasmin-mediated induction of the MesoMT phenotype exhibited by primary human PMCs. Similar effects were demonstrated through blockade of the NF-κB signaling cascade using two distinctly different NF-κB inhibitors, SN50 and Bay-11 7085. Conversely, expression of constitutively active Akt-induced mesenchymal transition in human PMCs whereas the process was blocked by PX866 and AKT8. Furthermore, thrombin-mediated MesoMT is dependent on PAR-1 expression, which is linked to PI3K/Akt signaling downstream. These are the first studies to demonstrate that PI3K/Akt and/or NF-κB signaling is critical for induction of MesoMT.

Targeting of plasminogen activator inhibitor 1 improves fibrinolytic therapy for tetracycline-induced pleural injury in rabbits.

Endogenous active plasminogen activator inhibitor 1 (PAI-1) was targeted in vivo with monoclonal antibodies (mAbs) that redirect its reaction with proteinases to the substrate branch. mAbs were used as an adjunct to prourokinase (single-chain [sc] urokinase [uPA]) intrapleural fibrinolytic therapy (IPFT) of tetracycline-induced pleural injury in rabbits. Outcomes of scuPA IPFT (0.25 or 0.0625 mg/kg) with 0.5 mg/kg of mouse IgG or mAbs (MA-33H1F7 and MA-8H9D4) were assessed at 24 hours. Pleural fluid (PF) was collected at 0, 10, 20, and 40 minutes and 24 hours after IPFT and analyzed for plasminogen activating (PA), uPA, fibrinolytic activities, levels of total plasmin/plasminogen, α-macroglobulin (αM), mAbs/IgG antigens, free active uPA, and αM/uPA complexes. Anti-PAI-1 mAbs, but not mouse IgG, delivered with an eightfold reduction in the minimal effective dose of scuPA (from 0.5 to 0.0625 mg/kg), improved the outcome of IPFT (P < 0.05). mAbs and IgG were detectable in PFs at 24 hours. Compared with identical doses of scuPA alone or with IgG, treatment with scuPA and anti-PAI-1 mAbs generated higher PF uPA amidolytic and PA activities, faster formation of αM/uPA complexes, and slower uPA inactivation. However, PAI-1 targeting did not significantly affect intrapleural fibrinolytic activity or levels of total plasmin/plasminogen and αM antigens. Targeting PAI-1 did not induce bleeding, and rendered otherwise ineffective doses of scuPA able to improve outcomes in tetracycline-induced pleural injury. PAI-1-neutralizing mAbs improved IPFT by increasing the durability of intrapleural PA activity. These results suggest a novel, well-tolerated IPFT strategy that is tractable for clinical development.

Thrombin down-regulates tissue factor pathway inhibitor expression in a PI3K/nuclear factor-κB-dependent manner in human pleural mesothelial cells.

Tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the extrinsic coagulation cascade, and its expression is reported to be relatively stable. Various pathophysiologic agents have been shown to influence TFPI activity by regulating its expression or by modifying the protein. It is not clear how TFPI activity is regulated in normal physiology or in injury. Because thrombin and TFPI are locally elaborated in pleural injury, we sought to determine if thrombin could regulate TFPI in human pleural mesothelial cells (HPMCs). Thrombin significantly decreased TFPI mRNA and protein levels by > 70%. Thrombin-mediated down-regulation of TFPI promoted factor X activation by HPMCs. The ability of thrombin to significantly decrease TFPI mRNA and protein levels was maintained at nanomolar concentrations. Protease-activated receptor (PAR)-1, a mediator of thrombin signaling, is detectable in the mesothelium in human and murine pleural injury. PAR-1 silencing blocked thrombin-mediated decrements of TFPI in HPMCs. Thrombin activates PI3K/Akt and nuclear factor κB (NF-κB) signaling in HPMCs. Inhibition of PI3K (by PX-866) and NF-κB (by SN50) prevented thrombin-mediated TFPI mRNA and protein down-regulation. These are the first studies to demonstrate that thrombin decreases TFPI expression in HPMCs. Our findings demonstrate a novel mechanism by which thrombin regulates TFPI expression in HPMCs and promotes an unrestricted procoagulant response, and suggest that interactions between PI3K and NF-κB signaling pathways are linked in HPMCs and control TFPI expression. These findings raise the possibility that targeting this pathway could limit the ability of the mesothelium to support extravascular fibrin deposition and organization associated with pleural injury.

