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Paul (2018a, 2018b) discussed the concept of critical thinking in a series of American Annals of the Deaf editorials examining how critical thinking might serve as a "springboard" to deep knowledge or wisdom and wondering if critical thinking should be viewed as a noble endeavor or hopeless cause. Paul explored three questions in which he considered (a) types of critical thinkers, (b) teaching and evaluating critical thinking, and (c) empathy's role in critical thinking. Responding to Paul, the author focuses on the same questions by summarizing Paul's view, then following with his own. He also explores the question What is critical thinking? Mostly, the author's views resemble Paul's, but he elaborates on places where he thinks gaps or possible misunderstandings exist. The author concludes that critical thinking is indeed a noble endeavor because it is not just what you think that matters, but how you think. [ABSTRACT FROM AUTHOR]

Experts frequently assess competency in criminal settings where the rate of feigning cognitive deficit is demonstrably elevated. We describe the construction and validation of the Denney Competency Related Test (D-CRT) to assess feigned incompetency of defendants in the criminal adjudicative setting. It was expected the D-CRT would prove effective at identifying feigned incompetence based on its two alternative, forced-choice and performance curve characteristics. Development and validation of the D-CRT occurred in described phases. Items were developed to measure competency based upon expert review. Item analysis and adjustments were completed with 304 young teenage volunteers to obtain a proper spread of item difficulty in preparation for eventual performance curve analysis (PCA). Test-retest reliability was assessed with 44 adult community volunteers. Validation included an analog simulation design with 101 jail detainees using MacArthur Competency Assessment Test-Criminal Adjudication and Word Memory Test as criterion measures. Effects of racial/ethnic demographic differences were examined in a separate study of 208 undergraduate volunteers. D-CRT specificity was identified with 46 elderly clinic referrals diagnosed with mild cognitive impairment and dementia. Item development, adjustment, and repeat analysis resulted in item probabilities evenly spread from.28 to 1.0. Test-retest correlation was good (.83). Internal consistency of items was excellent (KR-20 >.91). D-CRT demonstrated convergent validity in regard to measuring competency related information and as well as malingering. The test successfully differentiated between jail inmates asked to perforfm their best and inmates asked to simulate incompetency (AUC =.945). There were no statistically significant differences found in performance across racial/ethnic backgrounds. D-CRT specificity remained excellent among elderly clinic referrals with significant cognitive compromise at the recommended total score cutoff. D-CRT is an effective measure of feigned criminal incompetency in the context of potential cognitive deficiency, and PCA is assistive in the determination. Additional validation using knowns groups designs with various mental health-related conditions are needed. [ABSTRACT FROM AUTHOR]

Paul (2018a, 2018b) discussed the concept of critical thinking in a series of American Annals of the Deaf editorials examining how critical thinking might serve as a "springboard" to deep knowledge or wisdom and wondering if critical thinking should be viewed as a noble endeavor or hopeless cause. Paul explored three questions in which he considered (a) types of critical thinkers, (b) teaching and evaluating critical thinking, and (c) empathy's role in critical thinking. Responding to Paul, the author focuses on the same questions by summarizing Paul's view, then following with his own. He also explores the question What is critical thinking? Mostly, the author's views resemble Paul's, but he elaborates on places where he thinks gaps or possible misunderstandings exist. The author concludes that critical thinking is indeed a noble endeavor because it is not just what you think that matters, but how you think. [ABSTRACT FROM AUTHOR]

The short story "Dirty Lightning" by Patrick Michael Finn is presented.

Purpose: I respond to Kamhi's (2011) conclusion in his article "Balancing Certainty and Uncertainty in Clinical Practice" that rational or critical thinking is an essential complement to evidence-based practice (EBP). Method: I expand on Kamhi's conclusion and briefly describe what clinicians might need to know to think critically within an EBP profession. Specifically, I suggest how critical thinking is relevant to EBP, broadly summarize the relevant skills, indicate the importance of thinking dispositions, and outline the various ways our thinking can go wrong. Conclusion: I finish the commentary by suggesting that critical thinking skills should be considered a required outcome of our professional training programs. [ABSTRACT FROM AUTHOR]

