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The complex-systems approach to cognitive science seeks to move beyond the formalism of information exchange and to situate cognition within the broader formalism of energy flow. Changes in cognitive performance exhibit a fractal (i.e., power-law) relationship between size and time scale. These fractal fluctuations reflect the flow of energy at all scales governing cognition. Information transfer, as traditionally understood in the cognitive sciences, may be a subset of this multiscale energy flow. The cognitive system exhibits not just a single power-law relationship between fluctuation size and time scale but actually exhibits many power-law relationships, whether over time or space. This change in fractal scaling, that is, multifractality, provides new insights into changes in energy flow through the cognitive system. We survey recent findings demonstrating the role of multifractality in (a) understanding atypical developmental outcomes, and (b) predicting cognitive change. We propose that multifractality provides insights into energy flows driving the emergence of cognitive structure., (Copyright © 2011 Cognitive Science Society, Inc.)

Objective: Patients with severe left ventricular pressure overload secondary to aortic stenosis can present with signs and symptoms of heart failure despite normal left ventricular ejection fraction. This process occurs, at least in part, as a result of left ventricular pressure overload-induced extracellular matrix remodeling that promulgates increased left ventricular stiffness and impaired diastolic function. However, the determinants that drive extracellular matrix remodeling in this form of left ventricular pressure overload remain to be fully defined., Methods: Left ventricular pressure overload was induced in mature pigs (n = 15) by progressive ascending aortic cuff inflation (once per week for 4 weeks), whereby left ventricular mass, left ventricular ejection fraction, and regional myocardial stiffness (rK(m)) were compared with referent controls (n = 12). Determinants of extracellular matrix remodeling were assessed by measuring levels of mRNA expression for fibrillar collagens, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinase 1 and 4., Results: With left ventricular pressure overload, left ventricular mass and rK(m) increased by 2- and 3-fold, respectively, compared with control, with no change in left ventricular ejection fraction. Left ventricular myocardial collagen increased approximately 2-fold, which was accompanied by reduced solubility (ie, increased cross-linking) with left ventricular pressure overload, but mRNA expression for fibrillar collagen and matrix metalloproteinases remained relatively unchanged. In contrast, a robust increase in mRNA expression for tissue inhibitors of matrix metalloproteinase-1 and 4 occurred with left ventricular pressure overload., Conclusions: In a progressive model of left ventricular pressure overload, which recapitulates the phenotype of aortic stenosis, increased extracellular matrix accumulation and subsequently increased myocardial stiffness were not due to increased fibrillar collagen expression but rather to determinants of post-translational control that included increased collagen stability (thereby resistant to matrix metalloproteinase degradation) and increased endogenous matrix metalloproteinase inhibition. Targeting these extracellular matrix post-translational events with left ventricular pressure overload may hold both diagnostic and therapeutic relevance., (Published by Mosby, Inc.)

The neurobiological sciences have struggled to resolve the physical foundations for biological and cognitive phenomena with a suspicion that biological and cognitive systems, capable of exhibiting and contributing to structure within themselves and through their contexts, are fundamentally distinct or autonomous from purely physical systems. Complexity science offers new physics-based approaches to explaining biological and cognitive phenomena. In response to controversy over whether complexity science might seek to "explain away" biology and cognition as "just physics," we propose that complexity science serves as an application of recent advances in physics to phenomena in biology and cognition without reducing or undermining the integrity of the phenomena to be explained. We highlight that physics is, like the neurobiological sciences, an evolving field and that the threat of reduction is overstated. We propose that distinctions between biological and cognitive systems from physical systems are pretheoretical and thus optional. We review our own work applying insights from post-classical physics regarding turbulence and fractal fluctuations to the problems of developing cognitive structure. Far from hoping to reduce biology and cognition to "nothing but" physics, we present our view that complexity science offers new explanatory frameworks for considering physical foundations of biological and cognitive phenomena.

