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Glycogen storage disease (GSD) type 1a is an inherited autosomal recessive metabolic disease caused by a deficiency in glucose-6-phosphatase activity. The objectives of this research were to systematically review the published literature on the epidemiology of GSD 1a and to assess the performance of reported epidemiology measures in a simulation model. In this systematic literature review 2,539 record titles and abstracts were screened. Of these, only 11 studies contained relevant data on GSD 1a disease epidemiology. Reported disease frequency ranged from 0.085/100,000 to 10.3/100,000 newborns when considering all the GSD literature. When this was narrowed to GSD 1 and GSD 1a, the range was tightened to 0.25–3.02/100,000 and 0.085–4.9/100,000 newborns, respectively. Most of the identified studies counted the number of diagnoses in a defined period and related to the number of births in the same (Dx method) or different time period (DoB method). The simulation model results indicate that in most of the situations, the Dx method provides a closer estimate to the true disease incidence than the DoB method. Despite the scarcity of epidemiology data, the results of this systematic review strongly support that GSD 1a and its parent disease groups (GSD and GSD 1) are rare diseases.

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 hASLmRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASLmRNA 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.

Citrin deficiency is an autosomal recessive disorder caused by loss-of-function mutations in SLC25A13, encoding the liver-specific mitochondrial aspartate/glutamate transporter. It has a broad spectrum of clinical phenotypes, including life-threatening neurological complications. Conventional protein replacement therapy is not an option for these patients because of drug delivery hurdles, and current gene therapy approaches (e.g., AAV) have been hampered by immunogenicity and genotoxicity. Although dietary approaches have shown some benefits in managing citrin deficiency, the only curative treatment option for these patients is liver transplantation, which is high-risk and associated with long-term complications because of chronic immunosuppression. To develop a new class of therapy for citrin deficiency, codon-optimized mRNA encoding human citrin (hCitrin) was encapsulated in lipid nanoparticles (LNPs). We demonstrate the efficacy of hCitrin-mRNA-LNP therapy in cultured human cells and in a murine model of citrin deficiency that resembles the human condition. Of note, intravenous (i.v.) administration of the hCitrin-mRNA resulted in a significant reduction in (1) hepatic citrulline and blood ammonia levels following oral sucrose challenge and (2) sucrose aversion, hallmarks of hCitrin deficiency. In conclusion, mRNA-LNP therapy could have a significant therapeutic effect on the treatment of citrin deficiency and other mitochondrial enzymopathies with limited treatment options.

PurposePeer-reviewed research is the typical pathway for research to be implemented into clinical practice. However, the Internet, digital technology, and social media have introduced significant changes for how this information is shared, publicized, evaluated, and utilized. Some of these changes are positive, such as rapid distribution of needed information, whereas others are negative, such as widespread dissemination and influence of fake news and misinformation. The purpose of this editorial is to provide a brief look at how these negative changes have affected the helping professions.ConclusionIn view of the wide-ranging challenges and influences described here, this editorial is a call for action to our researchers, educators, and clinicians to examine how social media has impacted the scientific practice of communication sciences and disorders. It concludes with a series of questions and examples for how this examination might unfold.

Critical thinking is increasingly recognized as an essential knowledge and skill for the helping professions. Yet, our pedagogical literature has provided infrequent guidance on how instructors can help students to understand what “critical thinking” means or how it might contribute to their professional lives. Therefore, the purpose of this tutorial is to provide guidelines on how instructors might teach future practitioners to become critical thinkers. The main topics address an instructional definition of critical thinking, the basic knowledge and skills that comprise critical thinking, a broad view of instructional approaches, and a summary of developmental milestones of adult critical thinkers. Specific teaching strategies from instructors who have hands-on experience with guiding their students to become critical thinkers are included.

Presents the short story "In What She Has Done, and in What She Has Failed to Do," by Patrick Michael Finn.