Purpose: To respond to several of the issues raised in J. Kalinowski, T. Saltuklaroglu, A. Stuart, and V. K. Guntupalli's (2007) critique of our previous article (P. Finn, A. K. Bothe, & R. E. Bramlett, 2005). Method: Information is provided to refute criticisms raised by Kalinowski et al. about the Finn et al. article, including with respect to that report 's methodology, previous research about fluency-inducing conditions in stuttering, and the SpeechEasy device. Conclusions: Available data show that delayed auditory feedback, frequency-altered feedback, masking, and chorus reading can result in reduced stuttering for some speakers, and the inconsistencies and variability in available reports suggest that further careful and creative research could be very valuable. Neither the information about the SpeechEasy provided by its developers, however, nor the manner in which that information has been presented and discussed by its developers rises to the standards of a science-based clinical service discipline. [ABSTRACT FROM AUTHOR]

Abstract: Mammals survive starvation by activating proteolysis and lipolysis in many different tissues. These responses are triggered, at least in part, by changing hormonal and neural statuses during starvation. Pathways of proteolysis that are activated during starvation are surprisingly diverse, depending on tissue type and duration of starvation. The ubiquitin-proteasome system is primarily responsible for increased skeletal muscle protein breakdown during starvation. However, in most other tissues, lysosomal pathways of proteolysis are stimulated during fasting. Short-term starvation activates macroautophagy, whereas long-term starvation activates chaperone-mediated autophagy. Lipolysis also increases in response to starvation, and the breakdown of triacylglycerols provides free fatty acids to be used as an energy source by skeletal muscle and other tissues. In addition, glycerol released from triacylglycerols can be converted to glucose by hepatic gluconeogenesis. During long-term starvation, oxidation of free fatty acids by the liver leads to the production of ketone bodies that can be used for energy by skeletal muscle and brain. Tissues that cannot use ketone bodies for energy respond to these small molecules by activating chaperone-mediated autophagy. This is one form of interaction between proteolytic and lipolytic responses to starvation. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to investigate the nature of recovery from stuttering based on the experiences of adults who recovered without treatment. Using a semi-structured, open-ended interview format, 15 speakers verified as persons who recovered without treatment were asked to describe their status as everyday speakers. Seven speakers reported that they no longer stuttered and eight reported that they still stuttered on occasion. Interview material was coded and analyzed by the investigators and checked by independent judges. Results suggested that complete recovery was possible for speakers who reported that they no longer stuttered; whereas, those who still stuttered occasionally appeared to no longer be handicapped by stuttering, but required some vigilance to maintain their relatively fluent speech. Educational objectives: After completing this activity, the learner will be able to: (1) describe the relevance of self-report data for evaluating the nature of recovery from stuttering without treatment; (2) describe the differences in self-perception concerning the nature of recovery for those who no longer have any tendency to stutter compared to those who still have an occasional tendency to stutter; and (3) suggest the possible implications for understanding the nature of recovery from persistent stuttering based on investigations of late recovery without treatment. [Copyright &y& Elsevier]

Purpose: The purpose of this tutorial is to describe 10 criteria that may help clinicians distinguish between scientific and pseudoscientific treatment claims. The criteria are illustrated, first for considering whether to use a newly developed treatment and second for attempting to understand arguments about controversial treatments. Method: Pseudoscience refers to claims that appear to be based on the scientific method but are not. Ten criteria for distinguishing between scientific and pseudoscientific treatment claims are described. These criteria are illustrated by using them to assess a current treatment for stuttering, the SpeechEasy device. The authors read the vailable literature about the device and developed a consensus set of decisions about the 10 criteria. To minimize any bias, a second set of independent judges evaluated a sample of the same literature. The criteria are also illustrated by using them to assess controversies surrounding 2 treatment approaches: Fast ForWord and facilitated communication. Conclusions: Clinicians are increasingly being held responsible for the evidence base that supports their practice. The power of these 10 criteria lies in their ability to help clinicians focus their attention on the credibility of that base and to guide their decisions for recommending or using a treatment. [ABSTRACT FROM AUTHOR]