Background: The present study examined a cardiac passive restraint device which applies epicardial pressure (HeartNet Implant; Paracor Medical, Inc, Sunnyvale, Calif) in a clinically relevant model of dilated cardiomyopathy to determine effects on hemodynamic and myocardial blood flow patterns., Methods: Dilated cardiomyopatht was established in 10 pigs (3 weeks of atrial pacing, 240 beats/min). Hemodynamic parameters and regional left ventricular blood flow were measured under baseline conditions and after acute placement of the HeartNet Implant. Measurements were repeated after adenosine infusion, allowing maximal coronary vasodilation and coronary flow reserve to be determined., Results: Left ventricular dilation and systolic dysfunction occurred relative to baseline as measured by echocardiography. Left ventricular end-diastolic dimension increased and left ventricular fractional shortening decreased (3.8 ± 0.1 vs 6.1 ± 0.2 cm and 31.6% ± 0.5% vs 16.2% ± 2.1%, both P < .05, respectively), consistent with the dilated cardiomyopathy phenotype. The HeartNet Implant was successfully deployed without arrhythmias and a computed median mid-left ventricular epicardial pressure of 1.4 mm Hg was applied by the HeartNet Implant throughout the cardiac cycle. Acute HeartNet placement did not adversely affect steady state hemodynamics. With the HeartNet Implant in place, coronary reserve was significantly blunted., Conclusions: In a large animal model of dilated cardiomyopathy, the cardiac passive restraint device did not appear to adversely affect basal resting myocardial blood flow. However, after acute HeartNet Implant placement, left ventricular maximal coronary reserve was blunted. These unique results suggest that cardiac passive restraint devices that apply epicardial transmural pressure can alter myocardial blood flow patterns in a model of dilated cardiomyopathy. Whether this blunting of coronary reserve holds clinical relevance with chronic passive restraint device placement remains unestablished., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Although localized delivery of biocomposite materials, such as calcium hydroxyapatite (CHAM), have been demonstrated to potentially attenuate adverse left ventricular (LV) remodeling after myocardial infarction (MI), the underlying biological mechanisms for this effect remain unclear. This study tested the hypothesis that targeted CHAM injections would alter proteolytic pathways (matrix metalloproteinases [MMPs] and tissue inhibitors of MMPs [TIMPs]) and would be associated with parameters of post-MI LV remodeling., Methods and Results: MI was induced in adult sheep followed by 20 targeted injections of a total volume of 1.3 mL (n=6) or 2.6 mL of CHAM (n=5) or saline (n=13) and LV end-diastolic volume (EDV) and MMP/TIMP profiles in the MI region were measured at 8 weeks after MI. LV EDV decreased with 2.6 mL CHAM versus MI only (105.4 ± 7.5 versus 80.6 ± 4.2 respectively, P<0.05) but not with 1.3 mL CHAM (94.5 ± 5.0, P=0.32). However, MI thickness increased by 2-fold in both CHAM groups compared with MI only (P<0.05). MMP-13 increased 40-fold in the MI only group (P<0.05) but fell by >6-fold in both CHAM groups (P<0.05). MMP-7 increased approximately 1.5-fold in the MI only group (P<0.05) but decreased to referent control values in both CHAM groups in the MI region (P<0.05). Collagen content was reduced by approximately 30% in the CHAM groups compared with MI only (P<0.05)., Conclusions: Differential effects on LV remodeling and MMP/TIMP profiles occurred with CHAM. Thus, targeted injection of a biocomposite material can favorably affect the post-MI remodeling process and therefore holds promise as a treatment strategy in and of itself, or as a matrix with potentially synergistic effects with localized pharmacological or cellular therapies.

Background: Antifibrinolytic therapy, such as the use of the serine protease inhibitor aprotinin, was a mainstay for hemostasis after cardiac surgery. However, aprotinin was empirically dosed, and although the pharmacological target was the inhibition of plasmin activity (PLact), this was never monitored, off-target effects occurred, and led to withdrawn from clinical use. The present study developed a validated fluorogenic microdialysis method to continuously measure PLact and tested the hypothesis that standardized clinical empirical aprotinin dosing would impart differential and regional effects on PLact., Methods/results: Pigs (30 kg) were instrumented with microdialysis probes to continuously measure PLact in myocardial, kidney, and skeletal muscle compartments (deltoid) and then randomized to high-dose aprotinin administration (2 mKIU load/0.5 mKIU/hr infusion; n = 7), low-dose aprotinin administration (1 mKIU load/0.250 mKIU/hr infusion; n = 6). PLact was compared with time-matched vehicle (n = 4), and PLact was also measured in plasma by an in vitro fluorogenic method. Aprotinin suppressed PLact in the myocardium and kidney at both high and low doses, indicative that both doses exceeded a minimal concentration necessary for PLact inhibition. However, differential effects of aprotinin on PLact were observed in the skeletal muscle, indicative of different compartmentalization of aprotinin., Conclusions: Using a large animal model and a continuous method to monitor regional PLact, these unique results demonstrated that an empirical aprotinin dosing protocol causes maximal and rapid suppression in the myocardium and kidney and in turn would likely increase the probability of off-target effects and adverse events. Furthermore, this proof of principle study demonstrated that continuous monitoring of determinants of fibrinolysis might provide a novel approach for managing fibrinolytic therapy.

The focus of this review is on translational studies utilizing large-animal models and clinical studies that provide fundamental insight into cellular and extracellular pathways contributing to post-myocardial infarction (MI) left ventricle (LV) remodeling. Specifically, both large-animal and clinical studies have examined the potential role of endogenous and exogenous stem cells to alter the course of LV remodeling. Interestingly, there have been alterations in LV remodeling with stem cell treatment despite a lack of long-term cell engraftment. The translation of the full potential of stem cell treatments to clinical studies has yet to be realized. The modulation of proteolytic pathways that contribute to the post-MI remodeling process has also been examined. On the basis of recent large-animal studies, there appears to be a relationship between stem cell treatment post-MI and the modification of proteolytic pathways, generating the hypothesis that stem cells leave an echo effect that moderates LV remodeling.

After a myocardial infarction (MI), an episode of ischemia-reperfusion (I/R) can result in a greater impairment of left ventricular (LV) regional function (LVRF) than that caused by an initial I/R episode in the absence of MI. Membrane type-I matrix metalloproteinase (MT1-MMP) proteolytically processes the myocardial matrix and is upregulated in LV failure. This study tested the central hypothesis that a differential induction of MT1-MMP occurs and is related to LVRF after I/R in the context of a previous MI. Pigs with a previous MI [3 wk postligation of the left circumflex artery (LCx)] or no MI were randomized to undergo I/R [60-min/120-min left anterior descending coronary artery (LAD) occlusion] or no I/R as follows: no MI and no I/R (n = 6), no MI and I/R (n = 8), MI and no I/R (n = 8), and MI and I/R (n = 8). Baseline LVRF (regional stroke work, sonomicrometry) was lower in the LAD region in the MI group compared with no MI (103 ± 12 vs. 188 ± 26 mmHg·mm, P < 0.05) and remained lower with peak ischemia (35 ± 8 vs. 88 ± 17 mmHg·mm, P < 0.05). Using a novel interstitial microdialysis method, MT1-MMP was directly measured and was over threefold higher in the LCx region and over twofold higher in the LAD region in the MI group compared with the no MI group at baseline. MT1-MMP fluorogenic activity was persistently elevated in the LCx region in the MI and I/R group but remained unchanged in the LAD region. In contrast, no changes in MT1-MMP occurred in the LCx region in the no MI and I/R group but increased in the LAD region. MT1-MMP mRNA was increased by over threefold in the MI region in the MI and I/R group. In conclusion, these findings demonstrate that a heterogeneous response in MT1-MMP activity likely contributes to regional dysfunction with I/R and that a subsequent episode of I/R activates a proteolytic cascade within the MI region that may contribute to a continued adverse remodeling process.

Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated O-H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition.

Despite advances in reperfusion therapy, acute coronary syndromes can still result in myocardial injury and subsequent myocardial infarction (MI). Molecular, cellular, and interstitial events antecedent to the acute MI culminate in deleterious changes in the size, shape, and function of the left ventricle (LV), collectively termed LV remodeling. Three distinct anatomic and physiologic LV regions can be described after MI: the infarct, border zone, and remote regions. Given the complexity of post-MI remodeling, imaging modalities must be equally diverse to elucidate this process. The focus of this review will first be on cardiovascular MRI of the anatomic and pathophysiologic LV regions of greatest interest with regard to the natural history of the post-MI remodeling process. This review will then examine imaging modalities that provide translational and molecular insight into burgeoning treatment fields for the attenuation of post-MI remodeling, such as cardiac restraint devices and stem cell therapy.

Background: Epsilon aminocaproic acid (EACA) is used in cardiac surgery to modulate plasmin activity (PLact). The present study developed a fluorogenic-microdialysis system to measure in vivo region specific temporal changes in PLact after EACA administration., Methods: Pigs (25 to 35 kg) received EACA (75 mg/kg, n = 7) or saline in which microdialysis probes were placed in the liver, myocardium, kidney, and quadricep muscle. The microdialysate contained a plasmin-specific fluorogenic peptide and fluorescence emission, which directly reflected PLact, determined at baseline, 30, 60, 90, and 120 minutes after EACA/vehicle infusion., Results: Epsilon aminocaproic acid caused significant decreases in liver and quadricep PLact at 60, 90, 120 minutes, and at 30, 60, and 120 minutes, respectively (p < 0.05). In contrast, EACA induced significant biphasic changes in heart and kidney PLact profiles with initial increases followed by decreases at 90 and 120 minutes (p < 0.05). The peak EACA interstitial concentrations for all compartments occurred at 30 minutes after infusion, and were fivefold higher in the renal compartment and fourfold higher in the myocardium, when compared with the liver or muscle (p < 0.05)., Conclusions: Using a large animal model and in vivo microdialysis measurements of plasmin activity, the unique findings from this study were twofold. First, EACA induced temporally distinct plasmin activity profiles within the plasma and interstitial compartments. Second, EACA caused region-specific changes in plasmin activity profiles. These temporal and regional heterogeneic effects of EACA may have important therapeutic considerations when managing fibrinolysis in the perioperative period., (Copyright (c) 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Recent work in embodied cognition has proposed that representations and actions are inextricably linked. The current study examines a developmental account of this relationship. Specifically, we propose that children's actions are foundational for novel representations. Thirty-two preschoolers, aged 3.4 to 5.7 years, were asked to solve a set of simple gear-system problems. Participants' motions and verbalizations were coded to establish the strategies they used. The preschoolers initially solved the problems by simulating the turning and pushing of the gears. Subsequently, most participants discovered a new representation of the problems: the turning direction of the gears alternates. Results show that the number of actions that embodied alternation information, during their simulation of the system, predicted the later emergence of the higher-order representation (i.e. that the gears alternate turning direction). Thus, it appears that the preschoolers discovered a new representation based on their own actions. These results are consistent with the developmental embodiment hypothesis: actions are central to the emergence of new representations.

Background: A major complication associated with cardiac surgery is excessive and prolonged bleeding in the perioperative period. Improving coagulation by inhibiting fibrinolysis, primarily through inhibition of plasmin activity (PLact) with antifibrinolytics such as tranexamic acid (TXA), has been a pharmacological mainstay in cardiac surgical patients. Despite its almost ubiquitous use, the temporal and regional modulation of PLact profiles by TXA remains unexplored. Accordingly, we developed a fluorogenic-microdialysis system to measure in vivo dynamic changes in PLact after TXA administration in a large animal model., Methods: Pigs (25-35 kg) were randomly assigned to receive TXA (30 mg/kg, diluted into 50 mL normal saline; n = 9) or vehicle (50 mL normal saline; n = 7). Microdialysis probes were placed in the liver, myocardium, kidney, and quadriceps muscle compartments. The microdialysate infusion contained a validated plasmin-specific fluorogenic peptide. The fluorescence emission (standard fluorogenic units [SFU]) of the interstitial fluid collected from the microdialysis probes, which directly reflects PLact, was determined at steady-state baseline and 30, 60, 90, and 120 min after TXA/vehicle infusion. Plasma PLact was determined at the same time points using the same fluorogenic substrate approach., Results: TXA reduced plasma PLact at 30 min after infusion by >110 SFU compared with vehicle values (P < 0.05). Specifically, there was a decrease in liver PLact at 90 and 120 min after TXA infusion of >150 SFU (P < 0.05) and 175 SFU (P < 0.05), respectively. The decrease in liver PLact occurred 60 min after the maximal decrease in plasma PLact. In contrast, kidney, heart, and quadriceps PLact transiently increased followed by an overall decrease at 120 min., Conclusions: Using a large animal model and in vivo microdialysis measurements of PLact, the unique findings from this study were 2-fold. First, TXA induced temporally distinct PLact profiles within the plasma and selected interstitial compartments. Second, TXA caused region-specific changes in PLact profiles. These temporal and regional differences in the effects of TXA may have important therapeutic considerations when managing fibrinolysis in the perioperative period.

