mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria.

The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using (S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [18F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria.

How a hobby can shape cognition: visual word recognition in competitive Scrabble players.

Competitive Scrabble is an activity that involves extraordinary word recognition experience. We investigated whether that experience is associated with exceptional behavior in the laboratory in a classic visual word recognition paradigm: the lexical decision task (LDT). We used a version of the LDT that involved horizontal and vertical presentation and a concreteness manipulation. In Experiment 1, we presented this task to a group of undergraduates, as these participants are the typical sample in word recognition studies. In Experiment 2, we compared the performance of a group of competitive Scrabble players with a group of age-matched nonexpert control participants. The results of a series of cognitive assessments showed that the Scrabble players and control participants differed only in Scrabble-specific skills (e.g., anagramming). Scrabble expertise was associated with two specific effects (as compared to controls): vertical fluency (relatively less difficulty judging lexicality for words presented in the vertical orientation) and semantic deemphasis (smaller concreteness effects for word responses). These results suggest that visual word recognition is shaped by experience, and that with experience there are efficiencies to be had even in the adult word recognition system.

Prognosis and prognostic factors for patients with persistent wrist pain who proceed to wrist arthroscopy.

UNLABELLED: Wrist pain is common. People with persistent pain commonly undergo arthroscopic investigation. Little is known about the prognosis or prognostic factors for these patients. The purpose of the study was to evaluate prognosis and prognostic factors for pain and functional disability in patients with persistent wrist pain who proceed to arthroscopic investigation. The study design used was a prospective cohort study. One hundred and five consecutive participants who underwent arthroscopic investigation for undiagnosed wrist pain for at least four-week duration were recruited. Patient-rated wrist and hand evaluation (PRWHE) scores were determined at baseline (before arthroscopy) and one year after arthroscopy. One-year follow-up data were obtained for 97 (92%) of 105 participants. Mean PRWHE total score declined from 49 of 100 (standard deviation [SD] 18.5) at baseline to 26 of 100 (SD 20.4) at one year. Two prognostic factors were identified: baseline PRWHE and duration of symptoms. These factors explained 19% and 5% of the variability in the final PRWHE score, respectively. Results of provocative wrist tests and arthroscopic findings did not significantly contribute to prognosis in this cohort. This study provides the first robust evidence of the prognosis of persistent wrist pain. Participants who underwent arthroscopic investigation for persistent wrist pain improved on average by approximately 50% at one year; however, most continued to have some pain and disability. Duration of pain and PRWHE at baseline explained 24% of the one-year PRWHE score. LEVEL OF EVIDENCE: Level 2.

A generic environmental risk assessment framework for deep-sea tailings placement.

Deep-sea tailings placement (DSTP) involves the oceanic discharge of tailings at depth (usually >100 m), with the intent of ultimate deposition of tailings solids on the deep-sea bed (>1000 m), well below the euphotic zone. DSTP discharges consist of a slurry of mine tailings solids (finely crushed rock) and residual process liquor containing low concentrations of metals, metalloids, flotation agents and flocculants. This slurry can potentially affect both pelagic and benthic biota inhabiting coastal waters, the continental slope and the deep-sea bed. Building on a conceptual model of DSTP exposure pathways and receptors, we developed a stressor-driven environmental risk assessment (ERA) framework using causal pathways/causal networks for each of eight pelagic and benthic impact zones. For the risk characterisation, each link in each causal pathway in each zone was scored using four levels of likelihood (not possible, possible, likely and certain) and two levels of consequence (not material, material) to give final risk rankings of low, potential, high or very high risk. Of the 246 individual causal pathways scored, 11 and 18 pathways were considered to be of very high risk and high risk respectively. These were confined to the benthic zones in the mixing zone (continental slope) and the primary and secondary deposition zones. The new risk framework was then tested using a case study of the Batu Hijau copper mine in Indonesia, the largest DSTP operation globally. The major risk of DSTP is smothering of benthic biota, even outside the predicted deposition zones. Timescales for recovery are slow and may lead to different communities than those that existed prior to tailings deposition. We make several recommendations for monitoring programs for existing, proposed and legacy DSTP operations and illustrate how georeferenced causal networks are valuable tools for ERA in DSTP.