Chaperone-mediated autophagy (CMA) is a selective lysosomal protein degradative process that is activated in higher organisms under conditions of prolonged starvation and in cell culture by the removal of serum. Ketone bodies are comprised of three compounds (β-hydroxybutyrate, acetoacetate, and acetone) that circulate during starvation, especially during prolonged starvation. Here we have investigated the hypothesis that ketone bodies induce CMA. We found that physiological concentrations of β-hydroxybutyrate (BOH) induced proteolysis in cells maintained in media with serum and without serum; however, acetoacetate only induced proteolysis in cells maintained in media with serum. Lysosomes isolated from BOH-treated cells displayed an increased ability to degrade both glyceraldehyde.3.phosphato dehydrogenase and ribonuclease A, substrates for CMA. Isolated lysosomes from cells maintained in media without serum also demonstrated an increased ability to degrade glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A when the reaction was supplemented with BOH. Such treatment did not affect the levels of lysosome-associated membrane protein 2a or lysosomal heat shock cognate protein of 70 kDa, two rate-limiting proteins in CMA. However, pretreatment of glyceraldehyde-3-phosphate and ribonuclease A with BOH increased their rate of degradation by isolated lysosomes. Lysosomes pretreated with BOH showed no increase in proteolysis, suggesting that BOH acts on the substrates to increase their rates of proteolysis. Using OxyBlot™ analysis to detect carbonyl formation on proteins, one common marker of protein oxidation, we showed that treatment of substrates with BOH increased their oxidation. Neither glycerol, another compound that increases in circulation during prolonged starvation, nor butanol or butanone, compounds closely related to BOH, had an effect on CMA. The induction of CMA by ketone bodies may provide an important physiological mechanism for the activation of CMA during prolonged starvation. [ABSTRACT FROM AUTHOR]

In light of emerging findings concerning untreated recovery and neural plasticity, this paper re-examines the viability of an NIH conference recommendation [Cooper, J. A. (1990). Research directions in stuttering: Consensus and conflict. In Cooper, I. A. (Ed.), Research needs in stuttering: Roadblocks and future directions (pp. 98-100). Rockville, MD: American Speech-Language-Hearing Association.] that adults who have recovered from stuttering might inform our understanding of the nature and treatment of persistent stuttering. It is suggested that those who have recovered could constitute a behavioral, cognitive, and neurophysiologic benchmark for evaluating stuttering treatment for adolescents and adults, while helping to identify the limits of recovery from a persistent disorder. This possibility seems especially promising because of findings from recent studies investigating untreated recovery during childhood and adulthood, the emerging evidence concerning neural plasticity and reorganization, and reports of neural system changes during stuttering treatment. Potential obstacles to applying findings from unassisted recovery to treatment do exist, but the benefits of attempts to fully understand stuttering certainly outweigh the difficulties. [ABSTRACT FROM AUTHOR]

An evidence-based framework can be described as an empirically-driven, measurement-based, client-sensitive approach for selecting treatments. It is believed that using such a framework is more likely to result in a clinically significant outcome. For this paper, a clinically significant outcome was defined as a meaningful treatment change. It was suggested that there are at least three groups for whom a treatment’s outcome is meaningful. These groups include clinicians/clinical researchers, the clients, and relevant others who have some interest in the outcome (e.g., parents of a child who stutters). The meaning and measurement of clinical significance was discussed for each of these three groups, based on research from the behavioral stuttering treatment literature.Educational objectives: The reader will learn about and be able to (1) broadly define a clinically significant outcome and identify some of the groups who are interested in such an outcome and (2) describe how clinical significance has been evaluated in stuttering treatment within an evidence-based framework. [Copyright &y& Elsevier]

There is an increasing interest in developing direct calculation methods and procedures for determining extreme wave loads on ship girders (e.g. ISSC, 2000 [1]). Ships experiencing bottom and bow flare slamming have heightened the need for computational tools suitable to accurately predict motion and structural responses. The associated nonlinear impact problem is complicated by the complex free surface and body boundary conditions. This paper examines a "blended" linear-nonlinear method by which extreme loads due to bottom impact and flare slamming can be determined. Using a high-speed container ship as an example, comparisons of motions, shear and bending moments, and pressures are made in head and oblique bow-quartering waves. The time-domain computer program used in the comparison is based upon partially nonlinear models. The program, NSHIPMO, is an blended strip theory method using "impact" stations over the forward part of the ship and partially nonlinear stations over the rest. Body exact hydrostatics and Froude-Krylov excitation are used over the entire hull. The impact theory of Troesch and Kang [2] is employed to estimate the sectional nonlinear impact forces acting upon the specified nonlinear sections, while the linear theory of Salvesen et al. (STF) [3] is used to blend the remainder of the hydrodynamic forces, that is the radiation and diffraction components. Results from the simulation are presented with discussions of accuracy and time of computation. Several issues associated with the blended nonlinear time-domain simulation are presented, including modeling issues related to directional yaw-sway control and a vertical plane dynamic instability in long waves that has not previously been recognized. [ABSTRACT FROM AUTHOR]

A four-color set of negatively charged, single dye as well as energy transfer dye labeled-ddNTPs were synthesized and evaluated in combination with a novel polymerase in a “direct-load” DNA sequencing, obviating the laborious and time consuming post-reaction work-up. [ABSTRACT FROM AUTHOR]