Plasminogen activator inhibitor-1 deficiency augments visceral mesothelial organization, intrapleural coagulation, and lung restriction in mice with carbon black/bleomycin-induced pleural injury.

Local derangements of fibrin turnover and plasminogen activator inhibitor (PAI)-1 have been implicated in the pathogenesis of pleural injury. However, their role in the control of pleural organization has been unclear. We found that a C57Bl/6j mouse model of carbon black/bleomycin (CBB) injury demonstrates pleural organization resulting in pleural rind formation (14 d). In transgenic mice overexpressing human PAI-1, intrapleural fibrin deposition was increased, but visceral pleural thickness, lung volumes, and compliance were comparable to wild type. CBB injury in PAI-1(-/-) mice significantly increased visceral pleural thickness (P < 0.001), elastance (P < 0.05), and total lung resistance (P < 0.05), while decreasing lung compliance (P < 0.01) and lung volumes (P < 0.05). Collagen, α-smooth muscle actin, and tissue factor were increased in the thickened visceral pleura of PAI-1(-/-) mice. Colocalization of α-smooth muscle actin and calretinin within pleural mesothelial cells was increased in CBB-injured PAI-1(-/-) mice. Thrombin, factor Xa, plasmin, and urokinase induced mesothelial-mesenchymal transition, tissue factor expression, and activity in primary human pleural mesothelial cells. In PAI-1(-/-) mice, D-dimer and thrombin-antithrombin complex concentrations were increased in pleural lavage fluids. The results demonstrate that PAI-1 regulates CBB-induced pleural injury severity via unrestricted fibrinolysis and cross-talk with coagulation proteases. Whereas overexpression of PAI-1 augments intrapleural fibrin deposition, PAI-1 deficiency promotes profibrogenic alterations of the mesothelium that exacerbate pleural organization and lung restriction.

The perception and identification of facial emotions in individuals with autism spectrum disorders using the Let's Face It! Emotion Skills Battery.

BACKGROUND: Although impaired social-emotional ability is a hallmark of autism spectrum disorder (ASD), the perceptual skills and mediating strategies contributing to the social deficits of autism are not well understood. A perceptual skill that is fundamental to effective social communication is the ability to accurately perceive and interpret facial emotions. To evaluate the expression processing of participants with ASD, we designed the Let's Face It! Emotion Skills Battery (LFI! Battery), a computer-based assessment composed of three subscales measuring verbal and perceptual skills implicated in the recognition of facial emotions. METHODS: We administered the LFI! Battery to groups of participants with ASD and typically developing control (TDC) participants that were matched for age and IQ. RESULTS: On the Name Game labeling task, participants with ASD (N = 68) performed on par with TDC individuals (N = 66) in their ability to name the facial emotions of happy, sad, disgust and surprise and were only impaired in their ability to identify the angry expression. On the Matchmaker Expression task that measures the recognition of facial emotions across different facial identities, the ASD participants (N = 66) performed reliably worse than TDC participants (N = 67) on the emotions of happy, sad, disgust, frighten and angry. In the Parts-Wholes test of perceptual strategies of expression, the TDC participants (N = 67) displayed more holistic encoding for the eyes than the mouths in expressive faces whereas ASD participants (N = 66) exhibited the reverse pattern of holistic recognition for the mouth and analytic recognition of the eyes. CONCLUSION: In summary, findings from the LFI! Battery show that participants with ASD were able to label the basic facial emotions (with the exception of angry expression) on par with age- and IQ-matched TDC participants. However, participants with ASD were impaired in their ability to generalize facial emotions across different identities and showed a tendency to recognize the mouth feature holistically and the eyes as isolated parts.

