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We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity. Here, we hypothesized that exogenous PA is also beneficial. To test that, we treated mice with a toxic APAP dose at 0 h, followed by PA or vehicle (Veh) post-treatment. We then collected blood and liver at 6, 24, and 52 h. Post-treatment with PA 2 h after APAP protected against liver injury at 6 h, and the combination of PA and N-acetyl-l-cysteine (NAC) reduced injury more than NAC alone. Interestingly, PA did not affect canonical mechanisms of APAP toxicity. Instead, transcriptomics revealed that PA activated interleukin-6 (IL-6) signaling in the liver. Consistent with that, serum IL-6 and hepatic signal transducer and activator of transcription 3 (Stat3) phosphorylation increased in PA-treated mice. Furthermore, PA failed to protect against APAP in IL-6-deficient animals. Interestingly, IL-6 expression increased 18-fold in adipose tissue after PA, indicating that adipose is a source of PA-induced circulating IL-6. Surprisingly, however, exogenous PA did not alter regeneration, despite the importance of endogenous PA in liver repair, possibly due to its short half-life. These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model.

Background: Aortic stenosis is a prevalent valvular heart disease that is treated primarily by surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR), which are common treatments for addressing symptoms secondary to valvular heart disease. This narrative review article focuses on the existing literature comparing recovery and cost-effectiveness for SAVR and TAVR. Methods: Major databases were searched for relevant literature discussing HRQOL and cost-effectiveness of TAVR and SAVR. We also searched for studies analyzing the use of wearable devices to monitor post-discharge recovery patterns. Results: The literature focusing on quality-of-life following TAVR and SAVR has been limited primarily to single-center observational studies and randomized controlled trials. Studies focused on TAVR report consistent and rapid improvement relative to baseline status. Common HRQOL instruments (SF-36, EQ-5D, KCCQ, MLHFQ) have been used to document that TF-TAVR is advantageous over SAVR at 1-month follow-up, with the benefits leveling off following 1 year. TF-TAVR is economically favorable relative to SAVR, with estimated incremental cost-effectiveness ratio values ranging from $50,000 to $63,000/QALY gained. TA-TAVR has not been reported to be advantageous from an HRQOL or cost-effectiveness perspective. Conclusions: While real-world experiences are less described, large-scale trials have advanced our understanding of recovery and cost-effectiveness of aortic valve replacement treatment strategies. Future work should focus on scalable wearable device technology, such as smartwatches and heart-rate monitors, to facilitate real-world evaluation of TAVR and SAVR to support clinical decision-making and outcomes ascertainment.

The hepatotoxicity of acetaminophen (APAP) occurs by initial metabolism to N-acetyl-p-benzoquinone imine which depletes GSH and forms APAP-protein adducts. Subsequently, the reactive nitrogen species peroxynitrite is formed from nitric oxide (NO) and superoxide leading to 3-nitrotyrosine in proteins. Toxicity occurs with inhibited mitochondrial function. We previously reported that in hepatocytes the nNOS (NOS1) inhibitor NANT inhibited APAP toxicity, reactive nitrogen and oxygen species formation, and mitochondrial dysfunction. In this work we examined the effect of trifluoperazine (TFP), a calmodulin antagonist that inhibits calcium induced nNOS activation, on APAP hepatotoxicity and reactive nitrogen formation in murine hepatocytes and in vivo. In freshly isolated hepatocytes TFP inhibited APAP induced toxicity, reactive nitrogen formation (NO, GSNO, and 3-nitrotyrosine in protein), reactive oxygen formation (superoxide), loss of mitochondrial membrane potential, decreased ATP production, decreased oxygen consumption rate, and increased NADH accumulation. TFP did not alter APAP induced GSH depletion in the hepatocytes or the formation of APAP protein adducts which indicated that reactive metabolite formation was not inhibited. Since we previously reported that TFP inhibits the hepatotoxicity of APAP in mice without altering hepatic APAP-protein adduct formation, we examined the APAP treated mouse livers for evidence of reactive nitrogen formation. 3-Nitrotyrosine in hepatic proteins and GSNO were significantly increased in APAP treated mouse livers and decreased in the livers of mice treated with APAP plus TFP. These data are consistent with a hypothesis that APAP hepatotoxicity occurs with altered calcium metabolism, activation of nNOS leading to increased reactive nitrogen formation, and mitochondrial dysfunction. Keywords: Acetaminophen, Neuronal nitric oxide, Oxidative stress, Mitochondria