Autophagy, including macroautophagy (MA), chaperone-mediated autophagy (CMA), crinophagy, pexophagy and microautophagy, are processes by which cells select internal components such as proteins, secretory vesicles, organelles, or foreign bodies, and deliver them to lysosomes for degradation. MA and CMA are activated during conditions of serum withdrawal in cell culture and during short-term (MA) and prolonged (CMA) starvation in organisms. Although MA and CMA are activated under similar conditions, they are regulated by different mechanisms. We used pulse/chase analysis under conditions in which most intracellular proteolysis is due to CMA to test a variety of compounds for effects on CMA. We show that inhibitors of MA such as 3-methyladenine, wortmannin, and LY294002 have no effect on CMA. Protein degradation by MA is sensitive to microtubule inhibitors such as colcemide and vinblastine, but protein degradation by CMA is not. Activators of MA such as rapamycin also have no effect on CMA. We demonstrate that CMA, like MA, is inhibited by protein synthesis inhibitors anisomycin and cycloheximide. CMA is also partially inhibited when the P38 mitogen activated protein kinase is blocked. Finally we demonstrate that the glucose-6-phophate dehydrogenase inhibitor, 6-aminonicotinamide, and heat shock protein of 90 kilodaltons inhibitor, geldanamycin, have the ability to activate CMA.

Self-regulation refers to a process by which individuals learn to direct and control their own behavior, thoughts, and feelings to manage or eliminate their stuttering. As a concept, it has been a vital and enduring component of most approaches to managing persistent and chronic stuttering. The theoretical basis for self-regulation is briefly reviewed and the main principles of self-regulation-goal setting, cue management, self-monitoring, and self-evaluation-are described and illustrated with clinical examples. Factors related to self-regulatory failure are also discussed.

Many alkylated sugars are surfactants, and show lamellar phases which prove to be identical to those of more conventional surfactants. Most, if not all, previous investigations focus on the behaviour of these compounds in pure form. Dodecyl maltoside shows the same lamellar phase as when dry, but on the addition of water the layer spacing expands, and on addition of more water, a hexagonal phase forms. The area per head group increases substantially with water addition, indicating that the water is incorporated into the layers, possibly at the head groups. We suggest that the hexagonal phase is the system's answer to the frustration caused by a large head group area compared with that of the tails.

The characteristics of stutterers' fluency has been the object of much research in recent years, but it is not always clear what the term "fluency" refers to in this research. This paper reviews the concept of fluency and considers the ways in which it has been employed in research on stuttering. The methods that have been used to identify fluent intervals in stutterers' speech are reviewed along with their reliability and validity. It is concluded that there is an urgent need to clarify the referent for fluency in such studies, and to develop procedures for measuring and quantifying fluency. Additional avenues for research are also discussed.

Using single-subject experiments with 3 adult stutterers, this study evaluated the effects of instructions to stutterers to rate and modify how natural their speech sounds on experimenters' ratings of speech naturalness, stuttering frequency, and speaking rate. The study also included an investigation of the reliability of stutterers' and listeners' naturalness ratings. The stutterers were partway through a therapy program using prolonged speech or rate control. Results showed the stutterers could modify their speech so that their naturalness ratings increased or decreased. These changes were independent of stuttering or speaking rate. Experimenter ratings of speech naturalness were unchanged in conditions where stutterers judged their speech to sound more natural, but paralleled the stutterers' ratings when they judged their speech to sound more unnatural. An attempt to see if stutterers differed in their ratings of how natural their speech sounded or felt showed differences for one stutterer. Reratings of randomized session recordings by experimenters and independent judges showed that their ratings were highly reliable. When the same randomized session recordings were rerated by the stutterers (1 and 3 months after the experiment), their judgments of changes in their speech naturalness, which were not found in the experimenters' ratings, remained consistent and reliable.