Lipoprotein receptor-related protein 1 regulates collagen 1 expression, proteolysis, and migration in human pleural mesothelial cells.

The low-density lipoprotein receptor-related protein 1 (LRP-1) binds and can internalize a diverse group of ligands, including members of the fibrinolytic pathway, urokinase plasminogen activator (uPA), and its receptor, uPAR. In this study, we characterized the role of LRP-1 in uPAR processing, collagen synthesis, proteolysis, and migration in pleural mesothelial cells (PMCs). When PMCs were treated with the proinflammatory cytokines TNF-α and IL-1ß, LRP-1 significantly decreased at the mRNA and protein levels (70 and 90%, respectively; P < 0.05). Consequently, uPA-mediated uPAR internalization was reduced by 80% in the presence of TNF-α or IL-1ß (P < 0.05). In parallel studies, LRP-1 neutralization with receptor-associated protein (RAP) significantly reduced uPA-dependent uPAR internalization and increased uPAR stability in PMCs. LRP-1-deficient cells demonstrated increased uPAR t(1/2) versus LRP-1-expressing PMCs. uPA enzymatic activity was also increased in LRP-1-deficient and neutralized cells, and RAP potentiated uPA-dependent migration in PMCs. Collagen expression in PMCs was also induced by uPA, and the effect was potentiated in RAP-treated cells. These studies indicate that TNF-α and IL-1ß regulate LRP-1 in PMCs and that LRP-1 thereby contributes to a range of pathophysiologically relevant responses of these cells.

Effects of risperidone and parent training on adaptive functioning in children with pervasive developmental disorders and serious behavioral problems.

OBJECTIVE: Children with Pervasive Developmental Disorders (PDDs) have social interaction deficits, delayed communication, and repetitive behaviors as well as impairments in adaptive functioning. Many children actually show a decline in adaptive skills compared with age mates over time. METHOD: This 24-week, three-site, controlled clinical trial randomized 124 children (4 through 13 years of age) with PDDs and serious behavioral problems to medication alone (MED; n = 49; risperidone 0.5 to 3.5 mg/day; if ineffective, switch to aripiprazole was permitted) or a combination of medication plus parent training (PT) (COMB; n = 75). Parents of children in COMB received an average of 11.4 PT sessions. Standard scores and Age-Equivalent scores on Vineland Adaptive Behavior Scales were the outcome measures of primary interest. RESULTS: Seventeen subjects did not have a post-randomization Vineland assessment. Thus, we used a mixed model with outcome conditioned on the baseline Vineland scores. Both groups showed improvement over the 24-week trial on all Vineland domains. Compared with MED, Vineland Socialization and Adaptive Composite Standard scores showed greater improvement in the COMB group (p = .01 and .05, and effect sizes = 0.35 and 0.22, respectively). On Age Equivalent scores, Socialization and Communication domains showed greater improvement in COMB versus MED (p = .03 and 0.05, and effect sizes = 0.33 and 0.14, respectively). Using logistic regression, children in the COMB group were twice as likely to make at least 6 months' gain (equal to the passage of time) in the Vineland Communication Age Equivalent score compared with MED (p = .02). After controlling for IQ, this difference was no longer significant. CONCLUSION: Reduction of serious maladaptive behavior promotes improvement in adaptive behavior. Medication plus PT shows modest additional benefit over medication alone. Clinical trial registration information-RUPP PI PDD: Drug and Behavioral Therapy for Children With Pervasive Developmental Disorders; http://www.clinicaltrials.gov; NCT00080145.

Using computerized games to teach face recognition skills to children with autism spectrum disorder: the Let's Face It! program.