Rosuvastatin lowers coenzyme Q10 levels, but not mitochondrial adenosine triphosphate synthesis, in children with familial hypercholesterolemia.

OBJECTIVE: To investigate whether statin therapy affects coenzyme Q10 (CoQ10) status in children with heterozygous familial hypercholesterolemia (FH). STUDY DESIGN: Samples were obtained at baseline (treatment naïve) and after dose titration with rosuvastatin, aiming for a low-density lipoprotein cholesterol level of 110 mg/dL. Twenty-nine patients were treated with 5, 10, or 20 mg of rosuvastatin for a mean period of 29 weeks. RESULTS: We found a significant (32%) decrease in peripheral blood mononuclear cell (PBMC) CoQ10 level (P = .02), but no change in PBMC adenosine triphosphate synthesis (P = .60). Uncorrected plasma CoQ10 values were decreased significantly, by 45% (P < .01). In contrast, ratios of plasma CoQ10/total cholesterol and CoQ10/low-density lipoprotein cholesterol remained equal during treatment. CONCLUSIONS: In children with FH, rosuvastatin causes a significant decrease in cellular PBMC CoQ10 status but does not affect mitochondrial adenosine triphosphate synthesis in children with FH. Further studies should address whether (rare) side effects of statin therapy could be explained by a deterioration in CoQ10 status.

Abnormalities of lexical and semantic processing in left temporal lobe epilepsy: an fMRI study.

PURPOSE: We examined the efficiency of lexical and semantic processing and associated brain activation using functional magnetic resonance imaging (fMRI) in patients with left temporal lobe epilepsy (TLE). METHODS: Twenty patients with left TLE (10 with hippocampal sclerosis, the HS group; and 10 with nonlesional MR scans, the NL group) and 12 healthy controls underwent an event-related fMRI analysis during a lexical decision task (LDT). Lexical and semantic processing were examined by comparing behavioral and imaging data associated with words and nonwords (lexicality) or with concrete and abstract words (concreteness). KEY FINDINGS: Although the control group showed greater activation associated with word stimuli than with nonword stimuli in a bilateral language network, both TLE groups showed greater activation for nonword stimuli than word stimuli, including greater activation of inferior frontal language areas (bilaterally in the HS group and left-lateralized in the NL group). The TLE groups also exhibited differential activation patterns during the processing of abstract and concrete words compared to controls, and compared to each other. For abstract words, in particular, the HS group showed activation of frontal areas typically associated with executive functions, whereas the NL group showed activation of more posterior semantic processing regions. SIGNIFICANCE: These results suggest that left TLE is associated with altered functional organization of cortical networks involved in lexical and semantic processing. In addition, the organization observed varies as a function of hippocampal pathology.

A feasibility, randomised controlled trial of a complex breathlessness intervention in idiopathic pulmonary fibrosis (BREEZE-IPF): study protocol.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease that causes breathlessness and cough that worsen over time, limiting daily activities and negatively impacting quality of life. Although treatments are now available that slow the rate of lung function decline, trials of these treatments have failed to show improvement in symptoms or quality of life. There is an immediate unmet need for evidenced-based interventions that improve patients' symptom burden and make a difference to everyday living. This study aims to assess the feasibility of conducting a definitive randomised controlled trial of a holistic, complex breathlessness intervention in people with IPF. METHODS AND ANALYSIS: The trial is a two-centre, randomised controlled feasibility trial of a complex breathlessness intervention compared with usual care in patients with IPF. 50 participants will be recruited from secondary care IPF clinics and randomised 1:1 to either start the intervention within 1 week of randomisation (fast-track group) or to receive usual care for 8 weeks before receiving the intervention (wait-list group). Participants will remain in the study for a total of 16 weeks. Outcome measures will be feasibility outcomes, including recruitment, retention, acceptability and fidelity of the intervention. Clinical outcomes will be measured to inform outcome selection and sample size calculation for a definitive trial. ETHICS AND DISSEMINATION: Yorkshire and The Humber - Bradford Leeds Research Ethics Committee approved the study protocol (REC 18/YH/0147). Results of the main trial and all secondary end-points will be submitted for publication in a peer-reviewed journal.

There are many ways to be rich: effects of three measures of semantic richness on visual word recognition.