Generalization and maintenance are a widely recognized challenge for stuttering treatment. There are many reasons why this is the case. First, there is no accepted model of recovery, though self-efficacy may be a helpful construct and, secondly, the client’s age, stuttering severity, and negative attitudes may be complicating factors.Three strategies for promoting generalization and maintenance in school settings are suggested based on current research evidence. They include probing and training for generalization, incorporating real-life elements into therapy, and training clients to self-regulate their behavior. These strategies appear to be viable and practical, but further research is needed to fully evaluate their effectiveness for school settings.: Learning outcomesReaders will learn about (1) typical approaches to managing stuttering in the school setting, (2) barriers to generalization and maintenance of stuttering treatment gains, and (3) three strategies for promoting generalization and maintenance. [Copyright &y& Elsevier]

This study investigated the modification of speech naturalness during stuttering treatment. It systematically replicated an earlier study (Ingham & Onslow, 1985) that demonstrated that unnatural-sounding stutter-free speech could be shaped into more natural-sounding stutter-free speech by using regular feedback of speech-naturalness ratings during speaking tasks. In the present study, the same procedure was used with three persons who stutter--2 adolescent girls and 1 adult man--during rhythmic stimulation conditions. The two adolescent participants spoke only English, but Spanish was the first and English the second language (ESL) of the adult participant. For the 2 adolescents, it was demonstrated that their unnatural-sounding rhythmic speech could be shaped to levels found among normally fluent speakers without losing the fluency-inducing benefits of rhythmic speech. The findings indicate that speech-naturalness feedback may be a powerful procedure for overcoming a problematic aspect of rhythmic speech treatments of stuttering. However, it was not possible to deliver reliable speech-naturalness feedback to the adult ESL speaker, who also displayed a strong dialect. The study highlights the need to find strategies to improve interjudge agreement when using speech-naturalness ratings with speakers who display a strong dialect. [ABSTRACT FROM AUTHOR]

Examines the speech perceptual differences in children who have recovered from stuttering without formal treatment from the children who never stuttered. Effect of discrimination or identification on speech perception in children; Measurement of speech naturalness; Factors responsible for recovery from stuttering; Use of the perceptual judgment task.

Presents a study determining the perceptual differences in the speech of adults who had recovered from stuttering without the assistance of treatment. Measurement of various speech behavior; Correlation of the perceptual differences with unnatural sounding speech and a high-frequency of part-word repetitions; Screening criteria used in normally fluent speakers.

Investigates the effect of speech dialect on listeners' speech naturalness ratings. Systematic replication of Martin, Haroldson and Triden's (1984) study using three groups of speaker samples; Stuttering; Speech fluency and speaking rate; Dialect as an important factor that needs to be incorporated within systems designed to train speech naturalness ratings.

Tests a hypothesis that states that massive proteolysis observed in critically ill patients is a result of cell shrinkage secondary to cellular dehydration. Measuring of changes in intracellular water (ICW), total body protein (TBP) and total body potassium (TBK) in patients; Massive proteolysis as the loss of body protein; Findings and interpretation.

Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the galactosidase alpha (GLA), which codes for α-Galactosidase A (α-GAL) enzyme, in a human cardiac model generated from induced pluripotent stem cells (iPSCs) derived from two individuals with Fabry disease. Consistent with the clinical phenotype, cardiomyocytes from iPSCs derived from Fabry-affected individuals showed accumulation of the glycosphingolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate. Furthermore, the Fabry cardiomyocytes displayed significant upregulation of lysosomal-associated proteins. Upon GLA modRNA treatment, a subset of lysosomal proteins were partially restored to wild-type levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA-treated cardiomyocytes, demonstrating that α-GAL enzymatic activity was restored. Together, our results validate the utility of iPSC-derived cardiomyocytes from affected individuals as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart. [Display omitted] Nucleoside-modified messenger RNA (modRNA) has shown great promise as an enzyme replacement tool. Here, we show that GLA modRNA almost completely abolishes the accumulation of globotriaosylceramides observed in cardiomyocytes derived from individuals with Fabry disease. Moreover, changes in the proteome between Fabry and healthy cardiomyocytes were rescued upon modRNA treatment. [ABSTRACT FROM AUTHOR]