There is no empirical basis for determining goals for stuttering treatment. One approach that might resolve this issue is to systematically investigate persons who claim to have recovered from stuttering without the assistance of treatment. However, critical methodological and conceptual issues must be overcome first in order to assure these persons had a valid stuttering problem and that their recovery was independent of treatment. This study examined a validation procedure for solving these issues based on the combination of two methods: independent verification and self-reports. Forty-two subjects participated: 14 adults who recovered from stuttering without assistance, 14 adults with persistent stuttering, and 14 adults who were normally fluent speakers. For the independent verification, a Speech Behavior Checklist was administered to 42 individuals familiar with the recovered subjects' past speech and the other subjects' current speech. Results indicated that persons who knew the recovered subjects when they used to stutter recalled speech behaviors consistent with subjects who still stuttered, but not the same as speech behaviors consistent with subjects who never stuttered. These findings were supported by an objective analysis of the recovered subjects' descriptions of their past stuttering. Furthermore, a content analysis of subjects' self-reports indicated that recovery was independent of treatment.

The efficacy of stuttering treatment has been a contentious issue in recent years. Two issues of primary concern include the treated stutterer’s abnormal speech quality and the problem of continually self-monitoring fluency skills. One approach to addressing these issues is to obtain stutterers’ self-ratings of speech quality and levels of speech monitoring. However, the reliability and validity of such self-ratings need to be assessed before they are suitable for use in stuttering treatment. The present study investigated one method of estimating the reliability and validity of stutterers’ self-ratings of how natural their speech sounds (speech naturalness), and how natural they feel about the amount of attention they are paying to the way they are speaking (feel naturalness). Twelve adult stutterers were instructed to self-rate the speech and feel naturalness of their speech under a variety of rhythmic stimulation conditions across repeated rating occasions. With some qualifications, the results showed that stutterers were relatively consistent and valid self-raters of speech quality and levels of speech monitoring.

The study reported in this paper was designed to replicate and extend the results of an earlier study (Ingham, Cordes, & Gow, 1993) that investigated time-interval judgments of stuttering. Results confirmed earlier findings that interjudge agreement is higher for these interval-recording tasks than has been previously reported for event-based analyses of stuttering judgments or for time-interval analyses of event judgments. Results also confirmed an earlier finding that judges with intrajudge agreement levels of 90% or better show higher interjudge agreement than judges with lower intrajudge agreement scores. This study failed to find differences between audiovisual and audio-only judgment conditions; between relatively experienced and relatively inexperienced student judges; and, most importantly, between the judgments made, and the agreement levels achieved, by judges from two different clinical research settings. The implications of these findings for attempts to develop a reliable measurement method for stuttering are discussed.

1.This report further demonstrates that etorphine influences presynaptic dopamine release, which in turn centrally modulates peripheral cilioinhibition.2.In older animals cilioinhibition has become enhanced due to a lack of responsiveness to endogenous opioids which results in greater dopamine release, causing a higher level of cilioinhibition as demonstrated by challenging the visceral ganglia with etorphine or destroying the dopaminergic component with 6-hydroxydopamine.3.Only the central cilioinhibitory, not the peripheral inhibitory response, mechanism appears to be altered in older animals. Thus, the alteration appears in the central integrative mechanisms involved with regulating ciliary activity.4.The KCl-stimulated release of dopamine is unaltered in both young and old organisms, whereas the opiate inhibition of the KCl-stimulated release of dopamine is reduced in older organisms. Thus, the aging-associated alteration is associated with a specific process.5.The reduction of opioid influence and the resulting enhanced cilioinhibitory activity may make the organisms more susceptible to environmental stress.

Several letters to the editor are presented in response to articles in previous issues including "Gender-bending Water" in the October 2014 issue, "Reeling in Alberta" by Mari Sasano in the October 2014 issue, and "One Party State" in the September 2014 issue.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.

Adenine, thymine and cytosine PNA monomers have been prepared using 3-amino-1,2-propanediol as a starting material. The benzoyl group was used to protect the exocyclic amines of the heterocyclic bases of A and C PNA monomers and the backbone primary amine was protected with the monomethoxytrityl group. The thymine and cytosine PNA monomers were used in conjunction with standard DNA synthesis monomers to produce chimeric PNA DNA (PDC) oligomers. Ultraviolet melting studies confirmed that these oligomers form stable hybrids with complementary DNA strands and that mismatches in the DNA but more so in the PNA sections lead to duplex destabilisation.