Objective: This study aimed to 1) understand factors impacting the implementation of exercise communication and referral, and 2) explore integrated clinical approaches to exercise communication and referral in cancer care., Methods: Seven focus groups (N = 53) were conducted with clinicians and exercise professionals throughout Sydney, Australia. A sub-sample of participants (n = 9) attended a half-day workshop to identifying best practice approaches for moving forward. Data were analysed using thematic content analysis., Results: Two themes emerged: 1) Factors impacting the knowledge-to-action gap, inclusive of limited exercise specific knowledge and training opportunities, funding structure, and current referral process, and 2) Recommendations for a consistent and efficient way forward, detailing the need for oncologist-initiated communication, distribution of cancer-exercise resources, and access to exercise professionals with cancer expertise., Conclusions: This study identified factors (e.g., cancer-exercise specific training, integration of exercise physiologists) influencing exercise counselling and referral. A potential implementation-referral approach accounting for these factors and how to incorporate exercise into a standard model of cancer care, is described. Future testing is required to determine feasibility and practicality of these approaches., Practical Implications: A pragmatic model is provided to guide implementation-referral, inclusive of oncologist-initiated communication exchange, relevant resources, and access to exercise professionals with cancer expertise., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In American Sign Language (ASL) spatial relationships are conveyed by the location of the hands in space, whereas English employs prepositional phrases. Using event-related fMRI, we examined comprehension of perspective-dependent (PD) (left, right) and perspective-independent (PI) (in, on) sentences in ASL and audiovisual English (sentence-picture matching task). In contrast to non-spatial control sentences, PD sentences engaged the superior parietal lobule (SPL) bilaterally for ASL and English, consistent with a previous study with written English. The ASL-English conjunction analysis revealed bilateral SPL activation for PD sentences, but left-lateralized activation for PI sentences. The direct contrast between PD and PI expressions revealed greater SPL activation for PD expressions only for ASL. Increased SPL activation for ASL PD expressions may reflect the mental transformation required to interpret locations in signing space from the signer's viewpoint. Overall, the results suggest both overlapping and distinct neural regions support spatial language comprehension in ASL and English., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In 2017, the directors of the American Board of Orthodontics (ABO) decided to move forward with a new clinical examination format-a scenario-based examination. The first examination of this type was administered in February 2019, and 2 more exams have been given since then. Each examination consisted of at least 6 scenarios with 4-7 questions for each scenario. Questions came from 4 domains or categories-data gathering and diagnosis, treatment objectives and planning, treatment implementation and management, and critical analysis and outcomes assessment. As of today, 49% of members of the American Association of Orthodontists are ABO certified. For more information about the scenario-based examination and ABO certification or certification renewal processes, go to AmericanBoardOrtho.com., (Copyright © 2020. Published by Elsevier Inc.)

Signing differs from typical non-linguistic hand actions because movements are not visually guided, finger movements are complex (particularly for fingerspelling), and signs are not produced as holistic gestures. We used positron emission tomography to investigate the neural circuits involved in the production of American Sign Language (ASL). Different types of signs (one-handed (articulated in neutral space), two-handed (neutral space), and one-handed body-anchored signs) were elicited by asking deaf native signers to produce sign translations of English words. Participants also fingerspelled (one-handed) printed English words. For the baseline task, participants indicated whether a word contained a descending letter. Fingerspelling engaged ipsilateral motor cortex and cerebellar cortex in contrast to both one-handed signs and the descender baseline task, which may reflect greater timing demands and complexity of handshape sequences required for fingerspelling. Greater activation in the visual word form area was also observed for fingerspelled words compared to one-handed signs. Body-anchored signs engaged bilateral superior parietal cortex to a greater extent than the descender baseline task and neutral space signs, reflecting the motor control and proprioceptive monitoring required to direct the hand toward a specific location on the body. Less activation in parts of the motor circuit was observed for two-handed signs compared to one-handed signs, possibly because, for half of the signs, handshape and movement goals were spread across the two limbs. Finally, the conjunction analysis comparing each sign type with the descender baseline task revealed common activation in the supramarginal gyrus bilaterally, which we interpret as reflecting phonological retrieval and encoding processes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We investigated word-level reading circuits in skilled deaf readers (N=14; mean reading age=19.5years) and less skilled deaf readers (N=14; mean reading age=12years) who were all highly proficient users of American Sign Language. During fMRI scanning, participants performed a semantic decision (concrete concept?), a phonological decision (two syllables?), and a false-font control task (string underlined?). No significant group differences were observed with the full participant set. However, an analysis with the 10 most and 10 least skilled readers revealed that for the semantic task (vs. control task), proficient deaf readers exhibited greater activation in left inferior frontal and middle temporal gyri than less proficient readers. No group differences were observed for the phonological task. Whole-brain correlation analyses (all participants) revealed that for the semantic task, reading ability correlated positively with neural activity in the right inferior frontal gyrus and in a region associated with the orthography-semantics interface, located anterior to the visual word form area. Reading ability did not correlate with neural activity during the phonological task. Accuracy on the semantic task correlated positively with neural activity in left anterior temporal lobe (a region linked to conceptual processing), while accuracy on the phonological task correlated positively with neural activity in left posterior inferior frontal gyrus (a region linked to syllabification processes during speech production). Finally, reading comprehension scores correlated positively with vocabulary and print exposure measures, but not with phonological awareness scores., (Copyright © 2016. Published by Elsevier Inc.)