Acid sphingomyelinase (ASM) deficiency is an autosomal recessive disorder resulting from a deficiency of the lysosomal enzyme ASM and subsequent accumulation of sphingomyelin (SM). A mouse model of ASM deficiency was created in which accumulation of SM occurs similar to the human form of the disease. Previously, we demonstrated a dose responsive toxicity following a rapid bolus administration of recombinant human ASM (rhASM) in this mouse model. Specifically, a reduction in heart rate, mean arterial pressure and activity was observed, as well as a dose-responsive increase in pro-inflammatory cytokines IL-6, IL-1α and IL-1β. Diminishing the substrate load in mice by administering low doses of rhASM prior to the known toxic dose prevented these toxic responses suggesting that the rate of SM degradation was related to the toxicity. To investigate the molecular mechanism of this effect, gene expression profiling of several tissues following rhASM administration was performed. The results of this analysis demonstrated an activation of stress and inflammatory gene pathways downstream of the cell signaling molecule ceramide. Since ceramide is a breakdown product of SM, these results confirmed that the mechanism of toxicity is related to the degradation of SM. Furthermore, this investigation may lead to the identification of early biomarkers of toxicity that could be monitored in the clinical setting. [ABSTRACT FROM AUTHOR]

This article reviews the motion picture Bowling for Columbine, directed by Michael Moore, which concerned the prevalence of violence in the U.S. The movie, which allegedly is the most commercially successful documentary of all time, looks at the U.S. gun debate through the lens of a number of tragedies involving gun deaths. The double frame story examines the April 20, 1999 shootings at Columbine High School by Eric Harris and Dylan Klebold, and the continuing saga of socioeconomic strife in and around Flint, Michigan. Bowling for Columbine is allegedly an engaging film that provides a lot of interesting information. Viewer reactions to the film seem to fall into two categories, wherein one sees more left wing claptrap from the filmmaker that brought the audience the other witnesses a scathing indictment of a gun-loving, fear ridden society that is a menace to itself and its neighbors. Such distinctions neatly divide across lines already established in the gun debate between conservative, pro-gun lobbyists and liberal anti-gun protestors. The film begins with a black and white NRA promo-clip. Using a mixture of stock footage, cartoons, montages, and inter-views, Moore creates a film that allegedly is both frightening and entertaining.

Glucose-6-phosphatase-α (G6Pase-α) catalyzes the hydrolysis of glucose-6-phosphate to glucose and functions as a key regulator in maintaining blood glucose homeostasis. Deficiency in G6Pase-α causes glycogen storage disease 1a (GSD1a), an inherited disorder characterized by life-threatening hypoglycemia and other long-term complications. We have developed a potential mRNA-based therapy for GSD1a and demonstrated that a human G6Pase-α (hG6Pase-α) variant harboring a single serine (S) to cysteine (C) substitution at the amino acid site 298 (S298C) had > twofold increase in protein expression, resulting in improved in vivo efficacy. Here, we sought to investigate the mechanisms contributing to the increased expression of the S298C variant. Mutagenesis of hG6Pase-α identified distinct protein variants at the 298 amino acid position with substantial reduction in protein expression in cultured cells. Kinetic analysis of expression and subcellular localization in mammalian cells, combined with cell-free in vitro translation assays, revealed that altered protein expression stemmed from differences in cellular protein stability rather than biosynthetic rates. Site-specific mutagenesis studies targeting other cysteines of the hG6Pase-α S298C variant suggest the observed improvements in stability are not due to additional disulfide bond formation. The glycosylation at Asparagine (N)-96 is critical in maintaining enzymatic activity and mutations at position 298 mainly affected glycosylated forms of hG6Pase-α. Finally, proteasome inhibition by lactacystin improved expression levels of unstable hG6Pase-α variants. Taken together, these data uncover a critical role for a single amino acid substitution impacting the stability of G6Pase-α and provide insights into the molecular genetics of GSD1a and protein engineering for therapeutic development. [ABSTRACT FROM AUTHOR]

A large amount of low grade heat is wasted at temperatures below 100 °C but its quantity remains mostly unknown. Therefore, the identification and quantitation of low grade heat availability enables further assessments on whether or not the recovery of this fraction of heat is convenient. By considering the countries composing the European Union (EU), this work quantifies the low grade heat from power generation and industrial sectors (mining, minerals, metals, chemicals, pulp and paper, food) with a particular focus on the faction of heat below 100 °C. The analysis shows that, in the year 2018, 8774.4∙106 GJ (2437.3 TWh) of heat was available in the EU below 100 °C, with the power generation sector accounting for 95% of the total low grade heat emitted. In addition, around 96% of the waste heat was in the temperature range from 25 °C to 80 °C, being of ultralow grade. Similar conclusions were obtained in terms of exergy loss, which was essentially from the power generation sector, especially in the range of temperatures between 40 °C and 60 °C. These results suggest that ultralow waste heat is an untapped source of energy which can be conveniently exploited by the same point-source emitters, primarily in the power generation sector or in wider industrial areas where infrastructure is present. • 8774.4∙106 GJ of heat below 100 °C in EU are from power generation and industrial sectors. • Largest fraction (7847.2⋅106 GJ) of ultralow heat in EU is between 40 °C and 60 °C. • The greatest contributor to ultralow grade waste heat is the power generation sector. • An exergy amount of 733.5∙106 GJ is available from ultralow grade waste heat. [ABSTRACT FROM AUTHOR]