Explaining how the cognitive system can create new structures has been a major challenge for cognitive science. Self-organization from the theory of nonlinear dynamics offers an account of this remarkable phenomenon. Two studies provide an initial test of the hypothesis that the emergence of new cognitive structure follows the same universal principles as emergence in other domains (e.g., fluids, lasers). In both studies, participants initially solved gear-system problems by manually tracing the force across a system of gears. Subsequently, they discovered that the gears form an alternating sequence, thereby demonstrating a new cognitive structure. In both studies, dynamical analyses of action during problem solving predicted the spontaneous emergence of the new cognitive structure. Study 1 showed that a peak in entropy, followed by negentropy, key indicators of self-organization, predicted discovery of alternation. Study 2 replicated these effects, and showed that increasing environmental entropy accelerated discovery, a classic prediction from dynamics. Additional analyses based on the relationship between phase transitions and power-law behavior provide converging evidence. The studies provide an initial demonstration of the emergence of cognitive structure through self-organization.

In recent work in cognitive science, it has been proposed that cognition is a self-organizing, dynamical system. However, capturing the real-time dynamics of cognition has been a formidable challenge. Furthermore, it has been unclear whether dynamics could effectively address the emergence of abstract concepts (e.g., language, mathematics). Here, we provide evidence that a quintessentially cognitive phenomenon-the spontaneous discovery of a mathematical relation-emerges through self-organization. Participants solved a series of gear-system problems while we tracked their eye movements. They initially solved the problems by manually simulating the forces of the gears but then spontaneously discovered a mathematical solution. We show that the discovery of the mathematical relation was predicted by changes in entropy and changes in power-law behavior, two hallmarks of phase transitions. Thus, the present study demonstrates the emergence of higher order cognitive phenomena through the nonlinear dynamics of self-organization.

Background: Age-related macular degeneration (AMD) affects > 14 million individuals worldwide. Although 90% of patients with AMD have the dry form, neovascular AMD accounts for the vast majority of patients who develop legal blindness. Until recently, few treatment options existed for treatment of neovascular AMD. The advent of anti-VEGF therapy has significantly improved the safe and effective treatment of neovascular AMD. In addition to two anti-VEGF drugs currently in widespread use, ranibizumab and bevacizumab, a number of medications that interrupt angiogenesis are currently under investigation. One promising new drug is aflibercept (VEGF Trap-Eye), a fusion protein that blocks all isoforms of VEGF-A and placental growth factors-1 and -2., Objective: To review the current literature and clinical trial data regarding VEGF Trap-Eye for the treatment of neovascular AMD., Methods: Literature review., Results/conclusion: VEGF Trap-Eye is a novel anti-VEGF therapy, with Phase I and II trial data indicating safety, tolerability and efficacy for the treatment of neovascular AMD. Two Phase III clinical trials (VIEW-1 and VIEW-2) comparing VEGF Trap-Eye to ranibizumab are currently continuing and will provide vital insight into the clinical applicability of this drug.

Injury to the common bile duct (CBD) during upper gastrointestinal surgery for peptic ulcer disease is a serious complication with an underestimated prevalence in light of the few cases reported in the surgical literature. Three cases of CBD injury were referred to a multidisciplinary specialized gastrointestinal unit for management over a 4-year period. Anomalous anatomy, adhesions, and potential duodenal shortening secondary to contracture all predispose the biliary ducts to intraoperative injury. The axial nature of the blood supply to the extrahepatic ducts and the tendency of bile itself to cause rapid collagen turnover and fibrosis, combined with the inflammation and subsequent fibrosis to the surrounding tissues caused by bile leakage, give the bile ducts a high propensity for stricture formation. Frequently presenting symptoms of CBD injury immediately after surgery include jaundice, elevated bilirubin values, elevated t-tube drainage, and symptoms of sepsis. The most common complaints noted in patients who present in a delayed manner are symptoms of cholangitis. Even when injuries are rapidly identified and corrected, the potential for lasting negative impact on quality of life is great in many cases. When CBD injury occurs, the pancreatic duodenal union can be concomitantly disrupted.

This study explores the diffusive properties of human eye movements during a language comprehension task. In this task, adults are given auditory instructions to locate named objects on a computer screen. Although it has been convention to model visual search as standard Brownian diffusion, we find evidence that eye movements are hyperdiffusive. Specifically, we use comparisons of maximum-likelihood fit as well as standard deviation analysis and diffusion entropy analysis to show that visual search during language comprehension exhibits Lévy-like rather than Gaussian diffusion.

Congestive heart failure (HF) is a clinical syndrome, with hallmarks of fatigue and dyspnea, that continues to be highly prevalent and morbid. Because of the growing burden of HF as the population ages, the need to develop new pharmacological treatments and therapeutic interventions is of paramount importance. Common pathophysiologic features of HF include changes in left ventricle structure, function, and neurohormonal activation. The recapitulation of the HF phenotype in large animal models can allow for the translation of basic science discoveries into clinical therapies. Models of myocardial infarction/ischemia, ischemic cardiomyopathy, ventricular pressure and volume overload, and pacing-induced dilated cardiomyopathy have been created in dogs, pigs, and sheep for the investigation of HF and potential therapies. Large animal models recapitulating the clinical HF phenotype and translating basic science to clinical applications have successfully traveled the journey from bench to bedside. Undoubtedly, large animal models of HF will continue to play a crucial role in the elucidation of biological pathways involved in HF and the development and refinement of HF therapies.