Previous studies have reported that semantic richness facilitates visual word recognition (see, e.g., Buchanan, Westbury, & Burgess, 2001; Pexman, Holyk, & Monfils, 2003). We compared three semantic richness measures--number of semantic neighbors (NSN), the number of words appearing in similar lexical contexts; number of features (NF), the number of features listed for a word's referent; and contextual dispersion (CD), the distribution of a word's occurrences across content areas-to determine their abilities to account for response time and error variance in lexical decision and semantic categorization tasks. NF and CD accounted for unique variance in both tasks, whereas NSN accounted for unique variance only in the lexical decision task. Moreover, each measure showed a different pattern of relative contribution across the tasks. Our results provide new clues about how words are represented and suggest that word recognition models need to accommodate each of these influences.

This is your brain on Scrabble: Neural correlates of visual word recognition in competitive Scrabble players as measured during task and resting-state.

Competitive Scrabble players devote considerable time to studying words and practicing Scrabble-related skills (e.g., anagramming). This training is associated with extraordinary performance in lexical decision, the standard visual word recognition task (Hargreaves, Pexman, Zdrazilova & Sargious, 2012). In the present study we investigated the neural consequences of this lexical expertise. Using both event-related and resting-state fMRI, we compared brain activity and connectivity in 12 competitive Scrabble experts with 12 matched non-expert controls. Results showed that when engaged in the lexical decision task (LDT), Scrabble experts made use of brain regions not generally associated with meaning retrieval in visual word recognition, but rather those associated with working memory and visual perception. The analysis of resting-state data also showed group differences, such that a different network of brain regions was associated with higher levels of Scrabble-related skill in experts than in controls.

Testing the Limits of Skill Transfer for Scrabble Experts in Behavior and Brain.

We investigated transfer of the skills developed by competitive Scrabble players. Previous studies reported superior performance for Scrabble experts on the lexical decision task (LDT), suggesting near transfer of Scrabble skills. Here we investigated the potential for far transfer to a symbol decision task (SDT); in particular, transfer of enhanced long-term working memory for vertically presented stimuli. Our behavioral results showed no evidence for far transfer. Despite years of intensive practice, Scrabble experts were no faster and no more accurate than controls in the SDT. However, our fMRI and EEG data from the SDT suggest that the neural repertoire that Scrabble experts develop supports task performance even outside of the practiced domain, in a non-linguistic context. The regions engaged during the SDT were different across groups: controls engaged temporal-frontal regions, whereas Scrabble experts engaged posterior visual and temporal-parietal regions. In Scrabble experts, activity related to Scrabble skill (anagramming scores) included regions associated with visual-spatial processing and long-term working memory, and overlapped with regions previously shown to be associated with Scrabble expertise in the near transfer task (LDT). Analysis of source waveforms within these regions showed that participants with higher anagramming scores had larger P300 amplitudes, potentially reflecting greater working memory capacity, or less variability in the participants who performed the task more efficiently. Thus, the neuroimaging results provide evidence of brain transfer in the absence of behavioral transfer, providing new clues about the consequences of long-term training associated with competitive Scrabble expertise.

Semantic classification of pictures and words.

We provide new behavioural norms for semantic classification of pictures and words. The picture stimuli are 288 black and white line drawings from the International Picture Naming Project ([Székely, A., Jacobsen, T., D'Amico, S., Devescovi, A., Andonova, E., Herron, D., et al. (2004). A new on-line resource for psycholinguistic studies. Journal of Memory & Language, 51, 247-250]). We presented these pictures for classification in a living/nonliving decision, and in a separate version of the task presented the corresponding word labels for classification. We analyzed behavioural responses to a subset of the stimuli in order to explore questions about semantic processing. We found multiple semantic richness effects for both picture and word classification. Further, while lexical-level factors were related to semantic classification of words, they were not related to semantic classification of pictures. We argue that these results are consistent with privileged semantic access for pictures, and point to ways in which these data could be used to address other questions about picture processing and semantic memory.

Get rich quick: the signal to respond procedure reveals the time course of semantic richness effects during visual word recognition.