Due to the lack of acid α-glucosidase (GAA) activity, Pompe mice develop glycogen storage pathology and progressive skeletal muscle dysfunction with age. Applying either gene or enzyme therapy to reconstitute GAA levels in older, symptomatic Pompe mice effectively reduces glycogen storage in skeletal muscle but provides only modest improvements in motor function. As strategies to stimulate muscle hypertrophy, such as by myostatin inhibition, have been shown to improve muscle pathology and strength in mouse models of muscular dystrophy, we sought to determine whether these benefits might be similarly realized in Pompe mice. Administration of a recombinant adeno-associated virus serotype 8 vector encoding follistatin, an inhibitor of myostatin, increased muscle mass and strength but only in Pompe mice that were treated before 10 months of age. Younger Pompe mice showed significant muscle fiber hypertrophy in response to treatment with follistatin, but maximal gains in muscle strength were achieved only when concomitant GAA administration reduced glycogen storage in the affected muscles. Despite increased grip strength, follistatin treatment failed to improve rotarod performance. These findings highlight the importance of treating Pompe skeletal muscle before pathology becomes irreversible, and suggest that adjunctive therapies may not be effective without first clearing skeletal muscle glycogen storage with GAA. [ABSTRACT FROM AUTHOR]

Abstract: Tissue turnover during wound healing, regeneration or integration of biomedical materials depends on the rate and extent of materials trafficking into and out of cells involved in extracellular matrix (ECM) remodeling. To exploit these processes, we report the first model for matrix trafficking in which these issues are quantitatively assessed for cells grown on both native collagen (normal tissue) and denatured collagen (wound state) substrates. Human fibroblasts more rapidly remodeled denatured versus normal collagen type I to form new ECM. Fluxes to and from the cells from the collagen substrates and the formation of new ECM were quantified using radioactively labeled substrates. The model can be employed for the systematic and quantitative study of the impact of a broad range of physiological factors and disease states on tissue remodeling, integrating extracellular matrix structures and cell biology. [Copyright &y& Elsevier]

This paper overviews recent developments in an ongoing program of brain imaging research on developmental stuttering that is being conducted at the University of Texas Health Science Center, San Antonio. This program has primarily used H215O PET imaging of different speaking tasks by right-handed adult male and female persistent stutterers, recovered stutterers and controls in order to isolate the neural regions that are functionally associated with stuttered speech. The principal findings have emerged from studies using condition contrasts and performance correlation techniques. The emerging findings from these studies are reviewed and referenced to a neural model of normal speech production recently proposed by Ju¨rgens [Neurosci. Biobehav. Rev. 26 (2002) 235]. This paper will report (1) the reconfiguration of previous findings within the Ju¨rgens Model; (2) preliminary findings of an investigation with late recovered stutterers; (3) an investigation of neural activations during a treatment procedure designed to produce a sustained improvement in fluency; and (4) an across-studies comparison that seeks to isolate neural regions within the Ju¨rgens Model that are consistently associated with stuttering. Two regions appear to meet this criterion: right anterior insula (activated) and anterior middle and superior temporal gyri (deactivated) mainly in right hemisphere. The implications of these findings and the direction of future imaging investigations are discussed.Educational objectives: The reader will learn about (1) recent uses of H215O PET imaging in stuttering research; (2) the use of a new neurological model of speech production in imaging research on stuttering; and (3) initial findings from PET imaging investigations of treated and recovered stutterers. [Copyright &y& Elsevier]

A number of different energy transfer dye labeled-cassettes were synthesized using aminoacid based trifunctional linkers and coupled to the propargylamino-substituted dideoxynucleoside-5′-triphosphates (ddNTPs). These terminators were evaluated for their energy transfer efficiency and DNA sequencing potential using thermostable DNA polymerase. [ABSTRACT FROM AUTHOR]