Purpose of Review: Numerous therapeutic options have been suggested for the treatment of central retinal artery occlusion (CRAO) such as ocular massage, anterior chamber paracentesis, physical exercise, and medication-induced reduction of intraocular pressure. Because of the lack of a proven effective treatment for CRAO, there has been a strong effort to develop alternative therapies. Recently, thrombolytic therapy has been suggested as a viable therapy for CRAO. The aim of this review is to provide an update on the progress of thrombolytic therapy for CRAO., Recent Findings: Although there is no consensus on a standardized treatment regimen for CRAO, emerging evidence suggests that thrombolytic therapy may be effective if administered promptly. Despite the benefit of thrombolytic therapy, on the basis of the results of case reports and case series, randomized controlled studies are necessary to ultimately prove the effectiveness of the treatment., Summary: Thrombolytic therapy has yet to be validated as an effective treatment of CRAO. The execution of randomized, controlled trials is greatly needed to establish whether thrombolytic therapy can be considered standard of care therapy for CRAO.

Previous research indicates that mental representations of word meanings are distributed along both semantic and syntactic dimensions such that nouns and verbs are relatively distinct from one another. Two experiments examined the effect of representational distance between meanings on recognition of ambiguous spoken words by comparing recognition of unambiguous words, noun-verb homonyms, and noun-noun homonyms. In Experiment 1, auditory lexical decision was fastest for unambiguous words, slower for noun-verb homonyms, and slowest for noun-noun homonyms. In Experiment 2, response times for matching spoken words to pictures followed the same pattern and eye fixation time courses revealed converging, gradual time course differences between conditions. These results indicate greater competition between meanings of ambiguous words when the meanings are from the same grammatical class (noun-noun homonyms) than they when are from different grammatical classes (noun-verb homonyms).

Time course estimates from eye tracking during spoken language processing (the "visual world paradigm", or VWP) have enabled progress on debates regarding fine-grained details of activation and competition over time. There are, however, three gaps in current analyses of VWP data: consideration of time in a statistically rigorous manner, quantification of individual differences, and distinguishing linguistic effects from non-linguistic effects. To address these gaps, we have developed an approach combining statistical and computational modeling. The statistical approach (growth curve analysis, a technique explicitly designed to assess change over time at group and individual levels) provides a rigorous means of analyzing time course data. We introduce the method and its application to VWP data. We also demonstrate the potential for assessing whether differences in group or individual data are best explained by linguistic processing or decisional aspects of VWP tasks through comparison of growth curve analyses and computational modeling, and discuss the potential benefits for studying typical and atypical language processing.

Many studies have shown that listeners can segment words from running speech based on conditional probabilities of syllable transitions, suggesting that this statistical learning could be a foundational component of language learning. However, few studies have shown a direct link between statistical segmentation and word learning. We examined this possible link in adults by following a statistical segmentation exposure phase with an artificial lexicon learning phase. Participants were able to learn all novel object-label pairings, but pairings were learned faster when labels contained high probability (word-like) or non-occurring syllable transitions from the statistical segmentation phase than when they contained low probability (boundary-straddling) syllable transitions. This suggests that, for adults, labels inconsistent with expectations based on statistical learning are harder to learn than consistent or neutral labels. In contrast, a previous study found that infants learn consistent labels, but not inconsistent or neutral labels.

Purpose: Heart rate recovery (HRR) immediately after peak exercise has utility as a predictor of all-cause mortality. However, a prognostic role for HRR has not been specifically evaluated in patients with type 2 diabetes mellitus (T2DM), nor has an association between HRR and cardiovascular (CV) events been documented. This study investigated whether HRR is predictive of all-cause mortality, CV mortality, and CV events in asymptomatic patients with T2DM., Methods: HRR in subjects with T2DM was obtained via chart review of peak exercise treadmill tests (N = 890) performed at entry into the Appropriate Blood Pressure Control in Diabetes trial. Survival analysis was used to test the association of 1- and 2-min HRR with all-cause mortality, CV mortality, and CV events during the follow-up period., Results: Subjects were followed for a median of 5.0 yr. All-cause mortality and CV events were significantly greater among the lowest quintile (< 12 bpm) of 1-min HRR compared with the fourth (23-28 bpm) quintile. Similarly all-cause mortality and CV events were significantly greater among the lowest quintile (< 28 bpm) of 2-min HRR compared with the third quintile (37-42 bpm) quintile. After adjustment for traditional cardiac risk factors, attenuated 1- and 2-min HRR remained significantly associated with increased risk of CV events as compared with those without attenuation., Conclusions: HRR provides information beyond traditional CV risk factors that could aid in the clinical risk stratification of patients with T2DM. The results suggest that HRR results should be incorporated into standard diagnostic treadmill testing reports and target those patients with T2DM and attenuated HRR who can benefit from directed therapies.

Theories of embodied, modal representation propose that concepts are grounded in the sensorimotor system. According to these theories, action (or the potential for action) creates meaning. An apparent challenge for these theories is the fact that higher-order relations (i.e., relations among relations), such as monotonic increase or alternation, have no straightforward sensorimotor analog. A single action can increase or alternate only relative to another action. Therefore, if embodied theories are to handle concepts more generally, patterns of action must provide meaning to the system. Previous research suggested that as participants simulated the motion of gear problems they discovered a higher-order relation, alternation, based on the episodic traces of their own alternating actions. The present study showed that the number of alternating actions in episodic memory prior to discovery of the alternation relation predicted its generalization to new problem types. Actions can function as the representational substrate of higher-order relations.