BACKGROUND: An emerging body of evidence indicates that relative to typically developing children, children with autism are selectively impaired in their ability to recognize facial identity. A critical question is whether face recognition skills can be enhanced through a direct training intervention. METHODS: In a randomized clinical trial, children diagnosed with autism spectrum disorder were pre-screened with a battery of subtests (the Let's Face It! Skills battery) examining face and object processing abilities. Participants who were significantly impaired in their face processing abilities were assigned to either a treatment or a waitlist group. Children in the treatment group (N = 42) received 20 hours of face training with the Let's Face It! (LFI!) computer-based intervention. The LFI! program is comprised of seven interactive computer games that target the specific face impairments associated with autism, including the recognition of identity across image changes in expression, viewpoint and features, analytic and holistic face processing strategies and attention to information in the eye region. Time 1 and Time 2 performance for the treatment and waitlist groups was assessed with the Let's Face It! Skills battery. RESULTS: The main finding was that relative to the control group (N = 37), children in the face training group demonstrated reliable improvements in their analytic recognition of mouth features and holistic recognition of a face based on its eyes features. CONCLUSION: These results indicate that a relatively short-term intervention program can produce measurable improvements in the face recognition skills of children with autism. As a treatment for face processing deficits, the Let's Face It! program has advantages of being cost-free, adaptable to the specific learning needs of the individual child and suitable for home and school applications.

Promoting social skill development in children with pervasive developmental disorders: a feasibility and efficacy study.

A randomized controlled design was employed to evaluate a social skills intervention for children with pervasive developmental disorders. Aims included evaluating the acceptability of the program and gathering preliminary evidence on efficacy. Forty-four children, ages 8-11 years, were randomly assigned to treatment or wait list. Treatment consisted of a 16-week group intervention designed to teach appropriate social behavior. Between group comparisons showed that children in treatment were rated as improved on the primary outcome measure, (unblinded parent report), but not on the secondary outcome measure, a parent questionnaire. Parents reported a high level of satisfaction with the intervention. The study supports the feasibility of this intervention to families and highlights challenges for future research in social skills intervention.

Medication and parent training in children with pervasive developmental disorders and serious behavior problems: results from a randomized clinical trial.

OBJECTIVE: Many children with pervasive developmental disorders (PDDs) have serious, functionally impairing behavioral problems. We tested whether combined treatment (COMB) with risperidone and parent training (PT) in behavior management is superior to medication alone (MED) in improving severe behavioral problems in children with PDDs. METHOD: This 24-week, three-site, randomized, parallel-groups clinical trial enrolled 124 children, aged 4 through 13 years, with PDDs, accompanied by frequent tantrums, self-injury, and aggression. The children were randomized 3:2 to COMB (n = 75) or MED (n = 49). The participants received risperidone monotherapy from 0.5 to 3.5 mg/day (with switch to aripiprazole if risperidone was ineffective). Parents in the COMB group (n = 75; 60.5%) received a mean of 10.9 PT sessions. The primary measure of compliance was the Home Situations Questionnaire (HSQ) score. RESULTS: Primary: intent-to-treat random effects regression showed that COMB was superior to MED on HSQ (p = .006) [effect size at week 24 (d) = 0.34]. The HSQ score declined from 4.31 (± 1.67) to 1.23 (± 1.36) for COMB compared with 4.16 (± 1.47) to 1.68 (± 1.36) for MED. Secondary: groups did not differ on Clinical Global Impressions-Improvement scores at endpoint; compared with MED, COMB showed significant reductions on Aberrant Behavior Checklist Irritability (d = 0.48; p = .01), Stereotypic Behavior (d = 0.23; p = .04), and Hyperactivity/Noncompliance subscales (d = 0.55; p = .04). Final risperidone mean dose for MED was 2.26 mg/day (0.071 mg/kg), compared with 1.98 mg/day for COMB (0.066 mg/kg) (p = .04). CONCLUSIONS: Medication plus PT resulted in greater reduction of serious maladaptive behavior than MED in children with PDDs, with a lower risperidone dose.