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare lethal autosomal recessive liver disorder caused by loss-of-function variations of the ABCB4 gene, encoding a phosphatidylcholine transporter (ABCB4/MDR3). Currently, no effective treatment exists for PFIC3 outside of liver transplantation. We have produced and screened chemically and genetically modified mRNA variants encoding human ABCB4 (h ABCB4 mRNA) encapsulated in lipid nanoparticles (LNPs). We examined their pharmacological effects in a cell-based model and in a new in vivo mouse model resembling human PFIC3 as a result of homozygous disruption of the Abcb4 gene in fibrosis-susceptible BALB/c. Abcb4 -/- mice. We show that treatment with liver-targeted h ABCB4 mRNA resulted in de novo expression of functional hABCB4 protein and restored phospholipid transport in cultured cells and in PFIC3 mouse livers. Importantly, repeated injections of the h ABCB4 mRNA effectively rescued the severe disease phenotype in young Abcb4 -/- mice, with rapid and dramatic normalisation of all clinically relevant parameters such as inflammation, ductular reaction, and liver fibrosis. Synthetic mRNA therapy also promoted favourable hepatocyte-driven liver regeneration to restore normal homeostasis, including liver weight, body weight, liver enzymes, and portal vein blood pressure. Our data provide strong preclinical proof-of-concept for h ABCB4 mRNA therapy as a potential treatment option for patients with PFIC3. This report describes the development of an innovative mRNA therapy as a potential treatment for PFIC3, a devastating rare paediatric liver disease with no treatment options except liver transplantation. We show that administration of our mRNA construct completely rescues severe liver disease in a genetic model of PFIC3 in mice. [Display omitted] • Synthetic liver-targeted h ABCB4 mRNA therapy was designed for PFIC3, a devastating rare paediatric liver disease. • Single injection restores hepatocyte ABCB4 expression and biliary phosphatidylcholine secretion in a genetic model of PFIC3. • Repeated administration rapidly and completely rescues PFIC3 disease in young Abcb4 -/- mice. • Treatment ameliorated liver injury, inflammation, ductular reaction, fibrosis, portal hypertension and 'failure to thrive'. [ABSTRACT FROM AUTHOR]

Fabry disease is an X-linked lysosomal storage disease caused by loss of alpha galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of globotriaosylceramide and its analogs in all cells and tissues. Although enzyme replacement therapy (ERT) is considered standard of care, the long-term effects of ERT on renal and cardiac manifestations remain uncertain and thus novel therapies are desirable. We herein report preclinical studies evaluating systemic messenger RNA (mRNA) encoding human α-Gal A in wild-type (WT) mice, α-Gal A-deficient mice, and WT non-human primates (NHPs). The pharmacokinetics and distribution of h-α-Gal A mRNA encoded protein in WT mice demonstrated prolonged half-lives of α-Gal A in tissues and plasma. Single intravenous administration of h-α-Gal A mRNA to Gla -deficient mice showed dose-dependent protein activity and substrate reduction. Moreover, long duration (up to 6 weeks) of substrate reductions in tissues and plasma were observed after a single injection. Furthermore, repeat i.v. administration of h-α-Gal A mRNA showed a sustained pharmacodynamic response and efficacy in Fabry mice model. Lastly, multiple administrations to non-human primates confirmed safety and translatability. Taken together, these studies across species demonstrate preclinical proof-of-concept of systemic mRNA therapy for the treatment of Fabry disease and this approach may be useful for other lysosomal storage disorders. [ABSTRACT FROM AUTHOR]

Background: Traditional journal club models based on didactic presentation sessions followed by group discussion have many limitations. To overcome some of these shortcomings, a virtual journal club (VJC) using social media and e-mail was developed. The aim of this study was to report the initial experience of this novel multimodal e-learning platform to facilitate journal club discussion and promote the development of critical appraisal skills. Methods: Journal articles were discussed monthly via e-mail and social media. After a 3-week period of discussion, all comments were collated and groupgenerated critical appraisal summaries were fed back to participants. In addition, letters to the journal editors based on the group appraisal were submitted. A questionnaire survey to evaluate the VJC concept was also conducted. Findings: After eight cycles of the VJC, the mean trainee participation rate was 29.6 per cent (range 21.1-42.1%). Senior trainees (≥4 years of postgraduate experience) were more likely to participate than more junior trainees (75.0 versus 21.1%; p = 0.005). The majority of participants thought that the VJC was educationally valuable, easy to participate in, helpful in keeping up to date with recent papers and useful in developing critical appraisal skills. Barriers to participation were lack of time, motivation and lack of experience in critical appraisal. In addition, the group- generated critical appraisal summaries derived from VJC discussions led to eight published 'letters to the editor'. Conclusion: This novel VJC model is a feasible and popular method of delivering a journal club in the postgraduate setting. [ABSTRACT FROM AUTHOR]