The sounds that make up spoken words are heard in a series and must be mapped rapidly onto words in memory because their elements, unlike those of visual words, cannot simultaneously exist or persist in time. Although theories agree that the dynamics of spoken word recognition are important, they differ in how they treat the nature of the competitor set-precisely which words are activated as an auditory word form unfolds in real time. This study used eye tracking to measure the impact over time of word frequency and 2 partially overlapping competitor set definitions: onset density and neighborhood density. Time course measures revealed early and continuous effects of frequency (facilitatory) and on set based similarity (inhibitory). Neighborhood density appears to have early facilitatory effects and late inhibitory effects. The late inhibitory effects are due to differences in the temporal distribution of similarity within neighborhoods. The early facilitatory effects are due to subphonemic cues that inform the listener about word length before the entire word is heard. The results support a new conception of lexical competition neighborhoods in which recognition occurs against a background of activated competitors that changes over time based on fine-grained goodness-of-fit and competition dynamics., (2007 Cognitive Science Society, Inc.)

Recent accounts of language acquisition propose that the knowledge structures that comprise language develop within a single, unified system that shares computational resources and representations. One implication of this approach is that developmental relations within the system become central to theorizing about language acquisition. Previous work suggested that lexical development preceded grammatical development, a developmental ordering with strong theoretical implications. One purpose of the current article is to test this developmental ordering hypothesis. Results showed that children (aged 16-30 months) developed lexicon and grammar synchronously. The second purpose is to demonstrate a recently developed method for testing developmental ordering, the nonlinear-mapping approach, and show how the method can be extended to capitalize on multiply determined developmental systems, such as language.

The use of chemical oil dispersants to minimize spill impacts causes a transient increase in hydrocarbon concentrations in water, which increases the risk to aquatic species if toxic components become more bioavailable. The risk of effects depends on the extent to which dispersants enhance the exposure to toxic components, such as polycyclic aromatic hydrocarbons (PAH). Increased salinities can reduce the solubility of PAH and the efficiency of oil dispersants. This study measured changes in the induction of CYP1A enzymes of fish to demonstrate the effect of salinity on PAH availability. Freshwater rainbow trout and euryhaline mummichog were exposed to water accommodated fractions (WAF), and chemically-enhanced water accommodated fractions (CEWAF) at 0 per thousand, 15 per thousand, and 30 per thousand salinity. For both species, PAH exposure decreased as salinity increased whereas dispersant effectiveness decreased only at the highest salinity. Hence, risks to fish of PAH from dispersed oil will be greatest in coastal waters where salinities are low.

Inhibition of vascular endothelial growth factor receptor (VEGFR) signalling, using either antibodies or small molecule inhibitors of the VEGFR kinase domain, has become a major area of research in oncology. The phthalazine PTK787/ZK222584, first published in the literature in 1998, is one of the most advanced VEGFR inhibitors in the clinic. This paper provides an update on the patenting activity related to the phthalazine class. In addition, newer kinase inhibitor pharmacophores derived from this class (e.g., anthranilamides) will be reviewed.

Developmental ordering is a fundamental prediction in developmental science. However, tests of ordering hypotheses are not generally available for continuously developing variables. One promising test of developmental ordering, the shape of the relationship between 2 variables, requires that changes in each underlying variable are captured equally well across the developmental span (measures are linearly related to the variables). If either measure is more sensitive to earlier or later developmental changes in the underlying variable, the shape of the relationship changes radically. The article demonstrates that the viable alternative hypotheses for an observed developmental relationship require specific types of nonlinearity in measurement and, therefore, have testable predictions for the residuals (the second moment). Ordering as evidence in developmental science is discussed.

This paper explores an accepted but under researched feature of national categories: their complex relationship with social constructions of place. We argue that social psychological work on national identification and mobilization would benefit from closer attention to this relationship. In order to develop this argument, we analyse a series of newspaper accounts published on behalf of the Countryside Alliance, a coalition formed to preserve rural 'ways of life' in the UK and, more specifically, to defend extant practices of hunting. Applying a discourse analytic method, we show how the Alliance has exploited the rhetoric of place in order to portray the preservation of hunting as an issue of national significance. By associating British identity with the 'rural idyll' of the English countryside, the organization has appealed to a place construction in which hunting and its associated activities become cast as essential expressions of the national character. Building on relevant work in geography and discursive psychology, we trace some wider implications of this process for social psychological research on category construction, reification and collective mobilization.

The authors investigated the effect of accent evaluation, evidence, and crime type on participants' perceptions of guilt and criminality. British student raters (n = 199) listened to a tape-recorded exchange between a male criminal suspect and a male policeman. The authors manipulated this exchange to produce a 2 (accent type: English regional or standard) x 2 (evidence type: strong or weak) x 2 (crime type: blue collar or white collar) factorial design. Dependent measures consisted of participants' ratings of the suspect's guilt and criminality. Contrary to previous research, accent did not significantly influence attributions of guilt either as a main effect or in interaction with the contextual variables. However, independent of evidence presented and crime type, the regional-accented suspect was evaluated as more typically criminal and more likely to be reaccused of a crime than the standard-accented suspect.

How relational information becomes disembedded from its original context is an important issue for theories of cognition. Two experiments tested the hypothesis that a process called redescription disembeds relations, resulting in abstract and, therefore, more transferable and robust representations. In Experiment 1, participants solved simple problems involving an alternating sequence. Participants who discovered the alternating-sequence relation through redescription transferred the relation to a second type of problem more quickly and used it more consistently than did participants who had been directly instructed on the alternating-sequence strategy. Experiment 2 showed similar effects for participants who discovered the alternating-sequence relation through redescription, as compared with participants who had discovered the relation through information available in the display. The present results converge with previous experimental and correlational evidence that suggests that redescription creates abstract representations of relations.