According to several current frameworks, semantic processing involves an early influence of language-based information followed by later influences of object-based information (e.g., situated simulations; Santos, Chaigneau, Simmons, & Barsalou, 2011). In the present study we examined whether these predictions extend to the influence of semantic variables in visual word recognition. We investigated the time course of semantic richness effects in visual word recognition using a signal-to-respond (STR) paradigm fitted to a lexical decision (LDT) and a semantic categorization (SCT) task. We used linear mixed effects to examine the relative contributions of language-based (number of senses, ARC) and object-based (imageability, number of features, body-object interaction ratings) descriptions of semantic richness at four STR durations (75, 100, 200, and 400ms). Results showed an early influence of number of senses and ARC in the SCT. In both LDT and SCT, object-based effects were the last to influence participants' decision latencies. We interpret our results within a framework in which semantic processes are available to influence word recognition as a function of their availability over time, and of their relevance to task-specific demands.

Does richness lose its luster? Effects of extensive practice on semantic richness in visual word recognition.

Previous studies have reported facilitatory effects of semantic richness on word recognition (e.g., Yap et al., 2012). These effects suggest that word meaning is an important contributor to lexical decision task (LDT) performance, but what are the effects of repeated LDT practice on these semantic contributions? The current study utilized data from the British Lexicon Project (BLP) in which 78 participants made lexical decision judgments for 28,730 words over 16 h. We used linear mixed effects to detect practice-driven changes in the explanatory variance accounted for by a set of lexical predictors that included numerous indices of relative semantic richness, including imageability, the number of senses and average radius of co-occurrence (ARC). Results showed that practice was associated with decreasing effects of predictors such as word frequency and imageability. In contrast, ARC effects were only slightly diminished with repeated practice, and effects of the number of senses and the age of acquisition were unaffected by practice. We interpret our results within a framework in which variables may dynamically influence lexical processing and the post-lexical decision making mechanisms that also contribute to LDT performance.

The question shapes the answer: the neural correlates of task differences reveal dynamic semantic processing.

Task effects in semantic processing were investigated by contrasting the neural activation associated with two semantic categorization tasks (SCT) using event-related fMRI. The two SCTs involved different decision categories: is it an animal? vs. is it a concrete thing? Participants completed both tasks and, across participants, the same core set of items were presented in both tasks. Results showed task differences in the neural activation associated with these items: in the animal SCT there was greater activation in a number of frontal and temporal regions, including left superior and middle temporal gyri, while in the concrete SCT there was greater activation in left medial frontal gyrus and bilaterally in the precentral gyri. These results are interpreted as evidence of top-down modulation of semantic processing; participants make adjustments to optimize performance in a given task and these adjustments have consequences for the activation observed.

An abundance of riches: cross-task comparisons of semantic richness effects in visual word recognition.

There is considerable evidence (e.g., Pexman et al., 2008) that semantically rich words, which are associated with relatively more semantic information, are recognized faster across different lexical processing tasks. The present study extends this earlier work by providing the most comprehensive evaluation to date of semantic richness effects on visual word recognition performance. Specifically, using mixed effects analyses to control for the influence of correlated lexical variables, we considered the impact of number of features, number of senses, semantic neighborhood density, imageability, and body-object interaction across five visual word recognition tasks: standard lexical decision, go/no-go lexical decision, speeded pronunciation, progressive demasking, and semantic classification. Semantic richness effects could be reliably detected in all tasks of lexical processing, indicating that semantic representations, particularly their imaginal and featural aspects, play a fundamental role in visual word recognition. However, there was also evidence that the strength of certain richness effects could be flexibly and adaptively modulated by task demands, consistent with an intriguing interplay between task-specific mechanisms and differentiated semantic processing.

Richer concepts are better remembered: number of features effects in free recall.

Many models of memory build in a term for encoding variability, the observation that there can be variability in the richness or extensiveness of processing at encoding, and that this variability has consequences for retrieval. In four experiments, we tested the expectation that encoding variability could be driven by the properties of the to-be-remembered item. Specifically, that concepts associated with more semantic features would be better remembered than concepts associated with fewer semantic features. Using feature listing norms we selected sets of items for which people tend to list higher numbers of features (high NoF) and items for which people tend to list lower numbers of features (low NoF). Results showed more accurate free recall for high NoF concepts than for low NoF concepts in expected memory tasks (Experiments 1-3) and also in an unexpected memory task (Experiment 4). This effect was not the result of associative chaining between study items (Experiment 3), and can be attributed to the amount of item-specific processing that occurs at study (Experiment 4). These results provide evidence that stimulus-specific differences in processing at encoding have consequences for explicit memory retrieval.