Code-blends (simultaneous words and signs) are a unique characteristic of bimodal bilingual communication. Using fMRI, we investigated code-blend comprehension in hearing native ASL-English bilinguals who made a semantic decision (edible?) about signs, audiovisual words, and semantically equivalent code-blends. English and ASL recruited a similar fronto-temporal network with expected modality differences: stronger activation for English in auditory regions of bilateral superior temporal cortex, and stronger activation for ASL in bilateral occipitotemporal visual regions and left parietal cortex. Code-blend comprehension elicited activity in a combination of these regions, and no cognitive control regions were additionally recruited. Furthermore, code-blends elicited reduced activation relative to ASL presented alone in bilateral prefrontal and visual extrastriate cortices, and relative to English alone in auditory association cortex. Consistent with behavioral facilitation observed during semantic decisions, the findings suggest that redundant semantic content induces more efficient neural processing in language and sensory regions during bimodal language integration., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: A high level of 'excess' mortality (i.e. that seemingly not explained by deprivation) has been shown for Scotland compared to England & Wales and, in particular, for its largest city, Glasgow, compared to the similarly deprived postindustrial English cities of Liverpool and Manchester. The excess has been observed across all social classes, but, for premature mortality, has been shown to be highest in comparison of those of lowest socio-economic status (SES). Many theories have been proposed to explain this phenomenon. One such suggestion relates to potential differences in social capital between the cities, given the previously evidenced links between social capital and mortality. The aim of this study was to ascertain whether any aspects of social capital differed between the cities and whether, therefore, this might be a plausible explanation for some of the excess mortality observed in Glasgow., Study Design: Cross-sectional study., Methods: A representative survey of Glasgow, Liverpool and Manchester was undertaken in 2011. Social capital was measured using an expanded version of the Office for National Statistics (ONS) core 'Social Capital Harmonised Question Set'. Differences between the cities in five sets of social capital topics (views about the local area, civic participation, social networks and support, social participation, and reciprocity and trust) were explored by means of a series of multivariate regression models, while controlling for differences in the characteristics (age, gender, SES, ethnicity etc.) of the samples., Results: Some, but not all, aspects of social capital were lower among the Glasgow sample compared to those in Liverpool and Manchester. A number of these differences were greatest among those of higher, rather than lower, SES. Levels of social participation, trust and (some measures of) reciprocity were lower in Glasgow, particularly in comparison with Liverpool. However, assessment of any potential impact of these differences is limited by the cross-sectional nature of the data., Conclusions: The analyses suggest it is at least possible that differences in some aspects of social capital could play some part in explaining Glasgow's excess mortality, especially among particular sections of its population (e.g. those of higher SES). However, in the absence of more detailed longitudinal data, this remains speculative., (Copyright © 2015 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