The sustainability of development is closely linked to changes in total per capita wealth. This paper presents estimates of the wealth of nations for nearly 100 countries, broken down into produced assets, natural resources and human resources. While the latter is the dominant form of wealth in virtually all countries, in low income natural resource exporters the share of natural resources in total wealth is equal to the share of produced assets. For low income countries in general, cropland forms the vast majority of natural wealth. The analysis suggests the process of development can be viewed as one of portfolio management: sustainable development entails saving the rents from exhaustible resources, managing renewable resources sustainably, and investing savings in both produced assets and human resources.

Previous evidence implicating Paramyxoviruses in the aetiopathology of Paget's disease of bone has proved controversial. Whilst several groups have demonstrated Paramyxoviruses using techniques such as in situ hybridisation (ISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and in situ-RT-PCR (IS-RT-PCR), others have found no evidence of viruses using only RT-PCR. To investigate this latter finding, we have now compared detection of canine distemper virus by ISH, RT-PCR (three different methods) and IS-RT-PCR, in 10 patients with Paget's disease, and samples of non-diseased bone from four patients. Canine distemper virus was detectable in six of the samples by ISH, but only in five of the samples by RT-PCR, using one of the methods. Neither of the other RT-PCR methods detected canine distemper virus. IS-RT-PCR demonstrated canine distemper virus in all 10 samples. There was no evidence of virus in the control samples. We have shown that the ability to detect canine distemper virus in bone is dependent on the technique used. IS-RT-PCR clearly showed that canine distemper virus was present in 100% of Pagetic samples, whereas canine distemper virus was only found in 60% by ISH and in 50% using one particular RT-PCR method. These results provide conclusive evidence that canine distemper virus is present within Pagetic bone, and provide a possible explanation for the failure of some groups to detect Paramyxovirus sequences. These findings also have wider implications for other studies investigating viral expression.

Microgenetic research has identified 2 different types of processes that produce representational change: theory revision and redescription. Both processes have been implicated as important sources of developmental change, but their relative status across development has not been addressed. The current study investigated whether (a) the process of representational change undergoes developmental change itself or (b) different processes occupy different niches in the course of knowledge acquisition. College, 3rd-, and 6th-grade students solved gear system problems over 2 sessions. For all grades, discovery of the physical principles of the gear system was consistent with theory revision, but discovery of a more sophisticated strategy, based on the alternating sequence of gears, was consistent with redescription. The results suggest that these processes may occupy different niches in the course of acquiring knowledge and that the processes are developmentally invariant across a broad age range.

Current theories of mathematical problem solving propose that people select a mathematical operation as the solution to a problem on the basis of a structure mapping between their problem representation and the representation of the mathematical operations. The structure-mapping hypothesis requires that the problem and the mathematical representations contain analogous relations. Past research has demonstrated that the problem representation consists of functional relationships, or principles. The present study tested whether people represent analogous principles for each arithmetic operation (i.e., addition, subtraction, multiplication, and division). For each operation, college (Experiments 1 and 2) and 8th grade (Experiment 2) participants were asked to rate the degree to which a set of completed problems was a good attempt at the operation. The pattern of presented answers either violated one of four principles or did not violate any principles. The distance of the presented answers from the correct answers was independently manipulated. Consistent with the hypothesis that people represent the principles, (1) violations of the principles were rated as poorer attempts at the operation, (2) operations that are learned first (e.g., addition) had more extensive principle representations than did operations learned later (multiplication), and (3) principles that are more frequently in evidence developed more quickly. In Experiment 3, college participants rated the degree to which statements were indicative of each operation. The statements were either consistent or inconsistent with one of two principles. The participants' ratings showed that operations with longer developmental histories had strong principle representations. The implications for a structure-mapping approach to mathematical problem solving are discussed.

Background: Our purpose is to examine levels of Fas mRNA expression in blood during human corneal transplant rejection., Methods: Fas mRNA expression was detected by reverse transcription-PCR in blood from normal controls, corneal recipients at the time of transplantation and during episodes of rejection., Results: Samples taken at the time of a corneal rejection episode showed Fas mRNA levels were significantly lower in these patients than either normal controls (P = 0.017) or corneal transplant recipients not undergoing graft rejection (P = 0.00052). Serial samples from five patients who suffered an episode of rejection showed that the level of Fas mRNA is reduced during the rejection episode and subsequently recovers., Conclusions: These results indicate low levels of Fas mRNA in blood may have a role in corneal transplant rejection.

Much of the knowledge that children and adults have about the world resides in intuitive models. Previous work shows that intuitive models allow for computation of specific outcomes given information about the system, but little is known about how such models are acquired. The current study tested three hypotheses about how children and adults construct intuitive models when they encounter a new property: (1) intuitive models are constructed by transferring principles from familiar properties; (2) with development, children shift from applying a default model to constructing specialized models; and (3) younger children's model construction is constrained by the domain, but becomes increasingly domain independent with development. Participants from three age groups (10, 13, and 19 years) made a series of judgments about two familiar properties and one novel property. Causal models showed that all age groups transferred principles from the familiar properties to the novel property. None of the age groups used a default model. There was developmental change in the effect of domain; younger, but not older, children's models were affected by domain. These findings suggest that the transfer process is developmentally invariant but that constraints on the process (i.e., domain dependence and understanding of base models) change with development., (Copyright 2001 by Academic Press.)