Purpose: This prologue serves to introduce a research forum composed of studies that address the topic of stuttering in school-age children and adolescents. Researchers are encouraged to continue to build the knowledge base that sustains evidence-based practice in this area. Method: The nature of stuttering as it evolves from early childhood into the school years is briefly described. Beyond the preschool years, children are unlikely to spontaneously recover from stuttering, and they often go on to suffer negative consequences, academically and socially, because of their disorder. If they are to overcome or manage their stuttering successfully, school-age children and adolescents require high-quality treatment. Three data-based studies that address the topic of stuttering in school-age children or adolescents are described, the ongoing need for empirical evidence regarding the management of stuttering is emphasized, and several issues relevant to future studies in this area are discussed. Conclusion: Progress has occurred in the management of stuttering in school-age children and adolescents. Nevertheless, important questions remain unanswered concerning the most effective techniques and strategies to use in helping students who stutter achieve more fluent and natural-sounding speech in their quest to become more confident and effective communicators. [ABSTRACT FROM AUTHOR]

Abstract: Pompe disease, also known as glycogen storage disease (GSD) type II, is caused by deficiency of lysosomal acid α-glucosidase (GAA). The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1–2years of age to a more slowly progressive course that causes significant morbidity and early mortality in children and adults. Recombinant human GAA (rhGAA) improves clinical outcomes with variable results. Adjunct therapy that increases the effectiveness of rhGAA may benefit some Pompe patients. Co-administration of the mTORC1 inhibitor rapamycin with rhGAA in a GAA knockout mouse reduced muscle glycogen content more than rhGAA or rapamycin alone. These results suggest mTORC1 inhibition may benefit GSDs that involve glycogen accumulation in muscle. [Copyright &y& Elsevier]

A number of terminal phosphate-labeled nucleotides with three or more phosphates and with varied length linkers attached between the terminal phosphate and the dye have been synthesized. These nucleotides have been tested as substrates for different DNA and RNA polymerases. We have also explored their utility in DNA sequencing, SNP analysis, nucleic acid amplification, quantitative PCR, and other biochemical assays. [ABSTRACT FROM AUTHOR]

• Techniques for late spontaneous recovery from stuttering clustered into six strategies. • The strategies reflect components of established treatments and naïve explanations. • Causal attributions of recovery clustered into three implicit theories about recovery. • Knowledge about strategies and implicit theories may help to improve treatment. (1) To survey the employed techniques and the reasons/occasions which adults who had recovered from stuttering after age 11 without previous treatment reported as causal to overcome stuttering, (2) to investigate whether the techniques and causal attributions can be reduced to coherent (inherently consistent) dimensions, and (3) whether these dimensions reflect common therapy components. 124 recovered persons from 8 countries responded by SurveyMonkey or paper-and-pencil to rating scale questions about 49 possible techniques and 15 causal attributions. A Principal Component Analysis of 110 questionnaires identified 6 components (dimensions) for self-assisted techniques (Speech Restructuring; Relaxed/Monitored Speech; Elocution; Stage Performance; Sought Speech Demands; Reassurance; 63.7% variance explained), and 3 components of perceived causal attributions of recovery (Life Change, Attitude Change, Social Support; 58.0% variance explained). Two components for self-assisted techniques (Speech Restructuring; Elocution) reflect treatment methods. Another component (Relaxed/Monitored Speech) consists mainly of items that reflect a common, non-professional understanding of effective management of stuttering. The components of the various perceived reasons for recovery reflect differing implicit theories of causes for recovery from stuttering. These theories are considered susceptible to various biases. This identification of components of reported techniques and of causal attributions is novel compared to previous studies who just list techniques and attributions. The identified dimensions of self-assisted techniques and causal attributions to reduce stuttering as extracted from self-reports of a large, international sample of recovered formerly stuttering adults may guide the application of behavioral stuttering therapies. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 68-year-old woman suffering from idiopathic peripheral neuropathy and hypertension as well as diarrhoea, abdominal pain and nausea. The patient underwent abdominal computed tomography (CT) scan before laparotomy which showed perforation at her distal signoid. An overview of pathological analysis and its uncovering of a segmental absence of the intestinal musculature (SAIM) is also presented.