We examined word-level reading circuits in skilled deaf readers whose primary language is American Sign Language, and hearing readers matched for reading ability (college level). During fMRI scanning, participants performed a semantic decision (concrete concept?), a phonological decision (two syllables?), and a false-font control task (string underlined?). The groups performed equally well on the semantic task, but hearing readers performed better on the phonological task. Semantic processing engaged similar left frontotemporal language circuits in deaf and hearing readers. However, phonological processing elicited increased neural activity in deaf, relative to hearing readers, in the left precentral gyrus, suggesting greater reliance on articulatory phonological codes, and in bilateral parietal cortex, suggesting increased phonological processing effort. Deaf readers also showed stronger anterior-posterior functional segregation between semantic and phonological processes in left inferior prefrontal cortex. Finally, weaker phonological decoding ability did not alter activation in the visual word form area for deaf readers., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Acetaminophen (APAP) toxicity is responsible for approximately half of all cases of acute liver failure in the United States. The mouse model of APAP toxicity is widely used to examine mechanisms of APAP toxicity. Noninvasive approaches would allow for serial measurements in a single animal to study the effects of experimental interventions on the development and resolution of hepatocellular necrosis. The following study examined the time course of hepatic necrosis using small animal magnetic resonance imaging (MRI) following the administration of 200 mg/kg ip APAP given to B6C3F1 male mice. Mice treated with saline served as controls (CON). Other mice received treatment with the clinical antidote N-acetylcysteine (APAP+NAC). Mouse liver pathology was characterized using T1- and T2-weighted sequences at 2, 4, 8 and 24 h following APAP administration. Standard assays for APAP toxicity [serum alanine aminotransaminase (ALT) levels and hematoxylin and eosin (H&E) staining of liver sections] were examined relative to MRI findings. Overall, T2 sequences had a greater sensitivity for necrosis and hemorrhage than T1 (FLASH) images. Liver injury severity scoring of MR images demonstrated increased scores in the APAP mice at 4, 8 and 24 h compared to the CON mice. APAP+NAC mice had MRI scores similar to the CON mice. Semiquantitative analysis of hepatic hemorrhage strongly correlated with serum ALT. Small animal MRI can be used to monitor the evolution of APAP toxicity over time and to evaluate the response to therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Interstitial deletions of chromosome 3q22.3-25.1 are very rare with only five previous reports of deletions in this region [1,2,4,7,9]. We describe a case of a female infant with a de novo deletion. Dysmorphic features and congenital heart disease led to a clinical genetics assessment on day 1 of life. Chromosomal analysis showed an interstitial deletion with a female karyotype 46,XX,del (3)(q23q25.1)dn. Subsequent array CGH demonstrated the breakpoints as 3q22.3q25.1. This is the first documented association with a truncus arteriosus. We identify an emerging clinical phenotype of microphthalmia, microcephaly, congenital heart disease, slow feeding, skeletal abnormalities, with an abnormal facies and developmental delay. Array CGH demonstrated that the FOXL2 gene responsible for BPES was not deleted in this patient., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Bimodal bilinguals are hearing individuals who know both a signed and a spoken language. Effects of bimodal bilingualism on behavior and brain organization are reviewed, and an fMRI investigation of the recognition of facial expressions by ASL-English bilinguals is reported. The fMRI results reveal separate effects of sign language and spoken language experience on activation patterns within the superior temporal sulcus. In addition, the strong left-lateralized activation for facial expression recognition previously observed for deaf signers was not observed for hearing signers. We conclude that both sign language experience and deafness can affect the neural organization for recognizing facial expressions, and we argue that bimodal bilinguals provide a unique window into the neurocognitive changes that occur with the acquisition of two languages.

Two experiments investigated categorical perception (CP) effects for affective facial expressions and linguistic facial expressions from American Sign Language (ASL) for Deaf native signers and hearing non-signers. Facial expressions were presented in isolation (Experiment 1) or in an ASL verb context (Experiment 2). Participants performed ABX discrimination and identification tasks on morphed affective and linguistic facial expression continua. The continua were created by morphing end-point photo exemplars into 11 images, changing linearly from one expression to another in equal steps. For both affective and linguistic expressions, hearing non-signers exhibited better discrimination across category boundaries than within categories for both experiments, thus replicating previous results with affective expressions and demonstrating CP effects for non-canonical facial expressions. Deaf signers, however, showed significant CP effects only for linguistic facial expressions. Subsequent analyses indicated that order of presentation influenced signers' response time performance for affective facial expressions: viewing linguistic facial expressions first slowed response time for affective facial expressions. We conclude that CP effects for affective facial expressions can be influenced by language experience.