The neural correlates of the body-object interaction effect in semantic processing.

The semantic richness dimension referred to as body-object interaction (BOI) measures perceptions of the ease with which people can physically interact with words' referents. Previous studies have shown facilitated lexical and semantic processing for words rated high in BOI, e.g., belt, than for words rated low in BOI, e.g., sun. These BOI effects have been taken as evidence that embodied information is relevant to word recognition (Siakaluk et al., 2008a). However, to date there is no evidence linking BOI manipulations to differences in the utilization of perceptual or sensorimotor areas of the brain. The current study used event-related functional magnetic resonance imaging (fMRI) to examine the neural correlates of BOI in a semantic categorization task (SCT). Sixteen healthy adults participated. Results showed that high BOI words were associated with activation in the left inferior parietal lobule (supramarginal gyrus, BA 40), a sensory association area involved in kinesthetic memory. These results provide evidence that the BOI dimension captures the relative availability of sensorimotor information, and that this contributes to semantic processing.

Provocative wrist tests and MRI are of limited diagnostic value for suspected wrist ligament injuries: a cross-sectional study.

QUESTION: What is the diagnostic value of provocative wrist tests and magnetic resonance imaging (MRI) for suspected wrist ligament injuries? DESIGN: Cross-sectional study. PARTICIPANTS: 105 people presenting to hand clinics with wrist pain and suspected wrist ligament injuries were evaluated prospectively. OUTCOME MEASURES: The integrity of wrist ligaments was tested with seven provocative tests. The results were compared to the reference standard of arthroscopy. In a subgroup of 55 participants, MRI findings were also compared to arthroscopy. The provocative tests were the scaphoid shift test (SS test), lunotriquetral test (LT test), midcarpal test (MC test), distal radioulnar joint test (DRUJ test), triangular fibrocartilage complex (TFCC) stress test (TFCC test), TFCC stress test with compression (TFCC comp test), and the gripping rotatory impaction test (GRIT). RESULTS: Most provocative tests and MRI findings were of little or no value for diagnosing wrist ligament injuries. Exceptions were the SS test (+ve LR 2.88 and -ve LR 0.28), MC test (+ve LR 2.67) and DRUJ test (-ve LR 0.30), all of which were of mild diagnostic usefulness. MRI was moderately useful for diagnosing TFCC injuries (+ve LR 5.56, -ve LR 0.15), and was mildly useful for diagnosing scapholunate (SL) ligament injuries (+ve LR 4.17, -ve LR 0.32) and lunate cartilage damage (+ve LR 3.67, -ve LR 0.33). Adding MRI to provocative tests improved the accuracy of diagnosis of TFCC injuries slightly (by 13%) and lunate cartilage damage (by 8%). CONCLUSION: Provocative wrist tests of SL ligament injuries and midcarpal ligament injuries are mildly useful for diagnosing wrist injuries. MRI diagnostic findings of SL ligament injuries, lunate cartilage damage, and TFCC are mildly to moderately useful. MRI slightly improves the diagnosis of TFCC injury and lunate cartilage damage compared to provocative tests alone.

Tolerating ambiguity: ambiguous words recruit the left inferior frontal gyrus in absence of a behavioral effect.

Many models of word recognition predict a lexical ambiguity disadvantage in semantic categorization tasks (SCTs). However, recent evidence suggests that an ambiguity disadvantage in SCT results from a bias in the decision-making phase of the task and not in the meaning-activation phase: Behavioral effects of ambiguity disappear when these decision biases are controlled (Pexman, Hino, & Lupker, 2004). The current study used event-related functional magnetic resonance imaging to examine the neural correlates of ambiguity in a task that produced no behavioral ambiguity effect (i.e., SCT with a well-defined decision category). Twenty healthy adults participated. Results showed that despite producing no behavioral effect of ambiguity, ambiguous words were associated with the recruitment of cortical structures implicated in top-down modulation of noisy activity (e.g., left inferior frontal gyrus) when compared to unambiguous words. These results are interpreted as evidence that multiple meanings are activated for ambiguous words in SCT.