Developmental ordering is a fundamental prediction of developmental theories and a central issue in developmental research. However, logically sound evidence of developmental ordering is difficult to obtain. This article analyzes the logical basis of testing developmental order hypotheses with categorical measures. Depending on whether saltatory (i.e., discrete) or continuous developmental changes are being assessed, the observed relationship between categorical measures yields very different types of information about developmental ordering. When change is continuous, the relationship between the measures does not confirm any one ordering hypothesis, but rather, disconfirms one or more hypotheses. Whether an underlying variable undergoes saltatory or continuous development has long been recognized as an important theoretical issue, but its impact on the interpretation of developmental ordering has not previously been explicated.

A key issue concerning the primary conversion (Q(O)) site function in the cytochrome bc(1) complex is the stoichiometry of ubiquinone/ubihydroquinone occupancy. Previous evidence suggests that the Q(O) site is able to accommodate two ubiquinone molecules, the double occupancy model [Ding, H., Robertson, D. E., Daldal, F., and Dutton, P. L. (1992) Biochemistry 31, 3144-3158]. In the recently reported crystal structures of the cytochrome bc(1) complex, no electron density was identified in the Q(O) site that could be ascribed to ubiquinone. To provide further insight into this issue, we have manipulated the cytochrome bc(1) complex Q(O) site occupancy in photosynthetic membranes from Rhodobacter capsulatus by using inhibitor titrations and ubiquinone extraction to modulate the amount of ubiquinone bound in the site. The nature of the Q(O) site occupants was probed via the sensitivity of the reduced [2Fe-2S] cluster electron paramagnetic resonance (EPR) spectra to modulation of Q(O) site occupancy. Diphenylamine (DPA) and methoxyacrylate (MOA)-stilbene are known Q(O) site inhibitors of the cytochrome bc(1) complex. Addition of stoichiometric concentrations of MOA-stilbene or excess DPA to cytochrome bc(1) complexes with natural levels of ubiquinone elicits the same change in the [2Fe-2S] cluster EPR spectra; the g(x)() resonance broadens and shifts from 1. 800 to 1.783. This is exactly the same signal as that obtained when there is only one ubiquinone present in the Q(O) site. Furthermore, addition of MOA-stilbene or DPA to the cytochrome bc(1) complex depleted of ubiquinone does not alter the [2Fe-2S] cluster EPR spectral line shapes, which remain indicative of one ubiquinone or zero ubiquinones in the Q(O) site, with broad g(x)() resonances at 1. 783 or 1.765, respectively. The results are quite consistent with the Q(O) site double occupancy model, in which MOA-stilbene and DPA inhibit by displacing one, but not both, of the Q(O) site ubiquinones.

An asymmetric, tandem inter [4 + 2]/intra [3 + 2] bridged mode (beta-tether) cycloaddition of nitroalkenes has been developed. This new sequence involves the Lewis acid-promoted [4 + 2] cycloaddition of nitro olefins with enantiopure 1-alkoxy-1,4-dienes. The resulting nitronates, bearing a C(5) tethered dipolarophile, undergo thermal, intramolecular [3 + 2] cycloaddition to afford stable tricyclic nitroso acetals, which can be subsequently reduced to provide interesting aminocyclopentanes. Thus, in three steps, highly functionalized, enantiomerically enriched aminocyclopentanes can be constructed with good yield and high ee. Additionally, the Lewis acid was found to impart a remarkable influence on the stereochemical outcome of the [4 + 2] cycloaddition.

A new variation of the tandem inter [4 + 2]/intra [3 + 2] cycloaddition of nitroalkenes has been developed. This method involves the Lewis acid-promoted [4 + 2] cycloaddition of nitro olefins 12 with 1-alkoxy-1,4-dienes 3. The resulting nitronates 13, bearing a C(5) tethered dipolarophile, undergo thermal, intramolecular [3 + 2] cycloaddition to afford stable tricyclic nitroso acetals 14, which can be subsequently reduced to unveil a new carbocycle 16. Thus, in three steps, highly functionalized aminocyclopentanes can be stereoselectively constructed in high yield.

Previous evidence implicating paramyxoviruses in the aetiopathology of Paget's disease of bone has been controversial. While several groups have demonstrated the presence of paramyxoviruses using electron microscopy, immunohistochemistry, and molecular biological techniques, others have found no evidence of viruses using reverse transcriptase-polymerase chain reaction (RT-PCR). We have previously provided evidence that canine distemper virus (CDV) is present in approximately 65% of samples of pagetic bone, using in situ hybridization and RT-PCR; however, these results have been criticized. To further investigate the possible Role of CDV, we have now developed the technique of in situ-RT-PCR (IS-RT-PCR) to examine for the presence of CDV-nucleocapsid (CDV-N) ribonucleic acid (RNA) in pagetic bone. Control samples consisted of uninvolved sites from patients with the disease, normal bone, and several active remodeling states. IS-RT-PCR was optimized to detect CDV-N using distemper-infected vero cells. The specificity of the technique was confirmed using vero cells infected with CDV, which showed amplified signal following IS-RT-PCR, and cells infected with measles virus (MV), in which no positive signal for CDV was detected by IS-RT-PCR. Following conventional in situ hybridization, CDV-N was detectable in 10 of 15 pagetic bone samples. However, after five, and particularly 10, cycles of IS-RT-PCR, CDV-N was found in all 15 samples. There was no evidence of CDV in four samples from uninvolved sites from pagetic patients, or in any of the other control samples. In this study, using the novel technique of IS-RT-PCR, CDV was found to be present in 100% of pagetic samples examined. There was no evidence of the virus in any of the control samples, including samples of bone from uninvolved sites from patients with Paget's disease. These results provide additional proof that CDV is present within pagetic bone and further support the hypothesis that paramyxoviruses are involved in the etiopathology of Paget's disease.