Hypoxia inducible factor (HIF) controls the transcription of genes involved in angiogenesis, erythropoiesis, glycolysis, and cell survival. HIF-1alpha levels are a critical determinant of HIF activity. The induction of HIF-1alpha was examined in the livers of mice treated with a toxic dose of APAP (300 mg/kg i.p.) and sacrificed at 1, 2, 4, 8, and 12 h. HIF-1alpha was induced at 1-12 h and induction occurred prior to the onset of toxicity. Pre-treatment of mice with N-acetylcysteine (1200 mg/kg i.p.) prevented toxicity and HIF-1alpha induction. In further studies, hepatocyte suspensions were incubated with APAP (1 mM) in the presence of an oxygen atmosphere. HIF-1alpha was induced at 1 h, prior to the onset of toxicity. Inclusion of cyclosporine A (10 microM), an inhibitor of mitochondrial permeability transition, oxidative stress, and toxicity, prevented the induction of HIF-1alpha. Thus, HIF-1alpha is induced before APAP toxicity and can occur under non-hypoxic conditions. The data suggest a role for oxidative stress in the induction of HIF-1alpha in APAP toxicity.

Positron emission tomography was used to investigate whether the motor-iconic basis of certain forms in American Sign Language (ASL) partially alters the neural systems engaged during lexical retrieval. Most ASL nouns denoting tools and ASL verbs referring to tool-based actions are produced with a handshape representing the human hand holding a tool and with an iconic movement depicting canonical tool use, whereas the visual iconicity of animal signs is more idiosyncratic and inconsistent across signs. We investigated whether the motor-iconic relation between a sign and its referent alters the neural substrate for lexical retrieval in ASL. Ten deaf native ASL signers viewed photographs of tools/utensils or of actions performed with or without an implement and were asked to overtly produce the ASL sign for each object or action. The control task required subjects to judge the orientation of unknown faces. Compared to the control task, naming tools engaged left inferior and middle frontal gyri, bilateral parietal lobe, and posterior inferotemporal cortex. Naming actions performed with or without a tool engaged left inferior frontal gyrus, bilateral parietal lobe, and posterior middle temporal gyrus at the temporo-occipital junction (area MT). When motor-iconic verbs were compared with non-iconic verbs, no differences in neural activation were found. Overall, the results indicate that even when the form of a sign is indistinguishable from a pantomimic gesture, the neural systems underlying its production mirror those engaged when hearing speakers name tools or tool-based actions with speech.

To determine the importance of IL-6 in acetaminophen (APAP) toxicity, wild type (WT) and IL-6 knock out (KO) mice were dosed with APAP (300 mg/kg i.p.) and sacrificed at 4 and 24h. No differences were found between the two groups by analysis of serum AST levels or histopathology. Also, the relative amounts of APAP protein binding and nitrotyrosine formation were equal. Subsequently, WT and KO mice were dosed with APAP (300 mg/kg i.p.) and sacrificed at 24, 48, and 72 h. AST normalized by 48 h in the WT mice, but not until 72 h in the KO mice. The severity of the histopathological alterations was comparable in the two groups of mice; however, fewer regenerating hepatocytes were present in the KO mice. Immunohistochemistry for proliferating cell nuclear antigen (PCNA) showed reduced staining in the KO mice. Pretreatment of KO mice with IL-6 lowered AST and normalized PCNA staining in the IL-6 KO mice. These data suggest that IL-6 is important in hepatocyte regeneration following APAP toxicity in the mouse.

The treatment of an Angle Class II, Division I malocclusion without the extraction of premolars is described. Treatment was accomplished with the standard edgewise appliance using Merrifield directional forces systems.

Primary tumors of the heart are rare; primary cardiac fibrosarcoma is even rarer. We report a patient with primary cardiac fibrosarcoma widespread metastases presenting with pulmonary metastases initially. The cardiac lesion was identified by bone-imaging localization on bone scan, by hypodense areas in the cardiac chambers of contrast computed tomography of the chest, and by protruding masses in ventricular cavities causing aortic valve outflow-tract obstruction by echocardiogram. At autopsy, a large tumor invaded the interventricular septum and both ventricular cavities of the heart (880 g in weight), and accounted for these imaging findings. While bone-agent localization in the heart does not differentiate malignant from benign conditions, computed tomography and echocardiography of the interatrial and interventricular septal, and right atrial and biventricular cavitary involvement may differentiate fibrosarcoma from myxoma.